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Crystal of doripenem intermediate and preparation method thereof

A technology for doripenem and intermediates, which is applied in the field of crystallization of pharmaceutical intermediates and their preparation, can solve the problems of high cost, unfavorable industrialization and the like, and achieve the effects of easy crystallization, good stability and high purity

Active Publication Date: 2010-06-23
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the defects that the existing doripenem intermediate (I) needs to be crystallized after purification by column chromatography, the cost is relatively high, and it is not conducive to industrialization, and a doripenem intermediate (I) is provided The crystallization of the body and the preparation method thereof, the crystallization of the present invention is easy to preserve, easy to operate, good in stability, and high in purity; and its preparation method is simple and reliable, saves cost, and is easy to separate, and is suitable for industrial implementation

Method used

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  • Crystal of doripenem intermediate and preparation method thereof
  • Crystal of doripenem intermediate and preparation method thereof
  • Crystal of doripenem intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0027] Preparation of Reference Example 1 Compound (I)

[0028]

[0029] According to the method described in Japanese Patent 5-294970, under nitrogen protection, add formula (III) compound (28.5g, 0.11mol), triphenylphosphine (33.2g, 0.127mol), formula (II) compound (25.9g, 0.132mol), add 200ml of dry ethyl acetate to dissolve and mix, cool in an ice bath to about 0°C, slowly add DIAD (diisopropyl azodicarboxylate) (26.7g, 0.132mol) dropwise, and stir at room temperature for about 12 After hours, the precipitated white solid (triphenoxyphosphine) was removed by filtration, and the solvent was removed under reduced pressure to obtain about 80.0 g of a yellow oil.

Embodiment 1～8

[0030] The preparation of the crystal of embodiment 1~8 compound (I)

[0031] The compound (I) crystals were prepared with soluble solvent and water, and the results are listed in Table 1.

[0032] The specific operation of each embodiment is as follows: 10 g of the yellow oil obtained in Reference Example 1 was dissolved in a soluble solvent, and after the solution was dissolved, water was continuously added dropwise thereto, and the solution was stirred at 10°C to 40°C for several hours .

[0033] Table 1

[0034] implement

example

Soluble

agent

ml

insoluble

solvent

ml

result

(g)

Powder X-ray Diffraction

analysis results

hour

between

temperature

purity

1

Methanol

5.0

water

5.0

+3.1

attached figure 1 and table 3

4h

20℃

96.0％

2

Methanol

8.0

water

8.0

+3.6

attached figure 1...

Embodiment 9～14

[0038] The preparation of the crystal of embodiment 9~14 compound (I)

[0039] Compound (I) crystals were prepared with methanol, and the results are listed in Table 2.

[0040] The specific operations of each embodiment are as follows: 10 g of the yellow oil obtained in Reference Example 1 is dissolved in methanol, wherein the volume-to-mass ratio of methanol to the mixture is 0.5 to 2.0 ml / g, and the solution is heated at 10° C. to 30° C. Stir for several hours.

[0041] Table 2

[0042] implement

example

Soluble

agent

ml

result

(g)

Powder X-ray Diffraction Analysis Results

fruit

hour

between

temperature

purity

9

Methanol

5.0

+2.5

attached figure 1 and table 3

4h

20℃

95.0％

10

Methanol

8.0

+2.8

attached figure 1 and table 3

6h

30℃

96.5％

11

Methanol

12

+1.5

Attached fi...

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PUM

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Abstract

The invention discloses a crystal of a doripenem intermediate compound (I). In an X-ray diffraction pattern of powder of the crystal, main peaks are present at a diffraction angle 2 theta which is equal to 10.27 degrees, 10.75 degrees, 12.28 degrees, 13.35 degrees, 17.33 degrees, 20.85 degrees, 21.24 degrees, 21.75 degrees or 22.31 degrees and an error range of a value of the 2 theta is + / -0.2 degree; and BOC is tert-butoxycarbonyl group. The invention also discloses two preparation methods for the crystal, which comprise the following steps: (1) dissolving a mixture of the compound (1) and triphenylphosphine oxide in a soluble solvent, adding water, and stirring to separate out the crystal of the compound (1); and (2) dissolving a mixture of the compound (1) and triphenylphosphine oxide in methanol, and stirring to separate out the crystal of the compound (I), wherein the volume / mass ratio of the methanol to the mixture is 0.5 to 2.0ml / g. The crystal has the advantages of easy storage, easy operation, good stability and high purity; and the preparation methods have the advantages of simpleness, reliability, cost conservation, simple separation, and suitability for industrial production.

Description

technical field [0001] The invention relates to a crystallization of a pharmaceutical intermediate and a preparation method thereof, in particular to a crystallization of a doripenem intermediate and a preparation method thereof. Background technique [0002] Pyrrolidinylthiocarbapenem derivative, common name doripenem (compound (II) below) is a known broad-spectrum antibiotic. [0003] [0004] Compound (I) is an important intermediate for preparing doripenem, and the method for preparing doripenem from it can be found in patent literature: P6-P16 of CN1747954 specification. [0005] [0006] There are many difficulties in refining, purifying, storing and using the amorphous compound of compound (I) in subsequent reactions to obtain high-purity compound II. It is well known that in chemical synthesis processes, especially in industrial manufacturing processes, it is preferred that a compound produced by a certain method be of high purity or be able to be isolated and...

Claims

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Application Information

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IPC IPC(8): C07D207/12
Inventor 曹旭峰袁哲东朱雪焱沈裕辉俞雄
Owner SHANGHAI INST OF PHARMA IND
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