Unlock instant, AI-driven research and patent intelligence for your innovation.

A kind of preparation method of tadalafil isomer

A technology of tadalafil and isomers, applied in the field of drug synthesis, can solve problems such as complex procedures, difficult purification, and low yield, and achieve the effects of high optical purity, easy purification, and high yield

Active Publication Date: 2020-05-26
ZHUHAI UNITED LAB
View PDF1 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current preparation methods for the above isomers have problems such as low yield, difficult purification, and complicated procedures, which cannot well meet the needs of research and development and reference substances

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of preparation method of tadalafil isomer
  • A kind of preparation method of tadalafil isomer
  • A kind of preparation method of tadalafil isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: the preparation of tadalafil isomer I

[0033] Add tadalafil (3.9g, 0.01mol) into 40mL of dimethylformamide, stir for 10min, add DMAP (1.2g, 0.01mol), react at 80°C for 6h, cool down to room temperature, and grow crystals for 1h , filtered, washed with acetone, and dried in vacuo to obtain 3.1 g of Isomer I with a yield of 79.5%.

[0034] MS: m / z(%)=390.5(M+H + );

[0035] 1 HNMR (DMSO-d 6 , 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).

Embodiment 2

[0036] Embodiment 2: the preparation of tadalafil isomer II

[0037] The synthetic route of tadalafil isomer II is as follows:

[0038]

[0039] The first step reaction: L-tryptophan is mixed with chlorination reagent for esterification reaction

[0040] Add 100 mL of anhydrous methanol and L-tryptophan (10 g, 0.05 mol), slowly add thionyl chloride (7.1 g, 0.06 mol) dropwise at room temperature, after the addition is complete, keep the reaction at 50°C for 3 h, and then add iso 100 mL of propyl ether was cooled to 0-5°C, grown for 1 h, filtered, washed with isopropyl ether, and dried in vacuo to obtain 10.5 g of compound 1 with a yield of 105%.

[0041] The second step reaction: Compound 1 reacts with 3,4-methylenedioxybenzaldehyde in an aprotic solvent

[0042] Add 80 mL of anhydrous THF, compound 1 (10 g, 0.04 mol), 3,4-methylenedioxybenzaldehyde (6 g, 0.04 mol), reflux for 10 h, cool down to room temperature, cool to 0-5 ° C, and grow crystals for 1 h , filtered, wash...

Embodiment 3

[0049] Embodiment 3: Preparation of Tadalafil Isomer III

[0050] Add Isomer II (3.9g, 0.01mol) to 40mL of dimethylformamide, stir for 10min, add DMAP (1.2g, 0.01mol), react at 80°C for 6h, cool down to room temperature, grow crystals for 1h, Filtration, washing with acetone, and vacuum drying gave 3.0 g of Isomer III with a yield of 76.9%.

[0051] MS: m / z(%)=390.5(M+H+);

[0052] 1 HNMR (DMSO-d 6, 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 structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a preparation method of a Tadalafil isomer, and belongs to the technical field of drug synthesis. The preparation method comprises the following steps: placing Tadalafil into anon-proton strong polar solvent, and performing partial racemization by using an organic base to obtain an isomer I; performing total synthesis on L-tryptophan serving as a raw material through a four-step reaction to obtain an isomer II; placing the isomer II into the non-proton strong polar solvent, and performing partial racemization by using an organic base to obtain an isomer III; performingstructure confirmation on the three isomers. The preparation method provided by the invention has the advantages of simple procedure, high yield, easiness in post-treatment and easiness in purification.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of tadalafil isomers. Background technique [0002] Tadalafil, chemical name: (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, developed by Eli Lilly and Company, trade name is Cialis (Cialis), in November 2002, Eli Lilly's Tadalafil was approved by the European Union for the treatment of ED, and in February 2003, it was first listed in the United Kingdom, Sweden, Denmark, Germany, Australia and other countries; in November 2003, the United States FDA approved Tadalafil for the treatment of ED; in July 2007, it was approved for marketing by PMDA in Japan. [0003] The structural formula is shown in Formula 1-1: [0004] There are 2 chiral centers in the molecular structure of tadalafil, which contains 3 isomers, including one enantiomer II and two diastereomers I and III, as sho...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 刘宏宇乔明福许华锋窦振国
Owner ZHUHAI UNITED LAB