CN103159730A

CN103159730A - Hepatitis-C-resisting drug intermediate preparation method

Info

Publication number: CN103159730A
Application number: CN 201110425505
Authority: CN
Inventors: 祁小伟; 汪秀菊; 孟磊; 龚彦春; 袁方
Original assignee: Jiangsu Vcare Pharmatech Co Ltd
Current assignee: Jiangsu Vcare Pharmatech Co Ltd
Priority date: 2011-12-19
Filing date: 2011-12-19
Publication date: 2013-06-19

Abstract

The invention provides a hepatitis-C-resisting drug intermediate preparation method, and relates to a preparation method of (2S, 3R)-3-((R)-2, 2-dimethyl-1, 3-dioxolame-4-base)-2, 3-dyhydroxyl-2-methyl propionic acid methyl ester. The method includes the following steps that: (1) (R)-2, 2-dimethyl-1, 3-dioxolame-4-methanal and 2-(triphenylphosphine alkene)-methyl propionate are subjected to a Wittig reaction to produce (S, E)-3-(2, 2-dimethyl-1, 3-dioxolame-4-goup)-2-methyl methacrylate; (2) a product of the step (1) is subjected to a dihydroxylation to obtain the target compound. The method is simple and convenient to operate, and suitable for industrial production.

Description

A kind of method for preparing anti-the third liver pharmaceutical intermediate

Technical field

The present invention relates to pharmacy field, be specifically related to (2S, 3R)-3-((R)-2,2-dimethyl-DOX-4-yl)-2, the preparation method of 3-dihydroxyl-2 Methylpropionic acid methyl esters.

Background technology

In several new drugs that treatment hepatitis C virus (HCV) infects, PSI-7977 is considered to have extraordinary DEVELOPMENT PROSPECT, and this medicine is in the II phase clinical study stage at present.Sofia etc. are published in J.Med.Chem.2010, disclose the structure (compound 51) of PSI-7977 in the article of 53,7202-7218.

(2S, the 3R)-3-of formula (I) ((R)-2,2-dimethyl-DOX-4-yl)-2,3-dihydroxyl-2 Methylpropionic acid methyl esters are the useful intermediates of preparation PSI-7977.The invention discloses the method for a kind of preparation formula (I), the method reaction conditions is gentle, is suitable for suitability for industrialized production.

Summary of the invention

The invention provides the preparation method of a kind of formula (I) compound, be shown below:

Aforesaid method specifically comprises the following steps:

(1) with (R)-2 of formula (II), 2-dimethyl-1,2 (triphenylphosphine alkene)-methyl propionates of 3-dioxolane-4-formaldehyde and formula (III) are through (the S of Wittig reaction production (IV), E)-3-(2,2-dimethyl-DOX-4-yl)-2-methyl methacrylate;

(2) formula (IV) compound is carried out dihydroxylation reaction, make formula (I) compound.

In above-mentioned steps (1), the solvent that adopts can be aprotic solvent or any mixed solvents wherein such as tetrahydrofuran (THF), acetonitrile, dioxan, methylene dichloride, ether, acetone, toluene, more preferably methylene dichloride; The temperature of reaction that adopts is-78～40 ℃, more preferably-5～5 ℃.

In above-mentioned steps (2), the dihydroxylation oxygenant that adopts can be potassium permanganate, Manganse Dioxide or hydrogen peroxide, preferred potassium permanganate; Preferred 1: 4 of the mol ratio of formula IV compound and oxygenant, more preferably 1: 1～1.2; The solvent that adopts can be the mixed solvent of acetone, tetrahydrofuran (THF) or acetonitrile and water, and the volume ratio of preferred acetone and water is 9: 1, and the weightmeasurement ratio of raw material and mixed solvent is 1: 10; The temperature of reaction that adopts is-20～40 ℃, more preferably-5～5 ℃.

Description of drawings

Fig. 1 is (2S, 3R)-3-((R)-2,2-dimethyl-DOX-4-yl)-2, the proton nmr spectra of 3-dihydroxyl-2 Methylpropionic acid methyl esters;

Fig. 2 is (2S, 3R)-3-((R)-2,2-dimethyl-DOX-4-yl)-2, the mass spectrum of 3-dihydroxyl-2 Methylpropionic acid methyl esters.

Embodiment

Further describe by the following examples the present invention, summary of the invention comprises but is not limited to concrete embodiment.

Embodiment 1

The preparation of (S, E)-3-(2,2-dimethyl-DOX-4-yl)-2-methyl methacrylate

At room temperature, 2-(triphenylphosphine alkene)-methyl propionate (6.3kg) is dissolved in methylene dichloride (20L), 0-5 ℃ slowly drips (R)-2,2-dimethyl-1, methylene dichloride (6L) solution of 3-dioxolane-4-formaldehyde (2.5kg), dropwise, naturally rise to room temperature, reacted 4 hours.Reaction solution is concentrated into dried, adds sherwood oil (40L) under stirring, have a large amount of white solids to separate out, suction filtration obtains crude product (S, E) 3 (2,2 dimethyl-1,3 dioxolane-4-yl)-2-methyl methacrylate (4.1kg), not purified next step reaction of direct input.

Embodiment 2

(2S, 3R)-3-((R)-2,2-methyl isophthalic acid, 3-dioxolane-4-yl)-2, the preparation of 3-dihydroxyl-2 Methylpropionic acid methyl esters

With (S, E) 3 (2,2 dimethyl-1,3 dioxolane 4 bases) 2 methyl methacrylates (4.1kg) are dissolved in the mixing solutions of acetone (37L) and water (4.1L), add potassium permanganate (3.87kg) in the time of 05 ℃ in batches, control temperature and be no more than 20 ℃, add insulation 4 hours.Add solid sodium sulfite (4kg) and water (15L) in reaction solution, stirred 30 minutes.Suction filtration, filter cake respectively washs once with 2L acetone and 2L water.Filtrate decompression is concentrated into acetone and substantially removes, and adds solid sodium chloride to saturated in residual solution, then uses ethyl acetate (8LX3) extraction.Merge organic layer, concentrated, get colourless liquid (2.5kg), under stirring, this liquid is poured in water (12L), crystallization, suction filtration, filter cake discards, filtrate, add solid sodium chloride to saturated, then use ethyl acetate (6LX3) extraction, merge organic layer, concentrate to get white solid 2kg.Under 55 ℃, with the mixed solvent recrystallization of ethyl acetate (4L) and sherwood oil (16L), be cooled to 0-5 ℃ and kept 4 hours, suction filtration, washing, the filter cake oven dry gets (2S, 3R)-3-((R)-2,2-dimethyl-DOX-4-yl)-2,3-dihydroxyl-2 Methylpropionic acid methyl esters (980g), white solid, purity is more than 99%.HNMR(300MHz，DMSO-d6)δ5.16(1H，d，J＝9Hz)，5.01(1H，s)，4.13(1H，m)，3.89(2H，m)，3.67(1H，m)，3.62(3H，s)，1.29(3H，s)，1.27(3H，s)，1.25(3H，s).

Claims

1. one kind prepares (2S, the 3R)-3-shown in compound formula (I) ((R)-2,2-dimethyl-DOX-4-yl)-2, the method for 3-dihydroxyl-2 Methylpropionic acid methyl esters:

Specifically comprise the steps:

(1) with (R)-2 of formula (II), 2-dimethyl-1, the 2-of 3-dioxolane-4-formaldehyde and formula (III) (triphenylphosphine alkene)-methyl propionate is through (the S of Wittig reaction production (IV), E)-3-(2,2-dimethyl DOX-4-yl)-2-methyl methacrylate:

2. preparation method according to claim 1, it is characterized in that, in the step (1) of claim 1, the solvent that adopts can be aprotic solvent or any mixed solvents wherein such as tetrahydrofuran (THF), acetonitrile, dioxan, methylene dichloride, ether, acetone, toluene, more preferably methylene dichloride.

3. according to claim 1 with 2 described preparation methods, is characterized in that, in the step (1) of claim 1, the temperature of reaction that adopts is-78～40 ℃, more preferably-5～5 ℃.

4. preparation method according to claim 1, is characterized in that, in the step (2) of claim 1, the dihydroxylation oxygenant that adopts can be potassium permanganate, Manganse Dioxide or hydrogen peroxide, preferred potassium permanganate; Preferred 1: 4 of the mol ratio of formula IV compound and oxygenant, more preferably 1: 1～1.2.

5. preparation method according to claim 1, it is characterized in that, in the step (2) of claim 1, the solvent that adopts can be the mixed solvent of acetone, tetrahydrofuran (THF) or acetonitrile and water, the volume ratio of preferred acetone and water is 9: 1, and the weightmeasurement ratio of raw material and mixed solvent is 1: 10.

6. preparation method according to claim 1, is characterized in that, in the step (2) of claim 1, the temperature of reaction that adopts is-20～40 ℃, more preferably-5～5 ℃.

7. (2S, the 3R)-3-shown in compound formula (I) ((R)-2,2-dimethyl-DOX-4-yl)-2,3-dihydroxyl-2 Methylpropionic acid methyl esters: