CN111675710A - Preparation method of dovinisine - Google Patents
Preparation method of dovinisine Download PDFInfo
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- CN111675710A CN111675710A CN202010692770.2A CN202010692770A CN111675710A CN 111675710 A CN111675710 A CN 111675710A CN 202010692770 A CN202010692770 A CN 202010692770A CN 111675710 A CN111675710 A CN 111675710A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
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.
Description
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'.
The first embodiment is as follows:
adding 2-chloro-6-methyl-N-phenyl benzoyl into a reaction bottleAmine (II) (12.3g, 50mmol) and dichloromethane (150 mL) were dissolved with stirring, and potassium bromide (7.1g, 60mmol) and potassium hydrogen persulfate (36.9g, 60mmol) were added as a 150mL aqueous solution. Stirring and reacting for 6-8 hours at 25-35 ℃ under the irradiation of sunlight. The aqueous phase was separated, the organic phase was extracted three times with dichloromethane, the organic phases were combined and washed successively with saturated sodium thiosulfate solution, brine and water. Drying and concentrating to obtain 15.8g of yellow oily 2-chloro-6-bromomethyl-N-phenyl benzamide (III), the yield is 97.5 percent, and the EI-MS M/z is 325[ M + H ]]+。
Example two:
2-chloro-6-bromomethyl-N-phenylbenzamide (III) (13g, 40mmol), 2, 4-pentanedione (6g, 60mmol), potassium carbonate (13.8g, 100mmol) and 200mL of acetone were added to a reaction flask, stirred at room temperature for 15 minutes, and then heated to 35-45 ℃ for reaction for 24 hours. Cool to room temperature and filter to remove solids. Concentrating under reduced pressure to one-fourth volume, and adjusting pH to neutral with diluted hydrochloric acid. Ethyl acetate was added and extracted 3 times. The organic phase was separated, dried and concentrated to give 11.5g of 2-chloro-6- (2, 4-pentanedion-3-yl) methyl-N-phenylbenzamide (IV) as a pale yellow viscous oil with a yield of 83.6%, EI-MS M/z 344[ M + H ],]+。
example three:
2-chloro-6- (2, 4-pentanedion-3-yl) methyl-N-phenylbenzamide (IV) (10.3g,30mmol), trifluoroperacetic acid (5.85g, 45mmol) and 100mL of toluene were added to a reaction flask, and the mixture was stirred at 25-35 ℃ for reaction for 4-6 hours. And continuously adding vanadium pentoxide (0.55g,3mmol), introducing oxygen, and continuously reacting for 24 hours at the temperature of 25-35 ℃. Insoluble matter was removed by filtration, and the organic phase was washed with a saturated sodium carbonate solution, a saturated brine and water, respectively. Drying and concentrating to obtain 7.4g of light yellow solid 2-chloro-6- (2, 3-butanedione) -N-phenyl benzamide (V), the yield is 78.3%, EI-MS M/z is 316[ M + H ]]+。
Example four:
adding 2-chloro-6- (2, 3-butanedione) -N-phenyl benzamide (V) (6.3g,20mmol), hydrogen chloride methanol solution (10M, 60mL) and toluene (100mL) into a reaction bottle, heating to 95-105 ℃, and stirring for reacting for 1-2 hours. Concentrating under reduced pressure, cooling to room temperature, and adding ethyl acetate to the residuePulping, crystallizing, and filtering to obtain white solid 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone (VI)5.2g with yield 87.5%, EI-MS M/z:298[ M + H ]/[]+。
Example five:
into a reaction flask were charged 3-acetyl-8-chloro-2-phenyl-1 (2H) -isoquinolinone (VI) (3.0g,10mmol), 6-amino-9H-purine (1.6g, 12mmol), p-toluenesulfonic acid (0.34g,20mmol) and toluene 50 mL. Heating to 105-115 ℃ under stirring, and carrying out reflux dehydration reaction for 24 hours. Concentrated under reduced pressure, and the residue was extracted 3 times with dichloromethane. The combined organic phase is washed by pure water and brine in turn, dried and concentrated, and the obtained oily matter is recrystallized by ethyl acetate to obtain a white solid 3- (N-9H-purine acetimido) -8-chloro-2-phenyl-1 (2H) -isoquinolone (VII)3.4g with the yield of 82.1 percent and EI-MS M/z:415[ M + H ] M/z]+。
Example six:
to an anhydrous and oxygen-free reaction flask was added 3- (N-9H-purine acetylimine) -8-chloro-2-phenyl-1 (2H) -isoquinolinone (VII) (2.1g,5mmol), (2S) -1-tert-butylformyl-N- [4- [ (1E) -2-phenylazo group]Phenyl radical]Stirring (0.19g, 0.5mmol) of-2-proline amide and 50mL of dichloromethane at room temperature for 15 minutes, cooling to-25-35 ℃, adding (0.47g, 15mmol) of trichlorosilane, and stirring for reaction for 48 hours. Heating to room temperature, washing with saturated sodium bicarbonate solution and water, drying, concentrating, recrystallizing with isopropanol to obtain vinixine as white solid with yield of 86.7%, and EI-MS M/z of 417[ M + H ]/(M + H)]+；1H NMR(DMSO d6)12.95(brs,1H),8.24(m,1H),8.25(s,2H),7.56(m,4H),7.45(m,4H),6.78(s,1H),4.73(dd,J＝5.6,2.8Hz,1H),1.39(t,J＝10.8,6.4Hz,3H)。
It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (14)
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 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012097000A1 (en) * | 2011-01-10 | 2012-07-19 | Pingda Ren | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
| CN103002738A (en) * | 2010-05-21 | 2013-03-27 | 英特利凯恩有限责任公司 | Chemical compounds, compositions and methods for kinase modulation |
| WO2015061204A1 (en) * | 2013-10-21 | 2015-04-30 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| CN108699061A (en) * | 2015-11-16 | 2018-10-23 | 纽弗姆制药有限公司 | For treating hematologic malignancies, inflammation and the deuterated compound of autoimmune disease |
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2020
- 2020-07-17 CN CN202010692770.2A patent/CN111675710B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103002738A (en) * | 2010-05-21 | 2013-03-27 | 英特利凯恩有限责任公司 | Chemical compounds, compositions and methods for kinase modulation |
| WO2012097000A1 (en) * | 2011-01-10 | 2012-07-19 | Pingda Ren | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
| WO2015061204A1 (en) * | 2013-10-21 | 2015-04-30 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| CN108699061A (en) * | 2015-11-16 | 2018-10-23 | 纽弗姆制药有限公司 | For treating hematologic malignancies, inflammation and the deuterated compound of autoimmune disease |
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| DR. QIANG LI: "Proline-derived Monodentate Organocatalyst for Asymmetric Reduction of Imine with HSiCl3", 《CHEMISTRYSELECT》 * |
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