Claims
- 1. Process for the production of di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate comprising converting racemic 3-chloro-2-oxypropyltrimethylammonium-chloride by racemate resolution with L-(+)-tartaric acid in the presence of a trialkyl amine into the di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate.
- 2. Process as claimed in claim 1 wherein each of the alkyl groups of the trialkylamine has 2 to 12 carbon atoms.
- 3. Process as claimed in claim 2 wherein the trialkylamine is triethylamine, tributylamine, tripropylamine, tripentylamine or trioctylamine.
- 4. Process for the production of di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate comprising converting racemic 3-chloro-2-oxy-propyltrimethylammonium chloride by racemate resolution with the silver salt of L-(+)-tartaric acid into the di-[(-)-3-chloro-2-oxypropyltrimethylammonium]-L-(+)-tartrate.
- 5. Process for the production of di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate comprising reacting L-(+)-tartaric acid, dissolved in water or suspended in an alcohol, with trimethyl amine and subsequently converting the reaction product thereof at a temperature of 10.degree. to 35.degree. C. with epichlorohydrin into the di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartate.
- 6. Process as claimed in claim 5 wherein the alcohol is a lower alkanol.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 1704/84 |
Apr 1985 |
CHX |
|
BROAD DESCRIPTION OF THE INVENTION
This is a divisional application of application Ser. No. 832,760, filed on Feb. 25, 1986, now U.S. Pat. No. 4,692,543, which is a continuation-in-part of application Ser. No. 717,547 filed on Mar. 29, 1985, now abandoned.
BACKGROUND OF THE INVENTION
1. Field Of The Invention
This invention relates to optically-active tartrate compounds, to methods of making such optically-active tartrate compounds and to the use of such optically-active tartrate compounds for the production of optically-active conversion products.
2. Prior Art
Due to the slight stability of the free group of acids, the racemic resolution of free carnitine causes difficulties; so the nitrile or the amides of carnitine are predominantly used for its racemic separation. For example, East German Pat. No. 23,217 teaches converting carnitine nitrile chloride, which has been converted by treatment with silver oxide into the hydroxide or by treatment with silver carbonate into the carbonate, with an optically-active acid into the diastereomers from which the suitable diastereomer is separated. The desired carnitine derivative is isolated from the suitable diastereomer. Another path, taught by Belgian Pat. No. 660,039, starts out from carnitine amide hydrochloride, which is converted with camphoric acid in the presence of AgNO.sub.3 into the diastereomeric mixture. The suitable diastereomer is again separted and analyzed.
However, the above processes have considerable disadvantages. Among such disadvantages is the difficultly-separable salt impurities obtained in large quantities, which make the dissociation of the racemate difficult. Also the numerous steps of the processes which are required to provide the carnitine amides, respectively, carnitine nitriles, accessible for the racemate dissociation make a technical or commercial application too expensive with regard to costs. These difficulties are increased, since as a result of the use of silver salts, one must operate with the exclusion of light in order to avoid any blackening of the reaction material.
An object of the invention is to provide the new compound di-[3-chloro-2-oxy-propyltrimethylammonium]-tartrate. Another object of the invention is to provide the new compound di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate (sometimes herein termed COP-tartrate). A further object of the invention is to provide a process for the production of such new compounds. A still further object of the invention is to provide a method for the production of optically-active carnitine nitrile chloride from such new compounds. Another object of the invention is to provide a process which produces, in a simple manner, optically-active carnitine nitrile chloride, especially (-)-carnitine nitrile chloride. Other objects and advantage of the invention are set out herein or are obvious herefrom to one skilled in the art.
The advantages and objects of the invention are achieved by the compounds and processes of the invention.
The invention includes optically-active di-[3-chloro-2-oxy-propyltrimethylammonium]-tartrate. For the production of (-)-carnitine nitrile chloride, one uses di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate (COP tartrate).
The new optically-active di-[3-chloro-2-oxy-proyltrimethylammonium]-tartrate has the formula: ##STR1## The invention also includes: (a) di[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate, and
The invention also involves producing the COP-tartrate. The COP-tartrate can be produced by several different methods. Preferably, the COP-tartrate is produced either by conversion of racemic 3-chloro-2-oxy-propyltrimethylammonium-chloride with L-(+)-tartaric acid, effectively in the presence of a trialkylamine, or by conversion of L-(+)-tartartic acid with trimethylamine and subsequent conversion with epichlorohydrin. When proceeding according to the first method, first the racemic 3-chloro-2-oxy-propyltrimethylammonium-chloride is produced from epichlorohydrin and trimethylamine and then the racemic 3-chloro-2-oxy-propyltrimethylammonium-chloride is converted with L-(+)-tartarric acid in the presence of a trialkylamines into the COP-tartrate.
The COP-tartrate can be dissociated from its diastereomer by crystallization.
The trialkylamine is preferably a trialkylamine wherein each of the alkyl groups has 2 to 12 carbon atoms. While the trialkylamine can have branched alkyl groups, preferably the trialkylamine only has straight-chain alkyl groups. Examples of the preferred trialkylamines are triethylamine, tributylamine, tripropylamine, tripentylamine and trioctylamine. Most preferably tributylamine is used.
A preferred embodiment for the production of the COP-tartrate according to the invention is described as follows: Starting out from 1 mole of dextrogyric tartaric acid, effectively 1.6 to 3 moles, preferably 1.8 to 2.5 moles, of tri-n-butylamine are converted with effectively 1.6 to 3 moles, preferably 1.8 to 2.2 moles, of racemic 3-chloro-2-oxy-propyltrimethylammonium-chloride for the production of the diastereomeric mixture. Preferably the conversion is operated in the presence of water and/or a solvent which is not miscible with water, such as, methylene chloride or chloroform, and at a temperature of 0.degree. to 30.degree. C., preferably 15 to 25.degree. C. After separation of the tri-n-alkylamine hydrochloride by extraction with an inert solvent, such as, methylene chloride or chloroform, the desired isomer is isolated by fractional crystallization after evaporation of the aqueous phase under reduced pressure. Effectively, the diastereomeric mixture is dissolved in a solvent, for example, water or a lower alkanol, such as, ethanol or preferably methanol. The crystallization of the desired isomer of the COP-tartrate is effectively achieved by the addition of a diluent, preferably acetone.
According to another production method of the invention L-(+)-tartaric acid dissolved in water or suspended in an alcohol (lower alkanol), effectively methanol or ethanol, is placed in a vessel, subsequently neutralized with trimethylamine, and then the di-[trimethylammonium]-tartrate formed as an intermediate product is converted with epichlorohydrin at a temperature of 17.degree. to 30.degree. C. into the desired COP-tartrate and its diastereomers.
A preferred embodiment for the production of the COP-tartrate according to the invention is as follows: Starting out with 1 mole of L-(+)-tartaric acid, dissolved in 200 to 250 g of water or suspended in a lower (alkanol) alcohol, 1.6 to 2.5 moles, preferably 1.8 to 2.1 moles, of trimethylamine is added at a temperature of 0.degree. to 30.degree. C. The pH of the solution effectively is 6.5 to 7.5. Subsequently and effectively, 1.6 to 3 moles of epichlorohydrin is added and the temperature is held at 15.degree. to 30.degree. C., preferably 20 .degree. to 28.degree. C.
Whenever the invention is operated with water, one aqueous phase develops. After evaporation of the water, effectively under vacuum, an oily residue results from which by treatment with organic solvent(s), effectively with methanol/acetone, the desired COP-tartrate is crystallized out. Whenever one operates with alcohols (e.g., lower alkanol, such as methanol or ethanol), then the desired COP-tartrate is precipitated and can be separated.
A further method for the production of COP-tartrate is where first the silver salt of the tartaric acid is produced from silver nitrate and alkali tartrate. Then the silver tartrate is suspended in water and is converted with racemic 3-chloro-2-oxy-propyltrimethylammonium-chloride. The desired COP-tartrate can be obtained by crystallization or can be separated from the diastereomeric salt.
The di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate (+)-tartrate of the invention has the following properties and characteristics:
Melting point of 159.degree. C. (after recrystallization from methanol/acetone).
[.alpha.].sub.D .sup.24 =-10.8.degree. (c=1.04 in water). pH of the solution (1 percent) is 7.
Analysis: C, calculated is 42.39%, found is 42.36%. H, calculated is 7.56%, found is 7.99%. N, calculated is 6.18%, found is 6.36%.
IR (KBr) spectrum: 3.5, 6.30, 7.20, 9.15, 10.25 micron.
For the production of di[(+)-3-chloro-2-oxy-propyl-trimethylammonium]-D-(-)-tartrate, the racemate dissociation is conducted using D-(-)-tartaric acid. Such product has the following properties and characteristics:
Melting point 159.degree. C. (after recrystallization from methanol/acetone).
[.alpha.].sub.D .sup.24 =+10.8.degree. (c=1.04 in water).
As a result of the process of the invention, the racemate dissociation takes place very early in such production schemes. Thus one can work starting with the further steps up to the carnitine nitrile chloride and carnitine still with only one antipode, as a result of which the load of the further reactions by the other antipode is omitted. One ordinarily skilled in the art could not anticipate that no further racemization would occur in the case of a subsequent reaction which in the end leads to the carnitine.
The di-[(-)-3-chloro-2-oxy-propyltrimethylammonium]-L-(+)-tartrate (COP tartrate) can be converted in a simple manner into the (-)-carnitine nitrile chloride and (-)-carnitine. At the same time, one can convert the COP-tartrate first of all with CaC1.sub. 2, followed by separating the Ga-tartrate and isolating the (-)-3-chloro-2-oxy-propyltrimethylammonium-chloride. The CaC1.sub. 2 can be replaced with, for example, 2 equivalents of HC1 (aqueous) and 1 equivalent of KDH (aqueous) or 1 equivalent of HC1 (aqueous) and 1 equivalent KC1 (aqueous). The latter can be converted using an alkali cyanide into the (-)-carnitine nitrile chloride. The alkali cyanide is, for example, LiCN or KCN, but preferably is NaCN. However, one can also carry out the decomposition, i.e., double salt conversion, of the COP-tartrate and the cyanide substitution reaction in one step. In that case, effectively an alkaline earth cynaide, preferably Ca(CN).sub. 2 is used. At the same time the tartaric acid precipitates as the Ca-salt and the (-)-carnitine nitrile chloride can be isolated from the reaction solution. No matter which method is used, the setting free or reaction is carried out preferably in water as a solvent.
According to another method of the invention, the optically active 3-chloro-2-oxy-propyltrimethylammonium-chloride isolated from the dissociation of the COP-tartrate is converted by treatment with a strong base, such as, an alkali hdroxide, an alkali alcoholate or an alkali tert.-butylate, into the (-)-glycidyltrimethylammonium-chloride and the latter is converted by treatment with acetone cyanohydrin or prussic acid into the L-earnitine nitrile chloride. This method is carried out preferably in an alcohol (lower alkanol) as a solvent at a temperature around ambient temperature.
The purification of the product can be achieved effectively by simple crystallization from a solvent, such as, a lower (alkanol) alcohol. Thus, products with optical purities of 98 plus are obtained.
However, according to this process, the di-[(+)-3-chloro-2-oxy-propyltrimethylammonium]-D-(-)-tratrate can also be converted into the corresponding (+)-carnitine nitrile chloride.
As used herein, all parts, percentages, ratios and proportions are on a weight basis unless otherwise stated herein or otherwise obvious herefrom to one skilled in the art.
US Referenced Citations (10)
Foreign Referenced Citations (6)
| Number |
Date |
Country |
| 660039 |
Aug 1965 |
BEX |
| 23217 |
May 1962 |
DDX |
| 0046625 |
Apr 1975 |
JPX |
| 717476 |
Oct 1954 |
GBX |
| 752681 |
Jul 1956 |
GBX |
| 218164 |
Aug 1968 |
SUX |
Divisions (1)
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Number |
Date |
Country |
| Parent |
832760 |
Feb 1986 |
|
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
717547 |
Mar 1985 |
|
Patent Grant
4732709
