AU4650493A - (Enantiomeric cis)-3-(4,6-dihydroxychroman-3-YL-methyl)benzoic acids - Google Patents
(Enantiomeric cis)-3-(4,6-dihydroxychroman-3-YL-methyl)benzoic acidsInfo
- Publication number
- AU4650493A AU4650493A AU46504/93A AU4650493A AU4650493A AU 4650493 A AU4650493 A AU 4650493A AU 46504/93 A AU46504/93 A AU 46504/93A AU 4650493 A AU4650493 A AU 4650493A AU 4650493 A AU4650493 A AU 4650493A
- Authority
- AU
- Australia
- Prior art keywords
- compound
- salt
- dihydroxychroman
- benzoic acid
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
ENANTIOMERIC C/S-3-(4.6-DlHYDROXYCHROMAN-3-YL-METHYϋBENZOIC ACIDS
BACKGROUND OF THE INVENTION
This invention relates to c/s-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acids and processes for the preparation of such compounds. The compounds are intermediates useful in the preparation of optically pufe enantiomers of c/s-3-(6- arylmethyloxy-4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides. The latter compounds are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases. More particularly it relates to (3R-c/s) - 3-(4,6- dihydroxychroman-3-ylmethyl)benzoic acid, processes for its preparation from racemic cis - 3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid and a novel process for the preparation of the racemic acid.
The use of the intermediates of this invention in preparing the c/s-3-(6- arylmethyloxy-4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides is described in the patent application of Marfat, et al. (attorney docket number PC 8230) filed concurrently herewith. SUMMARY OF THE INVENTION
The present invention relates to the compound of the formula
O H
novel processes for its preparation and a novel process for the preparation of the compound of the formula
0 H
( r ac e m l c )
useful in the preparation of the compound of formula I.
The present invention also relates to the optically pure diasteriomeri salts of the compound of formula I with the compound of formula
The compound of formula I is prepared, according to the invention, by acidifying the diasteriomeric salt of the compound of formula I with the compound of formula III.
The diasteriomeric salt of the compound of formula I with the compound of formula III is prepared according to the invention, by treating the compound of formula
II with the compound of formula III in the presence of a non-solvent for said salt. The present invention also relates to a novel method for preparing the compound of formula II by reducing the compound of formula
with a reducing agent selected from diisobutylaluminum hydride and borohydride ion in the presence of Ce (III) ion.
The overall reaction to prepare the compound I from the compound of formula IV through the above intermediate steps for the preparation of the compound of formula II is also part of the invention.
DETAILED DESCRIPTION OF THE INVENTION The compound of formula I, also referred to herein as (3R-c/s)-3-(4,6- dihydroxychroman-3-ylmethyl)benzoic acid, is a novel compound prepared by acidifying the diasteriomeric salt of the compound of formula I and the compound of formula III in the presence of a solvent for the free acid.
The acidification is effected using an acid with a pKa of about < 3 such as HCI, H2S04, oxalic and citric acids.
The diasteriomeric salt of the compound of formula I and the compound of formula III is prepared by heating the compounds of formulae II and III in the presence of a non-solvent for said salt and recovered, after cooling to room temperature, by filtration.
Non-solvents for the diasteriomeric salt include ethanol and isopropanol. The preferred non-solvent is ethanol. The reaction is preferably carried out at a temperature between about 0°C and about 80°C, preferably at the reflux temperature of the non-solvent. Most preferably the reaction is effected at about 80°C.
The treatment of the compound of formula II with the compound of formula III is carried out over a period of about 30 minutes to about 3 hours, preferably about 1 hour.
The salt is purified by slurrying with the non-soivent at an elevated temperature followed by filtration at about room temperature. The slurrying procedure is, preferably, effected two times.
If desired, the other cis enantiomer, i.e. (3S-c/s)-3-(4,6-dihydroxychroman-3- ylmethyl)benzoic acid may be prepared by substituting the (+) base for the compound of formula III. Alternatively, the 3S- acid may be prepared by treating the filtrate from the preparation of the diasteriomeric salt of the compound of formula I with acid followed by said (+ ) base followed by the above-indicated treatment for the salts with the (-) base.
Racemic c/s-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid (compound II) is prepared, according to the invention, by the novel process of treating the compound of formula IV with a solution of a reducing agent in tetrahydrofuran/methanol. Preferred reducing agents are diisobutylaluminum hydride and borohydride in the presence of a Ce (III) salt. A most preferred reducing agent is borohydride ion in the presence of a Ce(lll) salt.
The tetrahydrofuran and methanol may be present in a ratio of from about 3:1 to about 1 :2, preferably about 3:1.
The reduction may be effected at a temperature from about -78°C to about 60°C, preferably at about 0°C.
In the practice of using the novel compound of formula I said compound is converted to the optically pure enantiomeric compound of formula
O H
through a Curtius rearrangement followed by hydrogenation. The phenolic hydroxyl group of the compound of formula V is then converted to the alkyl or aryl ether of formula
by treatment with an alkyl or aryl halide in the presence of a base followed by sulfonation of the amino group of the compound of formula VI. The sulfonamides, especially the trifluoromethanesulfonamides, of the compound of formula VI are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases.
The following Examples illustrate but do not limit the scope of this invention.
EXAMPLE 1 Racemic c/s-3-(4,6-dihvdroxychroman-3-ylmethyl)benzoic acid
To a solution of 3-(6-hydroxy-4-oxo-chroman-3-ylmethyl)benzoic acid (2.00 gm, 6.70 mmol) in 24 ml tetrahydrofuran was added 12 ml methanol followed by 1.50 gm CeCI3 (4.02 mmol). The resulting hazy solution was cooled to 0°C and treated with a total of 0.52 gm NaBH4, portionwise, over 55 minutes. 1N HCI was added to the reaction mixture which was then concentrated on a rotary evaporator, transferred to a separatory funnel and partitioned between water and ethyl acetate. The organic phase was washed twice with 1 N HCI, once with water and once with brine followed by drying over Na2SO4 and filtration. The filtrate was concentrated to a light brown oil which was evacuated to a tan foam, yielding 1.93 gm (96%). 1H NMR (dimethylsulfoxide-d6) δ 7.88 (m, 2H), 7.44 (m, 2H), 6.64 (m, 3H), 4.40 (s, 1 H), 3.91 (m, 2H), 3.30 (m, 1 H), 2.91 (m, 1 H), 2.61 (m, 1h); 13C NMR (dimethylsulfoxide-d6) δ 167.492, 150.473, 146,386, 140.452, 133.621 , 130.876, 129.907, 128.568, 127.058, 125.866, 116.361 , 116.021 , 115.941 , 64.246, 63.532, 31.858.
EXAMPLE 2 (-)-c s-N-Benzyl-2-(hydroxymethyl)cyclohexylamine salt of f-)-c/s-3-(4.6- dihvdroxychroman-3-ylmethyl)benzoic acid
To a solution of 1.766 gm (5.88 mmol) of racemic c/s-3-(4,6-dihydroxychroman-3- ylmethyl)benzoic acid (prepared in Example 1) in 10 ml absolute ethyl alcohol was
added a solution of 1 .290 gm (5.88 mmol) (-)-c/s-N-benzyl-2-(hydroxymethyl)- cyclohexylamine in 9 ml ethyl alcohol. The resulting suspension was heated at reflux for 1 hour, cooled to room temperature, stirred for 1 hour and filtered. The resulting off- white solids (1.996 gm) were suspended in 20 ml absolute ethyl alcohol and heated at reflux for 3 hours followed by cooling to room temperature and stirring for an additional hour. Filtration yielded 1.295 gm of light gray solids which were again suspended in refluxing ethanol (15 ml) for 2 hours. After cooling the suspension was filtered to give 1.065 gm (63.2% of the available enantiomer) off-white solids, m.p. 216 - 218° C, [σ]D = +42.7° (c = 0.309, methanol). EXAMPLE 3
(3R-c/s)-3-(4.6-Dihydroxychroman-3-ylmethyl)benzoic acid A suspension of 1.061 gm (2.042 mmol) of the enantiomeric salt, prepared in Example 2, in water was adjusted to Ph 1 with 10% HCI and transferred to a separatory funnel charged with ethyl acetate. The organic layer was washed with twice with 1 N HCI, once with water and once with brine and thendried over Na2S04. Concentration on the rotary evaporator and evacuation under high vacuum yielded 0.604 gm of the title compound as a white foam, m.p. 85-95°C, [σ]D -= + 100° (c = 0.475, tetrahydrofuran).
Claims (15)
1. An optically pure enantiomer of c/s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid.
2. The compound of claim 1 consisting of ((3R-c/s)-3-(4,6- dihydroxychroman-3-yl methyl)benzoic acid.
3. A diastereomeric salt formed from the compound of formula I and the compound of formula III.
4. A process for preparing ((3R-c/s)-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid which comprises acidifying the diastereomeric salt of claim 3.
5. The process of claim 4 wherein said acidification is effected by means of an acid having a pKa < 3.
6. The process of claim 5 wherein said acid is HCI.
7. The process of claim 4 wherein said diastereomeric salt is prepared by treating racemic c/s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid with (-)-c/s-N- benzyl-2-(hydroxymethyl)cyclohexylamine in the presence of a non-solvent for said salt.
8. The process of claim 7 wherein racemic c/s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid is prepared by treating the compound of theformula
with a reducing agent selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride.
9. The process of claim 8 wherein said reducing agent is borohydride ion in the presence of a Ce (III) salt in 3:1 tetrahydrofuran:methanol.
10. The process of claim 8 wherein said reducing agent is diisobutylaluminum hydride.
11. The process of claim 9 wherein said reducing agent is sodium borohydride ion and said Ce(lll) salt is CeCI3.
12. The process of claim 4 for preparing (3R- c/'s)-3-(4,6-dihydroxychroman-3- yimethyl)benzoic acid comprising the steps of a) treating the compound of the formula
with a reducing agent to form racemic c s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid wherein said redoing agent is selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride. ; b) treating said acid with (-)-c/s-N-benzyl-2-(hydroxymethyl)cyclohexylamine to form a diasteriomeric salt in the presence of a non-solvent for said salt; and c) treating the diasteriomeric salt with an acid to release the desired benzoic acid.
13. The process of claim 12 wherein said reducing agent is borohydride ion in the presence of a Ce (III) salt in 3:1 tetrahydrofuran:methanol.
14. The process of claim 12 wherein said reducing agent is diisobutylaluminum hydride.
15. The process of claim 13 wherein said reducing agent is sodium borohydride ion and said Ce(lll) salt is CeCI3.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US96433692A | 1992-10-21 | 1992-10-21 | |
| US964336 | 1992-10-21 | ||
| PCT/US1993/006061 WO1994008986A1 (en) | 1992-10-21 | 1993-06-30 | Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU4650493A true AU4650493A (en) | 1994-05-09 |
Family
ID=25508434
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU46504/93A Abandoned AU4650493A (en) | 1992-10-21 | 1993-06-30 | (Enantiomeric cis)-3-(4,6-dihydroxychroman-3-YL-methyl)benzoic acids |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0665839A1 (en) |
| JP (1) | JPH07507811A (en) |
| KR (1) | KR950704291A (en) |
| CN (1) | CN1090577A (en) |
| AU (1) | AU4650493A (en) |
| CA (1) | CA2146005A1 (en) |
| CZ (1) | CZ100895A3 (en) |
| FI (1) | FI934624A (en) |
| HU (1) | HUT65128A (en) |
| IL (1) | IL107293A0 (en) |
| MX (1) | MX9306526A (en) |
| MY (1) | MY131378A (en) |
| NO (1) | NO951507D0 (en) |
| PL (1) | PL308473A1 (en) |
| WO (1) | WO1994008986A1 (en) |
| ZA (1) | ZA937737B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3117730B2 (en) * | 1996-09-16 | 2000-12-18 | ファイザー・インク | Methods and intermediates for preparing substituted chromal derivatives |
| MXPA02004225A (en) * | 1999-10-27 | 2002-10-17 | Nobex Corp | Resolution of intermediates in the synthesis of substantially pure bicalutamide. |
| MY128449A (en) | 2000-05-24 | 2007-02-28 | Sugen Inc | Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
| US6479692B1 (en) | 2001-05-02 | 2002-11-12 | Nobex Corporation | Methods of synthesizing acylanilides including bicalutamide and derivatives thereof |
| EP2407462B1 (en) | 2004-09-21 | 2014-07-30 | Marshall Edwards, Inc. | Substituted chroman derivatives, medicaments and use in therapy |
| US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
| EP2635121B1 (en) | 2010-11-01 | 2020-01-08 | MEI Pharma, Inc. | Isoflavonoid compounds and methods for the treatment of cancer |
| HUE054998T2 (en) | 2015-02-02 | 2021-10-28 | Mei Pharma Inc | Combination therapies for use in the treatment of breast cancer |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5059609A (en) * | 1987-10-19 | 1991-10-22 | Pfizer Inc. | Substituted tetralins, chromans and related compounds in the treatment of asthma, arthritis and related diseases |
-
1993
- 1993-06-30 AU AU46504/93A patent/AU4650493A/en not_active Abandoned
- 1993-06-30 EP EP93916752A patent/EP0665839A1/en not_active Withdrawn
- 1993-06-30 PL PL93308473A patent/PL308473A1/en unknown
- 1993-06-30 KR KR1019950701524A patent/KR950704291A/en not_active Application Discontinuation
- 1993-06-30 CZ CZ951008A patent/CZ100895A3/en unknown
- 1993-06-30 CA CA002146005A patent/CA2146005A1/en not_active Abandoned
- 1993-06-30 WO PCT/US1993/006061 patent/WO1994008986A1/en not_active Application Discontinuation
- 1993-06-30 JP JP6509963A patent/JPH07507811A/en active Pending
- 1993-10-14 IL IL107293A patent/IL107293A0/en unknown
- 1993-10-19 ZA ZA937737A patent/ZA937737B/en unknown
- 1993-10-20 MX MX9306526A patent/MX9306526A/en unknown
- 1993-10-20 MY MYPI93002174A patent/MY131378A/en unknown
- 1993-10-20 HU HU9302973A patent/HUT65128A/en unknown
- 1993-10-20 CN CN93119050A patent/CN1090577A/en active Pending
- 1993-10-20 FI FI934624A patent/FI934624A/en not_active Application Discontinuation
-
1995
- 1995-04-20 NO NO951507A patent/NO951507D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0665839A1 (en) | 1995-08-09 |
| JPH07507811A (en) | 1995-08-31 |
| NO951507L (en) | 1995-04-20 |
| CN1090577A (en) | 1994-08-10 |
| FI934624A (en) | 1994-04-22 |
| HUT65128A (en) | 1994-04-28 |
| IL107293A0 (en) | 1994-01-25 |
| KR950704291A (en) | 1995-11-17 |
| CA2146005A1 (en) | 1994-04-28 |
| MY131378A (en) | 2007-08-30 |
| PL308473A1 (en) | 1995-08-07 |
| NO951507D0 (en) | 1995-04-20 |
| WO1994008986A1 (en) | 1994-04-28 |
| ZA937737B (en) | 1995-04-19 |
| CZ100895A3 (en) | 1995-10-18 |
| HU9302973D0 (en) | 1993-12-28 |
| MX9306526A (en) | 1994-04-29 |
| FI934624A0 (en) | 1993-10-20 |
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