US20070173648A1 - Method for preparing n-aminopiperidine and its salts - Google Patents
Method for preparing n-aminopiperidine and its salts Download PDFInfo
- Publication number
- US20070173648A1 US20070173648A1 US11/625,367 US62536707A US2007173648A1 US 20070173648 A1 US20070173648 A1 US 20070173648A1 US 62536707 A US62536707 A US 62536707A US 2007173648 A1 US2007173648 A1 US 2007173648A1
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- US
- United States
- Prior art keywords
- process according
- formula
- solvent
- temperature
- compound
- 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
- LWMPFIOTEAXAGV-UHFFFAOYSA-N NN1CCCCC1 Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 3
- SXESBRNYONQKLV-UHFFFAOYSA-N CC(=O)NN1CCCCC1 Chemical compound CC(=O)NN1CCCCC1 SXESBRNYONQKLV-UHFFFAOYSA-N 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/28—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/28—Nitrogen atoms
- C07D295/30—Nitrogen atoms non-acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/98—Nitrogen atom
Definitions
- a subject-matter of the present invention is a novel process for the preparation of N-aminopiperidine of formula
- a salt of N-aminopiperidine (I) can be prepared by the action of an inorganic or organic acid.
- halogen atom is understood to mean a bromine, chlorine or iodine atom.
- Stage a) is carried out in a solvent, such as acetonitrile or toluene, at a temperature between ambient temperature and the reflux temperature of the solvent.
- a solvent such as acetonitrile or toluene
- Stage b) is carried out either in acidic medium, for example in the presence of hydrochloric or hydrobromic acid, or in basic medium, for example in the presence of potassium hydroxide or sodium hydroxide, in a solvent such as water or ethanol and at a temperature between ambient temperature and the reflux temperature of the solvent.
- acidic medium for example in the presence of hydrochloric or hydrobromic acid
- basic medium for example in the presence of potassium hydroxide or sodium hydroxide
- a compound of formula (II) in which R represents an ethyl radical is treated with a compound of formula (III) in which Hal represents a bromine atom, in acetonitrile, by heating at reflux of the solvent.
- the compound of formula (IV) in which R represents an ethyl radical is treated with sodium hydroxide in water by heating at reflux of the solvent.
- an N-aminopiperidine salt such as the hydrobromide, the hydrochloride or the oxalate
- N-aminopiperidine hydrobromide can be prepared in a solvent such as methyl tert-butyl ether (MTBE).
- MTBE methyl tert-butyl ether
- a mixture of 565.3 g of ethyl carbazate in 373 ml of acetonitrile is prepared.
- 415.4 g of 1,5-dibromopentane are run onto the preceding mixture brought to reflux. Reflux is maintained for 3 hours.
- the acetonitrile is removed by concentrating under vacuum. The residue thus obtained is dissolved in a toluene/water mixture.
- the aqueous phase is separated by settling and re-extracted with toluene. Water and 36% HCl are added to the combined toluene phases.
- the “rich” aqueous phase is washed 3 to 4 times with methyl tert-butyl ether (MTBE) to remove the neutral materials (impurities, diethyl carbazate, residual dibromopentane).
- the acidic aqueous phase is basified with NaOH and then NaHCO 3 in the presence of toluene.
- the aqueous phase is re-extracted with toluene.
- the toluene phases are washed separately with water in order to remove any residual ethyl carbazate.
- the toluene phases are concentrated to dryness. 252 g of the expected product are obtained in the form of a white powder which is purified by recrystallization from methylcyclohexane.
- a mixture of 160 g of compound obtained in the preceding stage, 214 ml of water and 120 g of sodium hydroxide beads is brought to reflux for 3 hours while flushing with argon. After cooling, 640 ml of MTBE are introduced before filtering off the inorganic materials present. A crude N-aminopiperidine solution in MTBE is thus obtained.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
- This application is a continuation of International application No. PCT/FR2005/002,016, filed Aug. 2, 2005, which is incorporated herein by reference in its entirety; which claims the benefit of priority of French Patent Application No. 04/08,700, filed Aug. 5, 2004.
- 1. Field of the Invention
-
- 2. Description of the Art
- Several processes for the preparation of N-aminopiperidine are known in the literature:
-
- Raschig process using piperidine and chloramine;
- process via hydrazine and N-acetylamino-piperidine;
- process via N-nitrosopiperidine (Lunn, Keefer, J. Org. Chem., 1984, 49 (19), 3470);
- process via glutaraldehyde and benzotriazole (Katritzky A. R., Wei-Ouiang Fan, J. Org. Chem., 1990, 55, 3205-3209).
- All of the references described herein are incorporated herein by reference in their entirety.
- The process for the preparation of N-aminopiperidine (I) and its salts according to the present invention is characterized in that:
-
- a) a carbazate of formula:
NH2—NH—COOR (II)
in which R represents a (C1-C6)alkyl group, a phenyl or a benzyl, is treated with a 1,5-dihalopentane of formula:
Hal—(CH2)5—Hal (III)
in which Hal represents a halogen atom;
- a) a carbazate of formula:
-
- If appropriate, a salt of N-aminopiperidine (I) can be prepared by the action of an inorganic or organic acid.
- The term “halogen atom” is understood to mean a bromine, chlorine or iodine atom.
- Stage a) is carried out in a solvent, such as acetonitrile or toluene, at a temperature between ambient temperature and the reflux temperature of the solvent.
- Stage b) is carried out either in acidic medium, for example in the presence of hydrochloric or hydrobromic acid, or in basic medium, for example in the presence of potassium hydroxide or sodium hydroxide, in a solvent such as water or ethanol and at a temperature between ambient temperature and the reflux temperature of the solvent.
- According to a preferred embodiment of the present invention, in stage a), a compound of formula (II) in which R represents an ethyl radical is treated with a compound of formula (III) in which Hal represents a bromine atom, in acetonitrile, by heating at reflux of the solvent.
- According to a preferred embodiment of the present invention, in stage b), the compound of formula (IV) in which R represents an ethyl radical is treated with sodium hydroxide in water by heating at reflux of the solvent.
- Preferably, an N-aminopiperidine salt, such as the hydrobromide, the hydrochloride or the oxalate, is prepared. For example, N-aminopiperidine hydrobromide can be prepared in a solvent such as methyl tert-butyl ether (MTBE).
- A—Ethyl piperidin-1-ylcarbamate
- A mixture of 565.3 g of ethyl carbazate in 373 ml of acetonitrile is prepared. 415.4 g of 1,5-dibromopentane are run onto the preceding mixture brought to reflux. Reflux is maintained for 3 hours. The acetonitrile is removed by concentrating under vacuum. The residue thus obtained is dissolved in a toluene/water mixture. The two-phase mixture is brought to pH=5 by addition of 30% NaOH. The aqueous phase is separated by settling and re-extracted with toluene. Water and 36% HCl are added to the combined toluene phases. The “rich” aqueous phase is washed 3 to 4 times with methyl tert-butyl ether (MTBE) to remove the neutral materials (impurities, diethyl carbazate, residual dibromopentane). The acidic aqueous phase is basified with NaOH and then NaHCO3 in the presence of toluene. The aqueous phase is re-extracted with toluene. The toluene phases are washed separately with water in order to remove any residual ethyl carbazate. The toluene phases are concentrated to dryness. 252 g of the expected product are obtained in the form of a white powder which is purified by recrystallization from methylcyclohexane.
- 1H NMR spectrum at 300 MHz: δ (ppm): 1.23: t: 3H; 4.14: qd: 2H; 2.70: t: 4H; 1.66: qt: 4H; 1.36: qt: 2H; 5.54: bs: 1H.
- B—N-Aminopiperidine
- A mixture of 160 g of compound obtained in the preceding stage, 214 ml of water and 120 g of sodium hydroxide beads is brought to reflux for 3 hours while flushing with argon. After cooling, 640 ml of MTBE are introduced before filtering off the inorganic materials present. A crude N-aminopiperidine solution in MTBE is thus obtained.
- C—Preparation of crude N-aminopiperidine hydrobromide Approximately 1 volume of a 36% w/w solution of hydrobromic acid in ethanol is run, at 25° C. and over 0.5 hour, onto the solution of N-aminopiperidine in MTBE obtained in the preceding stage. The formation of a precipitate is observed and the mixture is kept stirred for 1 hour. The hydrobromide is filtered off at 20° C. and washed with ethanol and then with MTBE. It is subsequently dried under vacuum at 45-50° C. and 156 g of the expected compound are obtained.
- M.p. =177-177.5° C. (literature 174-175° C.).
Claims (17)
1. A process for the preparation of N-aminopiperidine of formula (I):
or a salt thereof, comprising the steps of:
NH2—NH—COOR (II)
Hal—(CH2)5—Hal (III)
a) reacting a carbazate of formula (II):
NH2—NH—COOR (II)
in which R represents a (C1-C6)alkyl group, a phenyl or a benzyl, with a 1,5-dihalopentane of formula (III):
Hal—(CH2)5—Hal (III)
in which Hal represents a halogen atom to obtain piperidin-1-ylcarbamate of formula (IV):
in which R is as defined above;
b) treating the piperidin-1-ylcarbamate thus obtained in acidic medium or in basic medium to produce the compound of formula (I); and
c) optionally reacting the compound of formula (I) taken in a solvent with a suitable inorganic or organic acid to form the salt of the compound of formula (I).
2. The process according to claim 1 , wherein in step a), the reaction is carried out in a solvent chosen from acetonitrile or toluene at a temperature in the range of from about ambient temperature and about reflux temperature of the solvent.
3. The process according to claim 1 , wherein in step b), the reaction is carried out using an acid chosen from hydrochloric acid or hydrobromic acid in a solvent chosen from water or ethanol and at a temperature in the range of from about ambient temperature and about reflux temperature of the solvent.
4. The process according to claim 1 , wherein in step b), the reaction is carried out using a base chosen from potassium hydroxide or sodium hydroxide in a solvent chosen from water or ethanol and at a temperature in the range of from about ambient temperature and about reflux temperature of the solvent.
5. The process according to claim 2 , wherein in step b), the reaction is carried out using an acid chosen from hydrochloric acid or hydrobromic acid in a solvent chosen from water or ethanol and at a temperature in the range of from about ambient temperature and about reflux temperature of the solvent.
6. The process according to claim 2 , wherein in step b), the reaction is carried out using a base chosen from potassium hydroxide or sodium hydroxide in a solvent chosen from water or ethanol and at a temperature in the range of from about ambient temperature and about reflux temperature of the solvent.
7. The process according to claims 1, wherein, in step a), a compound of formula (II) in which R represents an ethyl radical is treated with a compound of formula (III) in which Hal represents a bromine atom, in acetonitrile, by heating at reflux of the solvent.
8. The process according to claim 1 , wherein, in step b), the compound of formula (IV) in which R represents an ethyl radical is treated with sodium hydroxide in water by heating at reflux of the solvent.
9. The process according to claim 1 , wherein in step c), the compound of formula (I) is reacted with an inorganic acid to form the salt.
10. The process according to claim 9 , wherein the inorganic acid is chosen from hydrochloric acid or hydrobromic acid.
11. The process according to claim 1 , wherein in step c), the compound of formula (I) is reacted with an organic acid to form the salt.
12. The process according to claim 11 , wherein the organic acid is oxalic acid.
13. The process according to claim 1 , wherein in step c), the solvent is methyl tert-butyl ether.
14. The process according to claim 1 , wherein in step c), the reaction is carried out in the temperature range of from about 0° C. to about 40° C.
15. The process according to claim 1 , wherein in step c), the reaction is carried out at a temperature of about 25° C.
16. The process according to claim 1 , wherein a salt of the compound of formula (I) chosen from the hydrobromide, the hydrochloride or the oxalate is prepared.
17. The process according to claim 1 , wherein the hydrobromide of the compound of formula (I) is prepared in methyl tert-butyl ether.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/164,379 US7951952B2 (en) | 2004-08-05 | 2008-06-30 | Method for preparing N-aminopiperidine and its salts |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0408700 | 2004-08-05 | ||
FR0408700A FR2874013B1 (en) | 2004-08-05 | 2004-08-05 | PROCESS FOR THE PREPARATION OF N-AMINOPIPERIDINE AND ITS SALTS |
PCT/FR2005/002016 WO2006024778A1 (en) | 2004-08-05 | 2005-08-02 | Method for preparing n-aminopiperedine and its salts |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2005/002016 Continuation WO2006024778A1 (en) | 2004-08-05 | 2005-08-02 | Method for preparing n-aminopiperedine and its salts |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/164,379 Continuation US7951952B2 (en) | 2004-08-05 | 2008-06-30 | Method for preparing N-aminopiperidine and its salts |
Publications (1)
Publication Number | Publication Date |
---|---|
US20070173648A1 true US20070173648A1 (en) | 2007-07-26 |
Family
ID=34947045
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/625,367 Abandoned US20070173648A1 (en) | 2004-08-05 | 2007-01-22 | Method for preparing n-aminopiperidine and its salts |
US12/164,379 Expired - Fee Related US7951952B2 (en) | 2004-08-05 | 2008-06-30 | Method for preparing N-aminopiperidine and its salts |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/164,379 Expired - Fee Related US7951952B2 (en) | 2004-08-05 | 2008-06-30 | Method for preparing N-aminopiperidine and its salts |
Country Status (16)
Country | Link |
---|---|
US (2) | US20070173648A1 (en) |
EP (1) | EP1776341A1 (en) |
JP (1) | JP2008509114A (en) |
KR (1) | KR20070048765A (en) |
CN (1) | CN101001839A (en) |
AR (1) | AR050089A1 (en) |
AU (1) | AU2005279087A1 (en) |
BR (1) | BRPI0514076A (en) |
CA (1) | CA2576718A1 (en) |
FR (1) | FR2874013B1 (en) |
IL (1) | IL180870A0 (en) |
MX (1) | MX2007001140A (en) |
RU (1) | RU2373196C2 (en) |
TW (1) | TW200621713A (en) |
UY (1) | UY29045A1 (en) |
WO (1) | WO2006024778A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2864081B1 (en) * | 2003-12-17 | 2006-04-28 | Isochem Sa | PROCESS FOR THE SYNTHESIS OF EXOCYCLIC CYCLOALKYL HYDRAZINE DERIVATIVES AND EXOCYCLIC HETEROCYCLOALKYL HYDRAZINE DERIVATIVES |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3317607A (en) * | 1959-07-30 | 1967-05-02 | Fmc Corp | Chemical reduction of nitrosamines |
US5514806A (en) * | 1991-11-20 | 1996-05-07 | Cassella Aktiengesellschaft | Method of preparing 1-amino-2, 6-dimethylpiperidine |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE338609C (en) | 1919-10-15 | 1921-06-22 | Fritz Sommer Dr | Process for the preparation of hydrazine and its alkyl or aryl substitution products |
US5977360A (en) * | 1996-12-27 | 1999-11-02 | Japan Hydrazine Co., Ltd. | Process for producing cyclic hydrazine derivatives, tetra-hydropyridazine and hexahydropyridazine |
JP4118559B2 (en) * | 2001-12-19 | 2008-07-16 | 日本曹達株式会社 | Method for producing alicyclic hydrazine |
JP2004137181A (en) * | 2002-10-17 | 2004-05-13 | Nippon Soda Co Ltd | Method for producing n-aminopiperidine |
JP2004137182A (en) * | 2002-10-17 | 2004-05-13 | Nippon Soda Co Ltd | Method for producing n-aminopiperidine |
-
2004
- 2004-08-05 FR FR0408700A patent/FR2874013B1/en not_active Expired - Fee Related
-
2005
- 2005-08-02 AR ARP050103210A patent/AR050089A1/en active IP Right Grant
- 2005-08-02 MX MX2007001140A patent/MX2007001140A/en active IP Right Grant
- 2005-08-02 JP JP2007524372A patent/JP2008509114A/en active Pending
- 2005-08-02 WO PCT/FR2005/002016 patent/WO2006024778A1/en active Application Filing
- 2005-08-02 CA CA002576718A patent/CA2576718A1/en not_active Abandoned
- 2005-08-02 UY UY29045A patent/UY29045A1/en not_active Application Discontinuation
- 2005-08-02 CN CNA2005800263491A patent/CN101001839A/en active Pending
- 2005-08-02 AU AU2005279087A patent/AU2005279087A1/en not_active Abandoned
- 2005-08-02 RU RU2007107806/04A patent/RU2373196C2/en not_active IP Right Cessation
- 2005-08-02 KR KR1020077005078A patent/KR20070048765A/en not_active Application Discontinuation
- 2005-08-02 BR BRPI0514076-5A patent/BRPI0514076A/en not_active IP Right Cessation
- 2005-08-02 EP EP05796225A patent/EP1776341A1/en not_active Withdrawn
- 2005-08-04 TW TW094126537A patent/TW200621713A/en unknown
-
2007
- 2007-01-22 US US11/625,367 patent/US20070173648A1/en not_active Abandoned
- 2007-01-22 IL IL180870A patent/IL180870A0/en unknown
-
2008
- 2008-06-30 US US12/164,379 patent/US7951952B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3317607A (en) * | 1959-07-30 | 1967-05-02 | Fmc Corp | Chemical reduction of nitrosamines |
US5514806A (en) * | 1991-11-20 | 1996-05-07 | Cassella Aktiengesellschaft | Method of preparing 1-amino-2, 6-dimethylpiperidine |
Also Published As
Publication number | Publication date |
---|---|
US7951952B2 (en) | 2011-05-31 |
FR2874013B1 (en) | 2006-09-29 |
RU2373196C2 (en) | 2009-11-20 |
JP2008509114A (en) | 2008-03-27 |
US20080306274A1 (en) | 2008-12-11 |
IL180870A0 (en) | 2009-02-11 |
AR050089A1 (en) | 2006-09-27 |
UY29045A1 (en) | 2006-03-31 |
CN101001839A (en) | 2007-07-18 |
CA2576718A1 (en) | 2006-03-09 |
TW200621713A (en) | 2006-07-01 |
MX2007001140A (en) | 2007-04-19 |
EP1776341A1 (en) | 2007-04-25 |
AU2005279087A1 (en) | 2006-03-09 |
KR20070048765A (en) | 2007-05-09 |
RU2007107806A (en) | 2008-09-10 |
BRPI0514076A (en) | 2008-05-27 |
FR2874013A1 (en) | 2006-02-10 |
WO2006024778A1 (en) | 2006-03-09 |
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AS | Assignment |
Owner name: SANOFI-AVENTIS, FRANCE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GROSSI, PIERRE JEAN;SOLE, RAPHAEL;REEL/FRAME:019172/0951;SIGNING DATES FROM 20070208 TO 20070313 |
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STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |