Process for crystallizing N.sup.2 - ((S) -1-ethoxycarbonyl-3-phe

Details Process for crystallizing N.sup.2 - ((S) -1-ethoxycarbonyl-3-phe Process for crystallizing N.sup.2 - ((S) -1-ethoxycarbonyl-3-phe

1994-08-26

1996-05-21

Brust, Joseph Paul

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D20712

Patent

active

055191460

DESCRIPTION:

BRIEF SUMMARY
This application is a 37/of PCT/JP93/01909 filed Dec. 27, 1993.


TECHNICAL FIELD

The present invention relates to a process for crystallizing N.sup.2 -((S)- 1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline which is useful as an intermediate for the preparation of an inhibitor of angiotensin converting enzyme (ACE), Lisinopril (N.sup.2 -((S)-1-carboxy-3-phenylpropyl)-L-lysyl-L-proline).


BACKGROUND ART

N.sup.2 -((S)- 1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline can be prepared by a method described in Japanese Unexamined Patent Publication No. 36297/1986, and the like. As a method for isolation and purification of thus obtained N.sup.2 -((S)-1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline, crystallizing method is extremely easy. In Japanese Unexamined Patent Publication No. 36297/1986, there is described a crystallizing method using methyl tert-butyl ether/cyclohexane (650 ml/240 ml). Also, in Journal of Organic Chemistry, 53, p836-843 (1988), there is disclosed a crystallizing method using methyl tert-butyl ether/cyclohexane or methyl tert-butyl ether/hexanes (C.sub.6 H.sub.14) (225 ml/85 ml cyclohexane). However, as to the methods using these solvents as crystallizing solvents, there are problems that the solvents are highly hazardous and that the crystal properties of the resulting N.sup.2 -((S)-1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline is unfavorable. Therefore these methods are not necessarily preferable. Due to the unfavorable crystal properties, solid-liquid separation takes long period and mother liquor cannot be sufficiently replaced when washing cake. Further, once obtained crystal easily melts or becomes oily (syrupy). So, during solid liquid separating step to drying step, there arise following problems. That is, the molten or oily state of some or almost of crystal results in unsuccessful separation and collection thereof. Also, the extreme difficulty of the removal of solvents from the obtained oily matter or molten matter, requires long period for drying step or results in stopping of drying step halfway.
Preliminary research of the present inventors for crystallizing solvents other than methyl tert-butyl ether/cyclohexane or methyl tert-butyl ether/hexanes (C.sub.6 H.sub.14) has shown problems that N.sup.2 -((S)-1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline is not crystallized or is obtained only in an oily state, or even if gelled matter obtained, collection by filtration cannot be done due to unsuccessful crystallization. Thus it has been proved that the crystallization is an extremely difficult technical subject.
An object to be solved by the present invention is to find out solvents which enable the crystallization of N.sup.2 -((S)-1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline with favorable crystal properties, instead of methyl tert-butyl ether/cyclohexane or methyl tert-butyl ether/hexanes (C.sub.6 H.sub.14).


DISCLOSURE OF THE INVENTION

As a result of continuous effort and earnest investigation of the present inventors with respect to solvents for crystallization of N.sup.2 -((S)-1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline, it has been found that solvents which enable the crystallization with favorable crystal properties have molecular structures quite similar to each other.
That is, the present invention relates to a process for crystallizing N.sup.2 -((S)-1-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline by using one or a mixture of at least two kinds of compound having the general formula: group, acetoxy group, chloromethyl group or phenyl group; R.sup.2 is hydrogen atom, chlorine atom, bromine atom, methyl group, ethyl group or methoxy group; R.sup.3 is chlorine atom, bromine atom, methyl group or methoxy group; R.sup.4 is chlorine atom, bromine atom, methyl group, ethyl group or methoxy group; provided that the combination wherein R.sup.1 i

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patent: 5227497 (1993-07-01), Inoue et al.
patent: 5359086 (1994-10-01), Merslavic et al.
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