CN109761959B - Method for synthesizing Abemaciclib mesylate - Google Patents

Method for synthesizing Abemaciclib mesylate Download PDF

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CN109761959B
CN109761959B CN201711098673.5A CN201711098673A CN109761959B CN 109761959 B CN109761959 B CN 109761959B CN 201711098673 A CN201711098673 A CN 201711098673A CN 109761959 B CN109761959 B CN 109761959B
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magnesium chloride
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toluene
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郑旭春
张一平
吴怡华
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Hangzhou Cheminspire Technologies Co ltd
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Abstract

The invention discloses a synthesis method of Abemaciclib mesylate, which comprises the following steps of (1) reacting a compound 9 with a compound 5 under the action of strong alkali to obtain a compound 10; (2) salifying the compound 10 in a proper solvent under the action of methanesulfonic acid to obtain Abemaciclib mesylate; the invention also discloses a synthesis method of the compound 5 and the compound 9, the synthesis route is simple to operate, the use of a noble metal catalyst is avoided, the route cost and the heavy metal residue of the product are reduced, the yield is high, the purity of the obtained product is high, and the method is suitable for large-scale production.

Description

Method for synthesizing Abemaciclib mesylate
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthesis method of Abemaciclib mesylate.
Background
Abemaciclib mesylate (code number LY-2835219) is a novel oral anticancer new drug which is developed by gift, is a dual inhibitor of highly specific cyclin dependent kinase (CDK4/6), and can restore cell cycle control and block tumor cell proliferation by selectively inhibiting cyclin dependent kinase 4/6. The single medicine has obvious curative effect on metastatic breast cancer, is approved by the FDA in the United states for 'breakthrough therapy' in 2015 10 months, is developed for treating various cancers at present, and has smooth clinical research progress and wide market prospect.
The chemical name of the Abemaciclib mesylate is N- [5- [ (4-ethyl-1-piperazine) methyl ] 2-pyridyl ] -5-fluoro-4- [ 4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl ] -2-pyrimidinamine mesylate, and the molecular structure is as follows:
Figure GDA0002459308350000012
abemaciclib mesylate
PCT patent WO2010075074A discloses that key intermediates of abemaciciclib and a method for preparing abemaciciclib mesylate are as follows:
Figure GDA0002459308350000011
Figure GDA0002459308350000021
the route mainly decomposes Abemaciclib into three heterocyclic fragments, and the three heterocyclic fragments are butted one by utilizing a three-step coupling reaction. The method has longer steps, expensive palladium catalyst and phosphine ligand are needed in the three-step coupling reaction, and the yield is low due to more coupling reaction byproducts; the yield of the synthetic intermediate 5- ((4-ethylpiperazin-1-yl) methyl) pyridine-2-amine is low by using a copper catalysis method, and the cost is too high by using palladium catalysis; the synthesis of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazole requires the use of a large amount of phosphorus oxychloride, has high toxicity, generates more waste water during treatment, and has high environmental protection pressure.
In general, the existing methods have low overall yield, high cost and difficult process scale-up, so that a new synthesis method which is simpler and more efficient still needs to be found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel synthesis method for preparing an Abemaciclib key intermediate and a mesylate finished product thereof, and the synthesis method has the advantages of simple process route, low cost and suitability for industrial production.
One of the purposes of the invention is to provide a novel synthesis method of an Abemaciclib key intermediate compound 5, which adopts the following technical scheme:
the synthesis method of the Abemaciclib key intermediate compound 5 comprises the following steps:
(1) in the presence of alkali, carrying out condensation reaction on N- (4-bromo-2, 6-difluorophenyl) acetamide compound 1 and isopropylamine in a sealed reactor to obtain a compound 2;
Figure GDA0002459308350000022
(2) cyclizing the compound 2 under the action of acid to obtain a compound 3;
Figure GDA0002459308350000031
(3) the intermediate state obtained by exchanging the compound 3 with a Grignard reagent or a lithium reagent is coupled with 2, 4-dichloro-5-fluoropyrimidine under the catalysis of iron or nickel to obtain a key compound 5;
Figure GDA0002459308350000032
preferably, in the condensation reaction in step (1), the base is selected from organic base or inorganic base, the inorganic base is selected from potassium carbonate, sodium hydroxide, potassium hydroxide and potassium bicarbonate, the organic base is selected from diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylenediamine; the reaction solvent is selected from dimethylformamide, dimethylacetamide, NMP, 1, 4-dioxane or acetonitrile; the reaction temperature is 0-120 ℃.
Preferably, in the cyclization reaction in the step (2), the acid is selected from hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, dimethylacetamide or NMP; the reaction temperature is-10 to 130 ℃.
Preferably, in the reaction in step (3), the grignard reagent exchange reaction is grignard exchange with isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride; carrying out lithium reagent exchange to directly extract halogen by n-butyl lithium, sec-butyl lithium or tert-butyl lithium reverse reaction to obtain aryl magnesium or aryl lithium reagent; selecting ferric trichloride, ferric tribromide, ferric triacetylacetone, nickel dichloride or bis (triphenylphosphine) nickel dichloride as a catalyst; the selected reaction solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane or methyl tertiary butyl ether; the reaction temperature is generally-70 to 110 ℃.
The second object of the invention is to provide a novel synthesis method of an Abemaciclib intermediate compound 9, which adopts the following technical scheme:
the synthesis method of the Abemaciclib intermediate compound 9 comprises the following steps:
(1) exchanging 2-chloro-5-bromopyridine by using a Grignard reagent, and then performing formylation reaction on the 2-chloro-5-bromopyridine and N, N-dimethylformamide to obtain a 2-chloro-5-pyridinecarboxaldehyde compound 7;
Figure GDA0002459308350000041
(2) carrying out reductive amination reaction on a 2-chloro-5-pyridinecarbaldehyde compound 7 and an N-ethylpiperazine compound 6 under the action of a reducing agent to obtain a compound 8;
Figure GDA0002459308350000042
(3) carrying out an ammoniation reaction on the compound 8 and ammonia water in a proper solvent by using a copper catalyst to obtain an intermediate compound 9;
Figure GDA0002459308350000043
preferably, step (1) is performed with isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride; the reaction solvent is tetrahydrofuran, toluene, 2-methyltetrahydrofuran or dichloromethane; the reaction temperature is generally-15 to 80 ℃.
Preferably, trimethyl orthoformate or triethyl orthoformate is used as a dehydrating agent in the reductive amination reaction in the step (2); the reducing reagent is formic acid; the reaction solvent is selected from toluene, xylene, chlorobenzene, acetonitrile, 1, 4-dioxane or 1, 2-dichloroethane; the reaction temperature is 50-130 ℃.
Preferably, the copper catalyst in the ammoniation reaction in step (3) is selected from cuprous iodide, cuprous bromide, cuprous oxide, cupric bromide or cupric chloride; the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethylene glycol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1, 4-dioxane or toluene; the reaction temperature is 50-150 ℃.
The invention also aims to provide a novel synthesis method of Abemaciclib mesylate, which adopts the following technical scheme:
a method for synthesizing Abemaciclib mesylate comprises the following steps:
(1) reacting the compound 9 with the compound 5 under the action of strong alkali to obtain a compound 10;
Figure GDA0002459308350000051
(2) salifying the compound 10 in a proper solvent under the action of methanesulfonic acid to obtain Abemaciclib mesylate;
Figure GDA0002459308350000052
preferably, the strong base in step (1) is selected from isopropyl magnesium chloride, cyclohexyl magnesium chloride, n-butyl magnesium chloride, lithium hexamethyldisilazide (LiHMDS) or Lithium Diisopropylamide (LDA); the selected reaction solvent is tetrahydrofuran, toluene, 2-methyltetrahydrofuran or dichloromethane; the reaction temperature is generally-70 to 80 ℃.
Preferably, in the salt-forming reaction of step (2), the reaction solvent is selected from dichloromethane, 1, 4-dioxane, toluene, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol, acetonitrile, or the like; the reaction temperature is-10 to 90 ℃.
According to the invention, compound 9 and compound 5 are subjected to nucleophilic substitution reaction under the action of strong alkali to obtain compound 10, and then compound 10 is subjected to salification to obtain Abemaciclib mesylate; the synthetic route improves the synthetic method of the compound 9 and the compound 5, the coupling reaction of the subsequent intermediate compound 3 and the 2, 4-dichloro-5-fluoropyrimidine is replaced by the Grignard coupling reaction catalyzed by iron or nickel on the basis of the original research, and the coupling reaction of the compound 5 and the compound 9 is replaced by the simple nucleophilic substitution reaction, and the route cost is greatly reduced by the improvements. The synthetic route is simple to operate, avoids using a noble metal catalyst, reduces the route cost and the heavy metal residue of the product, has high yield, obtains high product purity, is suitable for amplification production, and is characterized in that:
Figure GDA0002459308350000061
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
Figure GDA0002459308350000062
Adding N- (4-bromo-2, 6-difluorophenyl) acetamide compound 1(25.00g,100mmol), isopropylamine (6.50g,110mmol) and acetonitrile (125mL) into a sealed reactor, uniformly stirring, adding triethylamine (20.24g,200mmol), heating to an internal temperature of 90-95 ℃, reacting for 8-10 hours, cooling to room temperature after the reaction is finished, adding water, removing the acetonitrile by spinning, extracting for 2 times with dichloromethane (125mL), combining organic phases, washing for 2 times with saturated saline solution (125mL), drying with sodium sulfate, filtering, concentrating to obtain oily compound 2, and directly feeding into the next reaction.
In example 1, triethylamine may be replaced with potassium carbonate, sodium hydroxide, potassium bicarbonate, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylenediamine, and the solvent acetonitrile may be replaced with dimethylformamide, dimethylacetamide, NMP or 1, 4-dioxane.
Example 2
Figure GDA0002459308350000071
Adding compound 2(100mmol, obtained in example 1) and toluene (125mL) into a three-neck flask, adding p-toluenesulfonic acid (38.04g,200mmol), heating, refluxing, carrying out water separation reaction for 16-24 hours, cooling to room temperature after the reaction is finished, adding a 5% sodium hydroxide solution to adjust the pH to 11-12, carrying out liquid separation, extracting the aqueous phase for 1 time with ethyl acetate (125mL), combining the organic phase, washing with saturated saline for 2 times (125mL), drying with sodium sulfate, filtering, concentrating to remove part of the solvent, adding petroleum ether (125mL), separating out a solid, pulping, filtering, and drying to obtain compound 3(21.42g, 79% yield in two steps).
In example 2, p-toluenesulfonic acid can be replaced by hydrochloric acid, acetic acid, trifluoroacetic acid or fluoromethanesulfonic acid; the solvent toluene can be replaced by dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, dimethylacetamide or NMP.
Example 3
Figure GDA0002459308350000072
The compound 3(27.11g,100mmol) and tetrahydrofuran (136mL) were added to a three-necked flask, stirred and dissolved, cooled to 0 to 5 ℃ in an ice-salt bath, and then vacuum-switched with nitrogen gas 3 times, and then a 2.0M solution of isopropyl magnesium chloride in tetrahydrofuran (110mmol, 55.0mL) was added dropwise, and the reaction was carried out at an internal temperature of 0 to 5 ℃ for 0.5 to 1 hour. Dissolving 2, 4-dichloro-5-fluoropyrimidine (18.37g, 110mmol) in tetrahydrofuran (136mL) under the protection of nitrogen, adding a catalyst of ferric triacetylacetonate (1.78g,5mmol), stirring uniformly, dropwise adding the prepared Grignard reagent solution into a reaction bottle containing the pyrimidine, and heating to 55-60 ℃ for reacting for 4-6 hours after dropwise adding. After the reaction was completed, the reaction was quenched by addition of saturated aqueous ammonium chloride, the mixture was extracted 3 times with ethyl acetate (216mL), the combined organic phases were washed 2 times with water (216mL), dried over sodium sulfate, filtered, concentrated to remove most of the ethyl acetate, petroleum ether (125mL) was added, the solid was slurried, filtered and dried to give compound 5(24.53g, 76%).
In example 3 the isopropyl magnesium chloride can be replaced by cyclohexyl magnesium chloride or n-butyl magnesium chloride; the catalyst ferric triacetylacetonate can be replaced by ferric trichloride, ferric tribromide, nickel dichloride or bis (triphenylphosphine) nickel dichloride; the solvent tetrahydrofuran may be replaced by 2-methyltetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane or methyl tert-butyl ether.
Example 4
Figure GDA0002459308350000081
Adding 2-chloro-5-bromopyridine (19.24g,100mmol) and tetrahydrofuran (192mL) into a three-neck flask, stirring and dissolving, cooling by using a ice salt bath, switching nitrogen gas in vacuum, dropwise adding isopropyl magnesium chloride tetrahydrofuran solution (2.0M, 60mL), reacting at 10-0 ℃ for 1-2 hours, dropwise adding N, N-dimethylformamide (21.93g,300mmol), heating to room temperature after dropwise adding, reacting for 4-6 hours, adding saturated ammonium chloride solution (192mL) after the reaction is finished, quenching the reaction, extracting the mixed solution for 3 times by using ethyl acetate (96mL), combining organic phases, washing for 2 times (96mL), drying by using sodium sulfate, concentrating to 1/3 volume, adding petroleum ether (192mL), pulping, filtering and drying to obtain 2-chloro-5-pyridineformaldehyde (13.02g, 92%).
In example 4 the isopropyl magnesium chloride can be replaced by cyclohexyl magnesium chloride or n-butyl magnesium chloride; the solvent tetrahydrofuran is replaced by toluene, 2-methyltetrahydrofuran or dichloromethane.
Example 5
Figure GDA0002459308350000082
Adding 2-chloro-5-pyridinecarboxaldehyde 7(14.16g,100mmol), N-ethylpiperazine 6(12.56g,110mmol) and acetonitrile (142mL) into a three-neck flask, slowly adding trimethyl orthoformate (200mmol), then adding formic acid (12.01g,400mmol), slowly heating to reflux reaction for 6-8 hours, adding 142mL of water to quench the reaction, adding 10% sodium hydroxide solution to adjust the pH value to 12-13, removing most of acetonitrile under reduced pressure, extracting the aqueous phase with dichloromethane (142mL) for 2 times, combining organic phases, washing with saturated common salt water for 2 times (142mL), drying with sodium sulfate, filtering, and concentrating to obtain an oily crude product of a compound 1- ((6-chloropyridin-3-yl) methyl) -4-ethylpiperazine 8, and directly carrying out the next reaction.
Example 5 trimethyl orthoformate can be replaced by triethyl orthoformate; the solvent acetonitrile can be replaced by toluene, xylene, chlorobenzene, 1, 4-dioxane or 1, 2-dichloroethane.
Example 6
Figure GDA0002459308350000091
Transferring the crude 1- ((6-chloropyridin-3-yl) methyl) -4-ethylpiperazine 8 (100mmol, obtained from example 5) obtained in example 5 into a sealed reaction flask, adding ethylene glycol (70mL), cuprous iodide (952mg,5.0mmol), potassium carbonate (27.64g,200mmol), ammonia (25%, 35g), heating in oil bath to 110-115 ℃ for reaction for 36-48 hours, cooling to room temperature after the reaction is finished, adding 15% saline (140mL), adding isopropyl acetate (70mL) for extraction 3 times, combining organic phases, washing with saturated saline 2 times (70mL), drying with sodium sulfate, concentrating to remove most of the solvent, adding acetone (140mL), pulping, filtering and drying to obtain compound 9(15.20g, 69% in two steps).
The cuprous iodide catalyst in example 6 can be replaced by cuprous bromide, cuprous oxide, cupric bromide or cupric chloride; the solvent ethylene glycol can be replaced by methanol, ethanol, isopropanol, N-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1, 4-dioxane or toluene.
Example 7
Figure GDA0002459308350000092
Adding the compound 9(24.23g,110mmol) and toluene (160mL) into a three-neck flask, uniformly stirring, cooling to-5-0 ℃, adding a lithium hexamethyl-aminochloride tetrahydrofuran solution (1.0M,120mL,120mmol), stirring at low temperature for 30-45 minutes, dropwise adding the compound 5(32.27g,100mmol), and heating to room temperature of 25-30 ℃ for reaction for 10-16 hours. After completion of the reaction, saturated ammonium chloride (323mL) was added, extraction was performed 3 times with ethyl acetate (160mL), the combined organic phases were washed with saturated brine 2 times (160mL), dried over anhydrous sodium sulfate, concentrated, and recrystallized from a mixed solvent of dichloromethane and ethyl acetate to give compound 10(43.57g, 86%).
In example 7, lithium hexamethyldisilazide may be replaced with isopropyl magnesium chloride, cyclohexyl magnesium chloride, n-butyl magnesium chloride or lithium diisopropylamide; the solvent toluene can be replaced by tetrahydrofuran, 2-methyltetrahydrofuran or dichloromethane.
Example 8
Figure GDA0002459308350000101
Adding the compound 10(50.66g,100mmol) into a three-neck flask, adding absolute ethyl alcohol (251mL), stirring to dissolve, adding methanesulfonic acid (14.42g,150mmol), heating to 50-55 ℃ after adding, and reacting for 4-5 hours. After the reaction is finished, slowly cooling to 0-5 ℃, pulping for 1 hour, filtering, washing the solid with ethanol (50mL), and drying to obtain a product Abemaciclib mesylate 11(56.65g, 94%).

Claims (8)

  1. A synthesis method of Abemaciclib mesylate is characterized by comprising the following steps:
    (1) in the presence of alkali, carrying out condensation reaction on N- (4-bromo-2, 6-difluorophenyl) acetamide compound 1 and isopropylamine in a sealed reactor to obtain a compound 2;
    Figure FDA0002514794540000011
    (2) cyclizing the compound 2 under the action of acid to obtain a compound 3;
    Figure FDA0002514794540000012
    (3) the intermediate state obtained by exchanging the compound 3 with a Grignard reagent or a lithium reagent is coupled with 2, 4-dichloro-5-fluoropyrimidine under the catalysis of an iron-containing or nickel-containing compound to obtain a compound 5;
    Figure FDA0002514794540000013
    (4) reacting the compound 9 with a compound 5 under the action of alkali to obtain a compound 10;
    Figure FDA0002514794540000014
    (5) salifying the compound 10 in a solvent under the action of methanesulfonic acid to obtain Abemaciclib mesylate;
    Figure FDA0002514794540000015
    the compound containing iron or nickel in the step (3) is selected from ferric trichloride, ferric tribromide, ferric triacetylacetone, nickel dichloride or bis (triphenylphosphine) nickel dichloride;
    the alkali in the step (4) is selected from isopropyl magnesium chloride, cyclohexyl magnesium chloride, n-butyl magnesium chloride, hexamethyldisilazane lithium amide (LiHMDS) or diisopropylamide Lithium (LDA); the reaction solvent selected is tetrahydrofuran, toluene, 2-methyltetrahydrofuran or dichloromethane.
  2. 2. The method for synthesizing Abemaciclib mesylate according to claim 1, wherein in the condensation reaction in step (1), the base is selected from an organic base or an inorganic base, the inorganic base is selected from potassium carbonate, sodium hydroxide, potassium hydroxide, and potassium bicarbonate, the organic base is selected from diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylenediamine; the reaction solvent is selected from dimethylformamide, dimethylacetamide, NMP, 1, 4-dioxane or acetonitrile.
  3. 3. The method for synthesizing Abemaciclib mesylate according to claim 1, wherein in the cyclization reaction in step (2), the acid is selected from hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, dimethylacetamide or NMP.
  4. 4. The method for synthesizing Abemaciclib mesylate according to claim 1, wherein in the reaction in the step (3), grignard reagent exchange reaction is performed with isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride; exchanging a lithium reagent, and directly removing halogen by reacting n-butyl lithium, sec-butyl lithium or tert-butyl lithium to obtain an aryl lithium reagent; the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane or methyl tertiary butyl ether.
  5. 5. The method for synthesizing Abemaciclib mesylate according to claim 1, wherein the method for synthesizing compound 9 comprises the following steps:
    (A) exchanging 2-chloro-5-bromopyridine by using a Grignard reagent, and then performing formylation reaction on the 2-chloro-5-bromopyridine and N, N-dimethylformamide to obtain a 2-chloro-5-pyridinecarboxaldehyde compound 7;
    Figure FDA0002514794540000021
    (B) carrying out reductive amination reaction on a 2-chloro-5-pyridinecarbaldehyde compound 7 and an N-ethylpiperazine compound 6 under the action of a reducing agent to obtain a compound 8;
    Figure FDA0002514794540000031
    (C) carrying out an ammoniation reaction on the compound 8 and ammonia water in a solvent by using a copper catalyst to obtain an intermediate compound 9;
    Figure FDA0002514794540000032
  6. 6. the process according to claim 5, wherein step (A) is carried out by Grignard exchange with isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride; the reaction solvent is tetrahydrofuran, toluene, 2-methyltetrahydrofuran or dichloromethane.
  7. 7. The method of synthesizing Abemaciclib mesylate according to claim 5, wherein trimethyl orthoformate or triethyl orthoformate is used as a dehydrating agent in the reductive amination reaction in step (B); the reducing reagent is formic acid; the reaction solvent is selected from toluene, xylene, chlorobenzene, acetonitrile, 1, 4-dioxane or 1, 2-dichloroethane.
  8. 8. The process according to claim 5, wherein the copper catalyst in the amination step (C) is selected from cuprous iodide, cuprous bromide, cuprous oxide, cupric bromide or cupric chloride; the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethylene glycol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1, 4-dioxane or toluene.
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