CA2121898A1 - Synthesis of prototypes for renin inhibitors - Google Patents
Synthesis of prototypes for renin inhibitorsInfo
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- CA2121898A1 CA2121898A1 CA002121898A CA2121898A CA2121898A1 CA 2121898 A1 CA2121898 A1 CA 2121898A1 CA 002121898 A CA002121898 A CA 002121898A CA 2121898 A CA2121898 A CA 2121898A CA 2121898 A1 CA2121898 A1 CA 2121898A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/02—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from isocyanates with formation of carbamate groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Prototype renin inhibitors having the general structure where n is 0-3 inclusive, A are either both hydrogen atoms or together are a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy wherein the hydrocarbyl entity is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R2 is an alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of 1 to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, a phenylalkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups, R5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, primary and secondary amides, alkyl derivatives, are prepared by novel multistep synthesis. Such compounds are valuable intermediates for the manufacture of pharmaceuticals such as Renin inhibitors and IIIV-protease inhibitors.
Description
~~ SYNTHESIS OF PROTOTYPES FOR RENIN INHIBITORS
This application relates generally to Canadian Application No. ......... filed This invention relates to the field of biological activity relating to enzymatic and similar specific chemical breakdown of angiotensinogen by scission to angiotensin-I, then to angiotensin-II, which engages receptors initiating biological activity as is well known.
It is long known to use compounds of similar chemical properties and general stereochemical conformation either as substitutes for activators to produce positive effects or to block specific receptors to prevent negative effects. In practice despite massive advances in knowledge of conformational structure of chemical compounds, neither the exact conformation of a particular compound, nor its chemical synthesis, nor its biological properties are confidently predictable. In the present invention the compounds envisaged are important intermediates for the manufacture of prototype Renin-inhibitors. Renin inhibitors prevent the production of angiotensin-II, a potent vasoconstrictor and therefore are potent antihypertensives.
The present invention contemplates novel stereoselective chemical synthensis of compounds as of the general formula shown below OH R3 RlA~,f ~ 4 Although the invention will be described and referred to specifically as it relates to such compounds and their processes of preparation, it will be understood , 2121~g8 ~- that the principles of this invention are equally applicable to similar compounds and processes and accordingly, it will be understood that the invention is not limited to such compounds and processes.
BACKGROUND & PRIOR ART
The background is that of stereospecific synthetic organic chemistry, a voluminous and ever expanding field, in which it is a full time occupation to keep abreast of general trends, especially in areas relating to human medical applications.
Applicant is not aware of any prior art related to the specific subject matter described herein.
A principal object of the invention is to develop novel compounds suitable as prototypes for renin inhibitors. It is a related principal object to synthesize said novel compounds by novel chemical processes. It is a subsidiary object to devise practical synthetic schemes to prepare the novel compounds. It is a further subsidiary object to prepare the novel compounds as stereoisomerically pure as practicable. It is a further object to characterize all the compounds so prepared as fully as possible. Other objects would be readily apparent to skilled practitioners in the art, from the following specification, appended claims, and accompanying schemes and figures.
DESCRIPTION OF lNv~llON
In one broad aspect the invention is directed to a chemical compound having the structure 3~ 1 218~8 RlA~
A
where n is 0-3 inclusive, A are either both hydrogen atoms or together are a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy wherein the hydrocarbyl entity is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, Rz is an alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of 1 to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups, R5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, primary and secondary amides, alkyl derivatives. Preferably n is O.
Compounds of the formula 1, wherein n is O and both A are hydrogen atoms, and their pharmaceutically accepted salts exhibit Renin inhibitory activities which can be shown, for example, by their inhibitory action in vitro on Angiotensin-l formation in models substantially as described in United States Patent No. 488986g. They can, therefore, be used as agents for the treatment of circulatory and related disorders responsive to Renin inhibition, such as hypertension, congestive heart failure, cardiac fibrosis, coronary artery diseases, high eye pressure and glaucoma, etc.
Both A taken together may form a single carbon nitrogen bond. In one variation R1 is preferably alkylcarboxy and the alkyl group has l to 6 carbon atoms.-A preferred compound is (l'S,2S,3R,3' ,5S)-5-[(3'-Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-= 421218 98 -- ~ pyrrolidine-l-carboxylic acid tert-butyl ester. Another preferred compound is (l'S,2S,3_,3'B,5S)-5-[(3'-Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine.
In a second variation Rl is preferably aralkylcarboxy and the aralkyl group has 7 to lO carbon atoms. A
preferred compound is (l'S,2S,3B,3'_,5S)-5-[(3'-Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine-l-carboxylic acid benzyl ester.
Both A may be hydrogen, when R1 is preferably aralkylcarboxy and the aralkyl group has 7 to lO carbon atoms. A preferred compound is (2_,4S,5S,7_)-5-[[(l,l-Dimethylethoxy)carbonyl]amino]-4-hydroxy-2,7-dimethyl-8-phenyl octanoic acid butyl amide. This compound can - easily be converted into (2R,4R,5R,7R)-5-amino-4-hydroxy-2,7-dimethyl-8-phenyl-octanoic acid which may serve as a prototype for structurally related, more potent Renin inhibitors as well as for HIV-protease inhibitors.
In another broad aspect the invention is directed to processes of preparation of a first chemical compound of structure OH R3 RlA~ ~ NH~R4 R
where n is 0-3 inclusive, A are either both hydrogen atoms or form a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of l to 6 carbon atoms or aralkyl of 7 to lO carbon atoms, R2 is an alkyl of l to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of l to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, a phenylalkyl of 7 to lO
carbon atoms, R4 is alkyl of l to 6 carbon atoms or alkyl of l to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups, ~ is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, primary and secondary amides, alkyl derivatives. The processes include a step selected from the group consisting of (a) hydrogenolysis of a second compound of the above formula wherein both A together form a single carbon nitrogen bond and R1 is alkylcarboxy wherein said alkyl has 1 to 6 carbon atoms, in the presence of Pd(OH) 2/C; (b) hydrogenolysis of a third compound of the above formula wherein both A together form a single carbon nitrogen bond and R1 is aralkylcarboxy wherein said aralkyl has 7 to 10 carbon atoms, in the presence of Pd(OH)2/C, and dialkyl dicarbonate wherein both said dicarbonate alkyl groups are identical and have 1 to 6 carbon atoms; and (c) treating a fourth compound having the structure ~ O
Rl 0 ~ R3 n ~
20 where n is 0-3 inclusive, R1 is hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R2 iS an alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of l to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, a phenylalkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups Preferably n is zero, in both formulae. A preferred process of claim 1, comprises the step of hydrogenolysis of said second compound. Another preferred process, comprises the step of hydrogenolysis of said third compound. A
further preferred process comprises the step of treating said fourth compound, where in a preferred step R1 is ~~ alkylcarboxy, said alkyl group having l to 6 carbon atoms. Alternatively R1 may be aralkylcarboxy, said aralkyl having 7 to lO carbon atoms.
BRIEF DESCRIPTION OF THE APPENDED FIGURES AND SC~M~.
Figure l schematically indicates the cascade of enzymatic steps that lead to biological activity;
Figure 2 indicates chemical formula of some compounds of the invention;
Figure 3 indicates chemical formula and assigned molecular stereochemical structure of a first compound of the invention;
Figure 4 indicates chemical formula and assigned molecular stereochemical structure of a second compound of the invention;
Scheme l indicates a first synthetic route of the invention;
Scheme 2 indicates a second synthetic route of the invention;
Scheme 3 indicates a third synthetic route of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The basic action of renin is as shown in Figure l, wherein angiotensinogen is first cleaved to provide a specific fragment (angiotensin I), then subcleaved to a second specific fragment (angiotensin II), which engages the appropriate receptor to initiate biological activity.
Scheme l shows detailed steps of a synthetic route from ~S) methyl mandelate 4 to starting precursors (2S,3R)-3-Methyl-5-oxo-2-phenyl-pyrrolidine-l-carboxylic acid tert-butyl ester 12, and (2S,3R)-3-Methyl-2-phenyl-3,4 dihydro-2H-pyrrole 14.
Scheme 2, shows detailed steps of a subsequent 7 2 1218g8 synthetic route starting from 12 to (2R,4S,SS,7R)-5-t[(l,l-Dimethylethoxy)carbonyl~amino]-4-hydroxy-2,7-dimethyl-8-phenyl octanoic acid butyl amide 3a.
Scheme 3, shows detailed steps of a subsequent synthetic route starting from 14 to 3a.
Scheme 1, starts from methyl mandelate 4, wherein the hydroxyl is protected by forming a Bom (benzyloxymethyl) acetal 5 in 83% yield. The carbon chain is then extended to give the phenyl trans-2-butenoic acid 6 homolog by effective insertion of a trans double bond, in 75% yield, with 6% of cis isomer. 6 was then methylated to give 7 unpurified as a mixture of 94:6 of the diastereoisomers including 5% of the deconjugated product crude yield approximately 96%. Crude 7 was cyclized to lactone 8, phenyl methyl dihydrofuranone, in 72% yield (from 6). 8 was converted to the equivalent hydroxymethyl ester 9 by hydrolysis and methylation in 98% yield. 9 was converted to the equivalent azido ester 10 in 89% yield as 96:4 diastereoisomeric mixture.
10 in one avenue is cyclized to lactam 11, methyl phenyl pyrrolidinone in 86% yield, followed by protection of the amino-hydrogen with carboxybutyl ester to give 12 in 99%
yield. In an alternate avenue 10 was converted to the equivalent azido-aldehyde 13 in 77% yield, then cyclized to imine 1~, methyl phenyl dihydro H pyrrole.
Scheme 2 starts with protected lactam 12, whose amido-carbonyl is effectively reduced to hydroxyl to hemiaminal 15a, as a mixture anomers and rotamers in 72%
yield. This was then methylated to give 16a, as a mixture of four isomers, in 100% yield. ~his compound was then treated effectively displacing/replacing methoxy with the substituted furan, to form an unsaturated lactone ring, to give 17a, in 98% yield of 6:1 threo:erythro isomeric ratio. Pure erythro 17a was crystallized as a mixture of rotamers. 17a was hydrogenated saturating the double furan/lactone bond to ~, give 93% yield of 18a as a mixture of two rotamers. The saturated lactone ring of 18a was methylated, 67% of the desired monomethyl 19a, and 15% of the dimethyl lactone were obtained. Crystalline 19a was X-ray analyzed. The lactone ring was opened by formation of the butyl amide to give 2a in 76% yield. Then the pyrrolidine ring was hydrogenolyzed to give 3a in 73% yield.
Scheme 3 is generally analogous to scheme 2, starting with cyclized imine 14, and protecting the imino nitrogen with a carboxybenzyl group rather than a carboxybutyl group, to yield 67% (from 13) of 15b as a mixture of anomers and rotamers. Thereafter the steps are closely similar giving 89% of 16b, 78% of 17b, as 5:1 threo:erythro isomeric ratio. Pure erythro 17b was crystallized as a mixture of rotamers. Crystalline 17b was X-ray analyzed. Continuing gave 90% of 18b, 56% of l9b, 52% of 2b, which was directly converted to 3a, in 46% yield.
ORTEP X-ray structures of l9a and 17b are shown together with their chemical formulae in Figures 3 and 4.
~, . g - f - EXPERIMENl'AL DATA
V
(S)-~Benzyloxy-methoxy)-phenyl ~cetic acid methyl ester ~:
To the solution of 6.5 g (39.5 mmol) of (S)-methyl m~ndel ~e in 90 mL of anhydrous THF
were added successively 12.0 mL (69 mmol) ot i-Pr2EtN, 8.2 mL (59.5 mmol) of benzyl chloromethyl ether and 1.46 g (3.95 mmol) ot -Bu4N+I-. After the reaction was stirred at room temperature overnight, 4.0 mL (23.0 mmol) of i-Pr~EtN and 2.7 mL (19.65 mmol) of benzyl chlorome~hyl ether were added. The reaction was stirred at room temperature for 40 h and 2.0 mL
(1 l.5 mmol) of i-Pr2EtN and l.35 mL (9.8 mmol) of the alkylating agent were added and stirred :~t room temperature for another 44 h. Methanol (1.5 mL) was added to collsllme the excess alkylating agen~ After 30 min the reaction was parutioned bètween 150 mL of w~ter and 250 mL
of EtO~c. The organic layer was washed with 0.5 N HCl, pH 7 phosphate buffer, then with brine, dried over MgSO4 and concenLlated. Pllrific l~ion of ~e residue by column chroma~raphy ~silica ~el, 15% E~)Ac/heY:-nes~, gave 9.~5 g (83%), of the ester ~ as a colorless syrup.
.
Ea]D+ll9 (c 1-24, CHCI3);IR(thinfilm) 1730, 1445,1260,1200,1160,1040 cm~l;
lH NhIR (CDC13, 300 MHz) ~ 7.50-7.27 (m, 10H, ArH), 5.25 ls, lH, PhCHO), 4.92 and 4.84 (AB quartet, 2E~, J= 7Hz, oCH2oj, 4.69 ~nd 4.59 ( AB quartet, 2H, J= 12Hz, OCH2Ph3, 3.7 (s,3H,OCH3~;l3C(CDCl3,75MHz~ol71.1, 137.3, 135.9, 128.7; 128.6, 128.3, 127.8, 1''7.7, 1~7.3, 93.2, 70.0, 52.~; exact mass calculated for C~1Ht904281.128334. found 287.130.
( ~E, 4R)-4-~Benzyloxy-methoxy)-4-phenyl-but-2-enoic acid methyl ester 6:
To a cooled (-78 C) solution of 8.5 g (29.7 mmol) of the ester ~ in 100 mL of anhydrous toluene was added a cold (-78 C) solution of DIBAL-H (33 mL, lM in toluene, 33 mmol) in anhydrous toluene (20 mL) via canula dropwise over a period of 30 min. The l~,a.;lion was stirred at -78 C for another 3 h. Methanol (3.6 mL, 89 mmol~ was added dropwise and the resulting solution was stinred at -78 C for 30 min. The coolLng bath was removed and the reaction was allowed to warm to r~om tempe.~ . Methyl triphel~ylyhosphoranylidene acetate (15.0 g, 44.8 mmol) was added to the reaction mixture and stirred for 20 min. The ~II....il.l.... complex was filtered and the soIvent evaporated. Ether was added and the insoluble PPh30 and excess reagent fiitered. Solvent was e~,apol~ted and the residue purified by column chromatogr~phy (silica gel, 12% EtOAc/hPs~n~), to yieI'd 0.7 g (6~o i~or 2 steps), of the cis ester and 8.5 g (75% for 2 steps), of the tr~ns ester 6 as a-colorless syrup, [OC~D+ 85 (c 1.55, CHC13); IR (thin film) 1710, 1645, 1440, 1290, 1260, 10l0 cm-l; IH NMR (CDC13, 300MHz) o 7.39-7.27 (m, 10H, ArH), 7.0 (dd, lH, J= SHz, 16Hz, CHCH=), 6.13 (dd, lH, J= 2Hz, 16Hz, =CHCO2Me), 4.81 and 4.74 (AB
'' ' 10 qualte~, 2H J= 7Hz, OCH2O). 4.64 and ~.56 (AB quartet, 2H, J= l~Hz, OC~,Ph). 3.i4 (s, 3H, ~H3): 13C (CDCl3, 75 ~Hz) ~ 166.6, 1~7.1, 138.4, 138.3, 128.6, 128.3, 128.2, 127.9, 127.7 127.3, 120.4, 91.9, 76.3, 69.7, 51.5; ex~ct mass calcul~ted for ClgH2lO4 313,14398 1.
found 3l~..1433.
( 3R, 4R)}4-(Benzyloxy-methoxy)-3-methyl-4-phenyl-butyric ~cid methyl ester (7):
~ Iethyl lithium (116.6 mL, 1.4M in ether, 163.2 mmol) was added to the -78 C
suspensi~n of 15.54 g (81.6 mmol) of CuI in 400 mL of anhydrous-THF. The mixture was warmed to 0C, held at that temp~aL~ for 10 min, and then recooled to -78 C. This mixture was tre~ted with TMS-Cl (31 mL, 244.8 mmol) followed by a solution of the unsaturated ester 6 (8.49 g, 27.2 mmol) in anhydrous THF (40 mL). The reaction was stirred at -78 C for 2 h and then quenched with 15 mL of 1:1 5% aqueous N~I40H and saturated aqueous NH4Cl solution. The coolin~ bath w~s removed and the reaction allowed to warm to room temperature. Aqueous lO~o NH40H ~50 mL) and ether (300 mL) were then added and the r~s~ ing mixture was stirred until a homogenous org~nic phase and ~ d~r~ blue aqueous phase were ob~ined. The two layers were separated. the organic phase was washed with water, brine, dried over MgS04 and conce~ d~d to yield an insepar~ble mixture of 7 as a 94:6 di~stereomeric mixture and the deconjugated product (5% by IH NMR). IH N~IR (CDCl3, 300MHz) ~ 7.39-7.23 (m, 10H, ArH), 4.68 and 4.46 (AB
quartet. ~H. J= 12Hz, OCH;~O), 4.67 and 4.58 (AB quartet, 2H, J= 7Hz, OCH2Ph), 4.42 (d, lH, J= 8Hz, PhCHO), 3.67 (s, 3H, OCl'I3), 2.73 ~dd, lH, J= 5Hz, l5Hz, one of CH2CO2CH3), 2.42 (m~ lH, CHCH3), 2.24 (dd, lH, J= 9Hz, l5Hz, one of CH2CO2CH3), 0.83 (d, 3H, J=
7Hz, CHCH3); mass spectrum m/e 329 (M+ + H).
.
( 4R, 5R)-4-Methyl-5-phenyl-dihydro-furan-2-one 8:
To the cooled (-23 ocj solution of the unpurified ester 7 from the above reaction (8.55 g.
theore~ical yield 26.1 mmol) in 260 mL of anhydrous CH2Cl2 was added 10.3 mL ~78.3 mmol) ~f TMS-Br ~nd the solution was ~radually allowed to warm to room temperature overnight. The re~ction was diluted with more CH2CI2 (100 mL), w~shed with satur~ted aqueous NaHCO3 (2 x 50 mL), wa~er, brine, dned over MgSO4 and concentrated. The residue was purified by column chrom~tooraphy ~silica oel, 24~b EtoAc/h~y~r~s)~ to yield 3.45 g (72% for 2 steps), of 8 as a cryst~lline solid, mp 53-54 C; [a3365 -4 (C 0.88, CHC13); IR ~CHC13) 1780, 1280, 1150, 1005 crn~ H (CDC13, 300 MHz) ~ 7.44-7.27 (m, SH, ArH), 4.95 (d, lH, J= 8Hz, PhCHO), 2.81 ll 2121898 .. ~ ' - - , , ~dd7 lH. J= 7Hz. 17Hz, one of CH2CO~ 2.49 (m, lH, CHCH3), 2.3 (dd. lH7 J= 10Hz, 17Hz, on~ of CH2CO). 1.21 (d, 3H, J= 6Hz. CHCH3); ~3C (CDCl3, 75 MHz) ~ 176.V. 137.87 128.67 1. 5.~. 88.~. 39.7. 37.1, 16.3; e~act mass ~alculated for Cl IHI3O2 177.091555. tound 117.(~9()9.
(3R, 4~)-4-Hvdroxy-3-methyl-4-phenyl-butyric acid methvl ester 9:
To the cooled (0 C) solution of 2.43 g (13.8 mmol) of the l~ctone 8 in methanol (40 mL) was added 41 mL of 0.5 N aqueous ~aOH. The 7l~action was warmed to room temperature and sLilTed lor 2 h. Methanol was removed in vacuo and the residue diluted to 140 mL witll water.
The reaction mixture was cooled and the pH adjusted to 4 using lN aqueous HCI. Solid NaC1 was added and the mixture allowed to warm to room lel-lpel.lture. It was extracted with EtOAc (200 mL x 3). The combined or~ganic layer was washed with brine, dried over MgSO, andconcerltrated. The residue was dissolved in EtOAc and methylated with diazomethane in ether.
Evaporation of the solvent afforded 2.82 g (98%), of the hydroxy ester 9 which was used in the next step without further punfic~ion, IR (thin film) 3600-3260, 1740, 1725, 1460, 1170, 1020 H NMR (CDCl3, 300MHz) ~ 7.37-7.27 (m, 5H, ArH), 4.43 (d, lH, J= 7Hz, PhCHOH), 3.66 (s, 3H, OCH3), 2.63 (dd, lH, J= SHz, 15Hz, one of CH2CO2CH3), 2~.38 (br, s, lH, OH), 2.36 (m, lH, CHCH3), 2.26 (dd, lH, J- 8Hz, 15Hz, one of CH2CO2CH3), 0.85 (d, 3H, J=
7Hz, CHCH3); mass spectn~m m/e 209 (M~ + H).
(3R, 4R)-4-~zido-3-methyl-4-phenylbutyric acid methyl ester I0:
.
Triphenylphosphine (5.33 g, 20.3 mmol) was added to the solution of 2.82 g (13.56 mmol) of the hyd}oxyester 9 in 70 mL of anhydrous THF and cooled to 0 C. DEAD was added dropwise foliowed by the dropwise addition of (PhO)2P(O)N3. The reaction was gradually allowed to warm to room temperature overni~ht THF was removed and the residue purified by column chromatography (silica gel, 12% EtOAclh~ ), to yield 2.8 g (89%), of the azido ester 10 as a 96:4 diastereomeric mixture, [a]D -164 (c 1.27, CHCI3); IR (thin filrn) 2100,1740, 1450, 1250, 1165 cm-l; IH NMR (CDCI3,300 MHz) ~ 7.42-7.26 (m, 5H, ArH)7 4.48 (d, lH, J= 6Hz, PhCHN3),3.65 (s,3H, OCH3),2.37 (m, 2H, CHCH3, one of CH2CO2CH3), 2.09 (dd, lH, J= lOHz,17Hz, one of CH2CO2CH3),0.99 (d, 3H, J= 6Hz, CHCH3); 13C (CDC13,75 MHz) ~ 172.6,137.9,128.5,128.1,127.1,70.2,51.4,37.9,36.0,15.6; exact mass calculated for Cl 2HI 6N3O2 234.124252, found 234.125.
.
~ 12 2121898 - .
(4R, 55)-4-Methyl-~-phenyl-pyrrolidine-2~one 11:
To the solution ot 2.5 g (10.73 rnmol) of the azidoester 1 0 in meth~nol (55 mL) ;~t room temper~ture, was added succesively 14 mL (80.48 mmol) of i-Pr2EtN ~nd 5.39 mL (53.65 mmol) of 1,3-proap:~nedi~hiol and stirred for 48 h. M~thanol was removed in vacuo and the residue diluted with EtOAc. It was washed wit~ 0.5 N aqueous NaOH (80 mL x 2), water, brine, dried over MgS04 and concentrated. The n~sidue was purified by column chromatography (siLica gel, 25% EtOAcll.~ nes initi~lly and then 20% ~cetonelCHC13), to yield 1.62 g (86~o), of the lactam 11 as ;1 colorless solid, mp 105- 106 C; [a]D -27 (c 1.055, CHCI3); IR (CHCl3) 3460, 1710.
1450, 1340 cm-l; IH ~MR (CDCl3, 3()QMHz) o 7.4-7.17 (m, SH, ArH), 6.12 (br, s, lH, ~ihr), 4.79 (d, lH, J= 8Hz, PhC~N), 2. 86 (m, lH, CHCH3), 2.53 (dd, lH, J= 8Hz, 17Hz~ one of CH2CO), 2.13 (dd, lH, J= 8Hz, 17Hz, one ot C~2CO), 0.66 (d, 3H, J= 7Hz, CHCH3); l~C
NMR (CDC13, 75 MHz) ~ 178.1, 138.6, 128.4, 127.7, 126.5, 61.5, 37.6, 34.2, 16.2; exact mass calculated for Cl lH~3~O 175.09972, found 175.10029.
(2S, 3R~-3-Methyl-5-o~o-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 12:
To a solution of 1.37 g (7.83 mmol) of the lactam 11 in anhydrous CH2Cl2 (3~ m~ ~) was added succesively the solution of 3.76 g (17.2 mmol) of di tert-~utyl dicarbonate in CH2CI2 (~
mL), 3.4 mL (19.58 mmol~ of i-Pr2EtN and 96 mg (0.78 mmol) of DMAP and stirred at room temperature for 24 h The initially colorless reaction mL~t~ tumed darlc brown at the end of the reaction. Solvent was ~emoved in vacuo and the residue purified by column chromatography (silica gel, 30% E~tOAc/he~l~nes), to yield 2.12 g (99%) of the compound 1 2 as a colorless solid, mp 74-75 C; [a3D-4.6 (c 0.835, CHCl3~; IR (CHCI3) 1780, 1740, 1720, 1460, 1340 1150 cm-l, lH NMR (CDCl3, 3~)0 MHz) ~ 7.38-7.10 (m, SH, A~H), 5.10 (d, lH, J= 8Hz, PhCH~), 2.75 (m, lH, CHCH3), 2.58 (dd, lH, J= XHz, 17Hz, one of CH2CO), 2.37 (dd, lH, J= 12Hz, 17Hz, one of CH2CO), 1.27 (s, 9H, C(CH3)3), 0.69 (d, 3H, J_ 7Hz, CHCH3); 13C (CDCl3, 75 MHz) ~ 174.3, 149.3, 137.0, 128.3, 127.6, 126.2, 82.5, 65.5, 38.8, 30.8, 27.5, 15.7; exac~
mass cqlr~ ed for Cl6H2lNO3 275.15213, found 275.15394.
(25, 3~, 5R, SS)-5-Hydroxy-3-méthyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 15a:
-To a cooled (-78 C) solution of 1.1 ~ (4`mmol) of the compound 1 2 in 10 mL of /
~1898 .. '~ , anhydrous toluene was added DIBAL-H (4.4 mL. IM in toluene, 4.4 mmol) dropwise and stirred tor 4 h. Methanol (1.5 mL) was added and the reaction mixture stirred at -78 C for 30 min. The re~ction mixture was warrned to room temperature and 50 mL of ether and a-drop of water were ~Id~d. The ~lumin~lm comple:c was filtered and solvent evaporated. The residu~ was purified by column chromatography (silica oel, 20`'Yo EtOAc/hexanes), to yield 800 m~ (725~o), of 15a as a mixture of anomers and rotamers, 240 mg of the starting m~ H NMR (CDCl3, 300MHz~
7.33-7.2 (m, 16H, 4 x ArH), 7.02 (m, 4H, ~ Y ArH), 5.94, 5.82 and 5.83-5.56 (m, 4H, 4 .c CHOH), 4.89, 4.82, 4.74 (3 x d. 4H, ~= 8Hzt 4 x PhCHN), 4.47, 3.74, 3.52 ~nd 3.21 (4 :c br, s, 4H. 4 x ofO~ 2.98-2.86 and 2.S~.~i0 (2 x m, 4H, 4 x CHCH3), 2.33-1.64 (m, 8H, 4 x CH2CHOH), 1.2 and 1.18 (2 x s, 36H, 4 x C(GH3)3), 0.64 and 0.63 (2 x d, 12H, J= 7Hz, ~ ~c CHCH3); mass S~)eCl~ m/e 260 ~M+ - OH).
(2S, 3R, 5R, 5S)-5-Methoxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 16a:
To the solution of 745 mg (2.69 mmol) of the h~o...;;l.~.in~l 15a, in 20 mL of methanol was added 31 mg (0.133 mmol) of CSA and stirred at room temperature for 1 h. Et3N (10 drops) was added and me~hanol removed under reduced pressure. The residue was purified by column chromatography (silica ~ el, 209O EtOAc/hexanes), to yield 780 mg (lOO~o) of 16a as an anomeric and rotameric mixture of four isomers, lH NMR (CDC13, 3QOMHz) ~ 7.33-7.2 1 (m, 12H, 4 x ArH), 7.02 and 7.0 (2 x d, 8H, ~= 8Hz, 4 x ArH), 5.42 and 5.20 (2 x d, 2H, J= SHz, 2 x CHOCH3), 5.26 (br, s, 2H, 2 x CHOCH3), 4. 92 ( br, s, 2H, 2 x PhCHN), 4.88 and 4.78 (2 x d, 2H, J= ~E~z, 2 x PhCHN), 3.54, 3.48 and 3.43 (3 x s, 12H, 4 x OCH3), 2.93-1.63 (m, 12H, 4 x CHCH3 and 4 x CH2CHOHCH3), 1.44 and 1.08 (2 x s, 36H, 4 x C(CH3)3), 0.67, 0.59 and 0.57 (3 x d, 12H, J= 7Hz, 4 x CHCH3); mass spectrum m/e 290 (M ' - H).
(2S,2 'S, 3R, SS)-3-Methyl-5-o~o-(5' oxo-Z',5'-dihydro-furan-2-yl)-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 17a:
To a cooled ~-78 C) solution df 740 mg (2.54 mmol) of 1 6a in 26 mL of anhydrous CH2Cl2 was added succèsively 0.64 mL (3.81 mmol) of 2-(trimethylsiloxy)-furan and 0.19 mL
(1.52 mmol3 of BF3.Et20 and the solu~ion was stirred for 1 h. The reaction mixture was quenched with 10 mL of 2 N aqueous HCI and warmed to room temperature. The mixture was diluted with EtOAc, washed with waoer, brine, dried over M~S04 and concentrated to yield 860 mg (98%), of . ~
6~ H NMR) of threo:erythro isomers. The pure threo isomer 17a was obtained, as amiYture of rotamers, by fr~ctional crystal1iz~tion trom 30% EtOAc/he:~nes, mp 150-151 C;
[alD-l88o(c 1.155,CHCl3);IR(CHCI~) 1755, 1685, 1450, 1370, 1165, 1085cm~ HNMR
(CDCl~, 300 MHz) ~ 7.68 and 7.58 (2 x dd, 2H, J= 2Hz, 6Hz, 2 x OCHCH=), 7.31-7.17 (m, 6H, 2 ,~ Ar~), 7.0 and 6.97 (2 x d, 4H, J= 7Hz, ? x ArH), 6.~4 and 6.08 (2 x dd, 2H, J= 2Hz, 6Hz, 2 Y CH=CHCO), 5.55 (dt, 1H, ~= 2Hz, 4Hz, CHO), 5.40 (dt, lH, J= 2Hz, 3Hz, CHO), 4.8~ ~nd 4.71 ('~ x d, 2H, J= 8Hz. 2 x PhCHN), 4.66 (dt, lH, J= 3Hz, 4Hz, CHN), 4.62 (m, lH, CH~), 2.77 and 2.35 (2 x m, 2H, CHCH3), 2.05-1.83 (m, 2H, CW2CHN), 1.76 (dd, lH, J= 8Hz, 13Hz, one of CH2CHN), 1.60 (dd, lH, J= 7Hz, 13Hz, one of CH2C~IN), 1.44 and 1.02 (2 x s, 18H, 2 x C(CH3)3), 0.55 ~nd 0.53 (2 x d, 6H, J= 7Hz, 2 x CHCH3); l3C (CDC13, 7~ MHz3 ~ 173.1, 154.8, 154 ?~ 141.2, 127.8, 126.7, 126.3, 120.3, 84.7, 79.7, 66.7, 58.0, 36.1, 32.5, 27.5, 15.3; exact m~ss calculated for C2oH26NO4 344.18619, found 344.1867.
(2S,2'S,3R,55)-3-Methyl-5-~S'-oxo-tetrahydro~furan-2'-yl)-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 18a:
To the solution of 250 mg (0.73 mmol) of 17a in 3 mL of EtOAc was added 30 mg of 10%
P(IIC ~nd the mixture w;~s stirred under ~ H~ atmosphere for 1 h. The catalyst wa~ filtered through a pad of celite and the solvent evaporated to yield 230 mg (93%), of 18a as a mixture of two ro~mers, mp 123-125 C, ~alD- 49.6 (1.015, CHC13); IR (CHCl3~ 1760, 1675, 1440~1350, 1150 cm~ H NMR (CDC13, 300 MHz) ~ 7.31-7.21 ~m, 6H, 2 x ArH), 7.0 (d, 4H, J= 8Hz, 2 x ArH), 4.80 (dt, 2H, J= 3Hz, 7Hz, 2 x CHO), 4.91 and 4.76 (2 x d, 2H, J= 8Hz, 2 x PhCHN), 4.53 (dd, lH, J= 3Hz, 7Hz, CHN), 4.41 ~t, lH, J= 7Hz, CHN), 2.86 (m, lH, CHCH3), 2.68-2.22 (m, 4H, ~2CH2CO), 1.96-190 (m, 2H, CH2CHN), 2.86-1.79 (m, 7H, CHCH3, CH2CH2CO, CH2CHN), 1.42 and 1.05 (2 x s, 18H, 2 x C(CH3)3), 0.58 and 056 (2 x d, 6H, J= 7Hz, 2 x CHCH3); 13C (CDC13, 75 MHz) ~ 177.0, 155.3, 141.5, 127.7, 126.5, 126.2, 82.4, 79.4, 6?.0, 58.7, 35.9, 33.4, 28.3, 27.5, 24.6, 15.4; exact mass calculated for C2oH28NO4 346.20184, found 346.20230.
~ 25,2 'S, 3R,4 'R, SS)-3-Methyl-5-(4'-methyl-5'-oxo-tetrahydro-furan-2'yl)-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 19a:
To ~ cool~d (-78 C) solu~ion of (TMS)2NLi (0.27 mL, lM in THF, 0.27 mmol) was added .. 15 2121898 . ~
the solu~ion of 18a (85 mg, Q25 mmol) in 1 mL of anhydrous THF over a period of 3 min via canula and the solution was stirred for 40 min. MeI (0.16 mL,2.5 mmol) was added and the solution w~}s s~irred at -78 C for 90 min. a`ter which the reaction mixture was warmed to -50 C
and s~irred for another 1 h. The reac~ion mixture was quen~hed with a solution of AcOH (0.15 mL) in 0.4 mL anhydrous THF and allowed tO warm to room temperature, then diluted with EtOAc, washed with water, brine, dried over MgSO4 and concentrated. p~lrifir~tion of the residue by column chromatography (silica gel,25% ELOAc/hP,~:-n~s), afforded, 14 mg (15%) of the dimelhylated lactone and j9 mg (67%), of the monomethylated product 19a as a mixture of ro~mers,mpl43-144 C;[a]D-31.7(cO.85,CHCl3);IR(CHCI3) 1750, 1680, 1440, 1355, 1150 loao cm~ H NMR (CDC13, 300 MHz) o 7.3l-718 (m, 6H, 2 x ArH), 7.0 and 6.98 (2 x d, 4H, J= 7Hz, 2 x ArH), 4.91 and 4.73 ~2 x d. 2H. J= 8Hz, 2 x PhCHN), 4.65 (dt, lH, J-4Hz, 7Hz, CHO), 4.59 (dt, lH, J= 4Hz. 8Hz, CHO), 4.5 (dd, lH. J= 4Hz, 8Hz, CHN), 4.32 (t.
lH, J= 8Hz, CHN), 2.94-2.62 (m, 5H, 2 x CHCH3, 2 x CHCH3CO, one of OCHCH,CHCH3),2.62-2.29 (m, lH, one of OCHCH2), 2.03-1.81 (m, 5H, 3 x one of CH2CHN, 2 x one of the HCH2), 1.70 (dd, lH, J= 6HZ 13Hz. one of CH2N), 1.31 and 1.27 (2 x d, 6H, J= 7Hz, CHCH3CO), 1.39 and 1.03 (2 x s, 18H, 2 x C(CH3)3), 0.54 and 0.57 (2 x d,6H, J= 7Hz, 2 x CHCH3); l3C (CDCl3,75 MHz) ~i 180.2, 155.6, 141.7, 128.0, 127.8, 126.6, 126.4, 80.8, 79.6, 67.2, 59.3, 35.9, 35.1,34.2,33.7,33.3, 32.7, 28.0, 27.6, 16Ø 15.5; exact mass calculated ~r C2lH30NO4360.2175, found 360.2159.
(1 'S,25, 3R,3 'R, 3S )-5-(3'-Butylcarbamoyl)- 1 '-hvdroxy-butyl)-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 2a:
To the solution of 56 mg (0.156 mmol) of 19a in 0.9 mL of anhydrous CH2Cl2 w~s added BuNHALMe2 (0.28 m~, 0.67M in CH2C12, 0.23 mmol) and stirred at room tempe.~lu.c for 7 h.
~he re~ction ~ Lu~ was cooled to 0 C ~nd quenched with 2 mL of 1 N aqueous HCl, then diluted with EtOAc, washed with brine, dried over Na2SO4 and conce~ ed. Punfic~io~ of the residue by column ch~omatography (silica gel, 10% ~eton~lCHCI3), afforded 51 mg (765~o), of tl~e amide 2a ~s a syrup, ~a~D -79.9 (c 1.015 CHCl3); IR (CHCl3) 3480, 3500-3300, 1665, 1465~ 1415, 1155 cm-l; lH ~MR (CDCl3, 300 MHz) ~ 7.30-7.19 (m, 3H, ArH), 6.98 (d,2H, J=
7Hz, ArH3, 6.0 (br, t, lH, J= SHz, NH), 4.78 (d, lH, J= 6Hz, OH), 4.71 ~d, lH, J= 8Hz, PhCHN), 4.12 (t, lH, J= 8Hz, CHN), 3.50 (m, lH, CHOH), 3.35-3.15 (m, 2H, C~2NH),2.74-2.49 (m, 2H, CHCH3, CHCH3CO), 1.94-1.70 (m, 3H), 1.54-1.21 (m, 5H), 1.17 (d, 3H, J= 7Hi, CHCH3CO), 1.06 (s, 9H, C(CH3)3), 0.93 (t, 3H, J= 7Hz, CH2CH}), 0.55 (d. 3H, J=
7Hz, CHCH3); l3C NMR (CDCl3, 75 MHz) ~; 176.1, 158.0, 141.0, 127.8, 126.6, 80.3,74.5, .
63 4~ 4().9. 38.9, 37.1, 35.7, 32.9, 31.7. 27 7, 20.0, 18.5. 15.0, 13.7; mass sp~citrum m/e 433 (M+ ~ H).
(2R, 4S, SS, 7R)-5-[[1,1-Dimethylethoxy)c~rbonyl]amino]-4-hydroxy-~,7-dimèthyl-8-phenyl-octanoic acid butyl amide 3a:
To the solution of 40 m8 (0.93 mmol) of the amide 2a in 1 mL of ~0% EtOWEtOAc was added 40 mg of Pearlman's catalyst (20% Pd(OH)2/C) and the suspension w~s stirred under 56 psi H2 pressure for 2 days. The catalyst was filtered and the solvent evapor~ted. Purifi~ion of the residue using PTLC (lO~Yo ~eton~o~CH~13), afforded 4 mg of the starting m;lt~ l and 29 mg (73%) of 3, mp 83-84 C; [a3D -17.1 (c 1.47 CHCl3); ~ (CHCl3) 3460, 3400-3300, 1710, `J
1660, 1500, 1370, 1170 cm~ H NMR (CDCl3, 300MHz) ~ 7.29-7.15 (m, 5H, ArH), 5.82 ~br, sj CH2NH), 4.75 (d, lH, J= 8Hz, NHBoc), 3.72-3.61 (m, 2H, CHOH, CHNHBoc), 3.33-3.17 (m, 2H, CH2N), 2.86 (dd, lH, J= SHz. 13Hz, one of PhCH2), 2.55 (m, lH, CHCH3CO), 2.26 (dd, lH, J= 9Hz, 13Hz, one of PhCH2), 1.80 (m, lH, CHCH3), 1.68 (t, 2H, J= 6Hz), 1.55-1.23 (m, 6H), 1.47 (s, 9H, C(CH3)3), 1.20 (d, 3H? J= 7Hz, CHCH3CO), 0.93 (t, 3H, J= 7Hz, CH2CH3), 0.87 (d, 3H, J= 7Hz, CHCH3); 13C (CDCl3, 75 MHz) ~ 176.8, 156.4, 141.1, 129.1, 127.9, 125.6, 79.1, 70.1, 52.1, 42.6, 40.0, 39.1, 38.4, 37.6, 31.9, 31.6, ~8.3, 19.9, 19.8, 17.0, 13.6; mass spectrum m/e 435 (M+ + H~.
(3R, 4S)-4-Azido-3-methyl-4-phenyl-ibutyraldehyde 13:
To a cooled (-78 C) solution of 820 mg (3.52 mmol) of the compound 1 0 in 35 mL of - anhydrous toluene was added DIBAL-H (3.9 mL, lM in toluene, 3.9 mmol) dlu~ ise via canula over a period of lS min and was stirred for another 45 min. Meth~nol (0.43 mL, 10.6 mmol) was added and the reaction mixture stirred at -78 C for 20 min. The re~ction mixture was allowed to warm to room temperature and ether and a drop of water were added. The ~lumimlm complex was filtered and solvent evaporated. The residue was purified by column chroamatography (silica gel, 1% Et3N, 14~o EtOAc, 85%h~ nes), to yield 550 mg (77~o) of 1 3, ~O~]D -205 (C 1.33, CHCI3);
IR (thin film) 2100, 173~, 1450, 1245 cm~ H NMR (CDCI3, 300MHz) o 9.66 (s, lH, CHO), 7.~7.26 (m, SH, ArH), 4.46 (d, lH, J= 7Hz, PhCHN3), 2.48 (m, 2H, CHCH3, one of CH2CHO), 2.22 (dd, lH, J= 9Hz, 18Hz, one of CH2CHO), 1.02 (d, 3H, J= 7Hz, CHCH3);
7 21~1B98 ~J , - , ~ . . .
13C(CDCI3, 75 MHz) ~200.9, 137.7 128.7, 128.3, 127.2, 70.4, 47.4, 33.9, 16.1; m~ss spectrum m/e 203 (M+) (2S, 3R ?-3-Methyl-2-pheny!-3,4 dihydro-2H pyrrole 14:
Triphenylphosphine (750 mg, 2.86 mmol) was added to the solution of 527 mg (2.6 mmol) of the azidoald~hyde 1 3 in 26 mL of .mhydrous toluene and stirred for 16 h when the re~c~ion was judged complete by tlc ~Y:lmin:l~ion The above was used in the next step.
- - (2S, 3R, SR, 5S)-5-Hydroxy-3 methyl 2 phenyl~pyrrolidine~
c~rboxylic acid benzyl ester 15b:
.
To the above solution of the imine in toluene at -78 C was added benzyl chloroformate (0.37 mL, 2.6 mmol) and stirred for 1 h. The reaction was qu~-nched by adding 2 N aqueous HCl and allowed to warm to room t~ pel~ture. The lea~l.on mixture was diluted with EtOAc, washed with unsaturated brine. and bnne, dried over MgS04 and concentrated. The residue was purified by column ch~omato~Mphy (silica gel, 1% Et3~, 29% EtOAc, 70% hexanes), to yield 541 mg (67% for 2 steps) of the hemi:lmin~l l Sb as an anomeric and rotameric Illi~lUI~;, lH N~IR (CDCI3, 300 MHz) ~ 7.~7.16 (m, 18H, 2 x ArH), 7.37-7.02 (m, 18H, 2 x ArH), 6.9-6.87 (m, 2H, 2 x ArH), 6.80 (d, 2H, J= 7Hz, 2 x Arhr), 5.86 and 5.77 (2 x d, 2H, J= 6Hz, SHz, 2 x CHOH), 5.68 (t, 2H, J= 7Hz, 2 x CHOH), 5.21 and 5.12; 5.08 and 4.98 (2 x AB quartet, 4H, J= 13H~, 2 x CO2CH2Ph), 5.22 and 5.11; 5.07 and 4.93 (2 x AB quartet, 4H, J= 13Hz, 2 x CO2CH2Ph), 4.98 and 4.96 (2 x d7 2H, J= 9Hz, 2 x PhCHN), 4.95 and 4.88 (2 x d, 2H, J= 8Hz, PhCHN), 4.38,4.0,3.52and3.26(4xbr,s,4H,4xOH~, 2.g6and2.51 (2xm,4H,CHCH3), 2.30, 1.73 and 1.99-1.75 (3 x m, 8H, 4 x CH2CHOH), 0.65, 0.64 and 0.63 (3 x d, 12H, J= 7Hz, 4 x CHCH3); mass S~llulll (m/e) 310 (M+ - H).
(2S,3R,5R,SS~S-Methoxy-3-methyl~2-phenyl-pyrrolidine-1-carbo~ylic acid benzyl ester 16b:
To the solution of 540 mg (1.74 mmol) of the hemi:-min:ll. 15b, in 9 mL of methanol was added 18 mg (0.078 mmol) of CSA and s~irred at room tem~alule for 1 h. Et3N (10 drops) was added and methanol remov~d under reduced plCSSUlC. The residue was purified by column .. 18 2121898 .
chromatography (silica gel. 20% EtOAc/hex~nes~, to yield 502 mg (89%) of 1 6 b as amLlcture of anomers and rotamers, lH NMR (CDCl3, 300MHz) ~ 7.37-6.98 ( m, 36H, 4 x Ar~l), 6.82 and 6.6 (2 ~c d, 4H? ~= 7Hz, 4 x Ar~I), 5.16 and 5.30 (2 x d, 2H. J= SHz, CHOCH3), 5.34 (br, s, 2H, 2 x C~OCH3), 5.18 ~nd 5.08; 5.02 and 4.82 (2 x AB quartet, 8H, J= 13Hz, 4 %
CO2CH2Ph), 4.96 and 4.9l (2 x d, 4H, J= 7Hz, 4 x PhCHN), 3.56 (br, s, 3H, OCH3), 3.52, 3 5() ~nd 3.35 (3 x s, 9H, 3 x OCH3), ~.99-1.66 (m, 12H, 4 x CHCH3, 4 x CH2CHOCH3), 0.68 ~nd ~).61 ( x d, 12H, J= 7Hz. 4 x CHCH3); rnass s~,e~trulll m/e 324 (M+ - H).
(2S',2 'S, 3R, SS)-3-Methyl-5-oxo-(~'-oxo-2',5'-dihydro-furan-~-yl)-2-phenyl-pyrrolidine-1-carboxylic ac~d benzyl ester 17b:
To acooled (-78 C) solution of 500 mg (1.54 mmol) of 16b in 15 mL of anhydrous CH2Cl2 was- added ~uccesb~rely Q38 mL (2.31 mmol) of 2-(trimethylsiloxy)-furan and 0.11 mL
(0.92 mmol) of BF3.Et20 and the solution was stirred for 2 h. The reaction mixture was q~le~-ched with 5 mL of 2 N aqueous HCl and warmed to room temperature. The l~liAIul~ was diluted with EtOAc, washed with water, b~ine, dned over MgSO4 and concentrated to yield 452 mg (78%) of a 5:1 (by }H N~) of threo:erythro isomers. The pure threo isomer 17b was obtained, as a mixture of rotamers, by fractional cryst~lliz ~ion from EtOAc/h~ ~ ~nf5, mp 157- 158 C; [a~D - 168 (c 1.02, CHC13); IR (thin film) 1750, 1690, 1390, 1330, 1010 cm-l; IH NMR (CDCl3, 300 MHz), ~ 7.67 (dd, 2H, J= 2Hz, 6Hz, 2 x OCHCH=), 7.41-6.94 (m, 16H, 2 x ArH), 6.6 (d, 4H, J= 7Hz, 2 x ArW), 6.08 (dd, 2H, J= 2Hz, 6Hz, 2 x CH=CHCO), 5.48 (dt, 2H, J= 2Hz, 5Hz, 2 7c CHO), 5.16 and 5.07; 4.89 and 4.75 (2 x P~B quartet, 4H, J= 13EIz, 2 x CO2CH2Ph), 4.93 and 4.84 (2 x d, 2H, J= 8Hz, 2 x PhCHN), 4.71 (dd, 2H, J= 2Hz, SHz, 2 x CH~), 2.74 and 2.45 ~2 x m, 2H, 2 x CH~H3), 1-.92-1.61 (m, 4H, 2 x CH2CHN), 0.55 and 0.S3 (2 x d, 6H, J= 7Hz, 2 x CHCH3); 13C (CDCI3, 75 MHz) ~ 173.0, 154.4, 140.3, 135.7, 128.6, 128.3, 128.2, 128.0, 127.5, 127.2, 127.1, 127.0, 126.1, 120.8, 66.9, 66.4, 58.6, 36.3, 32.2, 15.2; exact mass c~lc~ ed for C23H231~O4 378.170534, found 3~8.1681.
(25,2 'S, 3R, SS)-3-Methyl-5-(5'-oxo--tetrahydro-furan-2'-yl)-2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester 18b:
To the solu~ion of 210 mg (0.56 mmol) of 17b in 4 mL of ~n7~.~ was added 20 mg of 5% Pt/C and the mixture was stirred under a H2 atrnosphere for 1 h. The catalyst was filtered through a pad of celite and the solvent evaporated to yield 190 mg (90%), of a ro~mpn~ mix~re o , .
e ~ .
18b as a syrup, ra]D- 52 (0.86, CHCI3); ~R (thin film) 1780, 1700, 1400,1340, 1160 cm-l;
I H NMR (CDCI3, 300 MHz) ~ 7.33-6.96 (m, 16H, 2 ~ ArH), 6.66 (d, 4H, J= 7Hz, 2 x ArH), 5.1 ~AB quartet, 2H, ~= 12Hz, CO2CH2Ph), 4 97 (d, lH, J= 8Hz, PhCHN), 4.90-4.68 (m. SH, 2 ~c OCH, PhCHN, CO2CH2Ph), 4.58 ~m, lH, CHN), 4.48 (t, lH, J= 7Hz, CHN), 2.88-1.83 (m, 14H), 0.58 and 0.57 (2 x d, 6H, J= 7Hz, CHCH3); 13C NMR (CDCI3, 75MHz) ~ 176.9, 156.0, 140.6, 135.8, 128.2, 128.0, 127.4, 12?.3, 126.9, 126.2, 81.8, 66.9, 66.6, 59.3, 36.3, 32.9, 28.5, 24.7, 15.5; ex~ct mass calculated for-C23H26NO4 380.186184, found 380.1822.
(2S j2 'S , 3R, 4 'R, SS)-3-Methyl-5-(4'-methyl-5'-oxo-tetrahydro-furan-~ 'yl)-2-phenyl-pyrrolidine-1-c~rboxylic acid benz~rl ester l9b:
To a cooled (-78 C) solution of (TMS)2NLi ~0.24 mL, IM in h~Y~n~s, 0.24 mmol) in 0.24 mL of anhydrous THF, was added-MeI (0.14 mL, 2.19 mmol) followed by the solution of 18b (79 mg, 0.21 mmol) in I mL of anhydrous THF and the solution was stirred for 40 min. The reaction mixture was yu~ ched with a saturated aqueous NaHCO3 solution and allowed to w~n to room temperature, then diluted with EtOAc, w~shed with water, brine, dried over MgS04 and concentrated. pllnfic~ion of the residue by column chromatography (silica gel, 35%
EtOAc/h.oY~n~c), af~orded 46 mg (56%), of the mono.~ làted produc`t l9b as a l~ e of rotamers, [a~D-32(c 1.43, CHCl3); ~ (thin film) 1155, 1675, 1440, 1390, 1225 cm~ H NMR
(CDCI3, 300 MHz) o 7.39-6.95 (m, 16H, 2 x ~rH), 6.65 ( d, 4H, J= 7Hz, 2 x ArH~, 5.07 and 4.82 (2 x AB quartet, 4H, J= 12Hz, 2 x CO2CH2Ph), 4.97 and 4.87 (2 x d, 2H, J= 8Hz, 2 x PhCHN), 4.71 and 4.62 ~2 x m, 2H, 2 x CHO~, 4.53 (dd, lH, J= 5Hz, 8Hz, CHN), 4.4 (t, lH, J= 7Hz, CHN), 2.9-1.7 (m, 12H), 1.27 and 1.18 (2 x d, 6H, J= 7Hz, 2 x CHCH3CO), 0.57 and 0.55 (2 x d, 6H, J= 7Hz, 2 x CHCH3); 13C NMR (CDC13, 75MH~) ~ 179.9, 156.1, 140.6, 135.8, 128.2, 128.0, 127.4, 126.8,~12ff.1, 80.0, 66.9, 66.6, 59.8, 36.1, 33.6, 33.5, 33.1, 15.9, 15.4; exact mass r!~lcu~ted for C24H28NO4 394.201834, found 394.20260.
(1'S,2S,3R,3'R,5S)-5~(3'-Butylcarbamoyl)-1'-hydroxy-butyl)-3-methyl-2-phenyl-pyrrolidine-l-carboxylic acidben~!l ester 2b:
To tne solution of 45 mg (0.11 mmol) of 19b in 0.5 mL of anhydrous CH2Cl2 was added BuNHAlMe2 (0.33 mL, 0.67M in CH2C12, 0.22 mmol) and stirred at room temperature for 2 h.
The reaction mixture was cooled to 0 C- and quenched with 2 mL of 1 N aqueous HCl, then diluted with EtOAc, washed with brine, dr;ed over Na2SO4 and concentrated. Purification of the 20 21218~8 .
residue by PTLC ( 10% ~oetom ~CHCl3), afforded 22 mg (52%), of the amide 2 b as a syrup, []D
-80.0 (c 0.99 CHCl~); IR (thin film) 3500-3300, 1710. 1670, 1550, 1410, 1340 cm~ H NMR
(CDCl3, 300 MHz) o 7.4-6.96 (m, 8H, Ar~l), 6.63 (~d. 2H, J= 7Hz, ArH), 5.9 (br. s, lH, ~H), 4.85 (d, IH, J= 7Hz, PhCHN), 4.89 (AB quartet, 2H, J= 13Hz, CO2CH2Ph), 4.63 (br, s, lH, OH), 4.17 (dt, lH, J= 2Hz, 9Hz, CHN), 3.56 (dt, lH~ J= 2Hz, 9Hz, CHOH), 3.36-3.17 (m, 2H, CH2NH), 2.75-2.51 (m, 2H, CHCH3, CHCH3CO), 1.96-1.72 (m, 3H), 1.55-1.23 (m, SH), 1. ~9 (d, 3H, J= 7Hz, CHCH3CO), 0.93 (t, 3H, J= 7Hz, CH2C~3), 0.57 (d, 3H, J= 7Hz, C~CH3); 13C (CDC13, 75MHz) ~ 176.0, 158.3, 140.2, 135.8, 128.1, 128.0, 127.4, 127.0, 126 9, 126.3, 74.3, 67.2, 66.2, 64Ø 40.6, 38.9, 37.1, 20.0, 18.4, 14.9, 13.6; exact mass calculated for C28H3gN204 467.290983, found 467.29'~5.
(2R, 45, 55, 7R)-S-[~ DimethyIethoxy~c~rbonyl]amino]-4-hydroxy-2,7-dimethyl-8-phenyl-octanoic acid butyl amide 3a:
To the mixture of 15 mg (0~032 mmol) of the amide 2b and 28 mg (0.129 mmol) of di tert-butyldicàrbonate in 0.5 mL of 40~; MeOH/EtOAc w~s added lS mg of Pe:~rlm~n~s catalyst (20% Pd(OH)2/C) and the susp~ncion was stirred under 60 psi H2 ~I~UI~, for 3 days. The catalyst was filtered and the solvent evaporated. Purification of the residue using PTLC (10%
acetone/CHC13), 6.4 mg (46%), of 3a identical to the sa~Tiple obtained from the hydrogenolysis of the amide 2a.
As those skilled in the art would realize-these preferred described details and processes can be subjected to substantial variation, modification, change, alteration, and substitution without affecting or modifying the function of the described embodiments.
Although embodiments of the invention have been described above, it is not limited thereto, and it will be apparent to persons skilled in the art that numerous modifications lo and variations form part of the present invention insofar as they do not depart from the spirit, nature and scope of the claimed and described invention.
This application relates generally to Canadian Application No. ......... filed This invention relates to the field of biological activity relating to enzymatic and similar specific chemical breakdown of angiotensinogen by scission to angiotensin-I, then to angiotensin-II, which engages receptors initiating biological activity as is well known.
It is long known to use compounds of similar chemical properties and general stereochemical conformation either as substitutes for activators to produce positive effects or to block specific receptors to prevent negative effects. In practice despite massive advances in knowledge of conformational structure of chemical compounds, neither the exact conformation of a particular compound, nor its chemical synthesis, nor its biological properties are confidently predictable. In the present invention the compounds envisaged are important intermediates for the manufacture of prototype Renin-inhibitors. Renin inhibitors prevent the production of angiotensin-II, a potent vasoconstrictor and therefore are potent antihypertensives.
The present invention contemplates novel stereoselective chemical synthensis of compounds as of the general formula shown below OH R3 RlA~,f ~ 4 Although the invention will be described and referred to specifically as it relates to such compounds and their processes of preparation, it will be understood , 2121~g8 ~- that the principles of this invention are equally applicable to similar compounds and processes and accordingly, it will be understood that the invention is not limited to such compounds and processes.
BACKGROUND & PRIOR ART
The background is that of stereospecific synthetic organic chemistry, a voluminous and ever expanding field, in which it is a full time occupation to keep abreast of general trends, especially in areas relating to human medical applications.
Applicant is not aware of any prior art related to the specific subject matter described herein.
A principal object of the invention is to develop novel compounds suitable as prototypes for renin inhibitors. It is a related principal object to synthesize said novel compounds by novel chemical processes. It is a subsidiary object to devise practical synthetic schemes to prepare the novel compounds. It is a further subsidiary object to prepare the novel compounds as stereoisomerically pure as practicable. It is a further object to characterize all the compounds so prepared as fully as possible. Other objects would be readily apparent to skilled practitioners in the art, from the following specification, appended claims, and accompanying schemes and figures.
DESCRIPTION OF lNv~llON
In one broad aspect the invention is directed to a chemical compound having the structure 3~ 1 218~8 RlA~
A
where n is 0-3 inclusive, A are either both hydrogen atoms or together are a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy wherein the hydrocarbyl entity is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, Rz is an alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of 1 to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups, R5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, primary and secondary amides, alkyl derivatives. Preferably n is O.
Compounds of the formula 1, wherein n is O and both A are hydrogen atoms, and their pharmaceutically accepted salts exhibit Renin inhibitory activities which can be shown, for example, by their inhibitory action in vitro on Angiotensin-l formation in models substantially as described in United States Patent No. 488986g. They can, therefore, be used as agents for the treatment of circulatory and related disorders responsive to Renin inhibition, such as hypertension, congestive heart failure, cardiac fibrosis, coronary artery diseases, high eye pressure and glaucoma, etc.
Both A taken together may form a single carbon nitrogen bond. In one variation R1 is preferably alkylcarboxy and the alkyl group has l to 6 carbon atoms.-A preferred compound is (l'S,2S,3R,3' ,5S)-5-[(3'-Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-= 421218 98 -- ~ pyrrolidine-l-carboxylic acid tert-butyl ester. Another preferred compound is (l'S,2S,3_,3'B,5S)-5-[(3'-Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine.
In a second variation Rl is preferably aralkylcarboxy and the aralkyl group has 7 to lO carbon atoms. A
preferred compound is (l'S,2S,3B,3'_,5S)-5-[(3'-Butylcarbamoyl)-l'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine-l-carboxylic acid benzyl ester.
Both A may be hydrogen, when R1 is preferably aralkylcarboxy and the aralkyl group has 7 to lO carbon atoms. A preferred compound is (2_,4S,5S,7_)-5-[[(l,l-Dimethylethoxy)carbonyl]amino]-4-hydroxy-2,7-dimethyl-8-phenyl octanoic acid butyl amide. This compound can - easily be converted into (2R,4R,5R,7R)-5-amino-4-hydroxy-2,7-dimethyl-8-phenyl-octanoic acid which may serve as a prototype for structurally related, more potent Renin inhibitors as well as for HIV-protease inhibitors.
In another broad aspect the invention is directed to processes of preparation of a first chemical compound of structure OH R3 RlA~ ~ NH~R4 R
where n is 0-3 inclusive, A are either both hydrogen atoms or form a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of l to 6 carbon atoms or aralkyl of 7 to lO carbon atoms, R2 is an alkyl of l to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of l to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, a phenylalkyl of 7 to lO
carbon atoms, R4 is alkyl of l to 6 carbon atoms or alkyl of l to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups, ~ is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, primary and secondary amides, alkyl derivatives. The processes include a step selected from the group consisting of (a) hydrogenolysis of a second compound of the above formula wherein both A together form a single carbon nitrogen bond and R1 is alkylcarboxy wherein said alkyl has 1 to 6 carbon atoms, in the presence of Pd(OH) 2/C; (b) hydrogenolysis of a third compound of the above formula wherein both A together form a single carbon nitrogen bond and R1 is aralkylcarboxy wherein said aralkyl has 7 to 10 carbon atoms, in the presence of Pd(OH)2/C, and dialkyl dicarbonate wherein both said dicarbonate alkyl groups are identical and have 1 to 6 carbon atoms; and (c) treating a fourth compound having the structure ~ O
Rl 0 ~ R3 n ~
20 where n is 0-3 inclusive, R1 is hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R2 iS an alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of l to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, a phenylalkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups Preferably n is zero, in both formulae. A preferred process of claim 1, comprises the step of hydrogenolysis of said second compound. Another preferred process, comprises the step of hydrogenolysis of said third compound. A
further preferred process comprises the step of treating said fourth compound, where in a preferred step R1 is ~~ alkylcarboxy, said alkyl group having l to 6 carbon atoms. Alternatively R1 may be aralkylcarboxy, said aralkyl having 7 to lO carbon atoms.
BRIEF DESCRIPTION OF THE APPENDED FIGURES AND SC~M~.
Figure l schematically indicates the cascade of enzymatic steps that lead to biological activity;
Figure 2 indicates chemical formula of some compounds of the invention;
Figure 3 indicates chemical formula and assigned molecular stereochemical structure of a first compound of the invention;
Figure 4 indicates chemical formula and assigned molecular stereochemical structure of a second compound of the invention;
Scheme l indicates a first synthetic route of the invention;
Scheme 2 indicates a second synthetic route of the invention;
Scheme 3 indicates a third synthetic route of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The basic action of renin is as shown in Figure l, wherein angiotensinogen is first cleaved to provide a specific fragment (angiotensin I), then subcleaved to a second specific fragment (angiotensin II), which engages the appropriate receptor to initiate biological activity.
Scheme l shows detailed steps of a synthetic route from ~S) methyl mandelate 4 to starting precursors (2S,3R)-3-Methyl-5-oxo-2-phenyl-pyrrolidine-l-carboxylic acid tert-butyl ester 12, and (2S,3R)-3-Methyl-2-phenyl-3,4 dihydro-2H-pyrrole 14.
Scheme 2, shows detailed steps of a subsequent 7 2 1218g8 synthetic route starting from 12 to (2R,4S,SS,7R)-5-t[(l,l-Dimethylethoxy)carbonyl~amino]-4-hydroxy-2,7-dimethyl-8-phenyl octanoic acid butyl amide 3a.
Scheme 3, shows detailed steps of a subsequent synthetic route starting from 14 to 3a.
Scheme 1, starts from methyl mandelate 4, wherein the hydroxyl is protected by forming a Bom (benzyloxymethyl) acetal 5 in 83% yield. The carbon chain is then extended to give the phenyl trans-2-butenoic acid 6 homolog by effective insertion of a trans double bond, in 75% yield, with 6% of cis isomer. 6 was then methylated to give 7 unpurified as a mixture of 94:6 of the diastereoisomers including 5% of the deconjugated product crude yield approximately 96%. Crude 7 was cyclized to lactone 8, phenyl methyl dihydrofuranone, in 72% yield (from 6). 8 was converted to the equivalent hydroxymethyl ester 9 by hydrolysis and methylation in 98% yield. 9 was converted to the equivalent azido ester 10 in 89% yield as 96:4 diastereoisomeric mixture.
10 in one avenue is cyclized to lactam 11, methyl phenyl pyrrolidinone in 86% yield, followed by protection of the amino-hydrogen with carboxybutyl ester to give 12 in 99%
yield. In an alternate avenue 10 was converted to the equivalent azido-aldehyde 13 in 77% yield, then cyclized to imine 1~, methyl phenyl dihydro H pyrrole.
Scheme 2 starts with protected lactam 12, whose amido-carbonyl is effectively reduced to hydroxyl to hemiaminal 15a, as a mixture anomers and rotamers in 72%
yield. This was then methylated to give 16a, as a mixture of four isomers, in 100% yield. ~his compound was then treated effectively displacing/replacing methoxy with the substituted furan, to form an unsaturated lactone ring, to give 17a, in 98% yield of 6:1 threo:erythro isomeric ratio. Pure erythro 17a was crystallized as a mixture of rotamers. 17a was hydrogenated saturating the double furan/lactone bond to ~, give 93% yield of 18a as a mixture of two rotamers. The saturated lactone ring of 18a was methylated, 67% of the desired monomethyl 19a, and 15% of the dimethyl lactone were obtained. Crystalline 19a was X-ray analyzed. The lactone ring was opened by formation of the butyl amide to give 2a in 76% yield. Then the pyrrolidine ring was hydrogenolyzed to give 3a in 73% yield.
Scheme 3 is generally analogous to scheme 2, starting with cyclized imine 14, and protecting the imino nitrogen with a carboxybenzyl group rather than a carboxybutyl group, to yield 67% (from 13) of 15b as a mixture of anomers and rotamers. Thereafter the steps are closely similar giving 89% of 16b, 78% of 17b, as 5:1 threo:erythro isomeric ratio. Pure erythro 17b was crystallized as a mixture of rotamers. Crystalline 17b was X-ray analyzed. Continuing gave 90% of 18b, 56% of l9b, 52% of 2b, which was directly converted to 3a, in 46% yield.
ORTEP X-ray structures of l9a and 17b are shown together with their chemical formulae in Figures 3 and 4.
~, . g - f - EXPERIMENl'AL DATA
V
(S)-~Benzyloxy-methoxy)-phenyl ~cetic acid methyl ester ~:
To the solution of 6.5 g (39.5 mmol) of (S)-methyl m~ndel ~e in 90 mL of anhydrous THF
were added successively 12.0 mL (69 mmol) ot i-Pr2EtN, 8.2 mL (59.5 mmol) of benzyl chloromethyl ether and 1.46 g (3.95 mmol) ot -Bu4N+I-. After the reaction was stirred at room temperature overnight, 4.0 mL (23.0 mmol) of i-Pr~EtN and 2.7 mL (19.65 mmol) of benzyl chlorome~hyl ether were added. The reaction was stirred at room temperature for 40 h and 2.0 mL
(1 l.5 mmol) of i-Pr2EtN and l.35 mL (9.8 mmol) of the alkylating agent were added and stirred :~t room temperature for another 44 h. Methanol (1.5 mL) was added to collsllme the excess alkylating agen~ After 30 min the reaction was parutioned bètween 150 mL of w~ter and 250 mL
of EtO~c. The organic layer was washed with 0.5 N HCl, pH 7 phosphate buffer, then with brine, dried over MgSO4 and concenLlated. Pllrific l~ion of ~e residue by column chroma~raphy ~silica ~el, 15% E~)Ac/heY:-nes~, gave 9.~5 g (83%), of the ester ~ as a colorless syrup.
.
Ea]D+ll9 (c 1-24, CHCI3);IR(thinfilm) 1730, 1445,1260,1200,1160,1040 cm~l;
lH NhIR (CDC13, 300 MHz) ~ 7.50-7.27 (m, 10H, ArH), 5.25 ls, lH, PhCHO), 4.92 and 4.84 (AB quartet, 2E~, J= 7Hz, oCH2oj, 4.69 ~nd 4.59 ( AB quartet, 2H, J= 12Hz, OCH2Ph3, 3.7 (s,3H,OCH3~;l3C(CDCl3,75MHz~ol71.1, 137.3, 135.9, 128.7; 128.6, 128.3, 127.8, 1''7.7, 1~7.3, 93.2, 70.0, 52.~; exact mass calculated for C~1Ht904281.128334. found 287.130.
( ~E, 4R)-4-~Benzyloxy-methoxy)-4-phenyl-but-2-enoic acid methyl ester 6:
To a cooled (-78 C) solution of 8.5 g (29.7 mmol) of the ester ~ in 100 mL of anhydrous toluene was added a cold (-78 C) solution of DIBAL-H (33 mL, lM in toluene, 33 mmol) in anhydrous toluene (20 mL) via canula dropwise over a period of 30 min. The l~,a.;lion was stirred at -78 C for another 3 h. Methanol (3.6 mL, 89 mmol~ was added dropwise and the resulting solution was stinred at -78 C for 30 min. The coolLng bath was removed and the reaction was allowed to warm to r~om tempe.~ . Methyl triphel~ylyhosphoranylidene acetate (15.0 g, 44.8 mmol) was added to the reaction mixture and stirred for 20 min. The ~II....il.l.... complex was filtered and the soIvent evaporated. Ether was added and the insoluble PPh30 and excess reagent fiitered. Solvent was e~,apol~ted and the residue purified by column chromatogr~phy (silica gel, 12% EtOAc/hPs~n~), to yieI'd 0.7 g (6~o i~or 2 steps), of the cis ester and 8.5 g (75% for 2 steps), of the tr~ns ester 6 as a-colorless syrup, [OC~D+ 85 (c 1.55, CHC13); IR (thin film) 1710, 1645, 1440, 1290, 1260, 10l0 cm-l; IH NMR (CDC13, 300MHz) o 7.39-7.27 (m, 10H, ArH), 7.0 (dd, lH, J= SHz, 16Hz, CHCH=), 6.13 (dd, lH, J= 2Hz, 16Hz, =CHCO2Me), 4.81 and 4.74 (AB
'' ' 10 qualte~, 2H J= 7Hz, OCH2O). 4.64 and ~.56 (AB quartet, 2H, J= l~Hz, OC~,Ph). 3.i4 (s, 3H, ~H3): 13C (CDCl3, 75 ~Hz) ~ 166.6, 1~7.1, 138.4, 138.3, 128.6, 128.3, 128.2, 127.9, 127.7 127.3, 120.4, 91.9, 76.3, 69.7, 51.5; ex~ct mass calcul~ted for ClgH2lO4 313,14398 1.
found 3l~..1433.
( 3R, 4R)}4-(Benzyloxy-methoxy)-3-methyl-4-phenyl-butyric ~cid methyl ester (7):
~ Iethyl lithium (116.6 mL, 1.4M in ether, 163.2 mmol) was added to the -78 C
suspensi~n of 15.54 g (81.6 mmol) of CuI in 400 mL of anhydrous-THF. The mixture was warmed to 0C, held at that temp~aL~ for 10 min, and then recooled to -78 C. This mixture was tre~ted with TMS-Cl (31 mL, 244.8 mmol) followed by a solution of the unsaturated ester 6 (8.49 g, 27.2 mmol) in anhydrous THF (40 mL). The reaction was stirred at -78 C for 2 h and then quenched with 15 mL of 1:1 5% aqueous N~I40H and saturated aqueous NH4Cl solution. The coolin~ bath w~s removed and the reaction allowed to warm to room temperature. Aqueous lO~o NH40H ~50 mL) and ether (300 mL) were then added and the r~s~ ing mixture was stirred until a homogenous org~nic phase and ~ d~r~ blue aqueous phase were ob~ined. The two layers were separated. the organic phase was washed with water, brine, dried over MgS04 and conce~ d~d to yield an insepar~ble mixture of 7 as a 94:6 di~stereomeric mixture and the deconjugated product (5% by IH NMR). IH N~IR (CDCl3, 300MHz) ~ 7.39-7.23 (m, 10H, ArH), 4.68 and 4.46 (AB
quartet. ~H. J= 12Hz, OCH;~O), 4.67 and 4.58 (AB quartet, 2H, J= 7Hz, OCH2Ph), 4.42 (d, lH, J= 8Hz, PhCHO), 3.67 (s, 3H, OCl'I3), 2.73 ~dd, lH, J= 5Hz, l5Hz, one of CH2CO2CH3), 2.42 (m~ lH, CHCH3), 2.24 (dd, lH, J= 9Hz, l5Hz, one of CH2CO2CH3), 0.83 (d, 3H, J=
7Hz, CHCH3); mass spectrum m/e 329 (M+ + H).
.
( 4R, 5R)-4-Methyl-5-phenyl-dihydro-furan-2-one 8:
To the cooled (-23 ocj solution of the unpurified ester 7 from the above reaction (8.55 g.
theore~ical yield 26.1 mmol) in 260 mL of anhydrous CH2Cl2 was added 10.3 mL ~78.3 mmol) ~f TMS-Br ~nd the solution was ~radually allowed to warm to room temperature overnight. The re~ction was diluted with more CH2CI2 (100 mL), w~shed with satur~ted aqueous NaHCO3 (2 x 50 mL), wa~er, brine, dned over MgSO4 and concentrated. The residue was purified by column chrom~tooraphy ~silica oel, 24~b EtoAc/h~y~r~s)~ to yield 3.45 g (72% for 2 steps), of 8 as a cryst~lline solid, mp 53-54 C; [a3365 -4 (C 0.88, CHC13); IR ~CHC13) 1780, 1280, 1150, 1005 crn~ H (CDC13, 300 MHz) ~ 7.44-7.27 (m, SH, ArH), 4.95 (d, lH, J= 8Hz, PhCHO), 2.81 ll 2121898 .. ~ ' - - , , ~dd7 lH. J= 7Hz. 17Hz, one of CH2CO~ 2.49 (m, lH, CHCH3), 2.3 (dd. lH7 J= 10Hz, 17Hz, on~ of CH2CO). 1.21 (d, 3H, J= 6Hz. CHCH3); ~3C (CDCl3, 75 MHz) ~ 176.V. 137.87 128.67 1. 5.~. 88.~. 39.7. 37.1, 16.3; e~act mass ~alculated for Cl IHI3O2 177.091555. tound 117.(~9()9.
(3R, 4~)-4-Hvdroxy-3-methyl-4-phenyl-butyric acid methvl ester 9:
To the cooled (0 C) solution of 2.43 g (13.8 mmol) of the l~ctone 8 in methanol (40 mL) was added 41 mL of 0.5 N aqueous ~aOH. The 7l~action was warmed to room temperature and sLilTed lor 2 h. Methanol was removed in vacuo and the residue diluted to 140 mL witll water.
The reaction mixture was cooled and the pH adjusted to 4 using lN aqueous HCI. Solid NaC1 was added and the mixture allowed to warm to room lel-lpel.lture. It was extracted with EtOAc (200 mL x 3). The combined or~ganic layer was washed with brine, dried over MgSO, andconcerltrated. The residue was dissolved in EtOAc and methylated with diazomethane in ether.
Evaporation of the solvent afforded 2.82 g (98%), of the hydroxy ester 9 which was used in the next step without further punfic~ion, IR (thin film) 3600-3260, 1740, 1725, 1460, 1170, 1020 H NMR (CDCl3, 300MHz) ~ 7.37-7.27 (m, 5H, ArH), 4.43 (d, lH, J= 7Hz, PhCHOH), 3.66 (s, 3H, OCH3), 2.63 (dd, lH, J= SHz, 15Hz, one of CH2CO2CH3), 2~.38 (br, s, lH, OH), 2.36 (m, lH, CHCH3), 2.26 (dd, lH, J- 8Hz, 15Hz, one of CH2CO2CH3), 0.85 (d, 3H, J=
7Hz, CHCH3); mass spectn~m m/e 209 (M~ + H).
(3R, 4R)-4-~zido-3-methyl-4-phenylbutyric acid methyl ester I0:
.
Triphenylphosphine (5.33 g, 20.3 mmol) was added to the solution of 2.82 g (13.56 mmol) of the hyd}oxyester 9 in 70 mL of anhydrous THF and cooled to 0 C. DEAD was added dropwise foliowed by the dropwise addition of (PhO)2P(O)N3. The reaction was gradually allowed to warm to room temperature overni~ht THF was removed and the residue purified by column chromatography (silica gel, 12% EtOAclh~ ), to yield 2.8 g (89%), of the azido ester 10 as a 96:4 diastereomeric mixture, [a]D -164 (c 1.27, CHCI3); IR (thin filrn) 2100,1740, 1450, 1250, 1165 cm-l; IH NMR (CDCI3,300 MHz) ~ 7.42-7.26 (m, 5H, ArH)7 4.48 (d, lH, J= 6Hz, PhCHN3),3.65 (s,3H, OCH3),2.37 (m, 2H, CHCH3, one of CH2CO2CH3), 2.09 (dd, lH, J= lOHz,17Hz, one of CH2CO2CH3),0.99 (d, 3H, J= 6Hz, CHCH3); 13C (CDC13,75 MHz) ~ 172.6,137.9,128.5,128.1,127.1,70.2,51.4,37.9,36.0,15.6; exact mass calculated for Cl 2HI 6N3O2 234.124252, found 234.125.
.
~ 12 2121898 - .
(4R, 55)-4-Methyl-~-phenyl-pyrrolidine-2~one 11:
To the solution ot 2.5 g (10.73 rnmol) of the azidoester 1 0 in meth~nol (55 mL) ;~t room temper~ture, was added succesively 14 mL (80.48 mmol) of i-Pr2EtN ~nd 5.39 mL (53.65 mmol) of 1,3-proap:~nedi~hiol and stirred for 48 h. M~thanol was removed in vacuo and the residue diluted with EtOAc. It was washed wit~ 0.5 N aqueous NaOH (80 mL x 2), water, brine, dried over MgS04 and concentrated. The n~sidue was purified by column chromatography (siLica gel, 25% EtOAcll.~ nes initi~lly and then 20% ~cetonelCHC13), to yield 1.62 g (86~o), of the lactam 11 as ;1 colorless solid, mp 105- 106 C; [a]D -27 (c 1.055, CHCI3); IR (CHCl3) 3460, 1710.
1450, 1340 cm-l; IH ~MR (CDCl3, 3()QMHz) o 7.4-7.17 (m, SH, ArH), 6.12 (br, s, lH, ~ihr), 4.79 (d, lH, J= 8Hz, PhC~N), 2. 86 (m, lH, CHCH3), 2.53 (dd, lH, J= 8Hz, 17Hz~ one of CH2CO), 2.13 (dd, lH, J= 8Hz, 17Hz, one ot C~2CO), 0.66 (d, 3H, J= 7Hz, CHCH3); l~C
NMR (CDC13, 75 MHz) ~ 178.1, 138.6, 128.4, 127.7, 126.5, 61.5, 37.6, 34.2, 16.2; exact mass calculated for Cl lH~3~O 175.09972, found 175.10029.
(2S, 3R~-3-Methyl-5-o~o-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 12:
To a solution of 1.37 g (7.83 mmol) of the lactam 11 in anhydrous CH2Cl2 (3~ m~ ~) was added succesively the solution of 3.76 g (17.2 mmol) of di tert-~utyl dicarbonate in CH2CI2 (~
mL), 3.4 mL (19.58 mmol~ of i-Pr2EtN and 96 mg (0.78 mmol) of DMAP and stirred at room temperature for 24 h The initially colorless reaction mL~t~ tumed darlc brown at the end of the reaction. Solvent was ~emoved in vacuo and the residue purified by column chromatography (silica gel, 30% E~tOAc/he~l~nes), to yield 2.12 g (99%) of the compound 1 2 as a colorless solid, mp 74-75 C; [a3D-4.6 (c 0.835, CHCl3~; IR (CHCI3) 1780, 1740, 1720, 1460, 1340 1150 cm-l, lH NMR (CDCl3, 3~)0 MHz) ~ 7.38-7.10 (m, SH, A~H), 5.10 (d, lH, J= 8Hz, PhCH~), 2.75 (m, lH, CHCH3), 2.58 (dd, lH, J= XHz, 17Hz, one of CH2CO), 2.37 (dd, lH, J= 12Hz, 17Hz, one of CH2CO), 1.27 (s, 9H, C(CH3)3), 0.69 (d, 3H, J_ 7Hz, CHCH3); 13C (CDCl3, 75 MHz) ~ 174.3, 149.3, 137.0, 128.3, 127.6, 126.2, 82.5, 65.5, 38.8, 30.8, 27.5, 15.7; exac~
mass cqlr~ ed for Cl6H2lNO3 275.15213, found 275.15394.
(25, 3~, 5R, SS)-5-Hydroxy-3-méthyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 15a:
-To a cooled (-78 C) solution of 1.1 ~ (4`mmol) of the compound 1 2 in 10 mL of /
~1898 .. '~ , anhydrous toluene was added DIBAL-H (4.4 mL. IM in toluene, 4.4 mmol) dropwise and stirred tor 4 h. Methanol (1.5 mL) was added and the reaction mixture stirred at -78 C for 30 min. The re~ction mixture was warrned to room temperature and 50 mL of ether and a-drop of water were ~Id~d. The ~lumin~lm comple:c was filtered and solvent evaporated. The residu~ was purified by column chromatography (silica oel, 20`'Yo EtOAc/hexanes), to yield 800 m~ (725~o), of 15a as a mixture of anomers and rotamers, 240 mg of the starting m~ H NMR (CDCl3, 300MHz~
7.33-7.2 (m, 16H, 4 x ArH), 7.02 (m, 4H, ~ Y ArH), 5.94, 5.82 and 5.83-5.56 (m, 4H, 4 .c CHOH), 4.89, 4.82, 4.74 (3 x d. 4H, ~= 8Hzt 4 x PhCHN), 4.47, 3.74, 3.52 ~nd 3.21 (4 :c br, s, 4H. 4 x ofO~ 2.98-2.86 and 2.S~.~i0 (2 x m, 4H, 4 x CHCH3), 2.33-1.64 (m, 8H, 4 x CH2CHOH), 1.2 and 1.18 (2 x s, 36H, 4 x C(GH3)3), 0.64 and 0.63 (2 x d, 12H, J= 7Hz, ~ ~c CHCH3); mass S~)eCl~ m/e 260 ~M+ - OH).
(2S, 3R, 5R, 5S)-5-Methoxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 16a:
To the solution of 745 mg (2.69 mmol) of the h~o...;;l.~.in~l 15a, in 20 mL of methanol was added 31 mg (0.133 mmol) of CSA and stirred at room temperature for 1 h. Et3N (10 drops) was added and me~hanol removed under reduced pressure. The residue was purified by column chromatography (silica ~ el, 209O EtOAc/hexanes), to yield 780 mg (lOO~o) of 16a as an anomeric and rotameric mixture of four isomers, lH NMR (CDC13, 3QOMHz) ~ 7.33-7.2 1 (m, 12H, 4 x ArH), 7.02 and 7.0 (2 x d, 8H, ~= 8Hz, 4 x ArH), 5.42 and 5.20 (2 x d, 2H, J= SHz, 2 x CHOCH3), 5.26 (br, s, 2H, 2 x CHOCH3), 4. 92 ( br, s, 2H, 2 x PhCHN), 4.88 and 4.78 (2 x d, 2H, J= ~E~z, 2 x PhCHN), 3.54, 3.48 and 3.43 (3 x s, 12H, 4 x OCH3), 2.93-1.63 (m, 12H, 4 x CHCH3 and 4 x CH2CHOHCH3), 1.44 and 1.08 (2 x s, 36H, 4 x C(CH3)3), 0.67, 0.59 and 0.57 (3 x d, 12H, J= 7Hz, 4 x CHCH3); mass spectrum m/e 290 (M ' - H).
(2S,2 'S, 3R, SS)-3-Methyl-5-o~o-(5' oxo-Z',5'-dihydro-furan-2-yl)-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 17a:
To a cooled ~-78 C) solution df 740 mg (2.54 mmol) of 1 6a in 26 mL of anhydrous CH2Cl2 was added succèsively 0.64 mL (3.81 mmol) of 2-(trimethylsiloxy)-furan and 0.19 mL
(1.52 mmol3 of BF3.Et20 and the solu~ion was stirred for 1 h. The reaction mixture was quenched with 10 mL of 2 N aqueous HCI and warmed to room temperature. The mixture was diluted with EtOAc, washed with waoer, brine, dried over M~S04 and concentrated to yield 860 mg (98%), of . ~
6~ H NMR) of threo:erythro isomers. The pure threo isomer 17a was obtained, as amiYture of rotamers, by fr~ctional crystal1iz~tion trom 30% EtOAc/he:~nes, mp 150-151 C;
[alD-l88o(c 1.155,CHCl3);IR(CHCI~) 1755, 1685, 1450, 1370, 1165, 1085cm~ HNMR
(CDCl~, 300 MHz) ~ 7.68 and 7.58 (2 x dd, 2H, J= 2Hz, 6Hz, 2 x OCHCH=), 7.31-7.17 (m, 6H, 2 ,~ Ar~), 7.0 and 6.97 (2 x d, 4H, J= 7Hz, ? x ArH), 6.~4 and 6.08 (2 x dd, 2H, J= 2Hz, 6Hz, 2 Y CH=CHCO), 5.55 (dt, 1H, ~= 2Hz, 4Hz, CHO), 5.40 (dt, lH, J= 2Hz, 3Hz, CHO), 4.8~ ~nd 4.71 ('~ x d, 2H, J= 8Hz. 2 x PhCHN), 4.66 (dt, lH, J= 3Hz, 4Hz, CHN), 4.62 (m, lH, CH~), 2.77 and 2.35 (2 x m, 2H, CHCH3), 2.05-1.83 (m, 2H, CW2CHN), 1.76 (dd, lH, J= 8Hz, 13Hz, one of CH2CHN), 1.60 (dd, lH, J= 7Hz, 13Hz, one of CH2C~IN), 1.44 and 1.02 (2 x s, 18H, 2 x C(CH3)3), 0.55 ~nd 0.53 (2 x d, 6H, J= 7Hz, 2 x CHCH3); l3C (CDC13, 7~ MHz3 ~ 173.1, 154.8, 154 ?~ 141.2, 127.8, 126.7, 126.3, 120.3, 84.7, 79.7, 66.7, 58.0, 36.1, 32.5, 27.5, 15.3; exact m~ss calculated for C2oH26NO4 344.18619, found 344.1867.
(2S,2'S,3R,55)-3-Methyl-5-~S'-oxo-tetrahydro~furan-2'-yl)-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 18a:
To the solution of 250 mg (0.73 mmol) of 17a in 3 mL of EtOAc was added 30 mg of 10%
P(IIC ~nd the mixture w;~s stirred under ~ H~ atmosphere for 1 h. The catalyst wa~ filtered through a pad of celite and the solvent evaporated to yield 230 mg (93%), of 18a as a mixture of two ro~mers, mp 123-125 C, ~alD- 49.6 (1.015, CHC13); IR (CHCl3~ 1760, 1675, 1440~1350, 1150 cm~ H NMR (CDC13, 300 MHz) ~ 7.31-7.21 ~m, 6H, 2 x ArH), 7.0 (d, 4H, J= 8Hz, 2 x ArH), 4.80 (dt, 2H, J= 3Hz, 7Hz, 2 x CHO), 4.91 and 4.76 (2 x d, 2H, J= 8Hz, 2 x PhCHN), 4.53 (dd, lH, J= 3Hz, 7Hz, CHN), 4.41 ~t, lH, J= 7Hz, CHN), 2.86 (m, lH, CHCH3), 2.68-2.22 (m, 4H, ~2CH2CO), 1.96-190 (m, 2H, CH2CHN), 2.86-1.79 (m, 7H, CHCH3, CH2CH2CO, CH2CHN), 1.42 and 1.05 (2 x s, 18H, 2 x C(CH3)3), 0.58 and 056 (2 x d, 6H, J= 7Hz, 2 x CHCH3); 13C (CDC13, 75 MHz) ~ 177.0, 155.3, 141.5, 127.7, 126.5, 126.2, 82.4, 79.4, 6?.0, 58.7, 35.9, 33.4, 28.3, 27.5, 24.6, 15.4; exact mass calculated for C2oH28NO4 346.20184, found 346.20230.
~ 25,2 'S, 3R,4 'R, SS)-3-Methyl-5-(4'-methyl-5'-oxo-tetrahydro-furan-2'yl)-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 19a:
To ~ cool~d (-78 C) solu~ion of (TMS)2NLi (0.27 mL, lM in THF, 0.27 mmol) was added .. 15 2121898 . ~
the solu~ion of 18a (85 mg, Q25 mmol) in 1 mL of anhydrous THF over a period of 3 min via canula and the solution was stirred for 40 min. MeI (0.16 mL,2.5 mmol) was added and the solution w~}s s~irred at -78 C for 90 min. a`ter which the reaction mixture was warmed to -50 C
and s~irred for another 1 h. The reac~ion mixture was quen~hed with a solution of AcOH (0.15 mL) in 0.4 mL anhydrous THF and allowed tO warm to room temperature, then diluted with EtOAc, washed with water, brine, dried over MgSO4 and concentrated. p~lrifir~tion of the residue by column chromatography (silica gel,25% ELOAc/hP,~:-n~s), afforded, 14 mg (15%) of the dimelhylated lactone and j9 mg (67%), of the monomethylated product 19a as a mixture of ro~mers,mpl43-144 C;[a]D-31.7(cO.85,CHCl3);IR(CHCI3) 1750, 1680, 1440, 1355, 1150 loao cm~ H NMR (CDC13, 300 MHz) o 7.3l-718 (m, 6H, 2 x ArH), 7.0 and 6.98 (2 x d, 4H, J= 7Hz, 2 x ArH), 4.91 and 4.73 ~2 x d. 2H. J= 8Hz, 2 x PhCHN), 4.65 (dt, lH, J-4Hz, 7Hz, CHO), 4.59 (dt, lH, J= 4Hz. 8Hz, CHO), 4.5 (dd, lH. J= 4Hz, 8Hz, CHN), 4.32 (t.
lH, J= 8Hz, CHN), 2.94-2.62 (m, 5H, 2 x CHCH3, 2 x CHCH3CO, one of OCHCH,CHCH3),2.62-2.29 (m, lH, one of OCHCH2), 2.03-1.81 (m, 5H, 3 x one of CH2CHN, 2 x one of the HCH2), 1.70 (dd, lH, J= 6HZ 13Hz. one of CH2N), 1.31 and 1.27 (2 x d, 6H, J= 7Hz, CHCH3CO), 1.39 and 1.03 (2 x s, 18H, 2 x C(CH3)3), 0.54 and 0.57 (2 x d,6H, J= 7Hz, 2 x CHCH3); l3C (CDCl3,75 MHz) ~i 180.2, 155.6, 141.7, 128.0, 127.8, 126.6, 126.4, 80.8, 79.6, 67.2, 59.3, 35.9, 35.1,34.2,33.7,33.3, 32.7, 28.0, 27.6, 16Ø 15.5; exact mass calculated ~r C2lH30NO4360.2175, found 360.2159.
(1 'S,25, 3R,3 'R, 3S )-5-(3'-Butylcarbamoyl)- 1 '-hvdroxy-butyl)-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 2a:
To the solution of 56 mg (0.156 mmol) of 19a in 0.9 mL of anhydrous CH2Cl2 w~s added BuNHALMe2 (0.28 m~, 0.67M in CH2C12, 0.23 mmol) and stirred at room tempe.~lu.c for 7 h.
~he re~ction ~ Lu~ was cooled to 0 C ~nd quenched with 2 mL of 1 N aqueous HCl, then diluted with EtOAc, washed with brine, dried over Na2SO4 and conce~ ed. Punfic~io~ of the residue by column ch~omatography (silica gel, 10% ~eton~lCHCI3), afforded 51 mg (765~o), of tl~e amide 2a ~s a syrup, ~a~D -79.9 (c 1.015 CHCl3); IR (CHCl3) 3480, 3500-3300, 1665, 1465~ 1415, 1155 cm-l; lH ~MR (CDCl3, 300 MHz) ~ 7.30-7.19 (m, 3H, ArH), 6.98 (d,2H, J=
7Hz, ArH3, 6.0 (br, t, lH, J= SHz, NH), 4.78 (d, lH, J= 6Hz, OH), 4.71 ~d, lH, J= 8Hz, PhCHN), 4.12 (t, lH, J= 8Hz, CHN), 3.50 (m, lH, CHOH), 3.35-3.15 (m, 2H, C~2NH),2.74-2.49 (m, 2H, CHCH3, CHCH3CO), 1.94-1.70 (m, 3H), 1.54-1.21 (m, 5H), 1.17 (d, 3H, J= 7Hi, CHCH3CO), 1.06 (s, 9H, C(CH3)3), 0.93 (t, 3H, J= 7Hz, CH2CH}), 0.55 (d. 3H, J=
7Hz, CHCH3); l3C NMR (CDCl3, 75 MHz) ~; 176.1, 158.0, 141.0, 127.8, 126.6, 80.3,74.5, .
63 4~ 4().9. 38.9, 37.1, 35.7, 32.9, 31.7. 27 7, 20.0, 18.5. 15.0, 13.7; mass sp~citrum m/e 433 (M+ ~ H).
(2R, 4S, SS, 7R)-5-[[1,1-Dimethylethoxy)c~rbonyl]amino]-4-hydroxy-~,7-dimèthyl-8-phenyl-octanoic acid butyl amide 3a:
To the solution of 40 m8 (0.93 mmol) of the amide 2a in 1 mL of ~0% EtOWEtOAc was added 40 mg of Pearlman's catalyst (20% Pd(OH)2/C) and the suspension w~s stirred under 56 psi H2 pressure for 2 days. The catalyst was filtered and the solvent evapor~ted. Purifi~ion of the residue using PTLC (lO~Yo ~eton~o~CH~13), afforded 4 mg of the starting m;lt~ l and 29 mg (73%) of 3, mp 83-84 C; [a3D -17.1 (c 1.47 CHCl3); ~ (CHCl3) 3460, 3400-3300, 1710, `J
1660, 1500, 1370, 1170 cm~ H NMR (CDCl3, 300MHz) ~ 7.29-7.15 (m, 5H, ArH), 5.82 ~br, sj CH2NH), 4.75 (d, lH, J= 8Hz, NHBoc), 3.72-3.61 (m, 2H, CHOH, CHNHBoc), 3.33-3.17 (m, 2H, CH2N), 2.86 (dd, lH, J= SHz. 13Hz, one of PhCH2), 2.55 (m, lH, CHCH3CO), 2.26 (dd, lH, J= 9Hz, 13Hz, one of PhCH2), 1.80 (m, lH, CHCH3), 1.68 (t, 2H, J= 6Hz), 1.55-1.23 (m, 6H), 1.47 (s, 9H, C(CH3)3), 1.20 (d, 3H? J= 7Hz, CHCH3CO), 0.93 (t, 3H, J= 7Hz, CH2CH3), 0.87 (d, 3H, J= 7Hz, CHCH3); 13C (CDCl3, 75 MHz) ~ 176.8, 156.4, 141.1, 129.1, 127.9, 125.6, 79.1, 70.1, 52.1, 42.6, 40.0, 39.1, 38.4, 37.6, 31.9, 31.6, ~8.3, 19.9, 19.8, 17.0, 13.6; mass spectrum m/e 435 (M+ + H~.
(3R, 4S)-4-Azido-3-methyl-4-phenyl-ibutyraldehyde 13:
To a cooled (-78 C) solution of 820 mg (3.52 mmol) of the compound 1 0 in 35 mL of - anhydrous toluene was added DIBAL-H (3.9 mL, lM in toluene, 3.9 mmol) dlu~ ise via canula over a period of lS min and was stirred for another 45 min. Meth~nol (0.43 mL, 10.6 mmol) was added and the reaction mixture stirred at -78 C for 20 min. The re~ction mixture was allowed to warm to room temperature and ether and a drop of water were added. The ~lumimlm complex was filtered and solvent evaporated. The residue was purified by column chroamatography (silica gel, 1% Et3N, 14~o EtOAc, 85%h~ nes), to yield 550 mg (77~o) of 1 3, ~O~]D -205 (C 1.33, CHCI3);
IR (thin film) 2100, 173~, 1450, 1245 cm~ H NMR (CDCI3, 300MHz) o 9.66 (s, lH, CHO), 7.~7.26 (m, SH, ArH), 4.46 (d, lH, J= 7Hz, PhCHN3), 2.48 (m, 2H, CHCH3, one of CH2CHO), 2.22 (dd, lH, J= 9Hz, 18Hz, one of CH2CHO), 1.02 (d, 3H, J= 7Hz, CHCH3);
7 21~1B98 ~J , - , ~ . . .
13C(CDCI3, 75 MHz) ~200.9, 137.7 128.7, 128.3, 127.2, 70.4, 47.4, 33.9, 16.1; m~ss spectrum m/e 203 (M+) (2S, 3R ?-3-Methyl-2-pheny!-3,4 dihydro-2H pyrrole 14:
Triphenylphosphine (750 mg, 2.86 mmol) was added to the solution of 527 mg (2.6 mmol) of the azidoald~hyde 1 3 in 26 mL of .mhydrous toluene and stirred for 16 h when the re~c~ion was judged complete by tlc ~Y:lmin:l~ion The above was used in the next step.
- - (2S, 3R, SR, 5S)-5-Hydroxy-3 methyl 2 phenyl~pyrrolidine~
c~rboxylic acid benzyl ester 15b:
.
To the above solution of the imine in toluene at -78 C was added benzyl chloroformate (0.37 mL, 2.6 mmol) and stirred for 1 h. The reaction was qu~-nched by adding 2 N aqueous HCl and allowed to warm to room t~ pel~ture. The lea~l.on mixture was diluted with EtOAc, washed with unsaturated brine. and bnne, dried over MgS04 and concentrated. The residue was purified by column ch~omato~Mphy (silica gel, 1% Et3~, 29% EtOAc, 70% hexanes), to yield 541 mg (67% for 2 steps) of the hemi:lmin~l l Sb as an anomeric and rotameric Illi~lUI~;, lH N~IR (CDCI3, 300 MHz) ~ 7.~7.16 (m, 18H, 2 x ArH), 7.37-7.02 (m, 18H, 2 x ArH), 6.9-6.87 (m, 2H, 2 x ArH), 6.80 (d, 2H, J= 7Hz, 2 x Arhr), 5.86 and 5.77 (2 x d, 2H, J= 6Hz, SHz, 2 x CHOH), 5.68 (t, 2H, J= 7Hz, 2 x CHOH), 5.21 and 5.12; 5.08 and 4.98 (2 x AB quartet, 4H, J= 13H~, 2 x CO2CH2Ph), 5.22 and 5.11; 5.07 and 4.93 (2 x AB quartet, 4H, J= 13Hz, 2 x CO2CH2Ph), 4.98 and 4.96 (2 x d7 2H, J= 9Hz, 2 x PhCHN), 4.95 and 4.88 (2 x d, 2H, J= 8Hz, PhCHN), 4.38,4.0,3.52and3.26(4xbr,s,4H,4xOH~, 2.g6and2.51 (2xm,4H,CHCH3), 2.30, 1.73 and 1.99-1.75 (3 x m, 8H, 4 x CH2CHOH), 0.65, 0.64 and 0.63 (3 x d, 12H, J= 7Hz, 4 x CHCH3); mass S~llulll (m/e) 310 (M+ - H).
(2S,3R,5R,SS~S-Methoxy-3-methyl~2-phenyl-pyrrolidine-1-carbo~ylic acid benzyl ester 16b:
To the solution of 540 mg (1.74 mmol) of the hemi:-min:ll. 15b, in 9 mL of methanol was added 18 mg (0.078 mmol) of CSA and s~irred at room tem~alule for 1 h. Et3N (10 drops) was added and methanol remov~d under reduced plCSSUlC. The residue was purified by column .. 18 2121898 .
chromatography (silica gel. 20% EtOAc/hex~nes~, to yield 502 mg (89%) of 1 6 b as amLlcture of anomers and rotamers, lH NMR (CDCl3, 300MHz) ~ 7.37-6.98 ( m, 36H, 4 x Ar~l), 6.82 and 6.6 (2 ~c d, 4H? ~= 7Hz, 4 x Ar~I), 5.16 and 5.30 (2 x d, 2H. J= SHz, CHOCH3), 5.34 (br, s, 2H, 2 x C~OCH3), 5.18 ~nd 5.08; 5.02 and 4.82 (2 x AB quartet, 8H, J= 13Hz, 4 %
CO2CH2Ph), 4.96 and 4.9l (2 x d, 4H, J= 7Hz, 4 x PhCHN), 3.56 (br, s, 3H, OCH3), 3.52, 3 5() ~nd 3.35 (3 x s, 9H, 3 x OCH3), ~.99-1.66 (m, 12H, 4 x CHCH3, 4 x CH2CHOCH3), 0.68 ~nd ~).61 ( x d, 12H, J= 7Hz. 4 x CHCH3); rnass s~,e~trulll m/e 324 (M+ - H).
(2S',2 'S, 3R, SS)-3-Methyl-5-oxo-(~'-oxo-2',5'-dihydro-furan-~-yl)-2-phenyl-pyrrolidine-1-carboxylic ac~d benzyl ester 17b:
To acooled (-78 C) solution of 500 mg (1.54 mmol) of 16b in 15 mL of anhydrous CH2Cl2 was- added ~uccesb~rely Q38 mL (2.31 mmol) of 2-(trimethylsiloxy)-furan and 0.11 mL
(0.92 mmol) of BF3.Et20 and the solution was stirred for 2 h. The reaction mixture was q~le~-ched with 5 mL of 2 N aqueous HCl and warmed to room temperature. The l~liAIul~ was diluted with EtOAc, washed with water, b~ine, dned over MgSO4 and concentrated to yield 452 mg (78%) of a 5:1 (by }H N~) of threo:erythro isomers. The pure threo isomer 17b was obtained, as a mixture of rotamers, by fractional cryst~lliz ~ion from EtOAc/h~ ~ ~nf5, mp 157- 158 C; [a~D - 168 (c 1.02, CHC13); IR (thin film) 1750, 1690, 1390, 1330, 1010 cm-l; IH NMR (CDCl3, 300 MHz), ~ 7.67 (dd, 2H, J= 2Hz, 6Hz, 2 x OCHCH=), 7.41-6.94 (m, 16H, 2 x ArH), 6.6 (d, 4H, J= 7Hz, 2 x ArW), 6.08 (dd, 2H, J= 2Hz, 6Hz, 2 x CH=CHCO), 5.48 (dt, 2H, J= 2Hz, 5Hz, 2 7c CHO), 5.16 and 5.07; 4.89 and 4.75 (2 x P~B quartet, 4H, J= 13EIz, 2 x CO2CH2Ph), 4.93 and 4.84 (2 x d, 2H, J= 8Hz, 2 x PhCHN), 4.71 (dd, 2H, J= 2Hz, SHz, 2 x CH~), 2.74 and 2.45 ~2 x m, 2H, 2 x CH~H3), 1-.92-1.61 (m, 4H, 2 x CH2CHN), 0.55 and 0.S3 (2 x d, 6H, J= 7Hz, 2 x CHCH3); 13C (CDCI3, 75 MHz) ~ 173.0, 154.4, 140.3, 135.7, 128.6, 128.3, 128.2, 128.0, 127.5, 127.2, 127.1, 127.0, 126.1, 120.8, 66.9, 66.4, 58.6, 36.3, 32.2, 15.2; exact mass c~lc~ ed for C23H231~O4 378.170534, found 3~8.1681.
(25,2 'S, 3R, SS)-3-Methyl-5-(5'-oxo--tetrahydro-furan-2'-yl)-2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester 18b:
To the solu~ion of 210 mg (0.56 mmol) of 17b in 4 mL of ~n7~.~ was added 20 mg of 5% Pt/C and the mixture was stirred under a H2 atrnosphere for 1 h. The catalyst was filtered through a pad of celite and the solvent evaporated to yield 190 mg (90%), of a ro~mpn~ mix~re o , .
e ~ .
18b as a syrup, ra]D- 52 (0.86, CHCI3); ~R (thin film) 1780, 1700, 1400,1340, 1160 cm-l;
I H NMR (CDCI3, 300 MHz) ~ 7.33-6.96 (m, 16H, 2 ~ ArH), 6.66 (d, 4H, J= 7Hz, 2 x ArH), 5.1 ~AB quartet, 2H, ~= 12Hz, CO2CH2Ph), 4 97 (d, lH, J= 8Hz, PhCHN), 4.90-4.68 (m. SH, 2 ~c OCH, PhCHN, CO2CH2Ph), 4.58 ~m, lH, CHN), 4.48 (t, lH, J= 7Hz, CHN), 2.88-1.83 (m, 14H), 0.58 and 0.57 (2 x d, 6H, J= 7Hz, CHCH3); 13C NMR (CDCI3, 75MHz) ~ 176.9, 156.0, 140.6, 135.8, 128.2, 128.0, 127.4, 12?.3, 126.9, 126.2, 81.8, 66.9, 66.6, 59.3, 36.3, 32.9, 28.5, 24.7, 15.5; ex~ct mass calculated for-C23H26NO4 380.186184, found 380.1822.
(2S j2 'S , 3R, 4 'R, SS)-3-Methyl-5-(4'-methyl-5'-oxo-tetrahydro-furan-~ 'yl)-2-phenyl-pyrrolidine-1-c~rboxylic acid benz~rl ester l9b:
To a cooled (-78 C) solution of (TMS)2NLi ~0.24 mL, IM in h~Y~n~s, 0.24 mmol) in 0.24 mL of anhydrous THF, was added-MeI (0.14 mL, 2.19 mmol) followed by the solution of 18b (79 mg, 0.21 mmol) in I mL of anhydrous THF and the solution was stirred for 40 min. The reaction mixture was yu~ ched with a saturated aqueous NaHCO3 solution and allowed to w~n to room temperature, then diluted with EtOAc, w~shed with water, brine, dried over MgS04 and concentrated. pllnfic~ion of the residue by column chromatography (silica gel, 35%
EtOAc/h.oY~n~c), af~orded 46 mg (56%), of the mono.~ làted produc`t l9b as a l~ e of rotamers, [a~D-32(c 1.43, CHCl3); ~ (thin film) 1155, 1675, 1440, 1390, 1225 cm~ H NMR
(CDCI3, 300 MHz) o 7.39-6.95 (m, 16H, 2 x ~rH), 6.65 ( d, 4H, J= 7Hz, 2 x ArH~, 5.07 and 4.82 (2 x AB quartet, 4H, J= 12Hz, 2 x CO2CH2Ph), 4.97 and 4.87 (2 x d, 2H, J= 8Hz, 2 x PhCHN), 4.71 and 4.62 ~2 x m, 2H, 2 x CHO~, 4.53 (dd, lH, J= 5Hz, 8Hz, CHN), 4.4 (t, lH, J= 7Hz, CHN), 2.9-1.7 (m, 12H), 1.27 and 1.18 (2 x d, 6H, J= 7Hz, 2 x CHCH3CO), 0.57 and 0.55 (2 x d, 6H, J= 7Hz, 2 x CHCH3); 13C NMR (CDC13, 75MH~) ~ 179.9, 156.1, 140.6, 135.8, 128.2, 128.0, 127.4, 126.8,~12ff.1, 80.0, 66.9, 66.6, 59.8, 36.1, 33.6, 33.5, 33.1, 15.9, 15.4; exact mass r!~lcu~ted for C24H28NO4 394.201834, found 394.20260.
(1'S,2S,3R,3'R,5S)-5~(3'-Butylcarbamoyl)-1'-hydroxy-butyl)-3-methyl-2-phenyl-pyrrolidine-l-carboxylic acidben~!l ester 2b:
To tne solution of 45 mg (0.11 mmol) of 19b in 0.5 mL of anhydrous CH2Cl2 was added BuNHAlMe2 (0.33 mL, 0.67M in CH2C12, 0.22 mmol) and stirred at room temperature for 2 h.
The reaction mixture was cooled to 0 C- and quenched with 2 mL of 1 N aqueous HCl, then diluted with EtOAc, washed with brine, dr;ed over Na2SO4 and concentrated. Purification of the 20 21218~8 .
residue by PTLC ( 10% ~oetom ~CHCl3), afforded 22 mg (52%), of the amide 2 b as a syrup, []D
-80.0 (c 0.99 CHCl~); IR (thin film) 3500-3300, 1710. 1670, 1550, 1410, 1340 cm~ H NMR
(CDCl3, 300 MHz) o 7.4-6.96 (m, 8H, Ar~l), 6.63 (~d. 2H, J= 7Hz, ArH), 5.9 (br. s, lH, ~H), 4.85 (d, IH, J= 7Hz, PhCHN), 4.89 (AB quartet, 2H, J= 13Hz, CO2CH2Ph), 4.63 (br, s, lH, OH), 4.17 (dt, lH, J= 2Hz, 9Hz, CHN), 3.56 (dt, lH~ J= 2Hz, 9Hz, CHOH), 3.36-3.17 (m, 2H, CH2NH), 2.75-2.51 (m, 2H, CHCH3, CHCH3CO), 1.96-1.72 (m, 3H), 1.55-1.23 (m, SH), 1. ~9 (d, 3H, J= 7Hz, CHCH3CO), 0.93 (t, 3H, J= 7Hz, CH2C~3), 0.57 (d, 3H, J= 7Hz, C~CH3); 13C (CDC13, 75MHz) ~ 176.0, 158.3, 140.2, 135.8, 128.1, 128.0, 127.4, 127.0, 126 9, 126.3, 74.3, 67.2, 66.2, 64Ø 40.6, 38.9, 37.1, 20.0, 18.4, 14.9, 13.6; exact mass calculated for C28H3gN204 467.290983, found 467.29'~5.
(2R, 45, 55, 7R)-S-[~ DimethyIethoxy~c~rbonyl]amino]-4-hydroxy-2,7-dimethyl-8-phenyl-octanoic acid butyl amide 3a:
To the mixture of 15 mg (0~032 mmol) of the amide 2b and 28 mg (0.129 mmol) of di tert-butyldicàrbonate in 0.5 mL of 40~; MeOH/EtOAc w~s added lS mg of Pe:~rlm~n~s catalyst (20% Pd(OH)2/C) and the susp~ncion was stirred under 60 psi H2 ~I~UI~, for 3 days. The catalyst was filtered and the solvent evaporated. Purification of the residue using PTLC (10%
acetone/CHC13), 6.4 mg (46%), of 3a identical to the sa~Tiple obtained from the hydrogenolysis of the amide 2a.
As those skilled in the art would realize-these preferred described details and processes can be subjected to substantial variation, modification, change, alteration, and substitution without affecting or modifying the function of the described embodiments.
Although embodiments of the invention have been described above, it is not limited thereto, and it will be apparent to persons skilled in the art that numerous modifications lo and variations form part of the present invention insofar as they do not depart from the spirit, nature and scope of the claimed and described invention.
Claims (7)
1. A process of preparation of a first compound having the structure where n is 0-3 inclusive, A are either both hydrogen atoms or form a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R2 is an alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R3 is an alkyl of 1 to 4 carbon atoms, an alkenyl of 2 to 4 carbon atoms, a phenylalkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups R5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, primary and secondary amides, alkyl derivatives, comprising a step selected from the group consisting of (a) hydrogenolysis of a second compound of the above formula wherein both A together form a single carbon nitrogen bond and R1 is alkylcarboxy wherein said alkyl has 1 to 6 carbon atoms, in the presence of Pd(OH) 2/C;
(b) hydrogenolysis of a third compound of the above formula wherein both A together form a single carbon nitrogen bond and R1 is aralkylcarboxy wherein said aralkyl has 7 to 10 carbon atoms, in the presence of Pd(OH)2/C, and dialkyl dicarbonate wherein both said dicarbonate alkyl groups are identical and have 1 to 6 carbon atoms;
(c) treating a fourth compound having the structure where n is 0-3 inclusive, R1 is hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups
(b) hydrogenolysis of a third compound of the above formula wherein both A together form a single carbon nitrogen bond and R1 is aralkylcarboxy wherein said aralkyl has 7 to 10 carbon atoms, in the presence of Pd(OH)2/C, and dialkyl dicarbonate wherein both said dicarbonate alkyl groups are identical and have 1 to 6 carbon atoms;
(c) treating a fourth compound having the structure where n is 0-3 inclusive, R1 is hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted by one or more oxygen or nitrogen containing groups
2. The process of claim 1, where n is zero, in both formulae.
3. The process of claim 2, comprising the step of hydrogenolysis of said second compound.
4. The process of claim 1, comprising the step of hydrogenolysis of said third compound.
5. The process of claim 1, comprising the step of treating said fourth compound.
6. The process of claim 5, wherein R1 is alkylcarboxy, said alkyl group having 1 to 6 carbon atoms.
7. The process of claim 5, wherein R1 is aralkylcarboxy, said aralkyl having 7 to 10 carbon atoms.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002121898A CA2121898A1 (en) | 1994-04-21 | 1994-04-21 | Synthesis of prototypes for renin inhibitors |
| AU20823/95A AU2082395A (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors |
| PCT/IB1995/000257 WO1995029150A1 (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors |
| JP7527500A JPH09512266A (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors |
| CN95192655A CN1147810A (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors |
| EP95913311A EP0756590A1 (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors |
| HU9602892A HUT74743A (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors and new intermediates |
| CZ963065A CZ306596A3 (en) | 1994-04-21 | 1995-04-12 | Process for preparing prototypes of renin inhibitors |
| PL95316677A PL316677A1 (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors |
| CA 2188294 CA2188294A1 (en) | 1994-04-21 | 1995-04-12 | Synthesis of prototypes for renin inhibitors |
| IL11340195A IL113401A0 (en) | 1994-04-21 | 1995-04-17 | Synthesis of prototypes for renin inhibitors |
| ZA953187A ZA953187B (en) | 1994-04-21 | 1995-04-20 | Synthesis of prototypes for renin inhibitors |
| NO963831A NO963831D0 (en) | 1994-04-21 | 1996-09-13 | Synthesis of prototypes for renin inhibitors |
| FI963743A FI963743A (en) | 1994-04-21 | 1996-09-20 | Synthesis of prototypes of renin inhibitors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002121898A CA2121898A1 (en) | 1994-04-21 | 1994-04-21 | Synthesis of prototypes for renin inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2121898A1 true CA2121898A1 (en) | 1995-10-22 |
Family
ID=4153433
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002121898A Abandoned CA2121898A1 (en) | 1994-04-21 | 1994-04-21 | Synthesis of prototypes for renin inhibitors |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0756590A1 (en) |
| JP (1) | JPH09512266A (en) |
| CN (1) | CN1147810A (en) |
| AU (1) | AU2082395A (en) |
| CA (1) | CA2121898A1 (en) |
| CZ (1) | CZ306596A3 (en) |
| FI (1) | FI963743A (en) |
| HU (1) | HUT74743A (en) |
| IL (1) | IL113401A0 (en) |
| PL (1) | PL316677A1 (en) |
| WO (1) | WO1995029150A1 (en) |
| ZA (1) | ZA953187B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10205862A1 (en) * | 2002-02-13 | 2003-08-21 | Bayer Cropscience Ag | DELTA 1 Pyrrolines |
| GB0511686D0 (en) * | 2005-06-08 | 2005-07-13 | Novartis Ag | Organic compounds |
| CN109422664B (en) * | 2017-08-23 | 2022-02-18 | 中国科学院福建物质结构研究所 | Interferon regulator and its prepn and use |
-
1994
- 1994-04-21 CA CA002121898A patent/CA2121898A1/en not_active Abandoned
-
1995
- 1995-04-12 CN CN95192655A patent/CN1147810A/en active Pending
- 1995-04-12 AU AU20823/95A patent/AU2082395A/en not_active Abandoned
- 1995-04-12 EP EP95913311A patent/EP0756590A1/en not_active Withdrawn
- 1995-04-12 HU HU9602892A patent/HUT74743A/en unknown
- 1995-04-12 WO PCT/IB1995/000257 patent/WO1995029150A1/en not_active Application Discontinuation
- 1995-04-12 PL PL95316677A patent/PL316677A1/en unknown
- 1995-04-12 JP JP7527500A patent/JPH09512266A/en active Pending
- 1995-04-12 CZ CZ963065A patent/CZ306596A3/en unknown
- 1995-04-17 IL IL11340195A patent/IL113401A0/en unknown
- 1995-04-20 ZA ZA953187A patent/ZA953187B/en unknown
-
1996
- 1996-09-20 FI FI963743A patent/FI963743A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995029150A1 (en) | 1995-11-02 |
| HUT74743A (en) | 1997-02-28 |
| IL113401A0 (en) | 1995-07-31 |
| ZA953187B (en) | 1995-10-23 |
| FI963743A0 (en) | 1996-09-20 |
| EP0756590A1 (en) | 1997-02-05 |
| HU9602892D0 (en) | 1996-12-30 |
| JPH09512266A (en) | 1997-12-09 |
| CZ306596A3 (en) | 1997-01-15 |
| AU2082395A (en) | 1995-11-16 |
| CN1147810A (en) | 1997-04-16 |
| PL316677A1 (en) | 1997-02-03 |
| FI963743A (en) | 1996-09-20 |
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