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Preparation method of fosinopril sodium intermediate

A technology of fosinopril sodium and intermediates, applied in the field of organic chemical synthesis, can solve the problems of low reaction diastereoselectivity, low yield, low total yield, etc., and achieve the reduction of waste solvent generation, non-reaction High correspondence selectivity, good effect of non-correspondence selectivity

Pending Publication Date: 2022-04-22
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This process requires recrystallization twice to obtain qualified Zuo-5, the operation is cumbersome and the total yield is low
[0016] To sum up, the preparation method of fosinopril sodium left-5 reported in the current patent has the disadvantages of low reaction diastereoselectivity, cumbersome operation, low atom economy, and low yield. Therefore, an operation Simple, environmentally safe, high yield, suitable for industrial production of fosinopril sodium left-5, the preparation method is very necessary

Method used

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  • Preparation method of fosinopril sodium intermediate
  • Preparation method of fosinopril sodium intermediate
  • Preparation method of fosinopril sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1 (screening of reaction base):

[0040] Add 300mL of toluene to a 1L three-necked flask, and then add 54g of the base shown in Table 1, 100g of [hydroxyl (4-phenylbutyl)phosphinyl] benzyl acetate (V) and 1-bromoisobutyl propionate (VIII) 105g was stirred and dissolved, reacted at 25°C for 20-24h, took the reaction solution to detect HPLC, and calculated the dr value of the reaction solution. The results are shown in Table 1:

[0041] Table I

[0042]

[0043]

Embodiment 2

[0044] Embodiment 2 (screening of reaction solvent):

[0045] Add 300mL of the organic solvent shown in Table 2 to a 1L three-necked flask, then throw 54g of N-methylmorpholine, 100g of [hydroxy(4-phenylbutyl)phosphinyl]benzyl acetate (V) and propionic acid 105 g of -1-bromoisobutyl ester (VIII) was stirred and dissolved, and reacted at 25°C for 20-24 hours. The reaction solution was taken for HPLC, and the dr value of the reaction solution was calculated. The results are shown in Table 2:

[0046] Table II

[0047] serial number solvent Reaction liquid dr value 1 Toluene 2.5:1 2 ethyl acetate 2.3:1 3 n-Hexane 2.4:1 4 Dichloromethane 2.2:1

Embodiment 3

[0048] Embodiment 3 (screening of feeding ratio):

[0049] Add 300mL of toluene to a 1L three-necked flask, and then throw N-methylmorpholine, [hydroxy(4-phenylbutyl)phosphinyl]benzyl acetate (V) 100g and propionate-1-bromoisobutyl ( VIII) stirring and dissolving, wherein compound (V): compound (VIII): the mass ratio of N-methylmorpholine is proportioned as shown in Table 3, reacted for 20~24h under the condition of 25 DEG C, and the reaction solution was taken to detect HPLC, The data are shown in Table 3:

[0050] Table three

[0051] serial number Compound (V): compound (VIII): the mass ratio of N-methylmorpholine Reaction liquid dr value 1 1:1.05:0.54 2.5:1 2 1:1.10:0.54 2.3:1 3 1:1.50:0.54 2.3:1 4 1:1.05:0.50 2.2:1 5 1:1.05:1.00 2.2:1

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Abstract

The invention provides a method for preparing a fosinopril sodium intermediate, which comprises the following steps: using propionic acid-1-bromoisobutyl ester to replace propionic acid-1-chloroisobutyl ester disclosed in the prior art, and reacting with [hydroxyl (4-phenylbutyl) phosphinyl] benzyl acetate, the method has higher non-enantioselectivity, so that the yield of the target product levo-5 is obviously improved, and the method is suitable for industrial production. And the product is easier to refine.

Description

technical field [0001] The invention relates to a preparation method of a fosinopril sodium intermediate, belonging to the field of organic chemical synthesis. [0002] technical background [0003] Fosinopril sodium is a potent and long-acting ACEI antihypertensive drug developed by Bristol-Myers Squibb, which is used to treat various types of hypertension and heart failure. [0004] The chemical name of fosinopril sodium is 4-cyclohexyl-1-[(2-methyl-1-(propionyloxy)propoxy)(4-phenylbutyl)phosphonoacetyl]-L -sodium proline, its structural formula is as shown in formula I: [0005] [0006] At present, the synthetic method of report fosinopril sodium has a lot, and fosinopril sodium intermediate left-5, is the key intermediate of synthetic fosinopril sodium, and it is formed by formula II-1 and formula II-2 A mixture of the two isomers shown: [0007] [0008] The synthesis of Zuo-5 is mainly synthesized by two-step reactions: in the first step, propionic acid shown ...

Claims

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Application Information

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IPC IPC(8): C07F9/32
CPCC07F9/3264C07F9/3241
Inventor 黄文锋余文龙王延安胡佳兴
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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