Synthesis method of (2S,4S)-4-thiophenyl-L-proline hydrochloride

Abstract

The invention discloses a synthesis method of (2S,4S)-4-thiophenyl-L-proline hydrochloride. The method comprises the following steps: adding L-oxyproline into a methanol-thionyl chloride reaction mixed solution, reacting, and separating to obtain a white solid L-oxyproline methyl ester; dissolving the L-oxyproline methyl ester in a tetrahydrofuran-water mixed solvent, adding a sodium bicarbonate solid and BOC acid anhydride to react, and separating to obtain colorless viscous grease BOC-L-oxyproline methyl ester; mixing the BOC-L-oxyproline methyl ester, diphenyl disulfide ether and tributyl phosphine in toluene, and reacting at 80-120 DEG C for 4-5 hours to obtain N-BOC-(2S,4S)-4-thiophenyl-L-proline methyl ester; and carrying out hydrolysis and recrystallization on the reaction solution to obtain the (2S,4S)-4-thiophenyl-L-proline pure product. The method has the advantages of low raw material price, mild reaction conditions, high selectivity, lower requirements for instruments and equipment, simple technical operation, high total yield, high product purity and simple purification process. The synthesis route has low pressure on environmental protection, and is more suitable for industrial mass production.

Description

technical field [0001] The invention relates to the field of amino acid synthesis, in particular to a synthesis method of (2S, 4S)-4-phenylthio-L-proline hydrochloride. Background technique [0002] (2S,4S)-4-Phenylthio-L-proline hydrochloride is a key intermediate in the synthesis of antihypertensive drug zofenopril calcium. The antihypertensive drug zofenopril calcium is the first third-generation long-acting angiotensin-converting enzyme inhibitor containing a sulfhydryl group, which is converted into the active effector zofenoprilat in the body to exert the antihypertensive effect. It is mainly used for mild to moderate Treatment of severe essential hypertension and patients with or without symptoms within 24 hours of acute myocardial infarction, hemodynamically stable and not receiving thrombolytic therapy. [0003] Zofenopril calcium achieves the purpose of lowering blood pressure by inhibiting the renin-angiotensin-aldosterone system. Angiotensin I is converted into...

AI Technical Summary

Problems solved by technology

[0006] The first step of the synthetic route uses N-acetyl-L-hydroxyproline as a raw material, catalyzed by p-toluenesulfonic acid, the price of the reaction raw material is high, and the price of the catalyst is expensive, which is harmful to the environment and the post-treatment is complicated.

The second step uses p-toluenesulfonyl chloride sulfonation reaction in pyridine solvent, which increases the cost in industry, and the reaction is not green enough and pollutes the environment

The third part uses thiophenol to replace N-acetyl-trans-4-p-toluenesulfonyl-L-hydroxyproline methyl ester, and uses sodium ethylate in the reaction process. The conditions are harsh and the industrial cost is high.

But in actual production process, still can't avoid the shortcoming that synthetic route is too long, and such synthetic route makes the total yield of reaction very low

Therefore, there are still great limitations in the actual production process

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