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Process for production of carbapenem derivative and crystalline intermediate therefor

A crystallization and compound technology, applied in the field of preparation of carbapenem derivatives and crystallization of intermediates, can solve problems such as unoptimized implementation, unseparated crystallization, etc.

Inactive Publication Date: 2011-06-22
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In addition, the above-mentioned compound (IV-a), which is a synthetic intermediate of compound (I-a), is described in Patent Document 1 (see: Preparation Example 8), but its crystals have not been isolated.
[0016] Furthermore, as the deprotection method of compound (I-a), although Sn reagent (reference: Patent Document 1) or Meizhong acid (Meldrum's acid) (reference: Patent Document 2) is used, but from the load on the environment or the reagent itself Stability considerations, not preferred for industrial implementation

Method used

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  • Process for production of carbapenem derivative and crystalline intermediate therefor
  • Process for production of carbapenem derivative and crystalline intermediate therefor
  • Process for production of carbapenem derivative and crystalline intermediate therefor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0081] (1) Preparation method of compound (I)

[0082] [化10]

[0083]

[0084] (In the formula, R is a hydrogen atom or a hydroxyl protecting group; R 1 Is a carboxy protecting group; R 2 Is an amino protecting group, Ph is phenyl).

[0085] After reacting compound (III) and compound (IV) or a pharmaceutically acceptable salt thereof in the presence of a base, the protective group of the hydroxyl group is deprotected as necessary to obtain compound (I), its pharmaceutically acceptable salt, and its solvate Or their crystals.

[0086] As the base, a secondary amine is used, and a secondary amine with a large steric hindrance is more preferable. Specifically, in NHR a R b Said, where R a And R b Each independently is an alkyl group or a phenyl group, etc., preferably R a And R b the same. The alkyl group is a linear or branched C1 to C10, preferably a C3 to C7 alkyl group, and more preferably a branched chain. As R a And R b , More preferably isopropyl, tert-butyl, isobutyl, pentyl a...

Embodiment 1

[0134] [化11]

[0135]

[0136] After dissolving the 2-propanol crystals of compound (Ia) described in WO2004 / 72073 with ethyl acetate (67ml) (3.340g, equivalent to 3.137g without solvent), the ethyl acetate and isopropyl were distilled off Alcohol gave ethyl acetate concentrate (4.551 g). Ethyl acetate (3.14 ml), benzyl alcohol (3.14 ml), and toluene (12.55 ml) were added thereto, and after stirring for 2 hours at room temperature, it was stirred for 1 hour at 5°C. The precipitated crystals were filtered, washed with toluene (6.26 ml), and air dried to obtain benzyl alcoholate crystals of compound (I-a) (3.668 g, equivalent to 3.037 g in solvent-free conversion, containing benzyl alcohol (1.0 mol)). Yield: 96.8%.

[0137] Mp.74.9℃

[0138] C 22 H 31 N 4 O 8 S 2 ·1.0C 7 H 8 O·0.2H 2 O element analysis

[0139] Theoretical value: C: 53.15, H: 6.06, N: 8.55, S: 9.79

[0140] Measured value: C: 53.19, H: 6.12, N: 8.65, S: 9.85

[0141] Powder X-ray diffraction: picture like figure 1 As s...

Embodiment 2

[0144] Amorphous and powdered compound (I-a) (100 mg) was dissolved in ethyl acetate (0.1 ml), benzyl alcohol (0.3 ml) was added, and the mixture was stirred at room temperature for 1 hour, and then left at 5°C for 2 days. The precipitated crystals were filtered and air-dried to obtain benzyl alcoholate crystals (79 mg) of compound (I-a) showing substantially the same powder X-ray pattern as in the case of Example 1.

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Abstract

Disclosed is an intermediate for the synthesis of a carbapenem which is advantageous for the industrial production of the carbapenem. A process for producing a compound (I) or a pharmaceutically acceptable salt or solvate thereof or a crystal thereof, comprising reacting a compound (III) with a compound (IV) in the presence of a secondary amine; a crystal of a benzyl alcohol-solvated form of the compound (I) or the like; a method for deprotecting the compound (I) by using a Pd catalyst; and a crystal of the compound (IV) or the like.

Description

Technical field [0001] The present invention relates to a preparation method of carbapenem derivatives and intermediate crystallization thereof. Background technique [0002] A pyrrolidinylthio carbapenem derivative (compound (II)) having a wide range of antibacterial spectrum is known as a useful antibiotic (refer to Patent Document 1). The compound (I) of the present invention is its synthesis intermediate. [0003] [化1] [0004] [0005] (In the formula, R 1 Is a carboxy protecting group, R 2 Is an amino protecting group). [0006] As an example of the preparation method of compound (I), although the following method is described in Patent Document 1 (Example 13, Step 3), the base used in the condensation reaction to introduce the 2-position side chain is diisopropylethyl Base amine (71% yield). [0007] [化2] [0008] [0009] In addition, although Patent Document 2 (Reference Example 1) also describes the following similar reaction, the base used in the condensation reaction is si...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/00
CPCC07D477/00C07D207/12A61P31/00A61P31/04C07D477/20
Inventor 上仲正朗保积靖之野口耕一小紫唯史
Owner SHIONOGI & CO LTD
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