NO173731B - PROCEDURE FOR THE PREPARATION OF CROTON BETAIN HYDROCHLORIDE - Google Patents
PROCEDURE FOR THE PREPARATION OF CROTON BETAIN HYDROCHLORIDE Download PDFInfo
- Publication number
- NO173731B NO173731B NO90903888A NO903888A NO173731B NO 173731 B NO173731 B NO 173731B NO 90903888 A NO90903888 A NO 90903888A NO 903888 A NO903888 A NO 903888A NO 173731 B NO173731 B NO 173731B
- Authority
- NO
- Norway
- Prior art keywords
- hydrochloride
- carnitine
- croton
- preparation
- procedure
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title abstract description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 title 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 18
- 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 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 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 229960003403 betaine hydrochloride Drugs 0.000 claims description 5
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 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
- 238000004519 manufacturing process 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
- 230000002378 acidificating effect Effects 0.000 claims 1
- 239000003054 catalyst Substances 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 10
- 230000002906 microbiologic effect Effects 0.000 abstract description 3
- 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 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- JXXCENBLGFBQJM-UHFFFAOYSA-N (3-carboxy-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC(O)=O JXXCENBLGFBQJM-UHFFFAOYSA-N 0.000 description 2
- 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
- 239000006227 byproduct Substances 0.000 description 2
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 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
- 229960000678 carnitine chloride Drugs 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
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000007306 turnover Effects 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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Oppfinnelsen vedrører en ny fremgangsmåte for fremstilling av krotonbetainhydroklorid fra karnitinhydroklorid, spesielt fra racemisk karnitinhydroklorid eller fra D-karnitinhydroklorid. The invention relates to a new process for producing croton betaine hydrochloride from carnitine hydrochloride, in particular from racemic carnitine hydrochloride or from D-carnitine hydrochloride.
Krotonbetainhydroklorid anvendes blant annet som utgangs-produkt ved den mikrobiologiske syntese av L-karnitin, sammen-lign f.eks. EP-A 0 158 194 eller EP-A 0 122 794. Croton betaine hydrochloride is used, among other things, as a starting product in the microbiological synthesis of L-carnitine, compare e.g. EP-A 0 158 194 or EP-A 0 122 794.
Det er ifølge Chemical Abstracts Vol. 59, 6248 (Binon et al.) kjent å fremstille krotonbetainhydroklorid i 78%-ig utbytte utifrå D,L-karnitinklorid ved omsetning med konsentrert svovelsyre ved 130°C, påfølgende utfelling med aceton og be-handling med bariumklorid. En stor ulempe ved denne fremgangsmåten er ved siden av håndteringen av konsentrert svovelsyre, det bariumsulfat som fremkommer og som ikke er re-sirkulerbart. According to Chemical Abstracts Vol. 59, 6248 (Binon et al.), it is known to produce crotonbetaine hydrochloride in 78% yield from D,L-carnitine chloride by reaction with concentrated sulfuric acid at 130°C, subsequent precipitation with acetone and treatment with barium chloride. A major disadvantage of this method is, in addition to the handling of concentrated sulfuric acid, the barium sulphate which is produced and which cannot be recycled.
Videre oppstår ved den klassiske kjemiske fremstilling av L-karnitin ved racematseparasjon, f.eks. ifølge DD 23.217, tvangsmessig det problem at D-karnitin fremkommer som biprodukt, som tidligere ikke hadde noen videre anvendelse. Furthermore, in the classic chemical preparation of L-carnitine by racemate separation, e.g. according to DD 23.217, forced the problem that D-carnitine appears as a by-product, which previously had no further application.
Oppgaven var derfor å finne en fremgangsmåte som ute-lukker de nevnte ulempene. Oppgaven kunne løses med en fremgangsmåte ifølge patentkrav 1. The task was therefore to find a method which excludes the aforementioned disadvantages. The task could be solved with a method according to patent claim 1.
Deri blir etter valg racemisk karnitinhydroklorid, D-karnitinhydroklorid eller også L-karnitinhydroklorid omsatt med 1,5 til 15 mol eddiksyreanhydrid i nærvær av en sur katalysator ved en temperatur på 90 til 130°C. Fortrinnsvis anvendes naturligvis det D-karnitin som fremkommer som biprodukt ved den klassiske L-karnitinsyntese eller det kostnadsgunstige D,L-karnitin. In this case racemic carnitine hydrochloride, D-carnitine hydrochloride or also L-carnitine hydrochloride is reacted with 1.5 to 15 mol of acetic anhydride in the presence of an acid catalyst at a temperature of 90 to 130°C. Preferably, of course, the D-carnitine that appears as a by-product in the classical L-carnitine synthesis or the cost-effective D,L-carnitine is used.
Fortrinnsvis velger man eddiksyreanhydridmengder i om-rådet fra 1,8 til 2 mol. Acetic anhydride amounts are preferably chosen in the range from 1.8 to 2 mol.
Som sur katalysator anvendes fortrinnsvis p-toluensulfonsyre i en mengde på 0,5 til 2 vekt-%, i forhold til det anvendte karnitinhydroklorid. As acid catalyst, p-toluenesulfonic acid is preferably used in an amount of 0.5 to 2% by weight, in relation to the carnitine hydrochloride used.
Reaksjonstemperaturen ligger fortrinnsvis mellom 110 og 125°C, spesielt foretrekkes mellom 115 og 120°C. Ved denne temperaturen er omsetningen som regel ferdig etter ca. 2 timer. The reaction temperature is preferably between 110 and 125°C, particularly preferably between 115 and 120°C. At this temperature, the turnover is usually complete after approx. 2 hours.
Ved tilsetning av en lavere alifatisk alkohol, fortrinnsvis etanol, til den varme, fortrinnsvis 70 til 80"C varme reaksjonsblandingen og ved påfølgende avkjøling, kan krotonbetainhydrokloridet felles ut på fordelaktig måte og isoleres med en allerede høy renhet. By adding a lower aliphatic alcohol, preferably ethanol, to the hot, preferably 70 to 80"C hot reaction mixture and by subsequent cooling, the croton betaine hydrochloride can be advantageously precipitated and isolated with an already high purity.
Etter fremgangsmåten ifølge oppfinnelsen kan oppnås ut-bytter på over 70%. According to the method according to the invention, yields of over 70% can be achieved.
Krotonbetainhydrokloridet kan avsaltes på vanlig måte, f.eks. ved elektrodialyse, og overføres til krotonbetain. The croton betaine hydrochloride can be desalted in the usual way, e.g. by electrodialysis, and is transferred to crotonbetaine.
Produktet som er fremstilt etter fremgangsmåten ifølge oppfinnelsen, egner seg på spesiell måte for anvendelse ved den mikrobiologiske fremstilling av L-karnitin. The product which is produced according to the method according to the invention is particularly suitable for use in the microbiological production of L-carnitine.
Eksempel Example
25,0 g (0,125 mol) D,L-karnitinhydroklorid, 0,25 g 25.0 g (0.125 mol) D,L-carnitine hydrochloride, 0.25 g
(1,5 mmol) p-toluensulfonsyre og 25,0 g (0,245 mol) eddiksyreanhydrid ble oppvarmet i 2 timer til 120°C. Man lot den mørk-fargede løsningen få avkjøle seg til ca. 80°C, og tilsatte 20 ml etanol. Deretter avkjølte man langsomt videre, hvorved produktet begynte å falle ut. Ved hjelp av et isvannbad ble oppslemmingen avkjølt til ca. 6°C, suget av og ettervasket med en liten mengde kald etanol. Produktet ble tørket under vakuum. (1.5 mmol) of p-toluenesulfonic acid and 25.0 g (0.245 mol) of acetic anhydride were heated for 2 hours at 120°C. The dark-colored solution was allowed to cool to approx. 80°C, and added 20 ml of ethanol. It was then slowly further cooled, whereby the product began to precipitate. Using an ice water bath, the slurry was cooled to approx. 6°C, aspirated off and washed with a small amount of cold ethanol. The product was dried under vacuum.
Man oppnådde 17,4 g beige-farget pulver med en renhet på 96% (HPLC). Dette tilsvarte et utbytte på 73,5%. 17.4 g of beige-colored powder with a purity of 96% (HPLC) was obtained. This corresponded to a yield of 73.5%.
4J-NMR, dmso d6: 3,19 (s, -CH3, 9H) 4H-NMR, dmso d6: 3.19 (s, -CH3, 9H)
4,38 (d 8Hz, -CH2, 2H) 4.38 (d 8Hz, -CH2, 2H)
6,33 (d 15Hz, CH=, 1H) 6.33 (d 15Hz, CH=, 1H)
6,90 (dt 15Hz, CH=, 1H) 6.90 (dt 15Hz, CH=, 1H)
13,0 (s breit, -C00H, 1H) 13.0 (s wide, -C00H, 1H)
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH325389 | 1989-09-07 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO903888D0 NO903888D0 (en) | 1990-09-06 |
| NO903888L NO903888L (en) | 1991-03-08 |
| NO173731B true NO173731B (en) | 1993-10-18 |
| NO173731C NO173731C (en) | 1994-01-26 |
Family
ID=4251970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO903888A NO173731C (en) | 1989-09-07 | 1990-09-06 | Procedure for Preparation of Croton Betaine 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 AT AT90117091T patent/ATE83768T1/en not_active IP Right Cessation
- 1990-09-05 DK DK90117091.0T patent/DK0416583T3/en not_active Application Discontinuation
- 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 ES ES199090117091T patent/ES2036386T3/en not_active Expired - Lifetime
- 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 DD DD90343872A patent/DD295340A5/en not_active IP Right Cessation
- 1990-09-07 CZ CS904362A patent/CZ278017B6/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO173731C (en) | 1994-01-26 |
| EP0416583B1 (en) | 1992-12-23 |
| ATE83768T1 (en) | 1993-01-15 |
| DD295340A5 (en) | 1991-10-31 |
| CA2023744A1 (en) | 1991-03-08 |
| HUT54971A (en) | 1991-04-29 |
| CZ278017B6 (en) | 1993-07-14 |
| IL95571A0 (en) | 1991-06-30 |
| ES2036386T3 (en) | 1993-05-16 |
| EP0416583A1 (en) | 1991-03-13 |
| KR910006227A (en) | 1991-04-27 |
| DE59000657D1 (en) | 1993-02-04 |
| NO903888L (en) | 1991-03-08 |
| JPH03106853A (en) | 1991-05-07 |
| DK0416583T3 (en) | 1993-02-01 |
| HU905808D0 (en) | 1991-03-28 |
| NO903888D0 (en) | 1990-09-06 |
| IE903111A1 (en) | 1991-03-13 |
| HU205065B (en) | 1992-03-30 |
| IE64605B1 (en) | 1995-08-23 |
| IL95571A (en) | 1995-05-26 |
| FI904363A0 (en) | 1990-09-04 |
| CZ436290A3 (en) | 1993-01-13 |
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