WO1996033990A1 - Synthesis of (s)-3-(2-thienylthio) butyric acid and analogs - Google Patents
Synthesis of (s)-3-(2-thienylthio) butyric acid and analogs Download PDFInfo
- Publication number
- WO1996033990A1 WO1996033990A1 PCT/US1996/005623 US9605623W WO9633990A1 WO 1996033990 A1 WO1996033990 A1 WO 1996033990A1 US 9605623 W US9605623 W US 9605623W WO 9633990 A1 WO9633990 A1 WO 9633990A1
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- WIPO (PCT)
- Prior art keywords
- acid
- compound
- synthesis
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Links
- 0 Cc1c([C@](C*I)O)cc[s]1 Chemical compound Cc1c([C@](C*I)O)cc[s]1 0.000 description 3
- JSDMMZGCZZVJKY-UHFFFAOYSA-N Cc([s]1)cc(C(C2)=O)c1SC2I Chemical compound Cc([s]1)cc(C(C2)=O)c1SC2I JSDMMZGCZZVJKY-UHFFFAOYSA-N 0.000 description 1
- JGYPTJWKZPTDET-ZCFIWIBFSA-N O=C(C[C@@H]1I)c(cc[s]2)c2S1(=O)=O Chemical compound O=C(C[C@@H]1I)c(cc[s]2)c2S1(=O)=O JGYPTJWKZPTDET-ZCFIWIBFSA-N 0.000 description 1
- IACMOXLJSXKKBG-RXMQYKEDSA-N OC(C[C@@H](Sc1ccc[s]1)I)=O Chemical compound OC(C[C@@H](Sc1ccc[s]1)I)=O IACMOXLJSXKKBG-RXMQYKEDSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
Definitions
- the current therapy for control of elevated intraocular pressure (IOP) or ocular hypertension which is believed to be a factor in the onset and progress of glaucoma is typically effected with a variety of topically applied agents which fall within four categories: ⁇ -blockers. sympathomimetic agents, parasympatho-mimetic agents and cholinesterase inhibitors.
- the adjuvant oral administration of a carbonic anhydrase inhibitor (CAI) is practised when the above-described topical agent's side effects limits its use and/or it fails to achieve adequate IOP control.
- the orally active CAI's can exhibit serious side-effects such as anorexia, gastrointestinal upset and parasthesias.
- R and Ri are lower alkyl, especially dorzolamide, wherein R is ethyl and R 1 is methyl.
- U.S. Patent 4,797,413 discloses a process for preparing the racemic modification of the alkyl 3-(thien-2-ylthio)butyrate and its homologs.
- the prior art process comprises addition of the 2-thienyl-thiol (II) across the double bond of a substituted acrylic acid (IV) to yield the acid I:
- This invention is concerned with an improved process for the synthesis of the acid of structural formula I
- R and Rl are lower alkyl, especially dorzolamide, wherein R is ethyl and R i is methyl, a carbonic anhydrase inhibitor topically effective in the treatment of ocular hypertension and glaucoma.
- the instant process reduces the reaction time from 3 to 4 days to from about 2 to about 4 hours while retaining the high enantiomeric purity of the product.
- R ⁇ is hydrogen, Cj -4 alkyl, or Cj -4 alkoxy-C i -4alkyl, comprises treating a compound of formula III:
- R and Rl independently are hydrogen, or C 1-4 alkyl
- R2 is tosyl, mesyl, p-methoxy benzenesulfonyl, p- or m-chloro-, or bromo-, benzenesulfonyl or -nitrobenzenesulfonyl in formamide or a mixture of an ethereal solvent and formamide at a temperature of about 41 °C to 60°C for about 2 to about 4 hours to produce Compound II, treating Compound II
- the mineral acid can be hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like.
- the alkylation can be conducted preferrably at about 41 - 45°C, until the reaction is substantially complete in about 2 to about 4 hours.
- the reaction time is shortened from 3 to 4 days to 2 to about 4 hours as a result of the heating, which is done without loss of chirality at the chiral carbon. This improvement was unexpected and significant because generally at temperatures above 40°C a competing elimination of tosic acid reaction would be expected. Under certain reaction conditions elimination of a proton adjacent to the ester, as well as the tosylate, produces the cx, ⁇ -unsaturated ester.
- the temperature range is high enough to allow for an increase in reaction rate, but low enough to prevent the undesired elimination reaction.
- the reaction can be quenched by addition of the reaction mixture to aqueous ethyl acetate, or addition of aqueous ethyl acetate to the reaction mixture.
- Ethyl acetate can be replaced by n-butyl acetate, methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, and the like.
- Hexane can be replaced by pentane, cyclohexane, cyclopentane, heptane, petroleum ether, and the like.
- Brine can be composed of aqueous solutions of sodium chloride, calcium chloride, sodium sulfate, calcium sulfate, magnesium sulfate, potassium carbonate, and the like.
- the hydrolysis reaction of the ester to the acid can be conducted preferrably at about 50 to 80°C.
- the instant acid hydrolysis of the ester is significant in that hydrolysis in the heterogeneous reaction medium of HC1 and H2 ⁇ produces, in addition to the desired (S)-3-(2- thienylthio)butyric acid, the regioisomeric (S)-3-(3-thienylthio)butyric acid and the corresponding ring closed product. Formation of these undesired regioisomers is reduced or eliminated through use of the instant homogeneous acetic acid and strong mineral acid hydrolysis conditions.
- the hydrolysis reaction can be worked up through distillation and extraction, as outlined in the experimental section.
- the distillation can be performed, and the crude reaction mixture carried on as a through-process in the subsequent ring closure step.
- the reaction steps are exemplified by the Examples that follows.
- the product of the novel process of this invention is a topically effective carbonic anhydrase inhibitor useful in the treatment of ocular hypertension. It is administered topically to the eye usually as a solution, comprising about 0.1 % to 15% by weight of compound, one or two drops at a time, one to four times a day.
- EXAMPLE 1 is a topically effective carbonic anhydrase inhibitor useful in the treatment of ocular hypertension. It is administered topically to the eye usually as a solution, comprising about 0.1 % to 15% by weight of compound, one or two drops at a time, one to four times a day.
- reaction course was monitored by HPLC, and the reaction was found to be complete within 2 to 4 hours. It was necessary to sample from both layers during monitoring due to the differential solubilities of reactants and products in the two layers.
- H2 ⁇ /ethyl acetate (2: 1 , 2162 mL). The mixture was allowed to stir for 30 minutes at 25°C, and the aqueous layer was then separated. The aqueous layer was washed with ethyl acetate/hexane ( 1 : 1 , 370 mL). The organic layers were combined, and washed with brine (420 mL).
- the product was concentrated to an oil and isolated chromatographically.
- the conditions for chromatography are a silica gel support with 10% ethyl acetate in hexanes as the eluting solvent.
- the second major fraction 0.52) represented the desired product.
- the product was converted to the acid by removing the ethyl acetate in vacuo, and adding water (350 mL). Distillation continued until the final volume was 260 mL.
- the product was then subjected to hydrolysis conditions to form the carboxylic acid.
- Chirality was determined on the corresponding acid after hydrolysis. Chirality >97.7:2.3.
- the acid was converted to the 3,5- dimethylanilide derivative, and analyzed on a column containing the (R,R) GEM CSP (Regis Technologies) with a mobile phase of 90: 10 hexane/THF.
- Derivatization procedure The acid ( 1 eq.) in CH2CI2 was treated with (2-ethoxy-l-ethoxycarbonyl-l ,2-dihydroquinoline (EEDQ, 111 eq.)). This was allowed to stir for 30 minutes. 3,5-Dimethylaniline was added, and the reaction allowed to proceed for 15 minutes. The organic layer was then washed with IN HCl (2 x 10 mL), H2 ⁇ (2 x 10 mL), and saturated NaHC03 (10 mL).
- Enantiomeric purity of the chiral ester can be determined directly by supercritical fluid chromatography using a Chiralpak AD column (Chiral Technologies, Inc.) Conditions: 300 bar C02 containing 2 vol. % methanol, 1 mL/min, 35 °C, detection with UV, 235 nm. The "S"-enantiomer elutes at 7.3 min and the “R"-enantiomer elutes at 8.1 min.
- the aqueous layer was washed with ethyl acetate (30 mL). The organic layers were combined and water (60 mL) was added. The pH of the aqueous system was adjusted to 8.5 by slow addition of 50% NaOH, and the layers separated. Water (30 mL) was again added to the organic layer, and the pH again adjusted to 8.5. To the combined aqueous layers was added toluene (90 mL) and concentrated HCl (6.8 mL). The mixture was stirred so that the white precipitate, which formed upon acidification, dissolved. The layers were separated, and the aqueous layer again washed with toluene (45 mL). The organic layers were combined and washed with brine (50 mL).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU54885/96A AU704210B2 (en) | 1995-04-26 | 1996-04-22 | Synthesis of (S)-3-(2-thienylthio) butyric acid and analogs |
JP8532643A JP3064017B2 (en) | 1995-04-26 | 1996-04-22 | Synthesis of (S) -3- (2-thienylthio) butyric acid and analogs |
EP96911821A EP0824532A1 (en) | 1995-04-26 | 1996-04-22 | Synthesis of (s)-3-(2-thienylthio) butyric acid and analogs |
CA002218654A CA2218654C (en) | 1995-04-26 | 1996-04-22 | Synthesis of (s)-3-(2-thienylthio) butyric acid and analogs |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/430,214 | 1995-04-26 | ||
US08/430,214 US5574176A (en) | 1995-04-26 | 1995-04-26 | Synthesis of an intermediate for the preparation of 5,6-dihydro-(s)-4-(ethylamino)-(s)-6-methyl-4h-thieno [2,3-b]thiopyran-2-sulfonamide 7,7-dioxide intermediates and related compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996033990A1 true WO1996033990A1 (en) | 1996-10-31 |
Family
ID=23706561
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/005623 WO1996033990A1 (en) | 1995-04-26 | 1996-04-22 | Synthesis of (s)-3-(2-thienylthio) butyric acid and analogs |
Country Status (10)
Country | Link |
---|---|
US (1) | US5574176A (en) |
EP (1) | EP0824532A1 (en) |
JP (1) | JP3064017B2 (en) |
AR (1) | AR000014A1 (en) |
AU (1) | AU704210B2 (en) |
CA (1) | CA2218654C (en) |
HR (1) | HRP960199B1 (en) |
TW (1) | TW394767B (en) |
WO (1) | WO1996033990A1 (en) |
YU (1) | YU25196A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0748803A1 (en) * | 1994-12-28 | 1996-12-18 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for producing carboxylic acid derivative |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3777408B2 (en) * | 1994-12-28 | 2006-05-24 | 株式会社カネカ | Method for producing carboxylic acid derivative |
US5760249A (en) * | 1995-08-29 | 1998-06-02 | Merck & Co., Inc. | Synthesis of hydroxysulfone and related compounds |
ATE380190T1 (en) * | 2004-07-09 | 2007-12-15 | Fdc Ltd | IMPROVED METHOD FOR PRODUCING 5,6-DIHYDRO-4H-4(S)-ETHYLAMIN-6(S)-METHYLTHIENO(2,3-B)THIOPYRAN-2-SULFONAMIDE-7,7-DIOXIDE AND ITS SALTS |
CN114891838B (en) * | 2022-04-29 | 2023-09-08 | 株洲壹诺生物技术有限公司 | Synthesis method of dorzolamide hydrochloride intermediate (S) -3- (2-thiophenyl) -butyric acid |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4968814A (en) * | 1990-04-18 | 1990-11-06 | Merck & Co., Inc. | (S)-Alkyl 3-(thien-2-ylthio)butyrate and analogs and synthesis thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4113968A (en) * | 1974-10-03 | 1978-09-12 | Kuraray Co., Ltd. | Process for preparation of substituted cyclopropane carboxylic acids and esters thereof and intermediates of said acids and esters |
US4797413A (en) * | 1986-05-14 | 1989-01-10 | Merck & Co., Inc. | Thieno thiopyran sulfonamide derivatives, pharmaceutical compositions and use |
US4968815A (en) * | 1990-04-16 | 1990-11-06 | Merck & Co., Inc. | Synthesis of (S)-3-(thien-2-ylthio)butyric acid analogs |
-
1995
- 1995-04-26 US US08/430,214 patent/US5574176A/en not_active Expired - Fee Related
-
1996
- 1996-04-18 TW TW085104640A patent/TW394767B/en active
- 1996-04-22 AU AU54885/96A patent/AU704210B2/en not_active Ceased
- 1996-04-22 WO PCT/US1996/005623 patent/WO1996033990A1/en not_active Application Discontinuation
- 1996-04-22 EP EP96911821A patent/EP0824532A1/en not_active Withdrawn
- 1996-04-22 JP JP8532643A patent/JP3064017B2/en not_active Expired - Fee Related
- 1996-04-22 CA CA002218654A patent/CA2218654C/en not_active Expired - Fee Related
- 1996-04-24 YU YU25196A patent/YU25196A/en unknown
- 1996-04-24 HR HR960199A patent/HRP960199B1/en not_active IP Right Cessation
- 1996-04-25 AR AR33628696A patent/AR000014A1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4968814A (en) * | 1990-04-18 | 1990-11-06 | Merck & Co., Inc. | (S)-Alkyl 3-(thien-2-ylthio)butyrate and analogs and synthesis thereof |
Non-Patent Citations (1)
Title |
---|
BLACKLOCK ET AL.: "An enantioselective synthesis of ...", J. ORG. CHEM., vol. 58, 1993, pages 1672 - 1679, XP002009305 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0748803A1 (en) * | 1994-12-28 | 1996-12-18 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for producing carboxylic acid derivative |
EP0748803A4 (en) * | 1994-12-28 | 1997-08-13 | Kanegafuchi Chemical Ind | Process for producing carboxylic acid derivative |
Also Published As
Publication number | Publication date |
---|---|
CA2218654A1 (en) | 1996-10-31 |
YU25196A (en) | 1999-03-04 |
EP0824532A1 (en) | 1998-02-25 |
CA2218654C (en) | 2002-09-17 |
AU704210B2 (en) | 1999-04-15 |
TW394767B (en) | 2000-06-21 |
HRP960199A2 (en) | 1998-02-28 |
JP3064017B2 (en) | 2000-07-12 |
US5574176A (en) | 1996-11-12 |
JPH10507774A (en) | 1998-07-28 |
HRP960199B1 (en) | 2002-02-28 |
AR000014A1 (en) | 1997-03-12 |
AU5488596A (en) | 1996-11-18 |
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