US20100137632A1 - Process for oseltamivir phosphate - Google Patents
Process for oseltamivir phosphate Download PDFInfo
- Publication number
- US20100137632A1 US20100137632A1 US12/702,471 US70247110A US2010137632A1 US 20100137632 A1 US20100137632 A1 US 20100137632A1 US 70247110 A US70247110 A US 70247110A US 2010137632 A1 US2010137632 A1 US 2010137632A1
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- US
- United States
- Prior art keywords
- amine
- organic
- reaction
- formula
- base
- 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
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- VSZGPKBBMSAYNT-RRFJBIMHSA-N CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 5
- MPTCBJSPQVJIPZ-RRFJBIMHSA-N CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1 Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1 MPTCBJSPQVJIPZ-RRFJBIMHSA-N 0.000 description 5
- UXJWNTIKRKKBGZ-YNEHKIRRSA-N CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1 Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1 UXJWNTIKRKKBGZ-YNEHKIRRSA-N 0.000 description 4
- 0 CCC(CC)O[C@@]([C@]([C@](*)C1)N)C=C1C(OCC)=O Chemical compound CCC(CC)O[C@@]([C@]([C@](*)C1)N)C=C1C(OCC)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/14—Compounds containing azido groups with azido groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- 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
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the present invention provides an improved and commercially viable process for the preparation of oseltamivir phosphate.
- Oseltamivir chemically Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate is a orally active inhibitor of influenza virus neuraminidase.
- Oseltamivir is represented by the following structure:
- acetic anhydride in hexanes or methylene chloride in the presence of aqueous sodium bicarbonate; or with acetyl chloride and pyridine.
- the base such as sodium bicarbonate is normally used to convert the acetic acid formed as by-product into a water soluble salt such as sodium acetate and the salt formed is extracted into water present so as to move the equilibrium towards the formation of acetylated product of the formula B.
- the reduction was carried out with hydrogen gas and a catalyst such as platinum on carbon or Lindlar's catalyst or reducing reagent such as trialkyl or triaryl phosphine.
- a catalyst such as platinum on carbon or Lindlar's catalyst or reducing reagent such as trialkyl or triaryl phosphine.
- the absence of water refers to the content of water in the reaction mass is less than 1.0%, preferably less than 0.5% and more preferably less than 0.2% of the reaction mass by volume.
- Preferable organic base used in the reaction is an organic amine base such as triethyl amine, trimethyl amine, tributyl amine and n-butyl amine; and preferable inorganic base is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. More preferable organic amine base is triethyl amine and more preferable inorganic base is sodium bicarbonate.
- the reaction is preferably carried out at about 0-35° C., more preferably at about 10-30° C. and still more preferably at about 15-25° C.
- Preferable organic solvent used in reaction is selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane; and a mixture thereof. More preferable organic solvent is selected from methylene chloride, n-hexane and a mixture thereof. Most preferable organic solvent is methylene chloride.
- reaction mass may then be subjected to usual work up such as washings, extractions etc.
- the reduction reaction is preferably carried out with hydrogen sulfide in presence of pyridine.
- Preferable organic amine base used in the reduction reaction with Na 2 S is triethyl amine or trimethyl amine and more preferable organic amine base being triethyl amine.
- Preferable alcoholic solvent is methanol, ethanol or isopropyl alcohol and more preferable alcoholic solvent being methanol.
- the reduction reaction is preferably carried out at about 0-45° C., more preferably at about 10-35° C. and still more preferably at about 20-35° C.
- Preferable organic base used in step-(a) is an organic amine base such as triethyl amine, trimethyl amine, tributyl amine and n-butyl amine; and preferable inorganic base is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. More preferable organic amine base is triethyl amine and more preferable inorganic base is sodium bicarbonate.
- step-(a) is preferably carried out at about 0-35° C., more preferably at about 10-30° C. and still more preferably at about 15-25° C.
- Preferable organic solvent used in step-(a) is selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane; and a mixture thereof. More preferable organic solvent is selected from methylene chloride, n-hexane and a mixture thereof. Most preferable organic solvent is methylene chloride.
- step-(b) is preferably carried out with hydrogen sulfide in presence of pyridine.
- Preferable organic amine base used in the reaction with Na 2 S in step-(b) is triethyl amine or trimethyl amine and more preferable organic amine base being triethyl amine.
- Preferable alcoholic solvent used in the reaction in step-(b) is methanol, ethanol or isopropyl alcohol and more preferable alcoholic solvent being methanol.
- step-(b) is preferably carried out at about 0-45° C., more preferably at about 10-35° C. and still more preferably at about 20-35° C.
- Ethyl (3R,4R,5S)-4-Amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate 14 gm was added to triethyl amine (10 gm) and methylene chloride (110 ml) and then the contents were cooled to 20° C. To the contents added acetic anhydride (5.6 gm) at 20-25° C. for 1 hour and then stirred for 3 hours at 20-25° C. The reaction mass was quenched into water (140 ml) and then separated the layers. The organic layer was washed with 8% sodium bicarbonate solution (140 ml) and then washed with 30% sodium chloride solution (140 ml).
- Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (8.5 gm) was dissolved in tetrahydrofuran (130 ml) and then triphenyl phosphine (10.5 gm) and water (50 ml) are added. The contents were heated to reflux, refluxed for 5 hours and then distilled off the solvent under vacuum. To the reaction mass added ethyl acetate (80 ml), washed with 30% sodium chloride solution (50 ml) and distilled off the solvent completely under vacuum.
- reaction mass was cooled to 25° C. and then stirred for 2 hours at 20-25° C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65° C. for 4 hours to give 6.9 gm of oseltamivir phosphate (HPLC purity: 99.8%).
Abstract
The present invention provides an improved and commercially viable process for the preparation of oseltamivir phosphate. Thus, for example, ethyl (3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate is acetylated with acetic anhydride in methylene chloride in the presence of triethyl amine in the absence of water to give ethyl (3R,4R,5S)-4-(acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.
Description
- The present invention provides an improved and commercially viable process for the preparation of oseltamivir phosphate.
- U.S. Pat. No. 5,763,483, which is herein incorporated by reference, disclosed carbocyclic compounds and pharmaceutically acceptable salts thereof. Among them Oseltamivir, chemically Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate is a orally active inhibitor of influenza virus neuraminidase. Oseltamivir is represented by the following structure:
- Various processes for preparation of oseltamivir were disclosed, for example, in U.S. Pat. No. 5,763,483, J. Org. Chem., Vol. 63, No. 13, 1998 (page: 4545-4550), J. Amer. Chem. Soc., Vol. 115, No. 4, 1997 (Page: 681-690), U.S. Pat. No. 5,952,375 and PCT Publication No. WO 99/44185.
- In the preparation of oseltamivir, the compound of formula B:
- is a key intermediate. According to the prior art processes, the intermediate of the formula B was prepared by acetylation of the compound of formula A:
- with acetic anhydride in hexanes or methylene chloride in the presence of aqueous sodium bicarbonate; or with acetyl chloride and pyridine. The base such as sodium bicarbonate is normally used to convert the acetic acid formed as by-product into a water soluble salt such as sodium acetate and the salt formed is extracted into water present so as to move the equilibrium towards the formation of acetylated product of the formula B.
- We have surprisingly found, in contrary to the prior art process and process normally followed, that acetylation reaction of compound of formula A proceeds with acetic anhydride in an organic solvent in the presence of an organic or inorganic base in the absence of water, cleanly to obtain acetyl derivative of the formula B in better purity and in better yield.
- In the preparation of oseltamivir, the azide intermediate of formula B is reduced to the corresponding amine, (oseltamivir) of the formula C:
- According to the prior art process, the reduction was carried out with hydrogen gas and a catalyst such as platinum on carbon or Lindlar's catalyst or reducing reagent such as trialkyl or triaryl phosphine.
- We have found that the reduction of the compound of formula B to obtain the compound of formula C may be carried out using hydrogen sulfide or Na2S under suitable conditions in an advantageous manner.
- According to one aspect of the present invention, there is provided a process for preparing the acetyl compound of formula III:
- which comprises acetylating the amino compound of formula II:
- with acetic anhydride in an organic solvent in the presence of an organic or inorganic base in the absence of water to give the acetyl compound of formula III. ‘The absence of water’ refers to the content of water in the reaction mass is less than 1.0%, preferably less than 0.5% and more preferably less than 0.2% of the reaction mass by volume.
- Preferable organic base used in the reaction is an organic amine base such as triethyl amine, trimethyl amine, tributyl amine and n-butyl amine; and preferable inorganic base is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. More preferable organic amine base is triethyl amine and more preferable inorganic base is sodium bicarbonate.
- The reaction is preferably carried out at about 0-35° C., more preferably at about 10-30° C. and still more preferably at about 15-25° C.
- Preferable organic solvent used in reaction is selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane; and a mixture thereof. More preferable organic solvent is selected from methylene chloride, n-hexane and a mixture thereof. Most preferable organic solvent is methylene chloride.
- After the reaction is completed, the reaction mass may then be subjected to usual work up such as washings, extractions etc.
- According to another aspect of the present invention, there is provided a process for preparing the oseltamivir of formula I:
- or a pharmaceutically acceptable salt thereof; which comprises reducing the compound of formula III:
- with hydrogen sulfide in presence of pyridine or ethanol or water or a mixture thereof; or with Na2S in presence of an organic amine base in an alcoholic solvent to give oseltamivir of formula I and optionally converting oseltamivir formed into a pharmaceutically acceptable acid addition salts of oseltamivir.
- The reduction reaction is preferably carried out with hydrogen sulfide in presence of pyridine.
- Preferable organic amine base used in the reduction reaction with Na2S is triethyl amine or trimethyl amine and more preferable organic amine base being triethyl amine. Preferable alcoholic solvent is methanol, ethanol or isopropyl alcohol and more preferable alcoholic solvent being methanol.
- The reduction reaction is preferably carried out at about 0-45° C., more preferably at about 10-35° C. and still more preferably at about 20-35° C.
- According to another aspect of the present invention, there is provided an improved process for preparing the oseltamivir of formula I:
- or a pharmaceutically acceptable salt thereof;
which comprises:
a) acetylating the amino compound of formula II: - with acetic anhydride in an organic solvent in the presence of an organic or inorganic base in the absence of water to give the acetyl compound of formula III:
- b) reducing the compound of formula III with hydrogen sulfide in presence of pyridine or ethanol or water or a mixture thereof; or with Na2S in presence of an organic amine base in an alcoholic solvent to give oseltamivir of formula I and optionally converting oseltamivir formed into a pharmaceutically acceptable acid addition salts of oseltamivir.
- Preferable organic base used in step-(a) is an organic amine base such as triethyl amine, trimethyl amine, tributyl amine and n-butyl amine; and preferable inorganic base is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. More preferable organic amine base is triethyl amine and more preferable inorganic base is sodium bicarbonate.
- The reaction in step-(a) is preferably carried out at about 0-35° C., more preferably at about 10-30° C. and still more preferably at about 15-25° C.
- Preferable organic solvent used in step-(a) is selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane; and a mixture thereof. More preferable organic solvent is selected from methylene chloride, n-hexane and a mixture thereof. Most preferable organic solvent is methylene chloride.
- The reaction in step-(b) is preferably carried out with hydrogen sulfide in presence of pyridine.
- Preferable organic amine base used in the reaction with Na2S in step-(b) is triethyl amine or trimethyl amine and more preferable organic amine base being triethyl amine. Preferable alcoholic solvent used in the reaction in step-(b) is methanol, ethanol or isopropyl alcohol and more preferable alcoholic solvent being methanol.
- The reaction in step-(b) is preferably carried out at about 0-45° C., more preferably at about 10-35° C. and still more preferably at about 20-35° C.
- The invention will now be further described by the following non-limiting examples.
- Ethyl (3R,4R,5S)-4-Amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (14 gm) was added to triethyl amine (10 gm) and methylene chloride (110 ml) and then the contents were cooled to 20° C. To the contents added acetic anhydride (5.6 gm) at 20-25° C. for 1 hour and then stirred for 3 hours at 20-25° C. The reaction mass was quenched into water (140 ml) and then separated the layers. The organic layer was washed with 8% sodium bicarbonate solution (140 ml) and then washed with 30% sodium chloride solution (140 ml). The organic layer was distilled and recrystallized from n-hexane (70 ml) to give 8.5 gm of Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethyl propoxy)-1-cyclohexene-1-carboxylate.
- Step-II:
- Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (8.5 gm) was dissolved in tetrahydrofuran (130 ml) and then triphenyl phosphine (10.5 gm) and water (50 ml) are added. The contents were heated to reflux, refluxed for 5 hours and then distilled off the solvent under vacuum. To the reaction mass added ethyl acetate (80 ml), washed with 30% sodium chloride solution (50 ml) and distilled off the solvent completely under vacuum. Acetone (130 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3 gm) and ethyl acetate (50 ml) was slowly added during 1 hour and then refluxed for 1 hour. The reaction mass was cooled to 25° C. and stirred for 2 hours at 20-25° C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65° C. for 4 hours to yield 6.5 gm of oseltamivir phosphate (HPLC Purity: 99.6%).
- Ethyl (3 R,4R,5S)-4-(Acetylam ino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (8.5 gm) was added to pyridine (200 ml) and then bubbled
- H2S gas for 3 hours at 25-35° C. Stopped the bubbling of H2S gas and then the reaction mixture was stirred for 5 hours at 25-35° C. The reaction mass was flushed with N2 gas for 20-30 minutes and distilled off the solvent completely under reduced pressure keeping the bath temperature below 50° C. To the residue added ethyl acetate (100 ml) and washed with 30% sodium chloride solution (50 ml). Distilled off the ethyl acetate completely under reduced pressure. Acetone (100 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3.2 gm) and ethanol (25 ml) was slowly added during 1 hour 30 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25° C. and then stirred for 2 hours at 20-25° C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65° C. for 4 hours to give 6.9 gm of oseltamivir phosphate (HPLC purity: 99.8%).
Claims (9)
2. The process as claimed in claim 1 , wherein the organic base used is an organic amine base such as triethyl amine, trimethyl amine, tributyl amine and n-butyl amine; and inorganic base is selected from the group consisting of sodium bicarbonate and potassium bicarbonate.
3. The process as claimed in claim 2 , wherein the organic amine base is triethyl amine.
4. The process as claimed in claim 2 , wherein the inorganic base is sodium bicarbonate.
5. The process as claimed in claim 1 , wherein the acetylation reaction is carried out at about 0-35° C.
6. The process as claimed in claim 5 , wherein the reaction is carried out at about 10-30° C.
7. The process as claimed in claim 6 , wherein the reaction is carried out at about 15-25° C.
8. The process as claimed in claim 1 , wherein the organic solvent is selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane; and a mixture thereof.
9. The process as claimed in claim 8 , wherein the organic solvent is methylene chloride.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/702,471 US20100137632A1 (en) | 2005-11-25 | 2010-02-09 | Process for oseltamivir phosphate |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN2005/000381 WO2007060681A1 (en) | 2005-11-25 | 2005-11-25 | Improved process for oseltamivir phosphate |
US71835907A | 2007-05-01 | 2007-05-01 | |
US12/702,471 US20100137632A1 (en) | 2005-11-25 | 2010-02-09 | Process for oseltamivir phosphate |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2005/000381 Division WO2007060681A1 (en) | 2005-11-25 | 2005-11-25 | Improved process for oseltamivir phosphate |
US71835907A Division | 2005-11-25 | 2007-05-01 |
Publications (1)
Publication Number | Publication Date |
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US20100137632A1 true US20100137632A1 (en) | 2010-06-03 |
Family
ID=38066948
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/718,359 Expired - Fee Related US7687658B2 (en) | 2005-11-25 | 2005-11-25 | Process for oseltamivir phosphate |
US12/702,471 Abandoned US20100137632A1 (en) | 2005-11-25 | 2010-02-09 | Process for oseltamivir phosphate |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
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US11/718,359 Expired - Fee Related US7687658B2 (en) | 2005-11-25 | 2005-11-25 | Process for oseltamivir phosphate |
Country Status (7)
Country | Link |
---|---|
US (2) | US7687658B2 (en) |
EP (2) | EP2204359A1 (en) |
AT (1) | ATE510813T1 (en) |
ES (1) | ES2366704T3 (en) |
PL (1) | PL1951654T3 (en) |
PT (1) | PT1951654E (en) |
WO (1) | WO2007060681A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103833570B (en) * | 2014-03-19 | 2015-05-27 | 浙江师范大学 | Synthesis method of oseltamivir |
CN113024396B (en) * | 2019-12-25 | 2024-01-30 | 上海奥博生物医药股份有限公司 | Preparation method of oseltamivir and intermediate thereof |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4147708A (en) * | 1975-10-30 | 1979-04-03 | Hoffmann-La Roche Inc. | Preparation of carotenoids using a π-allyl complex |
US4686207A (en) * | 1985-11-12 | 1987-08-11 | Abbott Laboratories | Erythromycin A 11,12-carbonates and method of use |
US5514505A (en) * | 1995-05-15 | 1996-05-07 | Xerox Corporation | Method for obtaining improved image contrast in migration imaging members |
US5563014A (en) * | 1995-05-15 | 1996-10-08 | Xerox Corporation | Migration imaging members |
US5866601A (en) * | 1995-02-27 | 1999-02-02 | Gilead Sciences, Inc. | Carbocyclic compounds |
US5981802A (en) * | 1995-12-14 | 1999-11-09 | The Trustees Of Columbia University In The City Of New York | Simple allylic amination procedure |
US6444221B1 (en) * | 1992-06-30 | 2002-09-03 | Howard K. Shapiro | Methods of treating chronic inflammatory diseases using carbonyl trapping agents |
US20050090553A1 (en) * | 1992-06-30 | 2005-04-28 | Shapiro Howard K. | Compositions and method for treatment of chronic inflammatory diseases |
US20080234380A1 (en) * | 1992-06-30 | 2008-09-25 | Shapiro Howard K | Compositions and method for treatment of chronic inflammatory diseases |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0759917T3 (en) | 1995-02-27 | 2000-07-31 | Gilead Sciences Inc | Novel selective inhibitors of viral or bacterial neuraminidases |
US5763483A (en) | 1995-12-29 | 1998-06-09 | Gilead Sciences, Inc. | Carbocyclic compounds |
DE69711395T2 (en) | 1996-08-23 | 2002-11-07 | Gilead Sciences Inc | METHOD FOR PRODUCING CYCLOHEXEN-CARBOXYLATE DERIVATIVES |
US5886213A (en) * | 1997-08-22 | 1999-03-23 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
ATE215251T1 (en) | 1998-02-27 | 2002-04-15 | Ip2H Ag | TRAFFIC MANAGEMENT SYSTEM |
AU3637699A (en) * | 1998-04-24 | 1999-11-16 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
-
2005
- 2005-11-25 AT AT05823580T patent/ATE510813T1/en active
- 2005-11-25 EP EP10156919A patent/EP2204359A1/en not_active Withdrawn
- 2005-11-25 PL PL05823580T patent/PL1951654T3/en unknown
- 2005-11-25 PT PT05823580T patent/PT1951654E/en unknown
- 2005-11-25 WO PCT/IN2005/000381 patent/WO2007060681A1/en active Application Filing
- 2005-11-25 ES ES05823580T patent/ES2366704T3/en active Active
- 2005-11-25 US US11/718,359 patent/US7687658B2/en not_active Expired - Fee Related
- 2005-11-25 EP EP05823580A patent/EP1951654B1/en not_active Not-in-force
-
2010
- 2010-02-09 US US12/702,471 patent/US20100137632A1/en not_active Abandoned
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4147708A (en) * | 1975-10-30 | 1979-04-03 | Hoffmann-La Roche Inc. | Preparation of carotenoids using a π-allyl complex |
US4686207A (en) * | 1985-11-12 | 1987-08-11 | Abbott Laboratories | Erythromycin A 11,12-carbonates and method of use |
US6444221B1 (en) * | 1992-06-30 | 2002-09-03 | Howard K. Shapiro | Methods of treating chronic inflammatory diseases using carbonyl trapping agents |
US20050090553A1 (en) * | 1992-06-30 | 2005-04-28 | Shapiro Howard K. | Compositions and method for treatment of chronic inflammatory diseases |
US20080234380A1 (en) * | 1992-06-30 | 2008-09-25 | Shapiro Howard K | Compositions and method for treatment of chronic inflammatory diseases |
US5866601A (en) * | 1995-02-27 | 1999-02-02 | Gilead Sciences, Inc. | Carbocyclic compounds |
US5514505A (en) * | 1995-05-15 | 1996-05-07 | Xerox Corporation | Method for obtaining improved image contrast in migration imaging members |
US5563014A (en) * | 1995-05-15 | 1996-10-08 | Xerox Corporation | Migration imaging members |
US5981802A (en) * | 1995-12-14 | 1999-11-09 | The Trustees Of Columbia University In The City Of New York | Simple allylic amination procedure |
Also Published As
Publication number | Publication date |
---|---|
EP1951654B1 (en) | 2011-05-25 |
PT1951654E (en) | 2011-08-30 |
ES2366704T3 (en) | 2011-10-24 |
US20090054682A1 (en) | 2009-02-26 |
ATE510813T1 (en) | 2011-06-15 |
US7687658B2 (en) | 2010-03-30 |
WO2007060681A1 (en) | 2007-05-31 |
EP2204359A1 (en) | 2010-07-07 |
EP1951654A1 (en) | 2008-08-06 |
EP1951654A4 (en) | 2009-12-30 |
PL1951654T3 (en) | 2011-11-30 |
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