阅读说明：本技术 一种巴洛沙韦酯中间体的合成方法 (Synthesis method of baroxavir pivoxil intermediate ) 是由 资春鹏 曾亮 王云春 于 2021-01-29 设计创作，主要内容包括：本发明公开了一种巴洛沙韦酯中间体的合成方法,以7,8-二氟二苯并[B,E]噻吩-11(6H)-酮为原料,采用氯(R,R)-N-(对甲苯磺酰)-1,2-二苯基乙二胺(氯)(对丙基甲苯)钌(II)或氯(S,S)-N-(对甲苯磺酰)-1,2-二苯基乙二胺(氯)(对丙基甲苯)钌(II)催化,将其羰基还原成手性醇,得到了手性7,8-二氟-6,11-二氢二苯并[b,e]硫杂卓-11-醇作为合成巴洛沙韦酯的中间体,采用该中间体合成的巴洛沙韦酯的光学纯度≥98.0％,减少了后续纯化,提高了收率,降低了成本,更加适用于商业化生产。(The invention discloses a synthesis method of a baroxavir ester intermediate, which takes 7, 8-difluorodibenzo [ B, E ] thiophene-11 (6H) -ketone as a raw material, adopts chlorine (R, R) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chlorine) (p-propyltoluene) ruthenium (II) or chlorine (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chlorine) (p-propyltoluene) ruthenium (II) as a catalyst to reduce carbonyl thereof into chiral alcohol, obtains chiral 7, 8-difluoro-6, 11-dibenzo [ B, E ] thiazepine-11-alcohol as an intermediate for synthesizing baroxavir ester, adopts the optical purity of the baroxavir ester synthesized by the intermediate to be more than or equal to 98.0 percent, reduces subsequent purification, the yield is improved, the cost is reduced, and the method is more suitable for commercial production.)

1. A synthetic method of a Baroswarriol ester intermediate is characterized in that the intermediate is chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepin-11-alcohol, 7, 8-difluorodibenzo [ B, E ] thiophene-11 (6H) -ketone is used as a raw material, and carbonyl is reduced into chiral alcohol under the catalytic action of a metal catalyst to obtain an R-configuration or S-configuration intermediate.

2. The method for synthesizing a baroxavir ester intermediate as claimed in claim 1, wherein the metal catalyst is chloro (R, R) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chloro) (p-propyltoluene) ruthenium (II), and the R-configuration intermediate is obtained by the following reaction:

3. the method for synthesizing a baroxavir ester intermediate as claimed in claim 1, wherein the metal catalyst is chloro (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chloro) (p-propyltoluene) ruthenium (II), and the reaction is carried out as follows to obtain an intermediate with S-configuration:

Technical Field

The invention relates to the field of medicine synthesis, in particular to a synthesis method of a baroxavir ester intermediate.

Background

The chemical name of the Baloxavir disoproxil (Baloxavir Marboxil) is ({ (12aR) -12- [ (11S) -7, 8-difluoro-6, 11-dihydrodiphenylAnd [ b, e ]]Thiepin-11-yl]-6, 8-dioxo-3, 4,6,8,12,12 a-hexahydro-1H- [1,4]Oxazino [3,4-c]Pyrido [2,1-f][1,2,4]Triazine-7-yl } oxy) methyl carbonate is a new drug for influenza A and B viruses discovered by Japanese salt wild-sense pharmacy (Shionogi Co) and developed together with Roche (Roche), and is firstly approved by PMDA on 23 days 2-24 days 2018 and then approved by FDA on 24 days 10-24 days the same year for marketing in Japan

The baloxavir disoproxil is a single-dose oral medicament, is used for treating acute and non-complication influenza of patients of 12 years old or more, is an initial single-dose oral medicament, and has a brand-new anti-influenza action mechanism different from other antiviral medicaments in the market. The medicine is an endonuclease inhibitor, and aims to inhibit CAP CAP structure-dependent endonuclease in influenza virus, which is essential for replication of influenza virus. In clinical tests, the duration of influenza symptoms can be greatly reduced by single treatment of the baroxavir disoproxil, virus discharge is obviously reduced in only one day, the treatment effect is obvious, and the method has a wide market prospect.

However, in the synthesis process of the baclovir ester, as the 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol is racemic, optical isomers are inevitably generated although the docking reaction has certain chiral selectivity, and the subsequent purification causes the yield reduction and the material waste, thereby increasing the cost.

Disclosure of Invention

Aiming at the problems, the invention provides a synthesis method of a baroxavir ester intermediate, which has the advantages of simple and convenient operation, low cost, high optical purity and easy commercial production.

The technical scheme of the invention is as follows:

a synthetic method of a Baroswarriol intermediate is characterized in that the intermediate is chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepin-11-alcohol, 7, 8-difluoro dibenzo [ B, E ] thiophene-11 (6H) -ketone is used as a raw material, and carbonyl is reduced into chiral alcohol under the catalytic action of a metal catalyst to obtain an R-configuration or S-configuration intermediate.

The synthesis method comprises the following specific steps:

mixing triethylamine and formic acid at a low temperature, adding 7, 8-difluorodibenzo [ B, E ] thiophene-11 (6H) -ketone and tetrahydrofuran, uniformly stirring, protecting with nitrogen, adding a metal catalyst, heating to 60-70 ℃ for complete reaction, cooling to room temperature, adding ethyl acetate and water, stirring, separating, concentrating under reduced pressure by an organic phase to obtain chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepin-11-ol with an R-configuration or an S-configuration, and detecting a chiral detection spectrum of a product.

In a further technical scheme, the metal catalyst is chlorine (R, R) -N- (p-toluenesulfonyl) -1, 2-diphenyl ethylene diamine (chlorine) (p-propyltoluene) ruthenium (II), and an R-configuration intermediate is obtained by the following reaction:

in a further technical scheme, the metal catalyst is chlorine (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenyl ethylene diamine (chlorine) (p-propyltoluene) ruthenium (II), and an intermediate with an S-configuration is obtained by the following reaction:

the invention has the beneficial effects that:

according to the invention, 7, 8-difluorodibenzo [ B, E ] thiophene-11 (6H) -ketone is used as a raw material, a metal catalyst is used for catalyzing and reducing carbonyl of the raw material into chiral alcohol, so that the chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepine-11-alcohol is obtained and is used as an intermediate for synthesizing the bacloshavir ester, the optical purity of the bacloshavir ester synthesized by the intermediate is more than or equal to 98.0%, the subsequent purification is reduced, the yield is improved, the cost is reduced, and the method is more suitable for commercial production.

Drawings

FIG. 1 is a reaction scheme for the synthesis of chiral R-configured baclovir ester intermediate in example 1 of the present invention;

FIG. 2 is a chiral detection spectrum of a chiral intermediate of R-configured baclovir hydrochloride in example 1;

FIG. 3 is a reaction scheme for the synthesis of S-configuration chiral intermediates of baclovir disoproxil in example 2 of the present invention;

FIG. 4 is a chiral detection pattern of the S-configuration chiral intermediate of Baroswarriol ester in example 2 of the present invention;

FIG. 5 is a structural formula of Baroswarriol ester according to an embodiment of the present invention;

FIG. 6 is a chiral detection spectrum of 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol of the baculovir dipivoxil intermediate racemate in comparative example 1;

figure 7 is a reaction scheme for the synthesis of baclofloxacin ester according to comparative example 1 of the present invention.

Detailed Description

The embodiments of the present invention will be further described with reference to the accompanying drawings.

Example 1:

a synthetic method of a Barlow Savir ester intermediate takes 7, 8-difluorodibenzo [ B, E ] thiophene-11 (6H) -ketone as a raw material, adopts chlorine (R, R) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chlorine) (p-propyltoluene) ruthenium (II) as a catalyst, reduces carbonyl in a structure of the raw material into chiral alcohol, obtains R-configuration chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepine-11-alcohol, and takes the chiral alcohol as an intermediate for synthesizing Barlow Savir ester, wherein the reaction formula is as follows:

the synthesis method specifically comprises the following steps:

mixing triethylamine and formic acid at low temperature, adding 7, 8-difluorodibenzo [ B, E ] thiophene-11 (6H) -ketone and tetrahydrofuran, stirring uniformly, protecting with nitrogen, adding chlorine (R, R) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chlorine) (p-propyltoluene) ruthenium (II), heating to 60-70 ℃ for reaction to be complete, cooling to room temperature, adding ethyl acetate and water, stirring, separating, concentrating under organic phase reduced pressure to obtain chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepin-11-ol with R-configuration, wherein the optical purity ee value is 98.62%, and the chiral detection spectrum is shown in figure 2.

Example 2:

in this example, 7, 8-difluorodibenzo [ B, E ] thiophen-11 (6H) -one was also used as a raw material, and carbonyl groups in the structure were reduced to chiral alcohols using chloro (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chloro) (p-propyltoluene) ruthenium (II) as a catalyst, to obtain S-configured chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepin-11-ol, which was used as an intermediate for synthesizing bacloxavir ester, according to the following reaction formula:

the synthesis method specifically comprises the following steps:

mixing triethylamine and formic acid at low temperature, adding 7, 8-difluorodibenzo [ B, E ] thiophene-11 (6H) -ketone and tetrahydrofuran, stirring uniformly, protecting with nitrogen, adding chlorine (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (chlorine) (p-propyltoluene) ruthenium (II), heating to 60-70 ℃ for reaction to be complete, cooling to room temperature, adding ethyl acetate and water, stirring, separating, concentrating organic phase under reduced pressure to obtain chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ B, E ] thiazepin-11-ol with S-configuration, wherein the optical purity ee value is 99.65%, and the chiral detection spectrum is shown in figure 4.

Comparative example 1:

japanese patent JP6212678B1 discloses a process for the preparation of baclovir hydrochloride which comprises condensing racemic 7, 8-difluoro-6, 11-dihydrodibenzo [ B, e ] thiazepin-11-ol with (12AR) -7- (hexyloxy) -3,4,12,12A tetrahydro-1H- [1,4] oxazino [3,4-C ] pyrido [2,1-F ] [1,2,4] triazine-6, 8-dione tosylate, deprotecting and reacting with methyl chloroformate carbonate to obtain baclovir hydrochloride, wherein the synthetic route is as follows:

in the synthetic route, as 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol is used as a racemate, and a chiral detection spectrum of the racemate is shown in fig. 6, although the racemate has certain chiral selectivity in the butt-joint reaction, optical isomers are inevitably generated, the yield is reduced due to subsequent purification, and materials are wasted, so that the cost is increased.

Comparative example 2:

chinese patent CN109504721A discloses a method for preparing chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol by using ketoreductase catalysis, and the used enzyme is expensive and is not suitable for commercial production.

Comparative example 3:

chinese patent CN110143944A discloses a method for obtaining chiral 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol by catalyzing with S-CBS or R-CBS and reducing with borane, but the obtained chiral purity is lower.

The above-mentioned embodiments only express the specific embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.