CA2023744A1 - Process for the production of crotonobetaine hydrochloride - Google Patents
Process for the production of crotonobetaine hydrochlorideInfo
- Publication number
- CA2023744A1 CA2023744A1 CA002023744A CA2023744A CA2023744A1 CA 2023744 A1 CA2023744 A1 CA 2023744A1 CA 002023744 A CA002023744 A CA 002023744A CA 2023744 A CA2023744 A CA 2023744A CA 2023744 A1 CA2023744 A1 CA 2023744A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrochloride
- carnitine
- production
- crotonobetaine
- process according
- 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
- 238000000034 method Methods 0.000 title claims abstract description 15
- PUKNFWRLBQXPFL-FXRZFVDSSA-N [(e)-3-carboxyprop-2-enyl]-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)C\C=C\C(O)=O PUKNFWRLBQXPFL-FXRZFVDSSA-N 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003377 acid catalyst Substances 0.000 claims abstract description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- JXXCENBLGFBQJM-FYZOBXCZSA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)C[C@H](O)CC(O)=O JXXCENBLGFBQJM-FYZOBXCZSA-N 0.000 claims 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 abstract description 11
- 230000002906 microbiologic effect Effects 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 3
- JXXCENBLGFBQJM-RGMNGODLSA-N (3s)-3-hydroxy-4-(trimethylazaniumyl)butanoate;hydrochloride Chemical compound [Cl-].C[N+](C)(C)C[C@@H](O)CC(O)=O JXXCENBLGFBQJM-RGMNGODLSA-N 0.000 description 2
- PHIQHXFUZVPYII-LURJTMIESA-N (S)-carnitine Chemical compound C[N+](C)(C)C[C@@H](O)CC([O-])=O PHIQHXFUZVPYII-LURJTMIESA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960000678 carnitine chloride Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GUYHPGUANSLONG-SNAWJCMRSA-N (E)-4-(trimethylammonio)but-2-enoate Chemical compound C[N+](C)(C)C\C=C\C([O-])=O GUYHPGUANSLONG-SNAWJCMRSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000000909 electrodialysis Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Steroid Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A process is disclosed for the production of crotonobetaine hydrochloride, which is a starting product in the microbiological production of L-carnitine. In the process, carnitine hydrochloride in its racemic form or in the form of its enantiomers is reacted at elevated temperature with acetic anhydride in the presence of an acid catalyst.
A process is disclosed for the production of crotonobetaine hydrochloride, which is a starting product in the microbiological production of L-carnitine. In the process, carnitine hydrochloride in its racemic form or in the form of its enantiomers is reacted at elevated temperature with acetic anhydride in the presence of an acid catalyst.
Description
This invention relates to a new process for the production of crotonobetaine hydrochloride from carnitine hydrochloride, especially from racemic carnitine hydrochloride or from D-carnitine hydrochloride.
Crotonobetaine hydrochloride is used, inter alia, as a starting material in the microbiological synthesis of L-carnitine, as described, for example, in European Published Patent Applications Nos. 0158194 and 0122794.
It is known according to Binon et al., Chemical lo Abstracts, Vol. 59, 6248, to obtain crotonobetaine hydrochloride in a 78 percent yield from D,L-carnitine chloride by reaction with concentrated sulfuric acid at 130C, then precipitation with acetone and treatment with barium chloride. A significant drawback of such process is, besides the problem of handling concentrated sulfuric acid, the resultant and nonrecyclable barium sulfate.
Furthermore, in the standard chemical production of L-carnitine by resolution of racemates, e.g., according to DD 23.217, the problem inevitably arises that D-carnitine results, for which so far it has not beenpossible to find any further use.
An object of the invention is to provide a process that avoids the above drawbacks.
Accordingly, the invention provides a process for the production of crotonobetaine hydrochloride, which comprises reacting carnitine hydrochloride as the racemate or in the form of its enantiomers with from 1.5 to 15 mol of acetic anhydride in the presence of an acid catalyst at a temperature between 90 and 130C.
In the process of the invention, racemic carnitine hydrochloride, D-carnitine hydrochloride or ~-carnitine hydrochloride is reacted with 1.5 mol to 15 mol of acetic anhydridP in the presence of an acid catalyst at a temperature of 90 to 13QC. Preferably, D-carnitine resulting from the standard L-carnitine synthesis or low-cost D,L-carnitine is used. Preferably the amount of ~ ~ ~ 3 ~r acetic anhydride is selected in the range of 1.8 to 2 mol.
Preferably p-toluenesulfonic acid is used as the acid catalyst in an amount of 0.5 to 2 percent by weight based on the carnitine hydrochloride used. The reaction temperature is preferably between 110 and 125C, especially between 115 and 120C. At this temperature, the reaction is generally complete after about 2 hours.
By the addition of a lower aliphatic alcohol, preferably ethanol, to the skill hot, preferably at 70 to 80C, reaction mixture, and by subsequent cooling, crotonobetaine hydrochloride can advantageously be precipitated and isolated with an already high purity.
Yields of over 70 percent are achieYed by the process according to the invention. The crotonobetaine hydrochloride can be desalted in the usual way, e.g. by electrodialysis, and converted into crotonobetaine.
The product produced by the process according to the invention is especially suitable for use in the microbiological production of L-carnitine.
The following Example illustrates the invention.
EXAMPLE
25.0 g (0.125 mol.) of D,L-carnitine chloride, O.25 g (1.5 mmol~ of p-toluenesulfonic acid and 25.0 g (0.245 mol) of acetic anhydride were heated for 2 hours at 120C. The darkly colored solution was allowed to cool to about 80C and 20 ml of ethanol was added. The mi~ture was again allowed to cool slowly, and the product began to precipitate. The suspension was cooled to about 6C with an ice water bath, subjected to suction and rewashed with a little cold ethanol. The product was dried under vacuum and 17.4 g of a beige-colored powder with a content of 96 percent (HPLC) was obtained. This corresponded to a yield of 73.5 percent. Other data regarding the product are as follows:
~t '~ '^J ~ ,~
H-NMR, DMSO d6: 3.19 (s, -CH3, 9H) 4 . 38 (d 8Hz, -CH2, 2H) 6.33 (d 15 Hz, CH=, lH) 6.90 (dt 15 Hz, CH=, lH) 13 . 0 (s broad, -COOH) lH)
Crotonobetaine hydrochloride is used, inter alia, as a starting material in the microbiological synthesis of L-carnitine, as described, for example, in European Published Patent Applications Nos. 0158194 and 0122794.
It is known according to Binon et al., Chemical lo Abstracts, Vol. 59, 6248, to obtain crotonobetaine hydrochloride in a 78 percent yield from D,L-carnitine chloride by reaction with concentrated sulfuric acid at 130C, then precipitation with acetone and treatment with barium chloride. A significant drawback of such process is, besides the problem of handling concentrated sulfuric acid, the resultant and nonrecyclable barium sulfate.
Furthermore, in the standard chemical production of L-carnitine by resolution of racemates, e.g., according to DD 23.217, the problem inevitably arises that D-carnitine results, for which so far it has not beenpossible to find any further use.
An object of the invention is to provide a process that avoids the above drawbacks.
Accordingly, the invention provides a process for the production of crotonobetaine hydrochloride, which comprises reacting carnitine hydrochloride as the racemate or in the form of its enantiomers with from 1.5 to 15 mol of acetic anhydride in the presence of an acid catalyst at a temperature between 90 and 130C.
In the process of the invention, racemic carnitine hydrochloride, D-carnitine hydrochloride or ~-carnitine hydrochloride is reacted with 1.5 mol to 15 mol of acetic anhydridP in the presence of an acid catalyst at a temperature of 90 to 13QC. Preferably, D-carnitine resulting from the standard L-carnitine synthesis or low-cost D,L-carnitine is used. Preferably the amount of ~ ~ ~ 3 ~r acetic anhydride is selected in the range of 1.8 to 2 mol.
Preferably p-toluenesulfonic acid is used as the acid catalyst in an amount of 0.5 to 2 percent by weight based on the carnitine hydrochloride used. The reaction temperature is preferably between 110 and 125C, especially between 115 and 120C. At this temperature, the reaction is generally complete after about 2 hours.
By the addition of a lower aliphatic alcohol, preferably ethanol, to the skill hot, preferably at 70 to 80C, reaction mixture, and by subsequent cooling, crotonobetaine hydrochloride can advantageously be precipitated and isolated with an already high purity.
Yields of over 70 percent are achieYed by the process according to the invention. The crotonobetaine hydrochloride can be desalted in the usual way, e.g. by electrodialysis, and converted into crotonobetaine.
The product produced by the process according to the invention is especially suitable for use in the microbiological production of L-carnitine.
The following Example illustrates the invention.
EXAMPLE
25.0 g (0.125 mol.) of D,L-carnitine chloride, O.25 g (1.5 mmol~ of p-toluenesulfonic acid and 25.0 g (0.245 mol) of acetic anhydride were heated for 2 hours at 120C. The darkly colored solution was allowed to cool to about 80C and 20 ml of ethanol was added. The mi~ture was again allowed to cool slowly, and the product began to precipitate. The suspension was cooled to about 6C with an ice water bath, subjected to suction and rewashed with a little cold ethanol. The product was dried under vacuum and 17.4 g of a beige-colored powder with a content of 96 percent (HPLC) was obtained. This corresponded to a yield of 73.5 percent. Other data regarding the product are as follows:
~t '~ '^J ~ ,~
H-NMR, DMSO d6: 3.19 (s, -CH3, 9H) 4 . 38 (d 8Hz, -CH2, 2H) 6.33 (d 15 Hz, CH=, lH) 6.90 (dt 15 Hz, CH=, lH) 13 . 0 (s broad, -COOH) lH)
Claims (5)
1. A process for the production of crotonobetaine hydrochloride, which comprises reacting carnitine hydrochloride as the racemate or in the form of its enantiomers with from 1.5 to 15 mol of acetic anhydride in the presence of an acid catalyst at a temperature between 90° and 130°C.
2. A process according to claim 1, wherein from 1.8 to 2 mol of acetic anhydride is used.
3. A process according to claim 1, wherein the acid catalyst is p-toluenesulfonic acid in an amount of from 0.5 to 2 percent by weight based on the carnitine hydrochloride.
4. A process according to claim 1, 2 or 3, wherein the reaction is performed at a temperature in the range of 110° to 125°C.
5. A process according to claim 1, 2 or 3, wherein, after the reaction is completed, a lower aliphatic alcohol is added to the reaction mixture and the crotonobetaine hydrochloride is precipitated by subsequent cooling and isolated.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH3253/89 | 1989-09-07 | ||
| CH325389 | 1989-09-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2023744A1 true CA2023744A1 (en) | 1991-03-08 |
Family
ID=4251970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002023744A Abandoned CA2023744A1 (en) | 1989-09-07 | 1990-08-22 | Process for the production of crotonobetaine hydrochloride |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0416583B1 (en) |
| JP (1) | JPH03106853A (en) |
| KR (1) | KR910006227A (en) |
| AT (1) | ATE83768T1 (en) |
| CA (1) | CA2023744A1 (en) |
| CZ (1) | CZ278017B6 (en) |
| DD (1) | DD295340A5 (en) |
| DE (1) | DE59000657D1 (en) |
| DK (1) | DK0416583T3 (en) |
| ES (1) | ES2036386T3 (en) |
| FI (1) | FI904363A0 (en) |
| HU (1) | HU205065B (en) |
| IE (1) | IE64605B1 (en) |
| IL (1) | IL95571A (en) |
| NO (1) | NO173731C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4713348B2 (en) * | 2006-01-13 | 2011-06-29 | 日本電産サンキョー株式会社 | Permanent magnet synchronous motor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1190280B (en) * | 1986-04-24 | 1988-02-16 | Sigma Tau Ind Farmaceuti | PROCEDURE FOR THE PREPARATION OF RANGE-BUTYROBETAIN |
-
1990
- 1990-08-22 CA CA002023744A patent/CA2023744A1/en not_active Abandoned
- 1990-08-27 IE IE311190A patent/IE64605B1/en not_active IP Right Cessation
- 1990-08-31 KR KR1019900013847A patent/KR910006227A/en not_active Application Discontinuation
- 1990-08-31 JP JP2232312A patent/JPH03106853A/en active Pending
- 1990-09-03 IL IL9557190A patent/IL95571A/en not_active IP Right Cessation
- 1990-09-04 FI FI904363A patent/FI904363A0/en not_active IP Right Cessation
- 1990-09-05 ES ES199090117091T patent/ES2036386T3/en not_active Expired - Lifetime
- 1990-09-05 AT AT90117091T patent/ATE83768T1/en not_active IP Right Cessation
- 1990-09-05 EP EP90117091A patent/EP0416583B1/en not_active Expired - Lifetime
- 1990-09-05 DE DE9090117091T patent/DE59000657D1/en not_active Expired - Fee Related
- 1990-09-05 DK DK90117091.0T patent/DK0416583T3/en not_active Application Discontinuation
- 1990-09-06 HU HU905808A patent/HU205065B/en not_active IP Right Cessation
- 1990-09-06 NO NO903888A patent/NO173731C/en unknown
- 1990-09-07 CZ CS904362A patent/CZ278017B6/en unknown
- 1990-09-07 DD DD90343872A patent/DD295340A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CZ436290A3 (en) | 1993-01-13 |
| KR910006227A (en) | 1991-04-27 |
| DE59000657D1 (en) | 1993-02-04 |
| DD295340A5 (en) | 1991-10-31 |
| EP0416583A1 (en) | 1991-03-13 |
| ES2036386T3 (en) | 1993-05-16 |
| NO173731C (en) | 1994-01-26 |
| DK0416583T3 (en) | 1993-02-01 |
| NO903888D0 (en) | 1990-09-06 |
| IL95571A (en) | 1995-05-26 |
| EP0416583B1 (en) | 1992-12-23 |
| IL95571A0 (en) | 1991-06-30 |
| CZ278017B6 (en) | 1993-07-14 |
| HUT54971A (en) | 1991-04-29 |
| ATE83768T1 (en) | 1993-01-15 |
| NO173731B (en) | 1993-10-18 |
| HU205065B (en) | 1992-03-30 |
| IE64605B1 (en) | 1995-08-23 |
| NO903888L (en) | 1991-03-08 |
| FI904363A0 (en) | 1990-09-04 |
| IE903111A1 (en) | 1991-03-13 |
| HU905808D0 (en) | 1991-03-28 |
| JPH03106853A (en) | 1991-05-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |