阅读说明：本技术 度维尼西的制备方法 (Preparation method of dovinisine ) 是由 许学农 于 2020-07-17 设计创作，主要内容包括：本发明揭示了一种度维尼西(Duvelisib)的制备方法,其步骤包括：以2-氯-6-甲基-N-苯基苯甲酰胺为起始原料,依次经过溴化、取代、氧化、环合、亚胺化和手性催化下的还原等反应生成目标化合物度维尼西。该制备方法原料易得,条件温和,安全环保,为度维尼西的工业化生产提供了一条新的途径。(The invention discloses a preparation method of Duvelisib, which comprises the following steps: the target compound, namely the compound dovinisine, is prepared by taking 2-chloro-6-methyl-N-phenyl benzamide as an initial raw material and sequentially carrying out bromination, substitution, oxidation, cyclization, imidization, reduction under chiral catalysis and the like. The preparation method has the advantages of easily available raw materials, mild conditions, safety and environmental protection, and provides a new way for the industrial production of the dovinisine.)

1. A preparation method of dovinisib (Duvelisib), wherein the chemical structural formula of the dovinisib is as follows:

the preparation method is characterized by comprising the following steps: carrying out bromination reaction on the 2-chloro-6-methyl-N-phenyl benzamide and potassium bromide under the action of potassium hydrogen persulfate to generate 2-chloro-6-bromomethyl-N-phenyl benzamide; the 2-chloro-6-bromomethyl-N-phenyl benzamide and 2, 4-pentanedione are subjected to substitution reaction under the action of potassium carbonate to generate 2-chloro-6- (2, 4-pentanedione-3-yl) methyl-N-phenyl benzamide; the 2-chloro-6- (2, 4-pentanedion-3-yl) methyl-N-phenyl benzamide is subjected to oxidation reaction under the action of trifluoroacetic acid and vanadium pentoxide to generate 2-chloro-6- (2, 3-butanedione) -N-phenyl benzamide; the 2-chloro-6- (2, 3-butanedione) -N-phenyl benzamide is subjected to cyclization reaction under the action of hydrogen chloride to generate 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone; the 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone and 6-amino-9H-purine are subjected to imidization reaction under the catalytic action of p-toluenesulfonic acid to generate 3- (N-9H-purine acetimido) -8-chloro-2-phenyl-1 (2H) -isoquinolinone; the 3- (N-9H-purine acetimide) -8-chloro-2-phenyl-1 (2H) -isoquinolone and trimethyl hydrosilane are subjected to reduction reaction under the action of a chiral catalyst to generate the dovinisine.

2. The method for preparing dovinisine according to claim 1, wherein the bromination is performed in the feed ratio of 2-chloro-6-methyl-N-phenylbenzamide (1 equivalent), potassium bromide (1-2 equivalents) and oxone (1-2 equivalents).

3. The process for preparing dovinisine according to claim 1, wherein the solvent for the bromination is benzene, toluene, xylene, dichloromethane, chloroform or 1, 2-dichloroethane; the temperature of the bromination reaction is 0-100 ℃.

4. The method for preparing dovinisine according to claim 1, wherein the substitution reaction is carried out in the feed ratio of 2-chloro-6-bromomethyl-N-phenylbenzamide (1 equivalent), 2, 4-pentanedione (1-2 equivalents) and potassium carbonate (2-3 equivalents).

5. The process for preparing dovinisine according to claim 1, wherein the solvent for the substitution reaction is benzene, toluene, acetonitrile, acetone or tetrahydrofuran; the temperature of the substitution reaction is 0-100 ℃.

6. The method for preparing dovinisine according to claim 1, wherein the oxidation reaction is carried out at a feed ratio of 2-chloro-6- (2, 4-pentanedion-3-yl) methyl-N-phenylbenzamide (1 equivalent), trifluoroperacetic acid (1-2 equivalents) and vanadium pentoxide (0.05-0.15 equivalent).

7. The process for preparing dovinisine according to claim 1, wherein the solvent for the oxidation reaction is benzene, toluene, xylene, tetrahydrofuran, acetonitrile or dioxane; the temperature of the oxidation reaction is 0-60 ℃.

8. The method for preparing dovinisine according to claim 1, wherein the cyclization reaction is carried out at a charge ratio of 2-chloro-6- (2, 3-butanedione) -N-phenylbenzamide (1 equivalent) and hydrogen chloride (2-4 equivalents).

9. The method for preparing dovinisine according to claim 1, wherein the solvent for the cyclization reaction is benzene, toluene, methanol, ethanol or isopropanol; the temperature of the cyclization reaction is 50-150 ℃.

10. The method of claim 1, wherein the imidization reaction is performed in a ratio of 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone (1 equivalent), 6-amino-9H-purine (1-2 equivalents), and p-toluenesulfonic acid (1-3 equivalents).

11. The method of claim 1, wherein the imidization solvent is benzene, toluene, xylene, tetrahydrofuran, acetonitrile or dioxane; the temperature of the imidization reaction is 50-150 ℃.

12. The method of claim 1, wherein the charge ratio of the reduction reaction is 3- (N-9H-purine acetimido) -8-chloro-2-phenyl-1 (2H) -isoquinolinone (1 equivalent), trichlorosilane (2-4 equivalents) and chiral catalyst (0.05-0.15 equivalent).

13. The process for preparing dovinisine according to claim 1, wherein the chiral catalyst for the reduction is (2S) -1-tert-butylformyl-N- [4- [ (1E) -2-phenylazo ] phenyl ] -2-proline amide.

14. The method for preparing dovinisine according to claim 1, wherein the solvent for the reduction reaction is benzene, toluene, xylene, tetrahydrofuran, dioxane or dichloromethane; the temperature of the reduction reaction is-50-0 ℃.

Technical Field

The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of an anti-tumor drug, namely WEINICI.

Background

Duvinisib (Duvelisib) is a phosphatidylinositol 3-kinase (PI) developed and marketed by Verastem corporation₃K) And (3) an inhibitor. The drug is approved by the Food and Drug Administration (FDA) in U.S. for marketing in the United states in 2018, 9 months, and is used for treating adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Under the trade name copira. Dovinexine is a novel oral delta/gamma dual-target inhibitor of phosphoinositide 3 kinase. Because the medicine is not yet on the market formally in China and does not have a standard Chinese translation name, the applicant translates the medicine into Vivinisin.

The chemical name of the ravinicil is: (S) -3- [1- (9H-purin-6-ylamino) ethyl ] -8-chloro-2-phenyl-1 (2H) -isoquinolinone.

International patents WO2011008302a1, WO2011146882a1 and WO2012097000a1 all report methods for the synthesis of dovinisine and its analogs. The existing synthesis thought is that according to the structural composition of target molecules, a parent nucleus A containing chiral amine is synthesized firstly, and then undergoes substitution reaction with a side chain containing halogen to prepare dovinisine. The synthetic route is as follows:

it is thus seen that the preparation of the chiral amine parent nucleus a is a central step in the overall synthesis of dovinisine. Although the sequence and reaction conditions of unit reaction are different, the basic idea is to use 2-chloro-3-methylbenzoic acid or ester thereof and S-alanine derivative as starting materials to prepare the intermediate A through a series of condensation, cyclization, protection and deprotection reactions. I.e. the chiral center of the target product is provided by the chiral source of chiral alanine. The specific synthetic route is as follows:

the synthesis method of the intermediate A is analyzed, so that the chiral source is well solved, the problems of long reaction steps and harsh reaction conditions still exist, the scale-up production of the product is bound to be limited, and the raw material and manufacturing cost are increased.

Achieving high conversion and high chiral purity is an important technical step in the preparation process of dovinisine. How to combine the latest technology of modern synthesis with the stereochemical structural characteristics of a target product and find a new replaceable chiral introduction mechanism to form an economic, environment-friendly, green and replaceable process route is important for the preparation technology of abundant vinisine and the economic and technical development of the bulk drug.

Disclosure of Invention

The invention aims to provide an improved preparation method of Duvelisib (I) by adopting the development achievement of a chiral synthesis technology according to a green chemical synthesis concept, and a new synthesis way can be provided for the preparation of Duvelisib. The preparation method is simple, convenient, economic and environment-friendly, is beneficial to the industrial production of the medicine, and can promote the development of the economic technology of the raw material medicine.

In order to achieve the purpose, the main technical scheme provided by the invention is as follows: a preparation method of a dovinisine (I),

the method comprises the following steps: the 2-chloro-6-methyl-N-phenyl benzamide (II) and potassium bromide have bromination reaction under the action of oxone to generate 2-chloro-6-bromomethyl-N-phenyl benzamide (III), the 2-chloro-6-bromomethyl-N-phenyl benzamide (III) and 2, 4-pentanedione have substitution reaction under the action of potassium carbonate to generate 2-chloro-6- (2, 4-pentanedione-3-yl) methyl-N-phenyl benzamide (IV), and the 2-chloro-6- (2, 4-pentanedione-3-yl) methyl-N-phenyl benzamide (IV) has oxidation reaction under the action of trifluoro peroxyacetic acid and vanadium pentoxide to generate 2-chloro-6- (2), 3-butanedione) -N-phenyl benzamide (V), 2-chloro-6- (2, 3-butanedione) -N-phenyl benzamide (V) generates cyclization reaction under the action of hydrogen chloride to generate 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone (VI), the 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone (VI) and 6-amino-9H-purine generate imidization reaction under the catalysis of p-toluenesulfonic acid to generate 3- (N-9H-purine acetimide) -8-chloro-2-phenyl-1 (2H) -isoquinolinone (VII), 3- (N-9H-purine acetimide) -8-chloro-2-phenyl-1 (2H) -isoquinolone (VII) and trimethyl hydrosilane are subjected to reduction reaction under the action of a chiral catalyst to generate the dovinisine (I).

The reaction scheme is schematically as follows:

in addition, the invention also provides the following auxiliary technical scheme:

the charge ratio of the bromination reaction is 2-chloro-6-methyl-N-phenyl benzamide (II) (1 equivalent), potassium bromide (1-2 equivalents) and oxone (1-2 equivalents), preferably 2-chloro-6-methyl-N-phenyl benzamide (II) (1 equivalent), potassium bromide (1.2 equivalents) and oxone (1.2 equivalents).

The solvent for the bromination reaction is benzene, toluene, xylene, dichloromethane, chloroform or 1, 2-dichloroethane, preferably dichloromethane.

The temperature of the bromination reaction is 0-100 ℃, and preferably 25-35 ℃.

The charge ratio of the substitution reaction is 2-chloro-6-bromomethyl-N-phenylbenzamide (III) (1 equivalent), 2, 4-pentanedione (1-2 equivalents) and potassium carbonate (2-3 equivalents), preferably 2-chloro-6-bromomethyl-N-phenylbenzamide (III) (1 equivalent), 2, 4-pentanedione (1.5 equivalents) and potassium carbonate (2.5 equivalents).

The solvent for the substitution reaction is benzene, toluene, acetonitrile, acetone or tetrahydrofuran, and acetone is preferred.

The temperature of the substitution reaction is 0-100 ℃, and preferably 35-45 ℃.

The feeding ratio of the oxidation reaction is 2-chloro-6- (2, 4-pentanedion-3-yl) methyl-N-phenyl benzamide (IV) (1 equivalent), trifluoro peroxy acetic acid (1-2 equivalents) and vanadium pentoxide (0.05-0.15 equivalent), preferably 2-chloro-6- (2, 4-pentanedion-3-yl) methyl-N-phenyl benzamide (IV) (1 equivalent), trifluoro peroxy acetic acid (1.5 equivalents) and vanadium pentoxide (0.10 equivalent).

The solvent for the oxidation reaction is benzene, toluene, xylene, tetrahydrofuran, acetonitrile or dioxane, preferably toluene.

The temperature of the oxidation reaction is 0-60 ℃, and preferably 25-35 ℃.

The charge ratio of the cyclization reaction is 2-chloro-6- (2, 3-butanedione) -N-phenylbenzamide (V) (1 equivalent) and hydrogen chloride (2-4 equivalents), preferably 2-chloro-6- (2, 3-butanedione) -N-phenylbenzamide (V) (1 equivalent) and hydrogen chloride (3 equivalents).

The solvent of the cyclization reaction is benzene, toluene, methanol, ethanol or isopropanol, and toluene is preferred.

The temperature of the cyclization reaction is 50-150 ℃, and preferably 95-105 ℃.

The ratio of the imidization reaction is 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone (VI) (1 equivalent), 6-amino-9H-purine (1-2 equivalents) and p-toluenesulfonic acid (1-3 equivalents), preferably 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone (VI) (1 equivalent), 6-amino-9H-purine (1.2 equivalents) and p-toluenesulfonic acid (2 equivalents).

The solvent for imidization is benzene, toluene, xylene, tetrahydrofuran, acetonitrile or dioxane, preferably toluene.

The temperature of the imidization reaction is 50-150 ℃, and preferably 105-115 ℃.

The feeding ratio of the reduction reaction is 3- (N-9H-purine acetimide) -8-chloro-2-phenyl-1 (2H) -isoquinolone (VII) (1 equivalent), trichlorosilane (2-4 equivalents) and chiral catalyst (0.05-0.15 equivalent), preferably 3- (N-9H-purine acetimide) -8-chloro-2-phenyl-1 (2H) -isoquinolone (VII) (1 equivalent), trichlorosilane (3 equivalents) and chiral catalyst (0.10 equivalent).

The chiral catalyst of the reduction reaction is (2S) -1-tert-butylformyl-N- [4- [ (1E) -2-phenylazo ] phenyl ] -2-proline amide.

The solvent for the reduction reaction is benzene, toluene, xylene, tetrahydrofuran, dioxane or dichloromethane, preferably dichloromethane.

The temperature of the reduction reaction is-50 to 0 ℃, and preferably-25 to-35 ℃.

Advantageous effects

According to the preparation method of the dovinisine, the target product is prepared by known raw materials through a common unit reaction and a chiral catalytic reduction method. The application of the method makes the preparation process simpler, the conditions are mild, the method is safe and environment-friendly, and a reasonable and practical preparation way is provided for the warfarin.

Detailed Description

The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments. Wherein the synthesis of 2-chloro-6-methyl-N-phenylbenzamide (II) can be found in the synthesis method of WO2011146882A 1; the synthesis of chiral catalysts (2S) -1-tert-butylformyl-N- [4- [ (1E) -2-phenylazo ] phenyl ] -2-proline amide is described in the literature "chemistry select,4 (33); 9590-9594; 2019'.