WO2005049567A1 - A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates - Google Patents
A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates Download PDFInfo
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- WO2005049567A1 WO2005049567A1 PCT/IN2003/000367 IN0300367W WO2005049567A1 WO 2005049567 A1 WO2005049567 A1 WO 2005049567A1 IN 0300367 W IN0300367 W IN 0300367W WO 2005049567 A1 WO2005049567 A1 WO 2005049567A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Definitions
- 2-Azabicyclo-3-carboxylic acids like 2-azabicyclo [3.3.0] octane-3-carboxylic acid and 2-azabicyclo [4.3.0] nonane carboxylic acid are important intermediates for the syntheses of ACE inhibitors like ramipril and perindopril respectively. These intermediates are prepared by initial reaction of N-acetyl- ⁇ -chloro-s-alaninate with enamines 1-(1-pyrrolidinyl)-cyclopentene and 1-(1- pyrrolidinyl)-cyclohexene receptively.
- Methyl - ⁇ -hydroxy alaninate hydrochloride (serine methylester hydrochloride) is first chlorinated with phosphorus pentachloride using chloroform as solvent and chloro derivative is acetylated using acetyl chloride.
- the first step involves the use of phosphorous pentachloride, which is a toxic and corrosive reagent.
- the preferred solvent for the reaction is chloroform. During the reaction, lot of solvent loss takes place due to evolution of hydrogen chloride.
- the invention relates to novel synthesis of 2-azabicyclo-3-carboxylic acid hydrochloride of formula I
- the reaction of compound of formula II was conducted with acetyl chloride or acetic anhydride in a non-polar solvent. Both the reagents are efficient for this reaction.
- the mole ratio of the substrate to the reagent was about 1 : 6 to 8. A mole ratio of 1 :5-6 was more preferred.
- the reaction was conducted in non-polar solvent like cyclohexane, benzene, toluene, xylenes, chlorobenzene etc. Toluene was the preferred solvent due to its efficiency as well as the recovery point of view.
- the preferred temperature for the reaction was 50°C to 120 °C. A temperature of 60-80 °C was more preferred.
- the reaction was conducted for duration of 2hours to ⁇ hours.
- a preformed solution of enamine was prepared by taking appropriate quantities of the cyclic ketone and pyrrolidine in toluene and after water removal was completed, the solution was cooled and taken for the next stage.
- the diacetyl compound in toluene solution containing an organic base was treated with a solution of enamine.
- the preferred organic bases were triethylamine, diisopropyl ethylamine and N-methyl morpholine.
- the mole ratio of organic base to that of the diacetyl derivative was about 1 :4-6.
- a mole ratio of 1 :2-3 of substrate to organic base was more preferred.
- the addition of enamine to the diacetyl compound was carried out a temperature of 10 °C to 40 °C.
- the addition was done preferably at a temperature of 25 °C to 30 °C. After the addition, the reaction mixture was preferably stirred for 12 hour to 14 hours at 25-30°C. At the end of maintenance, toluene was distilled off completely and the residue was dissolved in about 4 times water. The pH of the aqueous solution was adjusted to 2 at 10 °C to 20 °C. Then the aqueous solution was extracted with ethyl acetate. The ethyl acetate extract was washed with water and then concentrated.
- the residue, obtained, was treated with aqueous hydrochloric acid.
- the strength of the acid was 2N to 10N.
- the strength of the acid more preferred to be 4N to 6N.
- the mole ratio of the substrate to the acid was preferred to be 1 :2-4.
- the reaction was preferable heated at 70 °C to 100 °C for about 3hours to 6 hours. At the end maintenance, water was distilled off under reduced pressure.
- the residue obtained was dissolved in organic acid and was hydrogenated.
- the organic acid was preferably acetic acid or propionic acid.
- the preferred catalysts were palladium, platinum or rhodium.
- the temperature for the hydrogenation was preferably 40 °C to 60 °C and the pressure was 40 psi to 80 psi. When the hydrogen take up had ceased, the reaction mixture was cooled, filtered and then concentrated.
- the residue on treated with isopropanolic hydrogen chloride yield the title product of formula I.
- the invention is depicted
- the solution obtained under (b) was taken in the addition funnel and added drop wise to the stirred reaction mixture at 25 °C to 30 °C. After the addition, the reaction mixture was stirred at 25 °C to 30 °C for 12 hours to 14 hours. At the end of the maintenance, toluene was distilled off under reduced pressure, the residue was treated with 400ml of water, the pH was adjusted to 2 with hydrochloric acid and the reaction mixture was stirred for 15min.
- reaction mixture was extracted with ethyl acetate (3 X 250ml), the ethyl acetate extract was washed with water and ethyl acetate was distilled off under reduced pressure
- the residue obtained above was treated with 4N hydrochloric acid 500ml and taken in a 1 It RB flask fitted a stirrer, and condenser. The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure.
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A novel process for the preparation of 2-azabicyclo-3-carboxylic acid hydrochloride of formula (I), by reacting the compound of formula (II) with an acylating agent in a non-polar solvent at 0-150 °C to give a compound of formula (III), which is reacted with an enamine of formula (IV) in a non-polar solvent in the presence of an organic base at 0 °C to 150 °C to yield a compound of formula (V), which is hydrolytically cyclised to give a compound of formula (VI) and further catalytically hydrogenated to give the compound of formula (I).
Description
A NOVEL SYNTHESIS OF 2-AZABICYCLIC-3-CARBOXYLIC ACIDS, USEFUL AS IMPORTANT DRUG INTERMEDIATES
BACKGROUND OF THE INVENTION
2-Azabicyclo-3-carboxylic acids like 2-azabicyclo [3.3.0] octane-3-carboxylic acid and 2-azabicyclo [4.3.0] nonane carboxylic acid are important intermediates for the syntheses of ACE inhibitors like ramipril and perindopril respectively. These intermediates are prepared by initial reaction of N-acetyl- β -chloro-s-alaninate with enamines 1-(1-pyrrolidinyl)-cyclopentene and 1-(1- pyrrolidinyl)-cyclohexene receptively. The common intermediate for the above two reactions viz., methyl-N-acetyl-b-chloro alaninate is prepared by a two-step process. Methyl - β -hydroxy alaninate hydrochloride (serine methylester hydrochloride) is first chlorinated with phosphorus pentachloride using chloroform as solvent and chloro derivative is acetylated using acetyl chloride. The first step involves the use of phosphorous pentachloride, which is a toxic and corrosive reagent. The preferred solvent for the reaction is chloroform. During the reaction, lot of solvent loss takes place due to evolution of hydrogen chloride. While isolating the product, one has to handle chloroform mother liquor containing POCI3. Handling toxic and corrosive reagent makes the process a potential health hazard. Apart from that it is also harmful to the environment. . Loss of chloroform during the reaction makes the process uneconomical. Due to these factors, we wished to generate an alternate method for the preparation of 2-azabicyclo acids.
REFERENCES CITED:
US 4,727,160 US 5,053,519 US 5,061 ,722 US 5,175,306
Other References
Tetrahyedron Lett. 25 (1984) 4479
Arzneimittel Forsch. 34,1399 (1984) J.Prakt.Chem 332 (1990) 6 1111
SUMMARY OF THE INVENTION: The invention relates to novel synthesis of 2-azabicyclo-3-carboxylic acid hydrochloride of formula I
W ,„ .A. ' COOH n H "HCI Formula I
by the reaction of methyl-b-hydroxy-s-alaninate hydrochloride of formula II
with an acylating agent to give a compound of formula III
Formula III
which is subjected to Stork condensation with a compound of formula IV
to give a compound of formula V
NHCOR Formula V
Compound of formula V is subjected to hydrolytic cyclisation to give a compound of formula VI,
Which is hydrogenated to give a compound of formula
DESCRIPTION OF THE INVENTION
In order to replace methyl-N-acetyl- β -chloro alaninate as the reagent in the Stork condensation, we have to find a suitable leaving group instead of chloro. This reagent should be easier to prepare and handle. The easiest one, which comes to mind, is the acyl derivative viz., methyl-β-acyloxy-N-acyl -s- alaninate. Hence preparation of number of acyl derivatives was tried out. Reaction of methyl-B-hydroxy-s-alaninate hydrochloride (serine methylester hydrochloride) with acetyl chloride or acetic anhydride in toluene resulted in the formation of compound of formula III, where R = COCH3. Similar reaction using propionic anhydride or propionyl chloride yielded a compound of formula III, where R = COCH2CH3. Since acetyl chloride and acetic anhydride are cheaper, we wished to concentrate in the preparation of acetyl derivative.
The reaction of compound of formula II was conducted with acetyl chloride or acetic anhydride in a non-polar solvent. Both the reagents are efficient for this reaction. The mole ratio of the substrate to the reagent was about 1 : 6 to 8. A mole ratio of 1 :5-6 was more preferred. The reaction was conducted in non-polar solvent like cyclohexane, benzene, toluene, xylenes, chlorobenzene etc. Toluene was the preferred solvent due to its efficiency as well as the recovery point of view. The preferred temperature for the reaction was 50°C to 120 °C. A temperature of 60-80 °C was more preferred. The reaction was conducted for duration of 2hours to δhours. A duration of 3 hours to 4 hours
was more preferred. For the purpose of the characterizing the intermediate, it was isolated and characterized (see examples). Otherwise the solution of the intermediate was used for the next stage. At the end of maintenance for acetylation, toluene was distilled off almost completely under reduced pressure and fresh toluene was added to the residue and it was used for the Stork condensation. By using the diacetyl derivative, the advantages are a) avoiding a corrosive reagent like PCI5 b) avoiding a low boiling solvent like CHC and c) avoiding an additional stage in the synthesis.
A preformed solution of enamine was prepared by taking appropriate quantities of the cyclic ketone and pyrrolidine in toluene and after water removal was completed, the solution was cooled and taken for the next stage. The diacetyl compound in toluene solution containing an organic base was treated with a solution of enamine. The preferred organic bases were triethylamine, diisopropyl ethylamine and N-methyl morpholine. The mole ratio of organic base to that of the diacetyl derivative was about 1 :4-6. A mole ratio of 1 :2-3 of substrate to organic base was more preferred. The addition of enamine to the diacetyl compound was carried out a temperature of 10 °C to 40 °C. The addition was done preferably at a temperature of 25 °C to 30 °C. After the addition, the reaction mixture was preferably stirred for 12 hour to 14 hours at 25-30°C. At the end of maintenance, toluene was distilled off completely and the residue was dissolved in about 4 times water. The pH of the aqueous solution was adjusted to 2 at 10 °C to 20 °C. Then the aqueous solution was extracted with ethyl acetate. The ethyl acetate extract was washed with water and then concentrated.
The residue, obtained, was treated with aqueous hydrochloric acid. The strength of the acid was 2N to 10N. The strength of the acid more preferred to be 4N to 6N. The mole ratio of the substrate to the acid was preferred to be 1 :2-4. The reaction was preferable heated at 70 °C to 100 °C for about 3hours to 6 hours. At the end maintenance, water was distilled off under reduced pressure.
The residue obtained was dissolved in organic acid and was hydrogenated. The organic acid was preferably acetic acid or propionic acid. The preferred catalysts were palladium, platinum or rhodium. The temperature for the hydrogenation was preferably 40 °C to 60 °C and the pressure was 40 psi to 80 psi. When the hydrogen take up had ceased, the reaction mixture was cooled, filtered and then concentrated. The residue on treated with isopropanolic hydrogen chloride yield the title product of formula I. The invention is depicted in the scheme-l given below
COOH COOH ■HCI ■HCI Formula I Formula VI
SCHEME-!
EXAMPLES:
The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. Melting points were recorded in Metier Toledo FP-90 and uncorrected.
Example - 1
Preparation of ethyl-β-acyloxy-N-acyl-s-alaninate:
In a three necked one-liter flask fitted with a mechanical stirrer, condenser and an addition funnel was added toluene 500ml and methyl-β-hydroxy-s- alaninate hydrochloride 100gms. Acetic anhydride 400gms was added from the addition funnel at 25 °C to 30 °C. After the addition, the reaction mixture was slowly heated to about 70 °C to 80 °C and was maintained at that temperature for 3 hours. After the maintenance, toluene was distilled off under reduced pressure. Additional quantity of toluene (300ml) was added and the distillation process was continued.
The residue obtained, was dissolved in diethyl ether. The ethereal solution was diluted with hexane. On cooling a colourless solid precipitated out, which was filtered, washed with a mixture of diethyl ether and hexane and dried
M.P 74-76°C
I R 3276, 1744, 1645, 984, 829
NMR (CDCIs, δ): 2.06 (S, 6H, 2 X CH3) 3.79 (S, 3H, OCH3) 4.87 (M, 1H, CH) 6.31 (6d, 1H. NH)
Mass 204 (28%, M + 1) 162 (10%) 144 (100%)
Example - 2
Preparation of 2- azabicyclo [3.3.0] octane-3-carboxylic acid hydrochloride a) In a three necked 1 It RB flask fitted with a mechanical stirrer, condenser and an addition funnel was added toluene 500ml and methyl β-hydroxy-s-alaninate hydrochloride (L-serine methylester hydrochloride) 100gms was added. To the stirred reaction mixture was added acetic anhydride 300ml from the addition funnel. After the addition, the reaction mixture was heated to about 70°C to 80 °C under stirring and maintained at that temperature for about 3 hours. Subsequently toluene was distilled off under reduced pressure. The residue was taken in fresh toluene and used in stage C ' b) In a three-necked 1 It RB flask fitted with a mechanical stirrer, condenser and an addition funnel was added toluene 300ml, pyrroldine 50gms and cyclopentanone 60gms. The mixture was fitted with Dean and Stark apparatus. The reaction mixture was stirred under reflux and water was removed azeotripically. When the water collection had ceased, the reaction mixture was cooled and used in stage C c) The solution obtained under (a) was taken in a 2 It three-necked RB flask fitted with a mechanical stirrer, condenser carrying a guard tube and an addition funnel. The solution obtained under (b) was taken in the addition funnel and added drop wise to the stirred reaction mixture at 25 °C to 30 °C. After the addition, the reaction mixture was stirred at 25 °C to 30 °C for 12 hours to 14 hours. At the end of the maintenance, toluene was distilled off under reduced pressure, the residue was treated with 400ml of water, the pH was adjusted to 2 with hydrochloric acid and the reaction mixture was stirred for 15min. The reaction mixture was extracted with ethyl
acetate (3 X 250ml), the ethyl acetate extract was washed with water and ethyl acetate was distilled off under reduced pressure The residue obtained above was treated with 4N hydrochloric acid 500ml and taken in a 1 It RB flask fitted a stirrer, and condenser. The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure.
The residue obtained, after removal of water was dissolved in acetic acid 400ml and charged into a parr hydrogenator. A slurry of 10% Pd/C (2gms) in acetic acid was also charged into the hydrogenator. Hydrogenation was carried out at 40 °C to 50 °C under 50 psi pressure and when the hydrogen take up had ceased, the system was cooled and the reaction mixture was filtered to remove the catalyst. The acetic acid solution was concentrated under reduced pressure and the residue, obtained was stirred with 5% isopropanolic hydrogen chloride 200ml for 30min at 10-15 °C. The colourless solid was filtered, washed with cold isopropanol and then dried. Yield = 99.2gms (80.55%) Melting point: 207-209 °C
Example - 3
Preparation of 2- azabicyclo [4.3.0] nonane-3-carboxylic acid hydrochloride a) In a three necked 1 It RB flask fitted with a mechanical stirrer, condenser and an addition funnel was added toluene 500ml and methyl β-hydroxy-s-alaninate hydrochloride (L-serine methylester hydrochloride) 100gms was added. To the stirred reaction mixture was added acetic anhydride 300ml from the addition funnel. After the addition, the reaction mixture was heated to about 70°C to 80 °C under stirring and maintained at that temperature for about 3 hours.
Subsequently toluene was distilled off under reduced pressure. The residue was taken in fresh toluene and used in stage C
b) In a three-necked 1 It RB flask fitted with a mechanical stirrer, condenser and an addition funnel was added toluene 300ml, pyrroldine 50gms and cyclohexanone 70gms. The mixture was fitted with Dean and Stark apparatus. The reaction mixture was stirred under reflux and water was removed azeotripically. When the water collection had ceased, the reaction mixture was cooled and used in stage C
c) The solution obtained under (a) was taken in a 2 It three-necked RB flask fitted with a mechanical stirrer, condenser carrying a guard tube and an addition funnel. The solution obtained under (b) was taken in the addition funnel and added drop wise to the stirred reaction mixture at 25 °C to 30 °C. After the addition, the reaction mixture was stirred at 25 °C to 30 °C for 12 hours to 14 hours. At the end of the maintenance, toluene was distilled off under reduced pressure, the residue was treated with 400ml of water, the pH was adjusted to 2 with hydrochloric acid and the reaction mixture was stirred for 15min. The reaction mixture was extracted with ethyl acetate (3 X 250ml), the ethyl acetate extract was washed with water and ethyl acetate was distilled off under reduced pressure
The residue obtained above was treated with 4N hydrochloric acid 500ml and taken in a 1 It RB flask fitted a stirrer, and condenser. The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure. The residue obtained, after removal of water was dissolved in acetic acid 600ml and charged into a parr hydrogenator. A slurry of 10% platinum charcoal (3gms) in acetic acid was also charged into the hydrogenator. Hydrogenation was carried out at 40 °C to 50 °C under 60 psi pressure and when the hydrogen take up had ceased, the
system was cooled and the reaction mixture was filtered to remove the catalyst. The acetic acid solution was concentrated under reduced pressure. The residue obtained was dissolved in 400ml of hot ethyl alcohol and cooled to -20 °C to give 35gms 1 β, 3 β, 5aβ of the title compound. The mother liquors was concentrated under reduced pressure, the residue was stirred with 250ml of isopropyl alcohol and cooled to -10 °C to give 51.5gms of 1oc, 3β, 5α 2-azabicyclo [4.3.0] nonane-3-carboxylic acid hydrochloride Yield = 86.5 gms Melting point: 279-280 °C
Claims
CLAIMS:
We claim, 01. A novel process for the preparation of 2-azabicyclo-3-carboxylic acid hydrochloride of formula I
■HCI Formula I by the reaction of methyl-b-hydroxy-s-alaninate hydrochloride of formula-ll
^ . ^ COOCH3 I -HCI NH2 Formula II with an acylating agent in a non-polar solvent at 0-150°C to give a compound of formula-Ill
Formula III which is reacted with a enamine of formula-IV in a non-polar solvent in the presence of an organic base at 0 °C to 150 °C
02. A claim, as claimed in claim 01 , wherein the non-polar solvents are cyclohexane, benzene, toluene, xylenes and chlorobenzene
03. A claim, as claimed in claim 01 , wherein the acylating agents are acetic anhydride, acetyl chloride, propionic anhydride and propionyl chloride
04. A claim, as claimed in claim 01 , wherein the acetylation is carried out at a temperature of 50°C to 120°C
05. A claim, as claimed in claim 01 , wherein the organic bases are triethyl amine, diisopropyl ethylamine, N-methyl morpholine etc.
06. A claim, as claimed in claim 01 , wherein the Stork condensation is carried at 50°C to 120°C
07. A claim, as claimed in claim 01 , wherein the hydrolytic cycljsation is carried out with 2N to 10N hydrochloric acid at 50°C to 110°C
08. A claim, as claimed in claim 01 , wherein the hydrogenation is carried in an organic acid like acetic acid or propionic acid using catalyst like palladium, platinum or rhodium at 25°C to 50°C
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03782763A EP1692106A1 (en) | 2003-11-24 | 2003-11-24 | A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates |
| AU2003290400A AU2003290400A1 (en) | 2003-11-24 | 2003-11-24 | A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates |
| PCT/IN2003/000367 WO2005049567A1 (en) | 2003-11-24 | 2003-11-24 | A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000367 WO2005049567A1 (en) | 2003-11-24 | 2003-11-24 | A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates |
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| WO2005049567A1 true WO2005049567A1 (en) | 2005-06-02 |
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| PCT/IN2003/000367 WO2005049567A1 (en) | 2003-11-24 | 2003-11-24 | A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates |
Country Status (3)
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| EP (1) | EP1692106A1 (en) |
| AU (1) | AU2003290400A1 (en) |
| WO (1) | WO2005049567A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007079871A1 (en) * | 2005-12-21 | 2007-07-19 | Sanofi-Aventis Deutschland Gmbh | Improved method for the production of ramipril |
| CN100376556C (en) * | 2005-10-14 | 2008-03-26 | 浙江工业大学 | Preparation method of 2-azabicyclo[3,3,0] octane-1-carboxylic acid hydrochloride |
| WO2008067981A3 (en) * | 2006-12-04 | 2008-10-02 | Dsm Ip Assets Bv | Whole-cell catalytic system comprising a hydantoinase, a racemase and a carbamoylase |
| WO2009050041A1 (en) * | 2007-10-17 | 2009-04-23 | Dsm Ip Assets B.V. | Novel carbamoylglycine derivatives |
| WO2010049401A1 (en) * | 2008-10-30 | 2010-05-06 | Dsm Ip Assets B.V. | Method for the synthesis of a ramipril intermediate |
| CN104817486A (en) * | 2015-03-31 | 2015-08-05 | 浙江工业大学 | Ramipril intermediate synthesis method |
| WO2015189108A1 (en) * | 2014-06-11 | 2015-12-17 | Sanofi-Aventis Deutschland Gmbh | Process for the preparation of ramipril |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4886827A (en) * | 1984-08-28 | 1989-12-12 | Hoechst Aktiengesellschaft | Cis,endo-2-azabicycloalkane-3-carboxylic acid derivatives, their use and intermediates in their preparation |
-
2003
- 2003-11-24 AU AU2003290400A patent/AU2003290400A1/en not_active Abandoned
- 2003-11-24 EP EP03782763A patent/EP1692106A1/en not_active Withdrawn
- 2003-11-24 WO PCT/IN2003/000367 patent/WO2005049567A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4886827A (en) * | 1984-08-28 | 1989-12-12 | Hoechst Aktiengesellschaft | Cis,endo-2-azabicycloalkane-3-carboxylic acid derivatives, their use and intermediates in their preparation |
| US5550255A (en) * | 1984-08-28 | 1996-08-27 | Hoechst Aktiengesellschaft | Cis, endo-2-azabicycloalkane-3-carboxylic acid derivatives |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100376556C (en) * | 2005-10-14 | 2008-03-26 | 浙江工业大学 | Preparation method of 2-azabicyclo[3,3,0] octane-1-carboxylic acid hydrochloride |
| US8119375B2 (en) | 2005-12-21 | 2012-02-21 | Sanofi-Aventis Deutschland Gmbh | Method for the production of ramipril |
| WO2007079871A1 (en) * | 2005-12-21 | 2007-07-19 | Sanofi-Aventis Deutschland Gmbh | Improved method for the production of ramipril |
| JP2009520473A (en) * | 2005-12-21 | 2009-05-28 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Improved process in the manufacture of ramipril |
| CN101326151B (en) * | 2005-12-21 | 2015-01-07 | 塞诺菲-安万特德国有限公司 | Improved method for the production of ramipril |
| WO2008067981A3 (en) * | 2006-12-04 | 2008-10-02 | Dsm Ip Assets Bv | Whole-cell catalytic system comprising a hydantoinase, a racemase and a carbamoylase |
| WO2009050041A1 (en) * | 2007-10-17 | 2009-04-23 | Dsm Ip Assets B.V. | Novel carbamoylglycine derivatives |
| US8105807B2 (en) | 2007-10-17 | 2012-01-31 | Dsm Ip Assets B.V. | Carbamoylglycine derivatives |
| US8263784B2 (en) | 2008-10-30 | 2012-09-11 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Method for the synthesis of a ramipril intermediate |
| CN102197026A (en) * | 2008-10-30 | 2011-09-21 | 帝斯曼知识产权资产管理有限公司 | Method for the synthesis of a ramipril intermediate |
| WO2010049401A1 (en) * | 2008-10-30 | 2010-05-06 | Dsm Ip Assets B.V. | Method for the synthesis of a ramipril intermediate |
| WO2015189108A1 (en) * | 2014-06-11 | 2015-12-17 | Sanofi-Aventis Deutschland Gmbh | Process for the preparation of ramipril |
| CN106536541A (en) * | 2014-06-11 | 2017-03-22 | 赛诺菲-安万特德国有限公司 | Process for the preparation of ramipril |
| US10112973B2 (en) | 2014-06-11 | 2018-10-30 | Sanofi-Aventis Deutschland Gmbh | Process for the preparation of ramipril |
| CN106536541B (en) * | 2014-06-11 | 2021-01-08 | 赛诺菲-安万特德国有限公司 | Process for the preparation of ramipril |
| CN104817486A (en) * | 2015-03-31 | 2015-08-05 | 浙江工业大学 | Ramipril intermediate synthesis method |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1692106A1 (en) | 2006-08-23 |
| AU2003290400A1 (en) | 2005-06-08 |
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