阅读说明：本技术 一种ace-抑制剂合成中的药物中间体及其应用 (Pharmaceutical intermediate in synthesis of ACE-inhibitor and application thereof ) 是由 杨选峰 于 2018-08-29 设计创作，主要内容包括：通式(I)的化合物,其中R1是芳基或烷基；R2代表烷基；R3代表烷基或芳烷基,是有价值的药物中间体,它可以通过将通式(IV)的化合物(其中R1和R2的定义如上)反应而制备,通式(VI)化合物的至少2摩尔当量(其中X代表卤素或叔丁氧羰基氧基,R3如上所定义)。通式(II)的已知化合物(其中R1和R2如上所述)是通过将通式(I)化合物与亚硫酰氯反应制备的。通式(I)的化合物是用于合成药物活性成分的新中间体,特别是在制备ACE抑制剂中,例如依那普利、培哚普利或雷米普利。(A compound of formula (I) wherein R1 is aryl or alkyl; r2 represents alkyl; r3 represents alkyl or aralkyl, is a valuable pharmaceutical intermediate which can be prepared by reacting a compound of formula (IV) wherein R1 and R2 are as defined above, at least 2 molar equivalents of a compound of formula (VI) wherein X represents halogen or tert-butoxycarbonyloxy and R3 is as defined above. Known compounds of formula (II) wherein R1 and R2 are as described above, are prepared by reacting a compound of formula (I) with thionyl chloride. The compounds of the general formula (I) are novel intermediates for the synthesis of pharmaceutically active ingredients, in particular in the preparation of ACE inhibitors, such as enalapril, perindopril or ramipril.)

1. A compound characterized by: a compound of general formula (I) wherein R1 represents aryl or alkyl; r2 represents alkyl; r3 represents alkyl or aralkyl.

2. A compound according to claim 1, wherein: wherein R1 is phenyl, R2 is ethyl, and R3 is ethyl.

3. A compound according to claim 1, wherein: wherein R1 is methyl, R2 is ethyl, and R3 is ethyl.

4. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that R1, R2 and R3 are as defined in claim 1, which comprises reacting a compound of formula (IV) (wherein R1 and R2 have the meanings as indicated above) in an organic solvent I n XCOOR3 α (VI) (X represents halogen or tert-butoxycarbonyloxy and R3 has the meaning as indicated above) in the presence of an acid-binding reagent having at least 2 molar equivalents of a compound of formula (VI).

5. A process for the preparation of a compound of general formula (I) according to claim 1, characterized in that: tetrahydrofuran, ethyl acetate, dichloromethane or acetone were used as organic solvents.

6. A process according to claim 4 for the preparation of a compound of general formula (I) according to claim 1, characterized in that: organic amines or inorganic salts are used as acid binding agents.

7. A process according to claim 4 for the preparation of a compound of general formula (I) according to claim 1, characterized in that: compounds of the general formula (VI) are used in which X represents chlorine and R3 represents ethyl.

8. A process for the preparation of a compound of formula (II): wherein the meaning of R1 and R2 is as defined in claim 1, comprising reacting a compound of general formula (I) (wherein R1, R2 and R3 are as defined in claim 1) with thionyl chloride in an organosol.

Technical Field

The present invention relates to a novel pharmaceutical intermediate and use thereof. More specifically, the present invention relates to novel intermediates useful in the preparation of pharmaceutical products, particularly in the synthesis of ACE inhibitors, processes for their preparation and processes for converting said intermediates to pharmaceutically active I. Especially ACE inhibitors.

Background

N-ethoxycarbonylglycine is firstly used for reacting with thionyl chloride, and an acyl chloride intermediate is heated at 85 ℃ to prepare oxazolidinedione compounds, so that corresponding cyclic anhydride is obtained. Several methods for preparing the compounds of the general formula (II) are known from the prior art. Amino acids of the general formula (IV) are generally used as starting compounds. Oxazolidinediones of the formula (II) are prepared by reacting amino acids of the formula (IV) with phosgene derivatives. The reaction products are usually not isolated even if their formation is not mentioned, but the intermediates are reacted immediately in situ in the peptide coupling reaction. Similarly, in the first procedure for the preparation of N- (1- (S) -ethoxycarbonyl-3-phenylpropyl ] -4- (S) -methyl-oxazolidine-2, 5-dione (compound of formula (II) where R1 is phenyl and R2 is ethyl), a mixture of N-1- (S) -ethoxycarbonyl-3-phenylpropyl ] alanine (compound of formula (IV), R1 is phenyl and R2 is ethyl) is refluxed for 15 minutes in a nitrogen atmosphere and the resulting solution is used directly in the subsequent reaction step. Only a slight molar excess is required, the starting materials of the formula (IV) are consumed very slowly, D. The divergent products corresponding to the general formula (V) are likewise formed slowly and, according to chromatographic analysis, by-products are present in addition to the desired product of the general formula (V) after the starting compound has been used in the reaction. When a compound of formula (VI) is used in at least 2 molar equivalents relative to the amount of compound of formula (IV), the reaction proceeds rapidly to give a homogeneous product. Compounds of general formula (I) are isolated and identified, wherein R1 represents alkyl or aryl, R2 represents alkyl, and R3 represents alkyl or aralkyl. The compounds of formula (I) are novel.

Disclosure of Invention

The object of the present invention is to overcome the above-mentioned disadvantages of the prior art and to provide a pharmaceutical intermediate in the synthesis of ACE-inhibitors and the use thereof, the novel intermediate of general formula (I) being produced in a fast-reacting form and being obtained as a highly pure and homogeneous product which can be isolated in very high purity. The conversion of the compounds of the formula (I) into the corresponding oxazolidinediones of the formula (II) can be carried out easily and simply on an industrial scale.

The technical scheme of the invention is as follows: a compound of general formula (I) wherein R1 represents aryl or alkyl; r2 represents alkyl; r3 represents alkyl or aralkyl.

Wherein R1 is phenyl, R2 is ethyl, and R3 is ethyl.

Wherein R1 is methyl, R2 is ethyl, and R3 is ethyl.

A process for the preparation of a compound of formula (I) according to claim 1, R1, R2 and R3 being as defined in claim 1, which comprises reacting a compound of formula (IV) (wherein R1 and R2 have the meanings as indicated above) in an organic solvent I n XCOOR3 α (VI) (X represents halogen or tert-butoxycarbonyloxy and R3 has the meaning as indicated above) in the presence of an acid-binding reagent having at least 2 molar equivalents of a compound of formula (VI).

Tetrahydrofuran, ethyl acetate, dichloromethane or acetone were used as organic solvents.

Organic amines or inorganic salts are used as acid binding agents.

Compounds of the general formula (VI) are used in which X represents chlorine and R3 represents ethyl.

A process for the preparation of a compound of formula (II) wherein R1 and R2 have the meanings as defined in claim 1, comprising reacting a compound of formula (I) wherein R1, R2 and R3 have the same meanings as in claim 1, with thionyl chloride in an organosol.

The invention has the beneficial effects that: the novel intermediates of the general formula (I) are produced in a fast-reacting form and are obtained as highly pure and homogeneous products which can be isolated in very high purity. The conversion of the compounds of the formula (I) into the corresponding oxazolidinediones of the formula (II) can be carried out easily and simply on an industrial scale.

Drawings

Fig. 1 is a schematic structural view of the present invention.

Detailed Description

In FIG. 1 oxazolidinediones of formula (II) are important intermediates for the preparation of compounds of formula (III) in which R1 represents aryl or alkyl, R2 represents alkyl, R4 represents optionally substituted alkyl, R5 represents hydrogen or alkyl, or the group of formula (VII) consisting of R4, R5 and the carbon and nitrogen atoms attached in formula (III) is part of the ring system of formula (a), (b), (c), (d), (e), (f), (g), (h), (I) or (j) of Table 1, R6 is hydrogen, alkyl or aralkyl, in compounds of formula (III) there are several important pressure-reducing pharmaceutical active agents such as ramipril, perindopril and enalapril, "alkyl" representing a linear or branched saturated aliphatic hydrocarbon radical comprising 1 to 6, preferably 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, tert-butyl "for example, which is useful by filtration of the reaction of the aromatic compounds of formula (III) with the same or non-substituted benzyl alcohol (I) in which R639-2-ethyl ether, R6326-2-ethyl ether, preferably the reaction is carried out by filtration, the same or by evaporation of the reaction with the addition of a solvent (I) in the reaction of the crude aromatic carboxylic acid, the reaction of the crude compound of the aromatic compound of the addition of the formula (III) at least one or the reaction of the aromatic compound of the formula (III) with the name of the aromatic carboxylic acid, preferably the compound of the formula (I-2-ethyl ester of the formula (III) under stirring at room temperature, the name of the formula (III) under the name of the formula (III) of the formula (7-5-7-5-7-5-2-7-2-8-7-2-8-7-8-7-2-8-2-7-2-7-2-7-2-7-2-7-2-3-2-N-.