AP371A - Amine salts of leukotrine antagonist and its use for crystallizing selectively optical isomers thereof. - Google Patents
Amine salts of leukotrine antagonist and its use for crystallizing selectively optical isomers thereof. Download PDFInfo
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- AP371A AP371A APAP/P/1992/000462A AP9200462A AP371A AP 371 A AP371 A AP 371A AP 9200462 A AP9200462 A AP 9200462A AP 371 A AP371 A AP 371A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to certain salts of leukotriene antagonists and the use of a particular amine to form these salts as a means for selectively crystallizing optical isomers of the leukotriene disclosed herein.
Description
CRYSTALLIZATION OF OPTICAL ISOMERS OF LEUKOTRIENE ANTAGONISTS SCOPE OF THE INVENTION
This invention relates to certain amine salts of leukotriene antagonists and the use of an amine to form these salts as a means for crystallizing selectively optical isomers of the leukotriene antagonists recited herein.
BACKGROUND OF THE INVENTION
Slow Reacting Substance of Anaphylaxis (SRS-A) has been shown to be a highly potent bronchoconstricting substance which is released primarily from mast cells and basophils on antigenic challenge. SRS-A has been proposed as a primary mediator in human asthma. SRS-A, in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.
Antagonists to SRS substances have l>een developed in an attempt to provide relief from the disease conditions giving rise to or resulting from these compounds. A number of the compounds developed are normally prepared as a racemic mixture, though activity lies primarily or completely in just one of the optical isomers. Resolving these mixtures is a useful, if not necessary step, in preparing a useful formulation for treating these diseases. It has now been found that for certain compounds, the ones set out below, this can be accomplished most readily and inexpensively by means of (S)-amethylbenzenemethanamine. This amine is uniquely suited to resolving certain enantiomers of the compounds given below so that the most active isomer can be obtained for use in treating SRS-related diseases.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are (S)-a-methyl-benzenemethanamine salts of formula 1
Formula I /
(A) +
(X) where:
Rl is Cg to Cj3 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 to C12 1-alkyny; 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-Cj to C9 alkoxy, phenylihio-C3 to C9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Ci to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to Cjq alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to Cjo alkyl;
q is 0,1 or 2, with the proviso that R| is not alkylthio or phenylthioalkyl when q is I or 2;
Y is (CH2)mCOR3 or (CH2)m-tetrazol-5-yl;
R3 is O> amino, or Ci to C6 alkoxy, m is 0, 1, or 2;
R is (CH2)nCOR6; n is 0 to 6;
Rg is O', amino, or Cj to C6-alkoxy;
with the proviso that at least one of Y or R must have an R3 or R^ group respectively 1 5 which is O'.
This invention also relates to a process for separating an R or S isomer from a racemic mixture of a compound of formula II
where R, Ri, q and Y are defined above with the proviso that R3 and R$ are Ry and R# where R3' and Rg· are independently -OH, amino, or Ci to Q alkoxy, with the further proviso that at least one of R3' or R# must be -OH or a salt thereof, which process comprises treating a racemic mixture of formula II with about 0.5 to 1.5 equivalents, relative
5 to the number of carboxylic acid groups in the formula with (S)-amethylbenzenemethanamine, recovering a crystalline salt, and converting the salt to an acid or a pharmaceutically acceptable salt. It is preferred to use 0.75 to 1.25 equivalents (1.1 is optimal) of the amine per carboxylic acid group in formula II. This process yields a substantially pure single enantiomer from a racemic mixture.
(A) <x> (IA)
wherein A is 1, X is 1 or 2, and Ri and R are described above.
A more preferred subgroup of these salts are 3-aryl-propionates of formula (IB)
where Ri is defined above, particularly where R( is phenylalkyl and X is 2. Most preferred among the salts of this group are:
0 the bis-(S)-a-methylbenzenemethanamine salt of (S)-b-[(2-carboxyethyl)thio]-2-(ldodecyl)benzenepropanoic acid; and the bis-(S)-a-methylbenzenemethanamine salt of (S)-b-[(2-carboxyethyl)thio]-2-(8phenyloctyl)benzenepropanoic acid.
Another preferred group of salts are (he aryl-acetates of formula (IC).
L Jd) L J W (IC) where R| is described above, particularly where Rj is phenylalkyl and X is 2.
The salts of the formula (IC) are exemplified by the following compounds:
the bis-(S)-a-methylbenzenemethanamine salt of (R)-a-[(2-carboxyethyl)thio]-2-(ldodecyl)benzeneaceiic acid; and the
0 bis-(S)-a-methylbenzenemethanamine salt of (R)-a-f(2-carboxyethyl)thio]-2-(8phenyloctyljbenzeneacetic acid.
In a process for resolving racemates of formula II, the following sets of general and specific compounds are preferred.
BAD ORIGINAL ft
A set of preferred racemates are those of formula (ΠΒ),
more particularly those where Rj is a phenyl-C4 to Cio-alkyl. Most particularly racemates of formula (UB) can be treated with the (S)-a-methylbenzenemethanamine to obtain, after further manipulation, the isomers (S)-b-[(2-carboxyethyl)thio]-2-(l-dodecyl)benzenepropanoic acid and (S)-b-((2-carboxyethyl)thio]-2-(8-phenyloctyl)benzenepropanoic acid.
(ΠΒ)
Another set of preferred racemates are those of formula IIC /CH^COR^
S
COR3· (IIC) particularly those where Ri is a phenyl-C4 10 Cjo alkyl. Most particularly racemates of formula 1 0 (IIC) can be treated with (S)-a-methylbenzenemethanamine to obtain, after further manipulation, the isomers (R)-a-[(2-carboxyethyl)thio]-2-(l-dodecyl)benzeneacetic acid and (R)-a-[(2-carboxyethyl)thio]-2-(8-phenyioctyl)benzeneacetic acid.
The racemates of this invention can lie prepared according to the disclosure set out in United States Patent number 4,820,719 issued April 11, 1989. That disclosure, in full, is
5 incorporated herein by reference as if set out herein.
The amine, (S)-a-methylbenzenemeihanamine, can be purchased as the free amine from a commercial source such as Schwcizerhall, Inc.
This amine is a particularly effective resolving agent for separating out a particular isomer from a racemic mixture of compounds denoted by formula II. A salt is formed
0 between the amine and the carboxylate function. This salt can be fractionally crystallized, ( giving a salt comprising the amine and just one isomer of the acid. 2-Propanol in acetonitrile is the preferred solvent system for crystallization. A mixture of 30% 2-propanol and 70% acetonitrile (volume/volume) is believed to be the optimal mixture. Isobutyl acetate, isopropyl acetate and ethyl acetate (undiluted) can also be used in place of the 22 5 propanol/acetonitrile mixture.
These salts may be converted to the corresponding acid by means of a dilute acid. Or they may be converted to another salt, such as an alkali metal salt, by treating a solution of the isolated salt with a base. For example, the salt can be converted to the free acid by treating a solution of that salt with dilute mineral acid, for example 0.5N HCl at room
0 temperature or thereabouts. The mixture is then extracted with an appropriate organic solvent, or subjected to other convenient separatory means, and the pure isomer obtained as the free acid after removing the solvent.
IOUU4 0
The following examples illustrate the process for making and preparing the compounds of this invention. Being examples they are not to be considered as limiting the invention set forth in the claims appended hereto.
Example 1
Preparation of (S)-b-[(2-Carboxyethyl)thiol-2-(8-phenyloctvl)benzenepropanoic acid using (S)-a-Methvlbenzenemethanamine (1:2).
Racemic b-[(2-carboxyethyl)thio]-2-(8-phenyloctyl)benzenepropionic acid 67.2 g (74.7%, 113.4 mmole) was dissolved in 203 mL of 2-propanol and 474 mL of acetonitrile and treated with 30.5 g (99%, 249 mmol) of (S)-a-methylbenzenemethanamine. Under an
0 atmosphere of nitrogen, the mixture was heated to reflux over a period of 30 minutes, then allowed to cool to ambient temperature over a period of approximately 2.5 hours. When at 37°° C, 0.5 g of seed crystals of authentic (S)-b-[(2-carboxyethyl)thio]-2-(8r phenyloctyl)benzenepropanoic acid, compound with (S)-a-methylbenzenemethanamine (1:2) were added. The mixture was stirred at ambient temperature for approximately 38 hours
5 before cooling to 0-5°° C. After stirring at 0-5°° C for 4 hours, the resulting solids were isolated by filtration. Chiral HPLC analysis indicated 97.8% of the desired S enantiomer. After recystallizing from 2-propanol (30%) in acetonitrile (70%), the content of the Senantiomer was enhanced to >99.0%.
Example 2
0 Determination and Confirmation of Absolute Configuration (S)-b-[(2-carboxyethyl)thio]-2-(8-phenyloctyl)-benzenepropanoic acid reacts with two molar equivalents of (R)-4-iodo-a-mcthyIbenzenemethanamine to produce a highly crystalline salt. For this salt, the absolute configuration of the diacid portion was determined /- unambiguously by single crystal x-ray analysis.
5 In order to correlate this information to the salt obtained in Example 1, the salt was ( treated with aqueous acid and extracted with ethyl acetate. By analyzing the extract on an
HPLC column [cellulose Tris-(3,5-dimethylphenylcarbamate) chiral stationary phase, coated on silica gel] and comparing retention times to authentic samples of the racemates, it was determined that the diacid portion of the salt from Example 1 possessed the S-configuration.
Claims (10)
1 0 trifluoromethyl, Cj to C4 alkoxy, methylthio or trifluoromclhykhio, furyl-Gt to C10 alkyl, trifluoromcthyl-C7 to C12 alkyl or cyclohcxyl-C4 to Cjo alkyl;
q is 0, 1 or 2, with the proviso that R j is not alkyllhio or phcnyllhioalkyl when q is I or 2;
Y is (CH2)mCOR3, or (CH2)nrlc(raz°l*5-yl;
15 R3 is O', amino, or Ci to Co alkoxy, m is 0, 1, or 2;
R is (CH2)nCOR6; n is 0 to 6;
is O’, amino, or C| to Q-alkoxy;
1. Λ salt of formula 1 (Λ) (X) (i) where:
A is I and X is 1 or 2;
R| is C# lo C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkyllhio, Cjo to C10 1-alkynyl, 10-undccynyloxy, 11-dodccynyl, phcnyl-C^ to Cto alkyl, phcnyl-Cj to C9 alkoxy, phenylthio-Cj to Cy alkyl with the phenyl optionally mono substituted with bromo, chloro,
2. A salt of claim 1 represented by formula (I A).
(X) (IA) where R| is pheuylalkyl.
2 0 with the proviso that al least one of Y or R must have an R3 or R<, group resjxxtivdy which is O'.
3. A salt of claim 2 where R is (Cl l2) 1-3 CORf,.
bad original ( 20
4.
A sail of claim 3 represented by the 3-arylpropionatc of formula (IB).wherv X is
5. A salt of claim 4 where R j is pheny I-C4 to C jo alkyl.
6. A salt of claim 5 which is the bis-(S)-a-incthylbcnzcncinc(liaiiaininc salt of (S)b-[(2-carboxyclhyl)thio]-2-(8-phenyloclyl)bcnzcncpropanoie acid.
7. The use of (S)-a-methylbcnzcncmcthanaminc to form a salt with a compound of formula Π in a process for separating an isomer of said compound from a racemic mixture, said formula 11 being a compound of the following structure where:
Ri is Ce to Cj3 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, Ciq to Cj2 1-alkynyl, 10undecynyloxy, 11-dodecynyl, phcnyl-C410 ^10 alkyl. phcnyl-C3 to C9 alkoxy, phcnylthioQ 10 C9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromcthyl, Cj lo C4 alkoxy, methyithio or trifluoromcthylthio, furyI-C4 to Cjo alkyl, trifluoromcthyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
q is 0, I or 2, with the proviso that Rj is not alkylthio or phenylthioalkyl when q is 1 or 2,
Y is or (G^m-tetrazol-S-yk.
R3' is Oil, amino, or Ci 10 C$ alkoxy, m is 0, 1, or 2;
R is (Cfl^lnCORfi·; n is 0 to 6;
R# is OH, amino, or Ci lo C6-aIkoxy;
wirh the proviso that at least one of R3' or R^* is ΌΗ or a salt thereof, which process comprises:
BAD
8. The process of claim 7 where the use of said methanaminc salt results in the recovery of the isomer of the following formula.
oF ✓X^COFV COR/
9. The process of claim 8 where, in the compound of formula Π, Rj is a phenyl-Q to
Cio-alkyl.
j q
10. The process of claim 9 wherein the separated isomer is (S)-b-[(2carboxycthyl)thio]-2-(l-dodecyl)bcnzeneprcpanoic acid, or (S)-b-[(2-carboxycthy])thio]-2-(8phenyloctyl)bcnzenepropanoic acid.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/806,031 US5214201A (en) | 1991-12-12 | 1991-12-12 | Crystallization of optical isomers of leukotriene antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9200462A0 AP9200462A0 (en) | 1993-01-31 |
| AP371A true AP371A (en) | 1994-11-10 |
Family
ID=25193150
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1992/000462A AP371A (en) | 1991-12-12 | 1992-12-11 | Amine salts of leukotrine antagonist and its use for crystallizing selectively optical isomers thereof. |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5214201A (en) |
| EP (1) | EP0638055A1 (en) |
| JP (1) | JPH07501823A (en) |
| CN (1) | CN1074212A (en) |
| AP (1) | AP371A (en) |
| AU (1) | AU3243993A (en) |
| BG (1) | BG98842A (en) |
| BR (1) | BR9207022A (en) |
| CA (1) | CA2125495A1 (en) |
| CZ (1) | CZ141294A3 (en) |
| FI (1) | FI942746A0 (en) |
| HU (1) | HUT70850A (en) |
| IL (1) | IL104077A0 (en) |
| MA (1) | MA22742A1 (en) |
| MX (1) | MX9207252A (en) |
| NO (1) | NO942187D0 (en) |
| OA (1) | OA10025A (en) |
| SI (1) | SI9200386A (en) |
| SK (1) | SK69094A3 (en) |
| WO (1) | WO1993012054A1 (en) |
| ZA (1) | ZA929677B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4845272A (en) * | 1987-07-10 | 1989-07-04 | Kuraray Co., Ltd. | Process for the optical resolution of (±)-cis or (±)-trans-permethric acid |
| US4904822A (en) * | 1988-02-19 | 1990-02-27 | Kuraray Co., Ltd. | Process for the optical resolution of (+)-2-hydroxy-4-phenylbutanoic acid |
| US4939295A (en) * | 1988-07-26 | 1990-07-03 | Zambon Group S.P.A. | Process for the preparation of intermediates for the synthesis of diltiazem |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1217988B (en) * | 1988-01-28 | 1990-03-30 | Ind Chimica Profarmaco Spa | PROCEDURE FOR THE OPTICAL RESOLUTION OF A PACEMO |
| CA2018437A1 (en) * | 1989-06-14 | 1990-12-14 | James Simpson Frazee | Leukotriene antagonists |
-
1991
- 1991-12-12 US US07/806,031 patent/US5214201A/en not_active Expired - Fee Related
-
1992
- 1992-12-11 JP JP5511025A patent/JPH07501823A/en active Pending
- 1992-12-11 BR BR9207022A patent/BR9207022A/en not_active Application Discontinuation
- 1992-12-11 HU HU9401744A patent/HUT70850A/en unknown
- 1992-12-11 WO PCT/US1992/010583 patent/WO1993012054A1/en not_active Application Discontinuation
- 1992-12-11 SK SK690-94A patent/SK69094A3/en unknown
- 1992-12-11 CA CA002125495A patent/CA2125495A1/en not_active Abandoned
- 1992-12-11 CZ CZ941412A patent/CZ141294A3/en unknown
- 1992-12-11 AP APAP/P/1992/000462A patent/AP371A/en active
- 1992-12-11 AU AU32439/93A patent/AU3243993A/en not_active Abandoned
- 1992-12-11 EP EP93900975A patent/EP0638055A1/en not_active Withdrawn
- 1992-12-12 CN CN92115381A patent/CN1074212A/en active Pending
- 1992-12-13 IL IL104077A patent/IL104077A0/en unknown
- 1992-12-14 SI SI19929200386A patent/SI9200386A/en unknown
- 1992-12-14 MX MX9207252A patent/MX9207252A/en unknown
- 1992-12-14 ZA ZA929677A patent/ZA929677B/en unknown
- 1992-12-14 MA MA23032A patent/MA22742A1/en unknown
-
1994
- 1994-06-07 OA OA60521A patent/OA10025A/en unknown
- 1994-06-10 NO NO942187A patent/NO942187D0/en unknown
- 1994-06-10 FI FI942746A patent/FI942746A0/en not_active Application Discontinuation
- 1994-06-10 BG BG98842A patent/BG98842A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4845272A (en) * | 1987-07-10 | 1989-07-04 | Kuraray Co., Ltd. | Process for the optical resolution of (±)-cis or (±)-trans-permethric acid |
| US4904822A (en) * | 1988-02-19 | 1990-02-27 | Kuraray Co., Ltd. | Process for the optical resolution of (+)-2-hydroxy-4-phenylbutanoic acid |
| US4939295A (en) * | 1988-07-26 | 1990-07-03 | Zambon Group S.P.A. | Process for the preparation of intermediates for the synthesis of diltiazem |
Also Published As
| Publication number | Publication date |
|---|---|
| MX9207252A (en) | 1993-07-01 |
| EP0638055A4 (en) | 1994-10-19 |
| AU3243993A (en) | 1993-07-19 |
| OA10025A (en) | 1996-10-14 |
| NO942187L (en) | 1994-06-10 |
| AP9200462A0 (en) | 1993-01-31 |
| JPH07501823A (en) | 1995-02-23 |
| HU9401744D0 (en) | 1994-09-28 |
| FI942746A (en) | 1994-06-10 |
| BR9207022A (en) | 1995-12-12 |
| SI9200386A (en) | 1993-06-30 |
| US5214201A (en) | 1993-05-25 |
| HUT70850A (en) | 1995-11-28 |
| CN1074212A (en) | 1993-07-14 |
| EP0638055A1 (en) | 1995-02-15 |
| WO1993012054A1 (en) | 1993-06-24 |
| SK69094A3 (en) | 1995-03-08 |
| MA22742A1 (en) | 1993-07-01 |
| ZA929677B (en) | 1993-10-13 |
| IL104077A0 (en) | 1993-05-13 |
| CA2125495A1 (en) | 1993-06-24 |
| NO942187D0 (en) | 1994-06-10 |
| BG98842A (en) | 1995-05-31 |
| FI942746A0 (en) | 1994-06-10 |
| CZ141294A3 (en) | 1995-01-18 |
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