CA2224439A1 - Improved process for synthesizing carbapenem intermediates - Google Patents

Abstract

A process of synthesizing a compound of formula (1) or (2) is disclosed wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl. A compound of formula (3) or (4) is reacted with P-C1 wherein P is as defined above, in the presence of base and a substantially nonreactive solvent to produce (1) or (2).

Description

IMPROVED PROCESS FOR SYNTHESIZING CARBAPENEM
INTERMEDIATES

5 BACKGROUND OF THE INVENTlON
The present invention is related to an improved synthesis of carbapenem intermediate,s, and in particular, the following compounds:

PO

H3C~OPNE~ H3C/~ g =

.~ N~ o~ N
O H I and 2 CO2PNB

wherein R represents hydrogen or methyl and P represent.s triethyl,silyl or trimethylsilyl. Similar such intermediates have been used in the pa,st to ~synthesize carbapenem antibiotics. However, to date~ the ,synthesis pathway for these antibiotics has required the use of extremely un.stable 15 intermediates. Additionally, the syntheses disclosed in the past result in low yields and require numerous separation and purification steps.
The intermediates for carbapenem antibiotics de.scribed herein are addressed in, e.g., U. S. Pat. No. 4,350,631 issued to Christensen, et ah on September 21, 19~2 and U. S. Pat. No. 4,994,56~
20 issued to Christensen on February 19, 1991. In the process described in each of these patents, a diazo compound of the formula:

R3 ~~

~~ H N2 Co2R7 is cyclized using a catalyst or irradiation. This generates a mixture of l-o~
and 1-,~ methyl isomers, which in turn requires separation prior to further chemical modification.
Lastly, many of the prior processes of synthesizing 5 carbapenem antibiotic.s utilize an intermediate of the formula:

OH

H3C ~
/~ OTf ,~N ~

which has an active leaving group at position 2, namely the triflate. This 10 compound is extremely unstable, and cannot be utilized in large scale synthesis with an acceptable level of efficiency. As such, one of the objectives of the present invention is to avoid this intermediate.
The present invention overcomes these disadvantages, providing a scheme which avoids unstable intermediates, and in many 15 instances, producing intermediate~s which are in crystalline form, requiring little or no purification before futher use.

SUMMARY OF THE INVENTION
A process of synthe.sizing a compound of the formula:

OPNB ~ , O H 1 or 2 CO2PNB

~ is disclosed wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl. The process comprises treating a compound of the formula:

N ~ ~ H3 ~1~

.5 O H 3 or 4 CO2PNB

with P-CI wherein P is as defined above, in the presence of base and a substantially non-reactive solvent to produce:

H3~ ~~

O~ 'H I or 2 CO2P N B

DETAILED DESCRIPTION OF THE INVENTION
The 1-~ methyl i,~omer of the diazo compound I and the bicyclic ketoester 2 (R = methyl) which are shown above are highly 15 desired and useful as carbapenem intermediates, because 1-~ methyl carbapenem antibiotics have a reduced tendency toward biological inactivation by the enzyme dehydropeptidase when administered to a m~mm~ n patient to treat a bacterial infection. Generally, the l-,B
methyl isomer of the final product is more resistant to deactivation than 20 the 1 H or the 1 -oc methyl isomer.
The bicyclic ketoester 2 can be further reacted at the 2-position to establish a leaving group, e.g., L, which represents diphenyl phosphate, triflate, tosylate, mesylate, fluorosulfonate, chloride and the like, to form the appropriate activated carbapenem intermediate. The activated carbapenem intermediate i.s .suitable for coupling to a .substituent at position 2, for example, through the use of a palladium catalyst, e.g., Pd2(dba)3 CHC13, and tris(2, 4, 6-trimethoxyphenyl)phosphine in a .suitable solvent. Further details 5 regarding coupling reactions can be obtained from U.S. Patent No.
5,034,3~4.
In one preferred embodiment of the invention, a compound of formula 3 wherein R repre.sent,s H or methyl is reacted with P-CI in the pre.sence of base and a _stantially non-reactive .solvent to produce a 10 compound of formula 1:

H3C~OPNB

,~N~
O H

In a more preferred embodiment of the invention, a 15 compound of formula 3 is reacted with P-CI wherein P represents triethylsilyl to produce a compound of formula la:
TESO R
H3C ~OPNB

,~N~
o H la In another more preferred embodiment of the invention, a compound of forrnula 3 is reacted with P-CI wherein P represents trimethylsilyl to produce a compound of formula I h:

~ TMSO N2 ~ H3C~OPNB

,~N~
O H lb In another preferred embodiment, a compound of formula 4 wherein R represents H or methyl, is reacted with P-CI in the presence of 5 base and a substantially non-reactive solvent to produce a compound of formula 2:

PO R
H3C ~
o~ N <

In another more preferred embodiment of the invention, a compound of formula 4 is reacted with P-Cl wherein P repre.sent.s triethylsilyl to produce a compound of formula 2a:

TESO

H3C)\~=

o~N
2a CO2P N B
1~;
In another more preferred embodiment of the invention, ~ compound of formula 4 is reacted with P-CI wherein P represents trimethylsilyl to produce a compound of formula 2~:

TMSO R
11 =H _¦
H3C ~
o~ N <

2b CO2P N B

In another preferred embodiment, the substituted azetidinone is cyclized before protection of the hydroxyethyl side chain. After 5 cyclization, the side chain is protected with P.

H3C~OPNB H3C'~

,~ N~ o~ N

R
H3C~=
,~ N <

As used herein, PNB refers to the protecting group par~-~ 0 nitrobenzyl.The abbreviation THF refers to tetrahydrofuran.
The abbreviation OAc refers to acetate, CH3C(O)O-.
Hence, the solvent ethyl acetate is abbreviated as EtOAc and isopropyl acetate is abbreviated iPrOAc.
TES refers to the group triethylsilyl.
TMS refers to the group trimethylsilyl.
Et3N refers to triethylamine.
dba refers to dibenzylideneacetone.

Generally, the objects of the present invention are to utilize crystalline intermediates and to avoid unstable intermediates.
Additionally, stereospecificity and regiospecific reactions are favored.
The following schemes are representative.

H3C~CO P N B P-CI
~N O O

(Crystalline) PO H ~ R N2 Cyclize H ~Cl J~CO2PNB
.~ N O O

(Crystalline) PJO~ L X or LzO ~
2 CO2PNB X = leaving group 5 CO2PNB
(Stable) Coupling Reaction , 2-Substituted Carbapenems SCHFM~ 2 H3C~CO2P N B Cyclize ~N O O

(Crystalline) HO R
H H
H3C--~ P-CI
o~N ~ Solvent (Stable) H H R
H3CJ~O base (Stable) C 02P N B
PO R
~ H H ~ Coupling H ~C ~ ~ Reaction , 2-Substituted /,~L Carbapenems 5 o~N ~

The starting materials for scheme,s 1 and 2 can be obtained in accordance with U.S. Patent Nos. 4,454,332 (issued on June 12, 1984) S and 4,312,871 (issued on January 26, 1982). For each of the scheme.s noted above, by reacting compound 3 or 4 with P-CI in the presence of base, stable and even crystalline intermediates are realized. This is an unexpected and surprising advantage over other processes of synthesizing carbapenems.

There are numerous method~ of cyclizing the diazo intermediates noted above to produce the bicyclic ketoester 2 or 4. The preferred method of cyclization involves a reaction in the presence of a rhodium catalyst, such as rhodium acetate or rhodium octanoate.
Likewise, when activating the bicyclic ketoester 2 at position two, the anhydride L20 or the halide L-CI can be combined with the bicyclic ketoester in the presence of a nitrogen containing base and in a .substantially non-reactive .solvent to produce the activated carbapenem 5. The activated carbapenem 5~ with the appropriate group L at position 10 2, can then be coupled to an appropriate substituent according to the procedures set forth in U. S. Pat. No. 5,034,3~4. Carbapenem.~ which can be synthesized in accordance with the process described herein are disclosed, and the groups which are appropriate for such attachment, can be found, e.g., in U.S. Pat. No. 5,034,3P~4.
The preferred substantially non-reactive solvents used herein are dimethylformamide, tetrahydrofuran (THF), isopropyl acetate, ethyl acetate and methylene chloride. Mo.st preferably, mixtures thereof are used.
The preferred base used in the processes described herein i.
20 imidazole.
The nitrogen containing bases for use in the activating reaction with L2O or L-CI include triethylamine, diisopropylethylamine and diisopropylamine.
Preferred values for L include the sulfonate leaving groups, 2~ such as trifluoromethanesulfonate (triflate), methanesulfonate (me.sylate), toluenesulfonate (tosylate) and fluorosulfonate, the phosphonic acid residues, such as diphenylphosphonate and the halide leaving groups, such as chloride, bromide or iodide. Most preferred are triflate (OTf), flurorosulfonate (OSO2F), mesylate (OMs), diphenyl phosphate and 30 tosylate (OTs).

CA 02224439 l997-l2-ll W O 97/01564 PCTrUS96/10783 EXAMPLE ONE

H 3C ~o o/ TM S-C I ~ N~O P N B

O'~N'H CH2CI2 H 1c Compound 3a (7.~s g.) and imidazole (3.4 g.) are dissolved in 5 ethyl acetate (70 mL, sieve dried) and the solution i.s .stirred for 10 min. at room temperature. The solution is cooled ~nd trimethyl,silyl chloride (3.57 mL) i.s added while maintaining the temperature at -10 to -I ~C. A
white-yellow .suspen~sion formed.
The suspension i~s allowed to warm to room temperature and 10 .stirred at room temperature for 1.5 hrs. Pour into pho.sphate buffer (0.01 M, ~0 mL, pH 6.~). Separate phases and wash the organic phase with aq. NaHCO3 solution (saturated, 40 mL). Dry over Na2SO4. Filter and evaporate the filtrate to dryne.ss. Load the filtrate onto a flash silica column (40 cm diam x 1~0 cm high). packed in 30% EtOAc and hexane 15 (+ 0.025% Et3N). Fractions l~S - 55 contained compound Ic EXAMPLE TWO

H3C~fOPNB ~OPNB

~N imidazole ~N~
O' 'H CH2CI2 ~ H 1d A 250 mL 3-neck flask equipped with a N2 inlet, a thermocouple probe, and a dropping funnel was charged with THF (20 mL; KF < ~0 ,ug/mL), isopropylacetate (IPAC; 90 mL; KF < ~0 ,ug/mL), compound 3a (15 g; 3~.4 mmol) and imidazole (4.7 g; 69.0 mmol). The 25 slurry was ~stirred at room temperature for 10 minutes until dissolution wa~s complete (KF S 140 ~g/mL). The solution was maintained at 1~-22 ~C as TESCI (9.0 mL; 53.6 mrnol) wa,s added .slowly over 100 minutes.
After the addition was completed, the batch wa,s aged at 20 ~C for 2 hr.
The reaction mixture was assayed by HPLC. The ~staltin~ material should 5 be le.ss than 0.15 area % at 245 nm.
Reaction mixture was quenched into a mixture of heptane.s (30 mL) and 0.01 M phosphate buffer (100 mL; pH 6.~) at room temperature. After 30 minutes of stirring at room temperature, the organic layer was separated. The organic layer wa.s washed twice with l0 0.01 M phosphate buffer (pH 6.g; l00 mL each).
The organic layer was concentrated to about ~ mL at l ~ -20~C/110 - ~0 mm Hg (GC showed 6.3 v/v ~o heptane.s). Heptanes (30 mL) was slowly added during further concentration at l P~ - 20~C/1 10 - Ps0 mm Hg keeping the volume at about 40 mL.
After cryst~lli7.~tion took place, additional heptane (90 mL) wa,s added slowly at room temperature and the suspension wa,s aged at 20~C for I hr then 0~C for 1 hr.
The cry~tals were filtered and washed (~lurry then di,splacement) with a mixture of IPAC and heptane (3: 97 v/v; 1 00mL), 20 and then dried under a nitrogen ,stream. The product (I g g; 93 % yield;
99.6 area %.) wa,s obtained as a white crystalline solid.
EXAMPLE THREE

H 3C ~ TMS C I H3C ~/0 P N B

~N~ ~ ~ imid~ole ~N ~ ~
2~ 3b H CH2C12 0 H 1e Starting from compound 3h, using the procedure set forth in Example One, compound le is obtained.

W O 97/OlS64 rcTrusg6/lo783 EXAMPLE FOUR

H ~C ~O P N B ~O P N B
~--N ~ ~ Imldazole ~N~ ~

5To a solution of 31~ (245 mg) in a mixture of THF ( I mL) and EtOAc (2 mL) wa.s added imidazole (~0 mg) and TESCI (0.15 mL) at room temperature. After stirring for 2 hrs, the reaction mixture wa~
diluted with hexanels (3 mL) and washed with phosphate buffer (pH 7.0;
6 mL) twice. The organic layer was dried over MgSO4 and concentrated 10 to give crude If, which was further purified by silica gel column chromatography using a mixture of hexanes and EtOAc (3: 2 to 1: 1 ) to give pure If (310 mg).

EXAMPLE FIVE

H3T N OPNB H3~ l 1 o~ ' 2d CO2PNB

Compound I d (16.0 kg), rhodium octanoate (0.123 kg), anhydrous zinc bromide (71 g), and dry dichloromethane (63.42 L; KF <
20 100,ug/mL) are charged to a dry reactor. The solution is deoxygenated with three vacuum/nitrogen-fill cycles, then heated to reflux under nitrogen for 90 min to give a solution of Compound 2d.

EXAMPLE SIX
TMSO

H3 ~OPN B H3C~=

O H 1C 2c CO2P N B

' 5 Starting from compound 1(, u~ing the procedure set forth in Example Five, compound 2(~ is obtained.

EXAMPLE SEVEN

H3C~J~C 02PNB H3C~$
N O Rh2(octa)4 0 O H ZnBr2 4a C 02PNB
3a C H2C12 TESCI
Imidazole H3C ~= o O N ~/
2d CO2PNB
A solution of Compound 3a ( 1 .1 g) in methylene chloride (4 mL) wa,s heated under reflux with zinc bromide ( 10 mg) and rhodium octanate (10 mg) for 4 hours. The solution containing Compound 4a wa,s 15 cooled down to -7~ ~C. To this solution was added a mixture of triethylsilyl chloride (0.65 mL) and imidazole (285 mg) at -7g ~C. After aged for 1 hr at -7P~ ~C. The reaction mixture was slowly warmed up to 0 ~C. From NMR and HPLC analy~is, the .~olution contained mainly Compound 2d.
EXAMPLE EIGHT
TESO

~N OPNB H3C~$o 1f H 2f CO2PNB

A solution of If (291 mg) in methylene chloride (5 mL) i heated with 10 mg of rhodium octanoate dimer at 30~C for 3 hr.~i. The reaction mixture was concentrated under reduced pre.ssure to give crude 2f (260mg).

EXAMPLE NINE
TMSO
TMSO I H H

H3C ~ N O P N B H3C~o o H 1e 2e CO2PNB

Starting from compound l e, using the procedure set forth in Example Eight, the TMS protected interrnediate 2e is obtained.

WO 97/OlS64 PCT/US96110783 EXAMPLE TEN
OH OTES
I H H I H H
M e~O

4a 2f To a solution of 4a (0.97 g) and imidazole (343 mg) in a mixture of THF (5 mL) and EtOAc (5 mL) was slowly added TESCI
(0.66 mL) at room temperature. After .stirring for 2 hr~i, the reaction mixture was diluted with 10 mL of EtOAc and wa.shed with phosphate buffer (pH 7.0; 15 mL) twice. The organic layer wa.s dried over MgSO4, concentrated under reduced pressure to give crude 2f (1.235 g).

Claims (13)

WHAT IS CLAIMED IS:

1. A process of synthesizing a compound of the formula:

or wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl comprising treating a compound of the formula:

or with P-Cl wherein P is as defined above, in the presence of base and a substantially non-reactive solvent to produce:

or 1 2.

2. A process of synthesizing a compound of the formula:

wherein R represents H or methyl, comprising treating a compound of the formula:

with triethylsilyl chloride in the presence of base and a substantially non-reactive solvent to produce .

3. A process in accordance with claim 1 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.

4. A process in accordance with claim 3 wherein the base is imidazole.

5. A process of synthesizing a compound of the formula:

wherein R represents H or methyl, comprising treating a compound of the formula:

with triethylsilyl chloride in the presence of a nitrogen containing base and a substantially non-reactive solvent to produce:

.

6. A process in accordance with claim 5 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.

7. A process in accordance with claim 6 wherein the base is imidazole.

8. A process of synthesizing a compound of the formula:

wherein R represents H or methyl, comprising treating a compound of the formula:

with trimethylsilyl chloride in the presence of base and a substantially non-reactive solvent to produce .

9. A process in accordance with claim 8 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.

10. A process in accordance with claim 9 wherein the base is imidazole.

11. A process of synthesizing a compound of the formula:

wherein R represents H or methyl, comprising treating a compound of the formula:

with trimethylsilyl chloride in the presence of base and a substantially non-reactive solvent to produce:

.

12. A process in accordance with claim 11 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.

13. A process in accordance with claim 12 wherein the base is imidazole.