CN108069933B

CN108069933B - Synthetic method of sofosbuvir intermediate

Info

Publication number: CN108069933B
Application number: CN201611010943.8A
Authority: CN
Inventors: 秦勇; 陈悦
Original assignee: Shanghai Xipu Medicine Technology Co ltd
Current assignee: Shanghai Xipu Medicine Technology Co ltd
Priority date: 2016-11-10
Filing date: 2016-11-10
Publication date: 2020-06-02
Anticipated expiration: 2036-11-10
Also published as: CN108069933A

Abstract

The invention provides a synthesis method of Sofosbuvir intermediate (2E) -3- [ (4S) -2, 2-dimethyl-1, 3-dioxolane-4-yl ] -2-methyl-2-ethyl acrylate, which is obtained by taking (R) -epoxy chloropropane as a raw material, performing acetonide protection, triethyl phosphite phosphonylation and finally reacting with ethyl pyruvate.

Description

Synthetic method of sofosbuvir intermediate

Technical Field

The invention relates to the field of medicine synthesis, and in particular relates to a synthetic method of a sofosbuvir intermediate (2E) -3- [ (4S) -2, 2-dimethyl-1, 3-dioxolane-4-yl ] -2-methyl-2-ethyl acrylate.

Background

Hepatitis c is a liver disease caused by hepatitis c virus, and like hepatitis b, it also causes cirrhosis or liver cancer, threatening the health of many infected persons. The World Health Organization (WHO) recent statistics show that 1.3 to 1.5 million people worldwide have chronic hepatitis c infection. It is estimated that 80% of patients infected with hepatitis c develop chronic infection. In chronic hepatitis c, 20% of patients develop cirrhosis of the liver, and 25% of patients may develop liver cancer. Between 35 and 50 million people die each year from liver disease associated with hepatitis c. Hepatitis c virus is a blood-borne virus, and the most common modes of infection include unsafe medical procedures and sexual transmission. Antiviral drugs are always used for treating hepatitis C all over the world, but the problems of low cure rate, long treatment course, easy occurrence of drug side effects and the like still exist.

Sofosbuvir (Sofosbuvir) is a newly developed anti-hepatitis c drug by gilise, and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Chronic Hepatitis C (CHC) infection 12-6 days 2013. Sofosbuvir is an inhibitor of NS5B polymerase, which acts on the viral RNA polymerase to inhibit RNA synthesis and thereby block viral replication. The FDA has approved sofosbuvir in combination with ribavirin for the treatment of adult patients with genotype 2 and genotype 3 chronic hepatitis c. Sofosbuvir is therefore the first global full-oral combination therapy for treating hepatitis c without simultaneously using interferon, and it can be said that sofosbuvir and its combination drug are the most effective drugs for treating hepatitis c at present. Since the birth date, the Sofosbuvir tablets become the focus of industry attention, and the 2014-2016 continuous three-year sales amount exceeds 100 billion dollars, so that the Sofosbuvir tablets have a wide market prospect, and therefore, the upstream key intermediate of the Sofosbuvir also faces huge market demands. However, the pricing of Sofosbuvir tablets of $ 8.4 million per treatment ($ 1000/tablet) is also subject to dispute from each party.

In the prior art, methods for preparing sofosbuvir have been reported in many reports, for example, the synthetic route of sofosbuvir in patent WO2008045419 is as follows:

the compound A, the compound B and the compound C are important raw materials and intermediates necessary for synthesizing the sofosbuvir, and the chemical names of the compounds are as follows:

a compound A: (R) - (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde;

compound B: (2E) -ethyl 3- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] -2-methyl-2-acrylate;

compound C: (2S, 3R) -3- [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] -2, 3-dihydroxy-2-methylpropionic acid ethyl ester.

The current preparation of compound B and compound C is as follows US 20150284351:

the initial raw material is mannitol, the price is cheap and easy to obtain, but the defects are obvious: (1) the price of sodium periodate (KIO4) is very high, which directly restricts the cost of the compound A and the compound B; in the route, the purity of the compound B synthesized from the compound A is insufficient, so that the purity and the quality of the compound C are greatly influenced, and the influence of high price on downstream bulk drugs is caused.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a synthetic method of sofosbuvir intermediate (2E) -3- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] -2-methyl-2-ethyl acrylate.

In order to achieve the purpose, the invention is realized by the following technical scheme:

a compound of formula (I):

the synthetic method of the sofosbuvir intermediate comprises the following steps:

(1) taking (R) -epichlorohydrin (II) as a raw material, reacting with acetone, and generating an intermediate product (III) through acetone fork protection;

(2) carrying out phosphonylation reaction on the intermediate product (III) and triethyl phosphite to generate an intermediate product (IV);

(3) under the action of alkali, reacting the intermediate product (IV) with ethyl pyruvate to obtain a target product: the intermediate compound (2E) -3- [ (4S) -2, 2-dimethyl-1, 3-dioxolane-4-yl ] -2-methyl-2-ethyl acrylate of sofosbuvir is shown as a formula (I).

Preferably, the reaction temperature in the step (1) is-15 to 10 ℃, and the reaction time is 12 to 36 hours.

Preferably, the reaction temperature of the step (2) is 60-70 ℃, and the reaction time is 12-36 h.

Preferably, the reaction temperature of the step (3) is-10 to 25 ℃, and the reaction time is 12 to 36 hours.

Preferably, the base in step (3) is selected from one of sodium methoxide, sodium ethoxide and potassium tert-butoxide.

Compared with the prior art, the invention has the following advantages: the (R) -epichlorohydrin is used as a raw material, is cheap and easy to obtain, and other raw materials are conventional products in the market, so that the industrial production cost is greatly reduced, the production cost of the intermediate (2E) -3- [ (4S) -2, 2-dimethyl-1, 3-dioxolane-4-yl ] -2-methyl-2-ethyl acrylate can be reduced by more than 30%, the cost of downstream raw material medicines is reduced, and meanwhile, the prepared target product has high purity, is beneficial to stable production of downstream intermediate products, and has great industrial production prospect.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1: synthesis of intermediate (III)

Adding 300mL of acetone and 0.3mL of boron trifluoride diethyl etherate into a clean 500mL three-necked bottle, stirring, cooling to 0 ℃, slowly dropwise adding 18.5g of (R) -epichlorohydrin into the three-necked bottle, reacting for 13h after dropwise adding within 30min, stopping the reaction, evaporating the acetone, and distilling under reduced pressure to obtain a pure product 24g with the yield of 80%.

Example 2: synthesis of Intermediate (IV)

Adding 200mL of triethyl phosphite into a clean 500mL three-neck flask, adding 24g of the intermediate product (III), heating to 65 ℃, refluxing for 24h, stopping the reaction, distilling to remove excessive triethyl phosphite, and purifying the residual liquid in the three-neck flask by a silica gel column to obtain 36.2g of the product with the yield of 89.2%.

Example 3: synthesis of intermediate (I)

Adding the intermediate product (IV) into 500mL of toluene, cooling to 0 ℃, adding 18g of potassium tert-butoxide in batches, stirring for 30min, dropwise adding 17g of ethyl pyruvate into the mixture, controlling the reaction temperature to be 0-5 ℃, reacting for 12h after the dropwise addition is finished, stopping the reaction, cooling to 5 ℃, dropwise adding 2N hydrochloric acid to adjust the pH to 6-7, adding 300mL of water, stirring for layering, washing an organic layer with water, drying, concentrating, and distilling to obtain 24g of an intermediate product (I) pure product, wherein the yield is 79.1% and the purity is 99.82%. 1H-NMR (400Hz, CDCl3), δ 6.66(dd, J6.8, 8.0Hz, 1H), 4.81-4.86(m, 1H), 4.11-4.21(m, 3H), 3.60(t, J8.4 Hz, 1H), 1.87(d, J1.2 Hz, 3H), 1.43 (s, 3H), 1.38(s, 3H), 1.27(t, J6.8 Hz, 3H).

It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising an … …" does not exclude the presence of other identical elements in a process, method, article, or apparatus that comprises the element.

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. A compound of formula (I):

the synthetic method of the sofosbuvir intermediate is characterized in that the synthetic route is as follows:

the method comprises the following steps:

(1) taking (R) -epichlorohydrin (II) as a raw material, reacting with acetone, and generating an intermediate product (III) through acetonylidene protection;

(3) under the action of alkali, reacting the intermediate product (IV) with ethyl pyruvate to obtain a target product: the sofosbuvir intermediate compound (2E) -3- [ (4S) -2, 2-dimethyl-1, 3-dioxolane-4-yl ] -2-methyl-2-ethyl acrylate shown in the formula (I) is prepared, wherein the base in the step (3) is selected from one of sodium methoxide, sodium ethoxide and potassium tert-butoxide.

2. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, wherein the reaction temperature in the step (1) is-15 to 10 ℃ and the reaction time is 12 to 36 hours.

3. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, wherein the reaction temperature in the step (2) is 60-70 ℃ and the reaction time is 12-36 h.

4. The synthesis method of the sofosbuvir intermediate as claimed in claim 1, wherein the reaction temperature in the step (3) is-10 to 25 ℃ and the reaction time is 12 to 36 hours.