阅读说明：本技术 一种替格瑞洛重要中间体的制备方法 (Preparation method of ticagrelor important intermediate ) 是由 稂琪伟 高爽 丁小兵 于 2020-09-11 设计创作，主要内容包括：本发明属于医药合成技术领域,涉及一种替格瑞洛重要中间体的制备方法,具体涉及一种替格瑞洛重要中间体(S)-2-氯-1-(3,4-二氟苯基)乙醇的合成制备方法,由2-氯-1-(3,4-二氟苯基)乙-1-酮(II),在特定催化剂下转移氢化制备得到(S)-2-氯-1-(3,4-二氟苯基)乙醇(III)。本发明通过发展高效、绿色、高立体选择性的方法和工艺,提高替格瑞洛中间体的合成效率。(The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of an important intermediate of ticagrelor, in particular to a synthesis preparation method of (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol which is an important intermediate of ticagrelor. The synthesis efficiency of the ticagrelor intermediate is improved by developing a method and a process which are efficient, green and high in stereoselectivity.)

1. A preparation method of an important intermediate of ticagrelor is characterized in that a synthetic route comprises the following steps:

specifically, the structure of the catalyst used in the transfer hydrogenation process is shown below:

in catalyst cat. X, R₁Selected from hydrogen (H), methyl (Me), trifluoromethyl (CF)₃) Fluorine (F); r₂Selected from the group consisting of p-toluenesulfonyl (Ts), methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), camphor-10-sulfonyl (Cs).

2. The process according to claim 1, wherein the catalyst used has the following structure in the transfer hydrogenation:

3. the process according to claim 1 or2, wherein the solvent of the catalyst used in the transfer hydrogenation is selected from EtOAc, CH₂Cl₂、ClCH₂CH₂Cl、MeOH、EtOH、ⁱPrOH、(HOCH₂)₂、THF、PhMe。

4. The process according to claim 1 or2, wherein the catalyst used as hydrogen source in the transfer hydrogenation is selected from HCOOH/Et₃N、HCOOH/DIPEA、HCOOH/ⁱPr₂NH、HCOOH/Et₂NH、HCOOH/HCOOK、HCOOH/HCOONa。

5. The process according to claim 1 or2, wherein the solvent is preferably an alcoholic solvent, more preferably EtOH, or EtOH/H in a volume ratio of 1:1₂O, or MeOH, the hydrogen source being selected from HCOOH/Et in a molar ratio of 5:2₃N、HCOOH/DIPEA、HCOOH/ⁱPr₂NH、HCOOH/Et₂NH, HCOOH/HCOOK or HCOOH/HCOONa.

6. The preparation process according to claim 1 or2, characterized in that the hydrogen source is preferably used in an amount of 1.0-5.0 equivalents, more preferably 3.0 equivalents of [ H ] with respect to formula (II).

7. The process according to claim 1 or2, wherein the catalyst used has an S/C of 1000-10000 in the transfer hydrogenation.

8. The process according to claim 1 or2, wherein the catalyst used has a reaction temperature in the range of 20 to 50 ℃ during the transfer hydrogenation.

9. The process according to claim 1 or2, wherein the catalyst is used in a transfer hydrogenation process with a reaction time of 3h to 30 h.

10. A process for the preparation of ticagrelor, characterized in that it comprises a process according to any one of claims 1 to 9.

Technical Field

The invention belongs to the technical field of medicine synthesis, relates to a preparation method of an important intermediate of ticagrelor, and particularly relates to a synthesis preparation method of an important intermediate (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol of ticagrelor.

Background

Ticagrelor is a selective small-molecule anticoagulant at present, can act on purine 2 receptor (purinoceptor2, P2) subtype P2Y12 on vascular smooth muscle cells reversibly, does not need metabolic activation, has obvious inhibition effect on platelet aggregation caused by adenosine diphosphate, has quick oral administration effect, can effectively improve the symptoms of patients with acute coronary heart disease and reduce the incidence rate of thrombotic cardiovascular events.

The chemical structure of ticagrelor is as follows:

the (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine (VI) is an important intermediate in the synthesis of ticagrelor, and the main synthetic route is as follows:

the preparation of (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine (VI) in this route was first disclosed in patent WO 2008018822. Taking o-difluorobenzene as a starting material (I), carrying out Friedel-crafts acylation reaction with chloroacetyl chloride to obtain a compound 2-chloro-1- (3, 4-difluorophenyl) ethyl-1-ketone (II), reducing by CBS to obtain a chiral compound (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol (III), carrying out cyclopropanation reaction to obtain a compound (IV), and carrying out ammonolysis and Hofmann degradation on the compound (IV) to obtain a key intermediate (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine (VI) of ticagrelor.

The synthesis of (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol (III) is key to the preparation of (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine (VI). Because the catalyst for the CBS reduction reaction in the method has unstable property and is not commercialized, the catalyst needs to be prepared in situ, thereby increasing the operation procedures and being not beneficial to industrial production; and the reaction emits foul dimethyl sulfide gas during post-treatment, is not environment-friendly and is not beneficial to labor protection of production. In addition, the ee value of the compound III in the CBS reduction is 76%, and the ee value of the finally obtained key intermediate (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine is 81%, so that the optical purity is poor.

Thereafter, in patent CN104974017A, the CBS reduction reaction of the process is optimized, and the ee value is increased from 76% to 98-99%. Because the reaction has stricter control on reaction conditions, the quenching reaction has violent heat release when the reaction is amplified, and obvious potential safety hazard exists. Some patents (CN 107814692A, CN 107892693a, CN 108083997a) follow the CBS reduction reaction and other steps are optimized, but the problem is not solved fundamentally.

The chiral compound (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol (III) obtained by the method is a chemical method, and the chiral chlorohydrin (III) can be obtained by asymmetric reduction of the chloroketone derivative (II) through a biological catalysis method. In CN201610051136.4, wuzhongliu et al reported that ChKRED20 carbonyl reductase, which can stereoselectively reduce the substrate of the present invention. The patent CN 106701840A, WO 2018/090929Al, CN 107686447A and the like report the biological enzyme catalytic reduction technology of chiral chloroethanol. Although the enzyme catalysis method has better stereocontrol, the reaction in a two-phase medium is sometimes required, the complete conversion can not be realized in most cases, the raw material loss is large, in addition, the using amount of the enzyme is also large, and the generated wastewater amount is large.

It can be seen that the compound (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine is a key intermediate in the synthesis of the drug ticagrelor, and the efficient synthesis of its chiral precursor (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol (III) is a key step in the route. The problems of poor stereoselectivity, low reaction activity, large raw material loss and complex synthesis process exist in the prior art scheme. According to the invention, the synthesis efficiency of the ticagrelor intermediate is improved by developing a method and a process which are efficient, green and high in stereoselectivity.

Disclosure of Invention

In view of the problems in the prior art, the invention provides a synthesis preparation method of (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol which is an important intermediate of ticagrelor. Specifically, the invention is realized by the following technical scheme:

a preparation method of an important intermediate of ticagrelor comprises the following synthetic route:

specifically, the structure of the catalyst used in the transfer hydrogenation process is shown below:

in catalyst cat. X, R₁Selected from hydrogen (H), methyl (Me), trifluoromethyl (CF)₃) Fluorine (F), etc. R₂Selected from p-toluenesulfonyl (Ts), methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), camphor-10-sulfonyl (Cs) and the like.

As a preferred technical scheme of the invention, the structure of the catalyst used in the transfer hydrogenation process is shown as follows:

as a preferred technical scheme of the invention, the solvent of the catalyst used in the transfer hydrogenation process is preferably EtOAc or CH₂Cl₂、ClCH₂CH₂Cl、MeOH、EtOH、ⁱPrOH、(HOCH₂)₂THF, PhMe, etc.

As a preferred embodiment of the present invention, the hydrogen source of the catalyst used in the transfer hydrogenation process is preferably HCOOH/Et₃N、HCOOH/DIPEA、HCOOH/ⁱPr₂NH、HCOOH/Et₂NH、 HCOOH/HCOOK、HCOOH/HCOONa。

In a preferred embodiment of the present invention, the solvent is preferably an alcohol solvent, and more preferably the solvent is EtOH, EtOH/H₂O (1:1, volume ratio), or MeOH. The ratio (molar ratio) of the two substances in the hydrogen source is preferably 5: 2.

As a preferred embodiment of the present invention, the hydrogen source is preferably used in an amount of 1.0 to 5.0 equivalents, more preferably 3.0 equivalents, [ H ] with respect to formula (II).

As a preferred technical scheme of the invention, the S/C of the catalyst used in the transfer hydrogenation process is preferably 1000-10000.

As a preferred embodiment of the present invention, the reaction temperature of the catalyst used in the transfer hydrogenation is preferably from 20 to 50 ℃.

As a preferred technical scheme of the invention, the reaction time of the used catalyst in the transfer hydrogenation process is preferably 3h-30 h.

The beneficial effects of the invention compared with the prior art comprise:

compared with the existing similar intermediate preparation method, the method has the advantages that the operation is simple and convenient, the yield is greatly improved, and the diastereoselectivity proportion of the product reaches 98% ee.

In addition, the catalyst is low in consumption and high in catalytic efficiency, the reaction activity is improved, the raw material loss is low, the operation of the integral synthesis process of ticagrelor is simple and convenient, the waste emission is reduced, the cost is greatly reduced, and the industrial application is easy.

From the experimental results, it was found that different ligands show a certain specificity in yield and conversion when applied to the synthesis of the intermediate of the present invention.

Invention of attached drawing

Fig. 1 is a schematic diagram of a synthetic route of an important intermediate of ticagrelor.

FIG. 2, HPLC chromatogram of chiral compound III.

FIG. 3, HPLC chromatogram of racemic Compound III.

Detailed Description

The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.

Example 1

Compound II (0.2mmol) was added to ethanol (1mL) at 30 ℃ under argon or nitrogen blanket, with the addition of catalyst cat.1(S/C ═ 1000) and 50uL formic acid-triethylamine (HCOOH/Et)₃N, 5:2) (3.0 equivalents of [ H ]]Calculated as formic acid) mixture (catalyst is 0.002M ethanol solution, 100uL is taken), asymmetric transfer hydrogenation reaction is carried out for 3h, and TLC tracing reaction is carried out to obtain an intermediate III. The synthetic route is as follows:

the present invention was made to examine the influence of the kind of catalyst used in the asymmetric transfer hydrogenation reaction on the conversion (conv.) and the enantioselectivity (ee).

Wherein the synthetic route of the intermediate is further shown in figure 1 by using a ticagrelor important intermediate; the HPLC spectrogram of the chiral compound III is shown in figure 2; the HPLC chromatogram of racemic compound III is shown in FIG. 3.

Examples 2 to 10

On the basis of example 1, the catalyst cat.1 is replaced by cat.2, cat.3, cat.4, cat.5, cat.6, cat.7, cat.8 and cat.9 in sequence.

The results of the effect of the different catalysts of examples 1-10 on the conversion and ee of the reduction of chloroketones are shown in Table 1 below; wherein the conversion (conv.) and the enantioselectivity (e.e.) were determined by HPLC.

TABLE 1

Examples 10 to 17

To examine the influence of the base added to the reaction system on the reaction, ethanol was used as a solvent, and triethylamine was sequentially replaced with Diisopropylethylamine (DIPEA), diisopropylamine (diisopropylamine) (DIPEA) and ethanolⁱPr₂NH), diethylamine (Et)₂NH) and no base, reaction time 3h, S/C1000, the following examples 10-13 were carried out, the synthetic routes of which are shown below, and the results of which are shown in table 2 below.

TABLE 2

	Hydrogen source	Reaction solvent	conv.(％)	e.e.(％)
					Example 8	HCOOH/Et3N(5:2)	EtOH	>99.9	98
Example 10	HCOOH/DIPEA(5:2)	EtOH	>99.9	98
					Example 11	HCOOH/iPr2NH(5:2)	EtOH	>99.9	98
Example 12	HCOOH/Et2NH(5:2)	EtOH	>99.9	98
					Example 13	HCOOH/nobase	EtOH	>99.9	98

In addition to example 8, hydrogen source formic acid-triethylamine (5:2) was further replaced with formic acid-sodium formate (3:1), formic acid-potassium formate (3:1), sodium formate, potassium formate (3.0 equivalents of [ H ]), the reaction time was determined by TLC tracking, S/C was 1000, the reaction solvent was methanol, ethanol, or a mixture of methanol and water, ethanol and water in a volume ratio of 1:1, and the results of the effects on the conversion rate and ee value of reduction of chloroketones were shown in table 3 below. The results show that the reaction can be carried out even in aqueous solvents, and that both the conversion and the enantioselectivity are very good (> 99.9% conv., 98% ee).

TABLE 3

	Hydrogen source	Reaction solvent	conv.(％)	e.e.(％)
					Example 14	HCOOH/HCOONa(3:1)	EtOH	>99.9	98
Example 15	HCOOH/HCOOK(3:1)	EtOH	>99.9	98
					Example 16	HCOONa	EtOH/H2O	>99.9	98
Example 17	HCOOK	EtOH/H2O	>99.9	98

Further, using cat.8 as a catalyst, ethanol (EtOH) as a green solvent as a reaction solvent, triethylamine formate (5:2) as a hydrogen source, the amount of the hydrogen source was 3.0 equivalents (calculated as formic acid), and the reaction concentration was 0.5M, and the amount of the catalyst, the reaction time, the reaction temperature, and the like were changed, respectively, and the results are shown in table 4 below.

TABLE 4

S/C	Reaction temperature (. degree.C.)	Reaction time	conv.(％)	e.e.(％)
					1000	30	3h	>99.9	98
5000	30	30h	>99.9	98
					10000	30	30h	77	98
10000	50	30h	>99.9	98

Examples 19 to 23

On the basis of example 6, the solvent was sequentially replaced with MeOH, THF, EtOAc, DCM, MeCN, and the like.

The results of the effect of different solvents on the conversion and ee of the reduction of chloroketones in examples 18-22 are shown in Table 5 below; wherein the conversion (conv.) and the enantioselectivity (e.e.) were determined by HPLC.

TABLE 5

	Hydrogen source	Reaction solvent	conv.(％)	e.e.(％)
					Example 8	HCOOH/Et3N(5:2)	EtOH	>99.9	98
Example 18	HCOOH/Et3N(5:2)	MeOH	>99.9	98
					Example 19	HCOOH/Et3N(5:2)	THF	>99.9	98
Example 20	HCOOH/Et3N(5:2)	EtOAc	>99.9	97
					Example 21	HCOOH/Et3N(5:2)	DCM	>99.9	97
Example 22	HCOOH/Et3N(5:2)	MeCN	95	89

The chemical structures of the catalysts cat.1 to cat 9 in the preceding experimental examples are as follows:

the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.