Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1991-04-09
1994-03-08
Dees, Jose' G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
564304, 562430, C07B 5700
Patent
active
052929337
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a novel process for the resolution of an acid mixture (hereinafter: threo acid mixture) containing (+)-threo-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionic acid [hereinafter: (+)-threo acid] and (-)-threo-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionic acid [hereinafter: (-)-threo acid].
BACKGROUND OF THE INVENTION
The (+)-threo acid is an important raw material of the therapeutically active (2S,3S)-3-acetoxy-5-dimethylaminoethyl-2-(4-methoxyphenyl)-2,3-dihydro-1,5 -benzothiazepin-4(5H)-one hydrochloride (generic name: diltiazem), a known antianginal drug acting as a calcium antagonist.
There are several processes known from the literature for the preparation of the (+)-threo acid.
A resolution process using L-lysine as resolving agent is described in the published German patent application (DE-OS) No. 3,337,176. However, the particularly costly L-lysine is used in a 4-fold excess and,; in addition, it is difficult and expensive to recover L-lysine in its acid form from the mother liquors.
According to another method [Helv. Chim. Acta 67, 916 (1984)], the racemic threo acid is resolved by using cinchonidine in ethanol. This method is characterized by the use of an extraordinarily high amount of alcohol as solvent and by a 48-hour time demand of crystallization.
According to the method described in the U.S. Pat. No. 4,416,819, an equivalent amount of (+)-.alpha.-phenylethylamine each is employed for both forms of the racemic acid in order to resolve the racemic threo acid in water. In our own examinations, a (+)-threo acid with an optical purity of only 87%, [.alpha]sub.D.sup.20 =+302.degree. (c=0.3, ethanol), was obtained in a yield of 79% when the resolution and subsequent crystallization of the diastereomeric salt were carried out by using the method cited above.
In the process described in the Hungarian patent specification No. 193,230, the acid addition salt of 0.5 to 0.6 molar equivalent of (+)-.alpha.-phenylethylamine is used as resolving agent; a method, useful to enrich the valuable (+)-threo acid in the remaining threo acid mixture is also described in the above specification.
OBJECT OF THE INVENTION
It is the object of the present invention, to provide a process by providing the (+)-threo acid economically, in a high optical purity and good yield by using simple technological steps and to provide as well an inexpensive and easily available resolving agent.
DESCRIPTION OF THE INVENTION
The invention is based on the recognition that D-(-)-phenylglycine amide [hereinafter: (-)-PGA] and L-(+)-phenylglycine amide [hereinafter: (+)-PGA], respectively form a slightly (less) soluble diastereomeric salt with the (-)-threo or (+)-threo acid, respectively.
Thus, the present invention essentially relates to a novel process for the resolution of an acid mixture ("threo acid mixture") containing (+)-threo-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionic acid ["(+)-threo acid"] and (-)-threo-3-[2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionic acid ["(-)-threo acid"], which comprises using D-(-)-phenylglycine amide or L-(+)-phenylglycine amide, respectively as resolving agent.
Although (+)-PGA and (-)-PGA used for separating the threo acid mixture can be prepared in any optional way (see e.g. the German patent specification (DE-PS) No. 2,547,548), a particularly economical process for the preparation of the above resolving agents is also part of the present invention namely, racemic or nearly racemic .alpha.-phenylglycine amide (hereinafter: PGA mixture) can be separated to its enantiomers in a good, yield and satisfying purity by using (-)-threo acid which has been considered as a side product of no use up to the present. The racemic or nearly racemic threo acid mixture can be resolved to its enantiomers in a suitable quality by using the aqueous solutions containing (+)-PGA or (-)-PGA, respectively obtained according to the process of the present invention.
Thus, by using this most preferred variat
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Aracs nee Tischler Zsuzsanna
Berki Katalin
cs Maria
Fogassy Elemer
Gizur Tibor
Clarke Vera C.
Dees Jos,e G.
Dubno Herbert
Myers Jonathan
Richter Gedeon Vegyeszeti Gyar Rt
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