Synthesizing method using serine to prepare Ramipril key intermediate

A synthesis method and a technology for intermediates, which are applied in the field of synthesis of pharmaceutical and chemical intermediates, can solve the problems of low yield, unfavorable industrial production, large amount of concentrated sulfuric acid, expensive raw materials, etc., and achieve low-cost raw materials, avoid heavy metal pollution, and reduce three wastes. Effect

CN105777611AInactive Publication Date: 2016-07-20ZHEJIANG UNIV OF TECH +1
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Patent Information

Authority / Receiving Office
CN · China
Current Assignee / Owner
Publication Date
2016-07-20
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention relates to a synthesizing method using serine to prepare a Ramipril key intermediate. The Ramipril key intermediate is 2-azabicyclo[3.3.0] octane-3-carboxylic acid hydrochloride or benzyl ester hydrochloride. The synthesizing method includes: using the serine as the initial raw material, and sequentially performing esterification, acyl chloride acylation, deacidification, Michael addition, hydrolysis and hydrogenation reduction to obtain the Ramipril key intermediate. The synthesizing method has the advantages that the key intermediate is synthesized by a five-step method, and the synthesizing method is cheap in raw material, environmentally friendly, simple in preparation process, simple to operate, mild in reaction condition, short in reaction cycle, convenient in post-treatment, low in equipment requirement, capable of avoiding heavy metal pollution and the use of expensive catalysts, few in three wastes, high in product yield and purity and suitable for industrial production.
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Description

technical field

[0001] The invention relates to the field of synthesis of pharmaceutical and chemical intermediates, especially the preparation of ramipril key intermediate 2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride or benzyl ester hydrochloride by using serine as raw material synthetic method. Background technique

[0002] Ramipril (Ramipril) is a long-acting, potent angiotensin-converting enzyme inhibitor (ACEI), which is one of the global products of Aventis and developed by its predecessor Hoechst (EP0079022). It is the drug of choice for the treatment of mild and essential hypertension and malignant congestive heart failure. This product has the characteristics of quick onset, long duration, high tissue specificity, good tolerance, and low toxicity and side effects. Chemical name: (S)-2-[N-(1-ethoxycarbonyl-3-phenyl-propyl)alanyl]-2-azabicyclo[3.3.0]octane-3-carboxylate Acid, CAS number: 87333-19-5, the structure is as follows:

[0003]

[0004] In thi...

Examples

Embodiment 1

[0046] The preparation of embodiment 1, DL-serine methyl ester hydrochloride (Ⅲ)

[0047] Add 30mL of methanol into a 100mL three-necked flask, and slowly add 5.4mL of thionyl chloride dropwise under the condition of mechanical stirring in an ice-water bath. , heated to reflux for reaction, and after a reaction time of 20 h, the solvent was distilled off under reduced pressure, and 8.28 g of DL-serine methyl ester hydrochloride (Ⅲ) was obtained after drying, with a yield of 93.7%.

Embodiment 2

[0048] The preparation of embodiment 2, DL-serine methyl ester hydrochloride (Ⅲ)

[0049] Add 30mL of methanol into a 100mL three-necked flask, and slowly add 6.6mL of thionyl chloride dropwise under the condition of mechanical stirring in an ice-water bath. After the dropwise addition, continue to stir for 1h, and put 6.00g (57mmol) of DL-serine (II) into the three-necked flask , heated to reflux for reaction, and after a reaction time of 18 hours, the solvent was distilled off under reduced pressure and dried to obtain 8.32 g of DL-serine methyl ester hydrochloride (Ⅲ), with a yield of 94.2%.

Embodiment 3

[0050] The preparation of embodiment 3, L-serine methyl ester hydrochloride (Ⅲ)

[0051] Add 30mL of methanol into a 100mL three-necked flask, and slowly add 5.4mL of thionyl chloride dropwise under the condition of mechanical stirring in an ice-water bath. , heated to reflux for reaction, and after a reaction time of 10 h, the solvent was distilled off under reduced pressure to obtain 8.46 g of L-serine methyl ester hydrochloride (Ⅲ), with a yield of 95.8%.