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Preparation method and application of tadalafil cis-intermediate

A non-cis-intermediate technology, applied in the field of preparation of tadalafil cis-intermediate, can solve the problems of unfavorable industrial production, cumbersome operation, long reaction time, etc.

Inactive Publication Date: 2019-12-24
SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In summary, the problems in the prior art are: the prior art has a long reaction time and low yield, which is also unfavorable for industrialized production, and the production cost is increased simultaneously; raw materials use acid chlorides, which is not conducive to environmental protection, and the operation steps are long. Four steps, the yield is not high, only 67%, the operation is cumbersome, and low temperature is required

Method used

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  • Preparation method and application of tadalafil cis-intermediate
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preparation example Construction

[0031] Such as figure 1 As shown, the preparation method of the tadalafil cis intermediate provided by the embodiments of the present invention comprises the following steps:

[0032] S101: using D-tryptophan methyl ester hydrochloride as a starting material;

[0033] S102: Mixing with piperonal in a glycol ether solution to obtain a cis intermediate.

[0034] The ratio of D-tryptophan methyl ester hydrochloride to piperonal is 1:1.1-1.5, and the ratio of D-tryptophan methyl ester hydrochloride to glycol ether is listed as 1 g / 4 ml.

[0035] The preparation method of the tadalafil cis intermediate provided in the examples of the present invention uses D-tryptophan methyl ester hydrochloride I as the starting material, and mixes it with piperonal II in a glycol ether solution to obtain the cis Intermediate III. The chemical reaction formula is as follows:

[0036]

[0037] Further, as a preferred embodiment of the present invention, the glycol ethers are: ethylene glycol...

Embodiment 7

[0054] Example 7 cis intermediate HPLC detection conditions

[0055] (1) Chromatographic column: octaalkylsilane bonded silica gel column

[0056] (2) Mobile phase: 0.1% trifluoroacetic acid was used as mobile phase A, and acetonitrile was used as mobile phase B.

[0057] (3) Detection wavelength: 285nm

[0058] (4) Flow rate: 1.0ml / min

[0059] (5) Column temperature: 40°C

[0060] (6) Gradient elution program

[0061]

[0062]

[0063] (7) Determination method

[0064] According to the "Chinese Pharmacopoeia" 2015 edition four general rules 0512 high performance liquid chromatography test, according to the above chromatographic conditions, accurately measure 10ul of the test solution, inject it into the liquid chromatograph, record the chromatogram, and calculate the relative peak of the main peak according to the peak area normalization method. percentage content.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses a preparation method and an application of a tadalafil cis-intermediate, which comprises the following steps: by using D-tryptophan methyl ester hydrochloride as an initial raw material, mixing the raw material with heliotropin in a glycol ether solution to obtain a cis-intermediate, wherein the ratio of the D-tryptophan methyl ester hydrochloride to the heliotropin is 1:(1.1-1.5), and the ratio of the D-tryptophan methyl ester hydrochloride to the glycol ether is 1g to 4ml; the glycol ether is one or a mixtureof more of ethylene glycol monomethyl ether, propylene glycol monomethyl ether, butanediol monomethyl ether, propylene glycol dimethyl ether, ethylene glycol dimethyl ether and butanediol dimethyl ether. The method disclosed by the invention is short in synthesis time, simple to operate and high in yield, and the prepared cis-intermediate is high in purity. The intermediate does not need to be refined and can be directly used for preparing tadalafil.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method and application of a tadalafil cis intermediate. Background technique [0002] Currently, the closest prior art: Tadalafil, also known as (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3, 6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, represented by formula (I) The compound, trade name "Cialis", is an oral PDE5 inhibitor indicated for erectile dysfunction (ED). Tadalafil was launched in the U.S. in December 2003 as a once-a-day oral dosage form. It is also approved in the United States and Europe for benign prostatic hyperplasia and pulmonary hypertension. [0003] U.S. Patent No. 5,859,006 reports a synthetic route. This report uses D-tryptophan methyl ester and piperonal as raw materials in dichloromethane, and a Pictet-Spengler reaction occurs under the catalysis of trifluoroacetic acid to obtain a mixture ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D471/14A61P35/00A61P9/12A61P11/00
CPCA61P9/12A61P11/00A61P35/00C07D471/04C07D471/14
Inventor 邓俊丰谢娟徐明琴左玉碧邹俊肖聪郭小照
Owner SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP
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