CN107973796B

CN107973796B - Preparation method of tadalafil isomer

Info

Publication number: CN107973796B
Application number: CN201711295146.3A
Authority: CN
Inventors: 刘宏宇; 乔明福; 许华锋; 窦振国
Original assignee: Zhuhai United Laboratories Co Ltd
Current assignee: Zhuhai United Laboratories Co Ltd
Priority date: 2017-12-08
Filing date: 2017-12-08
Publication date: 2020-05-26
Anticipated expiration: 2037-12-08
Also published as: CN107973796A

Abstract

The invention discloses a preparation method of tadalafil isomers, belonging to the technical field of drug synthesis. The preparation method comprises the steps of placing tadalafil in an aprotic strong polar solvent, and performing partial racemization by using an organic base to obtain an isomer I; taking L-tryptophan as a raw material, and completely synthesizing to obtain an isomer II through four steps of reaction; placing the isomer II in an aprotic strong polar solvent, and performing partial racemization by using an organic base to obtain an isomer III; and the structures of the three isomers are confirmed. The preparation method provided by the invention has the advantages of simple process, high yield, simple post-treatment and easy purification.

Description

Preparation method of tadalafil isomer

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of tadalafil isomers.

Background

Tadalafil (Tadalafil), chemical name: (6R,12aR) -6- (1, 3-benzodioxol-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1 ', 2': 1,6] pyrido [3,4-b ] indole-1, 4-dione, developed by American Provisions under the trade name of Hizili (Cialis), 11 months 2002, Tadalafil from Gift Inc. obtained from the European Union approved for the treatment of ED, first marketed in 2 months 2003 in various countries, such as the United kingdom, Sweden, Denmark, Germany and Australia; 11 months 2003, Tadalafil was approved by the FDA in the united states for the treatment of ED; on month 7, 2007, approval for PMDA in japan was obtained for marketing.

The structural formula is shown as formula 1-1:

the molecular structure of tadalafil has 2 chiral centers and contains 3 isomers, wherein one enantiomer II and two diastereomers I and III are shown as formulas 1-2:

structural formula of Tadalafil isomer of formula 1-2

The three isomers are particularly critical in the development and verification of tadalafil medicaments, play an important role in the whole isomer risk control, and can powerfully help the completion of research and development and production. However, the existing preparation method for the isomers has the problems of low yield, difficult purification, complex process and the like, and can not well meet the requirements of research and development and reference substances.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide a preparation method of tadalafil isomer, which has the advantages of simple process, high yield, simple post-treatment and easy purification.

In order to solve the problems, the technical scheme adopted by the invention is as follows:

a preparation method of tadalafil isomer I comprises the step of carrying out partial racemization on tadalafil and an aprotic strong polar solvent under the condition of an organic base to obtain the isomer I, wherein the formula is shown as follows:

preferably, the aprotic strongly polar solvent is one or a mixture of any two or more of DMF, DMSO and NMP.

Preferably, the organic base is one or a mixture of more than two of DMAP, DBU and triethylamine.

The invention also provides a preparation method of the tadalafil isomer II, which comprises the following steps:

firstly, mixing L-tryptophan and a chlorinating agent for esterification reaction to obtain a compound 1;

secondly, reacting the compound 1 with 3, 4-methylene dioxybenzaldehyde under the condition of an aprotic solvent to obtain a compound 2;

thirdly, reacting the compound 2 with chloroacetyl chloride under the condition of anhydrous tetrahydrofuran to obtain a compound 3;

fourthly, reacting the compound 3 with acetonitrile and methylamine aqueous solution to obtain an isomer II;

the synthetic route is as follows:

preferably, in the first step of reaction, the chlorinating agent is one or a mixture of two of oxalyl chloride and thionyl chloride.

Preferably, in the second step of reaction, the aprotic solvent is one or a mixture of any two or more of acetonitrile, DMF and THF.

Preferably, in the third step of reaction, the dropping temperature of the chloracetyl chloride is-5-10 ℃.

Preferably, in the fourth step of reaction, the concentration of the methylamine water solution is preferably 30-40%.

The invention also provides a preparation method of the tadalafil isomer III, which comprises the step of carrying out partial racemization on the isomer II and an aprotic strong polar solvent under the condition of organic base to obtain the isomer III, wherein the isomer III is shown as the following formula:

preferably, the aprotic strongly polar solvent is one or a mixture of any two or more of DMF, DMSO and NMP; the organic base is one or a mixture of more than two of DMAP, DBU and triethylamine.

Compared with the prior art, the invention has the beneficial effects that:

according to the invention, the isomer I is obtained by partial racemization purification of tadalafil, the isomer II is obtained by total synthesis of 4 steps with L-tryptophan as a raw material, the isomer III is obtained by partial racemization purification of the isomer II, the preparation processes can be monitored by HPLC and are easy to control, and the structures of the three isomers are confirmed, so that the obtained isomer has high optical purity, meets the requirements of research and development and comparison products, can effectively help research and development and production completion, and is beneficial to isomer risk control. The preparation method has simple and reliable process, high yield, simple post-treatment and easy purification.

Detailed Description

The present invention will be described in further detail with reference to specific embodiments.

All reagents and starting materials used in the following examples are commercially available.

Example 1: preparation of tadalafil isomer I

Tadalafil (3.9g, 0.01mol) was added to 40mL dimethylformamide, stirred for 10min, DMAP (1.2g, 0.01mol) was added, reacted at 80 ℃ for 6h, cooled to room temperature, crystallized for 1h, filtered, washed with acetone, and vacuum dried to give isomer I3.1 g, with a yield of 79.5%.

MS：m/z(％)＝390.5(M+H⁺)；

¹HNMR(DMSO-d₆，400MHz)δ：2.85(s,3H)，2.96(m,1H)，3.27(dd,1H)，4.05(d,1H)，4.09(dd,1H)，4.26(d,1H)，6.01(dd,2H)，6.62(dd,1H)，6.77(d,1H)，6.84(s,2H)，6.88(d,1H)，7.02(m,1H)，7.02(m,1H)，7.32(d,1H)，7.51(d,1H)，11.07(s,1H)。

Example 2: preparation of tadalafil isomer II

The synthetic route for tadalafil isomer II is shown below:

the first step of reaction: mixing L-tryptophan and a chlorinating agent for esterification reaction

Adding 100mL of anhydrous methanol and L-tryptophan (10g, 0.05mol), slowly dropwise adding thionyl chloride (7.1g, 0.06mol) at room temperature, keeping the temperature at 50 ℃ for reaction for 3 hours after the addition is finished, adding 100mL of isopropyl ether after the reaction is finished, cooling to 0-5 ℃, growing crystals for 1 hour, filtering, washing with isopropyl ether, and drying in vacuum to obtain 10.5g of compound 1, wherein the yield is 105%.

The second step of reaction: reacting compound 1 with 3, 4-methylene dioxybenzaldehyde under the condition of aprotic solvent

Adding anhydrous THF80mL, compound 1(10g, 0.04mol) and 3, 4-methylene dioxybenzaldehyde (6g, 0.04mol), refluxing for 10h, cooling to room temperature, cooling to 0-5 ℃, growing crystals for 1h, filtering, washing with THF, and vacuum drying to obtain 13.5g of compound 2 with the yield of 135%.

The third step of reaction: reacting compound 2 with chloroacetyl chloride under the condition of anhydrous tetrahydrofuran

Adding 100mL of anhydrous tetrahydrofuran, a compound 2(11.6g, 0.03mol) and triethylamine (3g, 0.03mol), cooling to 0-5 ℃, slowly dropwise adding chloroacetyl chloride (3.4g, 0.03mol), heating to room temperature to react for 2h after the dropwise adding is finished, concentrating a half solvent under reduced pressure, growing crystals at room temperature for 1h, filtering, washing with tetrahydrofuran, and drying in vacuum to obtain 11.0g of a compound 3, wherein the yield is 94.8%.

And a fourth step of reaction: reaction of Compound 3 with aqueous acetonitrile and methylamine

Adding 90mL of acetonitrile and a compound 2(8.5g, 0.02mol), slowly dropwise adding 20mL of methylamine water solution at room temperature, keeping the temperature at 50 ℃ for reaction for 3h, reducing the temperature to room temperature, decompressing and concentrating about one third of the solvent, stirring at room temperature for crystal growth for 1h, filtering, washing with acetonitrile, and performing vacuum drying to obtain 6.8g of an isomer II with the yield of 80%.

MS：m/z(％)＝390.5(M+H⁺)；

¹HNMR(DMSO-d₆，400MHz)δ：2.93(s,3H)，2.99(m,1H)，3.52(dd,1H)，3.94(d,1H)，4.18(dd,1H)，4.39(dd,1H)，5.92(s,2H)，6.14(s,1H)，6.78(m,2H)，6.87(s,1H)，7.00(m,1H)，7.06(m,1H)，7.30(d,1H)，7.54(d,1H)，11.01(s,1H)。

Example 3: preparation of tadalafil isomer III

Adding the isomer II (3.9g, 0.01mol) into 40mL of dimethylformamide, stirring for 10min, adding DMAP (1.2g, 0.01mol), reacting at 80 ℃ for 6h, cooling to room temperature, growing crystals for 1h, filtering, washing with acetone, and drying in vacuum to obtain the isomer III 3.0g, wherein the yield is 76.9%.

MS：m/z(％)＝390.5(M+H+)；

¹HNMR(DMSO-d₆，400MHz)δ：2.86(s,3H)，2.95(m,1H)，3.27(dd,1H)，4.04(d,1H)，4.09(dd,1H)，4.25(d,1H)，6.01(d,2H)，6.62(dd,1H)，6.77(d,1H)，6.84(s,1H)，6.87(d,1H)，7.03(m,1H)，7.02(m,1H)，7.11(m,1H)，7.32(d,1H)，7.51(d,1H)，11.04(s,1H)。

The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.

Claims

1. A preparation method of tadalafil isomer is characterized by comprising the following steps: carrying out partial racemization on tadalafil and an aprotic strong polar solvent under the condition of an organic base to obtain an isomer I, which is shown as the following formula:

wherein the aprotic strongly polar solvent is DMF; the organic base is DMAP.

2. A preparation method of tadalafil isomer is characterized by comprising the following steps: carrying out partial racemization on the isomer II and an aprotic strong polar solvent under the condition of organic base to obtain an isomer III; isomers II and III are each represented by the following formula:

wherein the aprotic strongly polar solvent is DMF; the organic base is DMAP.