CN108117550B

CN108117550B - Preparation method of pyrido [2,3-d ] pyrimidine compound

Info

Publication number: CN108117550B
Application number: CN201611073881.5A
Authority: CN
Inventors: 马庆童; 单晓燕; 陈旭东; 陈雨
Original assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Current assignee: China Pharmaceutical Industry Research Institute Co ltd; Shanghai Pharmaceutical Industry Research Institute Co ltd
Priority date: 2016-11-29
Filing date: 2016-11-29
Publication date: 2020-08-14
Anticipated expiration: 2036-11-29
Also published as: CN108117550A

Abstract

The invention discloses a preparation method of a compound shown as a formula 1, which comprises the following steps of dissolving a water-soluble organic solvent at the temperature of 60-85 DEG CUnder the action of alkali and a catalyst, the compound 2 and the compound 3 are reacted as follows; wherein the catalyst is PdCl₂(ii) a Wherein, X is Br or I; r is H or C₁～C₃Alkyl group of (1).

Description

Preparation method of pyrido [2,3-d ] pyrimidine compound

Technical Field

The invention relates to a preparation method of a pyrido [2,3-d ] pyrimidine compound.

Background

Palbociclib (Palbociclib), developed by Pfizer, USA as an initial solution based on endocrine therapy, is combined with letrozole for estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER) that has not received systemic treatment⁺/HER2^-) In postmenopausal women for the treatment of advanced breast cancer. The compound 1 is an important intermediate in the preparation process of palbociclib.

At present, the compound 1 is mainly prepared from a compound 2, as shown in the following,

the main preparation method comprises the following steps:

with the compound 3 asThe method for preparing compound 1 from the starting material is described in chinese patent document CN201510646418A, and the reaction is performed with PdCl as shown below₂(Ph₃P)₂As a catalyst, the reaction temperature was 90 ℃ and the yield was 82%.

In the literature, the synthesis of compound 1 is reported to use Pd (OAc)2, PdCl2(PhCN)2, PdCl2(MeCN)2, PdCl2(Ph3P)2 in an amount of 0.05 equivalent. The yield of the method reported by the literature is generally low and is about 80 percent; the reaction temperature is between 65 and 90 ℃; the reaction time is longer than 6 h.

Disclosure of Invention

The invention aims to overcome the defects of low yield, long time consumption, high temperature, high equipment requirement and the like in the preparation process of a compound 1 in the prior art, thereby providing a preparation method of the compound 1, wherein the compound 2 and the compound 3 are used as raw materials, and PdCl is used as a material₂The method is a catalyst, has high yield and low requirement on equipment, shortens the reaction time, reduces the generation of byproducts and is beneficial to industrial production.

The invention provides a preparation method of a compound shown as a formula 1, which comprises the following steps: in a water-soluble organic solvent, under the action of alkali and a catalyst, at the temperature of 60-85 ℃, carrying out the following reaction on a compound 2 and a compound 3; wherein the catalyst is PdCl₂；

Wherein, X is Br or I; r is H or C₁～C₃Alkyl (methyl, ethyl, propyl).

Wherein, in the preparation method, the reaction temperature is adjusted according to the common knowledge in the field, and the reaction temperature is adjusted according to the boiling points of different solvents, such as reflux temperature; the temperature is preferably 65 ℃ to 75 ℃.

In the preparation method, the water-soluble organic solvent can be a conventional solvent suitable for the reaction in the field, and N-methyl-2-pyrrolidone and/or tetrahydrofuran are particularly preferred.

Among them, in the preparation method, the base can be the conventional organic base applicable to the reaction in the field, and the triethylamine (Et) is particularly preferred in the invention₃N) and/or N, N-Diisopropylethylamine (DIEA).

In the preparation method, the molar ratio of the catalyst to the compound 2 can be the conventional ratio of the reaction in the field, and the invention is particularly preferably 0.02-0.12, further preferably 0.03-0.1, and more preferably 0.03-0.05.

In the preparation method, the using amount of the compound 2 and the water-soluble organic solvent can be the conventional proportion of the reaction in the field, and the invention particularly preferably selects 0.5 mol/L-0.8 mol/L, and further preferably selects 0.724 mol/L.

Wherein, in the preparation method, the molar ratio of the compound 2 to the compound 3 can be the conventional ratio of the reaction in the field, and the invention particularly preferably comprises the following steps: (1:2) to (4:5), more preferably (3:5) to (7:10), and still more preferably 2: 3.

In the preparation method, the molar ratio of the compound 2 to the base can be the conventional ratio of the reaction in the field, and the molar ratio is particularly preferably 1: 2-1: 4, and further preferably 1: 3.

Wherein, in the preparation method, the reaction time can be detected by using the conventional method in the field (HPLC, TLC, GC, NMR and the like) to detect whether the reaction end point is reached, and the TLC (such as DCM: MeOH ═ 12:1) is particularly preferred in the invention.

The preparation method can also comprise post-treatment after the reaction is finished, the post-treatment can adopt a conventional method in the field, and the following post-treatment methods are particularly preferred in the invention: and after the reaction is finished, reacting the reaction solution of the reaction with acetic anhydride to obtain a reaction mixture, crystallizing, filtering, drying and washing. The dosage of the acetic anhydride can be the conventional dosage in the field, and the invention particularly preferably adopts 15-20 equivalents of the compound 1; the crystallization can be a conventional method in the field, and the invention particularly preferably reduces the temperature of the reaction mixture to 20-25 ℃ to react with triethylamine hydrobromide solution, wherein the dosage of the triethylamine hydrobromide solution can be the conventional dosage of the operation in the field; the suction filtration, drying and washing may refer to the conventional operations in the art.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the method takes a compound 2 and a compound 3 as raw materials, and PdCl₂The method is a catalyst, has high yield and low requirement on equipment, shortens the reaction time, reduces the generation of byproducts and is beneficial to industrial production.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1

Compound 2(10.0g, 36.2mmol, 1.0eq), N-methylpyrrolidinone (NMP, 50mL), crotonic acid (4.7g, 54.6mmol, 1.5eq) and triethylamine (14.7g, 144.9mol, 4.0eq) were added at room temperature. The vessel was purged with nitrogen three times, and PdCl was added to the purged reaction mixture₂(0.195g, 1.10mmol, 0.03 eq). And nitrogen gas was added three more times. Stirring and dissolving the raw materials at normal temperature, quickly heating to 75 ℃, sealing and stirring for reaction for 6h, sampling (diluting with ethyl acetate), detecting by TLC (DCM: MeOH: 12:1), completely reacting the raw material compound 1, adding acetic anhydride for reaction for 0.5h, completely reacting an intermediate, bringing the reaction mixture to 20 ℃, adding triethylamine hydrobromide solution (100mL), stirring for 1h, carrying out suction filtration, and washing with water to obtain a gray solid. Dissolving with ethyl acetate, adding anhydrous magnesium sulfate, drying the mixture, and filtering off insoluble substances (salt)And insoluble catalyst) was washed with ethyl acetate. The filtrate was concentrated to low volume, n-hexane was added, slurried at 65 ℃ for 30min, cooled to 20 ℃ and stirred for 1h, the solid was filtered and vacuum dried to give a tan solid, compound 1(9.04g, 94.8% yield, 99.1% purity).

With reference to example 1, the solvent or temperature was adjusted and the results were as follows:

example 5

Compound 2(36.2mmol, 1.0eq), N-methylpyrrolidinone (NMP, 72.4mL), crotonic acid (61.1mmol, 1.7eq) and triethylamine (144.9mol, 2.0eq) were added at room temperature. The vessel was purged with nitrogen three times, and PdCl was added to the purged reaction mixture₂(1.81mmol, 0.05 eq). And nitrogen gas was added three more times. Stirring and dissolving the raw materials at normal temperature, quickly heating to 70 ℃, sealing and stirring for reaction for 6h, sampling (diluting with ethyl acetate), detecting by TLC (DCM: MeOH: 12:1), completely reacting the raw material compound 1, adding acetic anhydride for reaction for 0.5h, completely reacting an intermediate, bringing the reaction mixture to 20 ℃, adding triethylamine hydrobromide solution (150mL), stirring for 1h, carrying out suction filtration, and washing with water to obtain a gray solid. Ethyl acetate was added to the reaction solution to dissolve the mixture, anhydrous magnesium sulfate was added to the mixture to dry the mixture, and insoluble matter (salt and insoluble catalyst) was filtered off and washed with ethyl acetate. Concentrating the filtrate to low volume, adding n-hexane, pulping at 65 deg.C for 30min, cooling to 20 deg.C, stirring for 1h, vacuum filtering the solid, and vacuum drying to obtain brown yellow solid, i.e. compound 1, with yield of 86.1% and purity of 98.8%.

Example 6

Compound 2(36.2mmol, 1.0eq), N-methylpyrrolidinone (NMP, 46mL), crotonic acid (51.4mmol, 1.42q) and triethylamine (144.9mol, 4.0eq) were added at room temperature. The vessel was purged with nitrogen three times, and PdCl was added to the purged reaction mixture₂(1.81mmol, 0.1 eq). And nitrogen gas was added three more times. Dissolving the raw materials under stirring at room temperature, rapidly heating to 70 deg.C, blocking, stirring, reacting for 6 hr, sampling (diluting with ethyl acetate), and detecting by TLC (DCM: MeOH ═ MeOH)12:1), completely reacting the raw material compound 1, adding acetic anhydride to react for 0.5h, taking a sample point plate, completely reacting an intermediate, bringing the reaction mixture to 20 ℃, adding triethylamine hydrobromide solution (200mL), stirring for 1h, performing suction filtration, and washing with water to obtain a gray solid. Ethyl acetate was added to the reaction solution to dissolve the mixture, anhydrous magnesium sulfate was added to the mixture to dry the mixture, and insoluble matter (salt and insoluble catalyst) was filtered off and washed with ethyl acetate. Concentrating the filtrate to low volume, adding n-hexane, pulping at 65 deg.C for 30min, cooling to 20 deg.C, stirring for 1h, vacuum filtering the solid, and vacuum drying to obtain brown yellow solid, i.e. compound 1, with yield of 88.9% and purity of 98.6%.

Comparative examples 1 to 7

Referring to example 1, the base, catalyst, solvent or temperature were adjusted and the results were as follows:

Claims

1. a preparation method of a compound shown as a formula 1 is characterized by comprising the following steps: in a water-soluble organic solvent, under the action of alkali and a catalyst, reacting a compound 2 with a compound 3 at a temperature of 65-75 ℃; wherein the catalyst is PdCl₂(ii) a The water-soluble organic solvent is N-methyl-2-pyrrolidone;

wherein, X is Br or I; r is H or C₁～C₃Alkyl group of (1).

2. The method of claim 1, wherein C is₁～C₃The alkyl group of (a) is methyl, ethyl or propyl.

3. The method of claim 1, wherein the base is one or both of triethylamine and N, N-diisopropylethylamine.

4. The method according to claim 1, wherein the molar ratio of the catalyst to the compound 2 is 0.02 to 1.2.

5. The method according to claim 4, wherein the catalyst and the compound 2 are used in a molar ratio of 0.03 to 1.

6. The method according to claim 4, wherein the molar ratio of the catalyst to the compound 2 is 0.03 to 0.05.

7. The method according to claim 1, wherein the amount of the water-soluble organic solvent and the compound 2 is 3 to 6: 1.

8. The method according to claim 7, wherein the water-soluble organic solvent and the compound 2 are used in an amount of 4: 1.

9. The preparation method according to claim 1, wherein the molar ratio of the compound 2 to the compound 3 is 4: 5-8.

10. The preparation method according to claim 9, wherein the molar ratio of the compound 2 to the compound 3 is 6-7: 10.

11. The method of claim 9, wherein the compound 2 and the compound 3 are used in a molar ratio of 2: 3.

12. The method of claim 1, wherein the reaction time is measured by HPLC, TLC, GC or NMR to determine whether the end point of the reaction is reached.

13. The method of claim 12, wherein the reaction time is checked by TLC to determine whether the end point of the reaction is reached.

14. The method of claim 1, further comprising a post-treatment after the reaction, the post-treatment comprising: and after the reaction is finished, reacting the reaction solution of the reaction with acetic anhydride to obtain a reaction mixture, crystallizing, filtering, drying and washing.

15. The method according to claim 14, wherein the acetic anhydride is used in an amount of 15 to 20 equivalents based on the compound 1.

16. The method according to claim 14, wherein the crystallization is carried out by cooling the reaction mixture to 20-25 ℃ and reacting with triethylamine hydrobromide solution.