CN114539251B - Pyrido [2,3-d ] pyrimidine derivative and preparation method and application thereof - Google Patents

Pyrido [2,3-d ] pyrimidine derivative and preparation method and application thereof Download PDF

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CN114539251B
CN114539251B CN202210267098.1A CN202210267098A CN114539251B CN 114539251 B CN114539251 B CN 114539251B CN 202210267098 A CN202210267098 A CN 202210267098A CN 114539251 B CN114539251 B CN 114539251B
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马肖克
黄国祥
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Hangzhou Brown Bio-Pharm Co ltd
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Abstract

The invention relates to a pyrido [2,3-d ] pyrimidine derivative, a preparation method and application thereof, which adopts cheap silver as a catalyst for catalytic reaction and directly synthesizes a key intermediate pyrido [2,3-d ] pyrimidine derivative of palbociclib by a one-step method. The invention shortens the synthetic route, adopts the reagent which has cheaper price and is easy to purchase and transport, has simple operation, stable product yield and high purity, and can be directly used for the next synthesis of the palbociclib medicament.

Description

Pyrido [2,3-d ] pyrimidine derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a pyrido [2,3-d ] pyrimidine derivative, and a preparation method and application thereof.
Background
Palbociclib (Palbociclib) is an oral cyclin-dependent kinase (CDKs) 4/6 inhibitor. (CDKs) 4/6 is a key regulator of the cell cycle, which can trigger cell cycle progression. IBRANCE in the united states is indicated for the treatment of metastatic disease in patients with estrogen receptor positive, HER2 negative (er+/HER 2-) post-menopausal advanced breast cancer in combination with letrozole as an initial endocrine therapy-based regimen. The structural formula is as follows:
at present, the preparation methods and the similar methods of the palbociclib disclosed in the international literature are not more, the research and development routes of most patents are similar, and patent WO 2016030439A1 discloses a synthetic route of the palbociclib, wherein 5-bromo-2, 4-dichloropyrimidine is used as a raw material to prepare a compound 1, in tetrahydrofuran, is subjected to Heck coupling with crotonic acid, and is condensed to prepare a compound 2,2 and NBS, and carbonyl alpha bromination is performed to prepare a key compound 5; and then condensing 5-bromo-2-nitropyridine serving as a raw material with Boc piperazine in DMSO to generate a compound, and hydrogenating and reducing nitro in isopropanol to obtain another key compound 2. The intermediate 2 and the intermediate 5 are condensed in the presence of an organomagnesium or organolithium reagent to prepare compounds 7 and 7, the compounds 7 and vinyl butyl ether are subjected to heck reaction again to prepare compounds 8 and 8, deprotection is carried out under acidic condition, and the target compound 9 is prepared through basification. The synthetic route is as follows:
in addition, other documents such as patent CN201010255766.6, CN201110115074.6, EP1740184A1, etc. describe the synthesis of palbociclib, and most of the patents describe similar development routes, the synthesis routes are as follows:
in summary, the following drawbacks exist in the process of preparing palbociclib; three steps are needed, namely three steps of reaction of bromination, palladium catalytic coupling of olefin, hydrolysis and carbonyl transformation, etc.; the C-3 acetyl pyrido [2,3-d ] pyrimidine derivatives can be obtained, the preparation yield of the intermediate is low, a plurality of complex noble metal auxiliary reagents and organometallic reagents which are harsh to the reaction conditions are used, and the industrial production is not easy.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a pyrido [2,3-d ] pyrimidine derivative, and a preparation method and application thereof. The key intermediate of the pyridine [2,3-d ] pyrimidine derivative of the palbociclib is directly synthesized by a one-step method, the synthesis route is shortened, the reagent which is cheaper in price and easy to purchase and transport is adopted, the operation is simple, the product yield is stable, the purity is high, and the intermediate can be directly used for the next synthesis of the palbociclib medicament.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the structural formula of the pyrido [2,3-d ] pyrimidine derivative is shown as (I):
in the formula (I), R 1 、R 2 、R 3 The combination mode of (a) and (b) is any one of the following:
(a)R 1 is chloro; r is R 2 Is any one of methyl, cyclopropyl and cyclopentyl; r is R 3 Is methyl or phenyl；
(b)R 1 Is any one of methyl, chloro and bromo; r is R 2 Is cyclopentyl; r is R 3 Is methyl or phenyl.
Preferably, the R 1 Is chloro; r is R 2 Is any one of methyl, cyclopropyl and cyclopentyl; r is R 3 Is methyl.
Preferably, the R 1 Is chloro; r is R 2 Is any one of cyclopentyl; r is R 3 Is phenyl.
When R is 1 When the compound is chloryl, R 2 Is methyl, cyclopropyl, cyclopentyl, R 3 Is methyl; pyrido [2,3-d ]]The structural formulas of the pyrimidine derivatives are respectively shown as (I-1), (I-2) and (I-3):
when R is 1 Is chloro, R 2 Is cyclopentyl, R 3 When phenyl; pyrido [2,3-d ]]The structural formula of the pyrimidine derivative is shown as (I-4):
the invention also provides a preparation method of the pyrido [2,3-d ] pyrimidine derivatives, which comprises the following steps:
(1) Adding a compound with a structural formula shown in (II), a compound with a structural formula shown in (III), an oxidant and a silver catalyst into a reaction vessel, adding a solvent, and placing the reaction vessel in an oil bath for reaction;
(2) After the reaction is finished, the pyrido [2,3-d ] pyrimidine derivatives with the structural formula shown in (I) are obtained through filtration, extraction, concentration, separation and purification.
Preferably, the excess silver salt is recovered and recycled after the reaction. The invention can be prepared by silver catalysis and one-step decarboxylation, wherein the silver catalyst can be recovered, the silver salt can be recycled, and the excessive Ag after the reaction 2 CO 3 And all silver species can be filtered with nitric acid and Na 2 CO 3 Treatment of recovered and regenerated Ag 2 CO 3 Such acylation functionalization can still be promoted in comparable yields without deactivation.
Preferably, the reaction temperature in step (1) is 60 to 80 ℃.
Preferably, the silver catalyst is one of silver carbonate, silver nitrate and silver acetate.
Preferably, the oxidant is K 2 S 2 O 8 。
Preferably, the molar ratio of the compound with the structural formula shown in the formula (II), the compound with the structural formula shown in the formula (III), the oxidant and the silver catalyst is 1:2:2:0.2 to 0.4; the solvent is acetonitrile water solution, wherein the mass ratio of acetonitrile to water is 1:0.5 to 1.
The application of the pyrido [2,3-d ] pyrimidine derivatives in preparing the drug of the palbociclib. The intermediate prepared by the invention can be directly used for the next step of synthesis of the palbociclib drug.
The synthetic method of the pyrido [2,3-d ] pyrimidine derivatives provided by the invention is scientific and reasonable, and adopts cheap silver as a catalyst to catalyze the reaction, and the key intermediate of the Palbociclib drug is synthesized by a green and efficient synthetic method.
The invention has the technical effects that:
(1) The metal silver is used as a catalyst, and the C-C decarboxylation coupling reaction of the pyrido [2,3-d ] pyrimidine derivative is carried out under a mild condition, so that the problems of the traditional noble metal Pd catalyst and the like are solved;
(2) The pyruvic acid is used as a raw material, the cost of the raw material is lower, and the key intermediate pyrido [2,3-d ] pyrimidine derivative of the palbociclib is directly synthesized by a one-step method, so that the synthetic route is shortened; solves the complex steps of performing Heck reaction and decarboxylation by using vinyl butyl ether as raw material in the prior art, and promotes the industrialization of a reaction system by using a green and efficient synthesis method;
(3) The pyrido [2,3-d ] pyrimidine compounds with different substituents are efficiently expanded, the 5-cyclopentyl substituted pyrido [2,3-d ] pyrimidine and pyruvic acid participate in the reaction, the operation is simple, the yield and purity of the product are greatly improved, the yield of the target product can be up to more than 83%, the product is an important intermediate of the palbociclib, and the intermediate can be directly used for the next step of synthesis of the palbociclib drug.
Drawings
FIG. 1 is a schematic illustration of a compound prepared in accordance with example 1 of the present invention 1 H NMR spectrum;
FIG. 2 is a schematic illustration of a compound prepared in accordance with example 1 of the present invention 13 C NMR spectrum.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto. Those skilled in the art can and should appreciate that any simple changes or substitutions based on the true spirit of the invention should fall within the scope of the invention as hereinafter claimed.
The experimental methods described in the examples, unless otherwise specified, are all conventional; the reagents and materials, unless otherwise specified, are commercially available.
Example 1
6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Preparation of pyrimidin-7 (8H) -ones (R 1 =chloro, R 2 =cyclopentyl, R 3 Methyl group =
2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] were each introduced into a 25mL reaction tube]Pyrimidin-7 (8H) -one (1.0 mmol,263 mg), pyruvic acid(2.0 mmol,176 mg), silver carbonate (0.2 mmol,55 mg), K 2 S 2 O 8 (2 mmol,540 mg) and 5mL of acetonitrile and 5mL of aqueous solution were reacted in an oil bath at 70℃for 6 hours, and detected by TLC. After the reaction is finished, filtering by diatomite, extracting by water and ethyl acetate, collecting an organic phase, concentrating under reduced pressure, using petroleum ether as a recrystallization solvent, cooling, crystallizing, separating and purifying to obtain a white solid product 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] with the purity of more than 99 percent]Pyrimidin-7 (8H) -one 253.78mg, 83% yield.
6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Structure of pyrimidin-7 (8H) -ones 1 H NMR spectrum 13 The C NMR spectra are shown in FIG. 1 and FIG. 2:
1 H NMR(400MHz,Chloroform-d)δ8.89(s,1H),5.94–5.83(m,1H),2.58(s,3H),2.43(s,3H),2.24(dt,J＝14.1,7.0Hz,2H),2.19–2.11(m,2H),1.96(dt,J＝9.9,4.9Hz,2H),1.75–1.68(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ201.60,160.45,157.18,155.36,140.01,135.15,113.06,31.32,28.75,26.10,14.23。
analysis results show that the obtained target product is correct.
Example 2
6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Preparation of pyrimidin-7 (8H) -ones (R 1 =chloro, R 2 =cyclopentyl, R 3 Methyl group =
2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] were each introduced into a 25mL reaction tube]Pyrimidin-7 (8H) -one (1.0 mmol,263 mg), pyruvic acid (2.0 mmol,176 mg), silver nitrate (0.2 mmol,35 mg), K 2 S 2 O 8 (2 mmol,540 mg) and 5mL of acetonitrile and 5mL of aqueous solution were reacted in an oil bath at 70℃for 6 hours, and detected by TLC. After the reaction is finished, filtering by diatomite, extracting by water and ethyl acetate, collecting an organic phase, concentrating under reduced pressure, using petroleum ether as a recrystallization solvent, cooling, crystallizing, separating and purifying to obtain a white solid product 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] with the purity of more than 99 percent]Pyrimidin-7 (8H) -one 235.43mg, 77% yield.
Structural identification of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one:
1 H NMR(400MHz,Chloroform-d)δ8.89(s,1H),5.94–5.83(m,1H),2.58(s,3H),2.43(s,3H),2.24(dt,J＝14.1,7.0Hz,2H),2.19–2.11(m,2H),1.96(dt,J＝9.9,4.9Hz,2H),1.75–1.68(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ201.60,160.45,157.18,155.36,140.01,135.15,113.06,31.32,28.75,26.10,14.23。
analysis results show that the obtained target product is correct.
Example 3
6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Preparation of pyrimidin-7 (8H) -ones (R 1 =chloro, R 2 =cyclopentyl, R 3 Methyl group =
2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] were each introduced into a 25mL reaction tube]Pyrimidin-7 (8H) -one (1.0 mmol,263 mg), pyruvic acid (2.0 mmol,176 mg), silver acetate (0.2 mmol,33 mg), K 2 S 2 O 8 (2 mmol,540 mg) and 5mL of acetonitrile and 5mL of aqueous solution were reacted in an oil bath at 70℃for 6 hours, and detected by TLC. After the reaction is finished, filtering by diatomite, extracting by water and ethyl acetate, collecting an organic phase, concentrating under reduced pressure, using petroleum ether as a recrystallization solvent, cooling, crystallizing, separating and purifying to obtain a white solid product 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] with the purity of more than 99 percent]Pyrimidin-7 (8H) -one 220.14mg with a yield of 72%.
Structural identification of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one:
1 H NMR(400MHz,Chloroform-d)δ8.89(s,1H),5.94–5.83(m,1H),2.58(s,3H),2.43(s,3H),2.24(dt,J＝14.1,7.0Hz,2H),2.19–2.11(m,2H),1.96(dt,J＝9.9,4.9Hz,2H),1.75–1.68(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ201.60,160.45,157.18,155.36,140.01,135.15,113.06,31.32,28.75,26.10,14.23。
analysis results show that the obtained target product is correct.
Example 4
6-benzoyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Pyrimidine-7 (8H)) Preparation of ketones (R 1 =chloro, R 2 =cyclopentyl, R 3 =phenyl group)
2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] were each introduced into a 25mL reaction tube]Pyrimidin-7 (8H) -one (1.0 mmol,263 mg), benzoylformic acid (2.0 mmol,300 mg), silver carbonate (0.2 mmol,55 mg), K 2 S 2 O 8 (2 mmol,540 mg) and 5mL of acetonitrile and 5mL of aqueous solution were reacted in an oil bath at 70℃for 6 hours, and detected by TLC. After the reaction is finished, filtering by diatomite, extracting by water and ethyl acetate, collecting an organic phase, concentrating under reduced pressure, using petroleum ether as a recrystallization solvent, cooling, crystallizing, separating and purifying to obtain a white solid product 6-benzoyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] with the purity of more than 99 percent]Pyrimidin-7 (8H) -one 338.40mg, 92% yield.
Structural identification of 6-benzoyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one:
1 H NMR(400MHz,Chloroform-d)δ8.90(s,1H),7.92(d,J＝7.4Hz,2H),7.66(t,J＝7.4Hz,1H),7.52(t,J＝7.7Hz,2H),5.91(p,J＝8.7Hz,1H),2.37(s,3H),2.25(dq,J＝14.0,7.1,6.7Hz,2H),2.11(td,J＝11.7,11.0,6.4Hz,2H),2.00–1.91(m,2H),1.68(dq,J＝10.1,5.1,4.6Hz,2H)。
analysis results show that the obtained target product is correct.
Example 5
6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Preparation of pyrimidin-7 (8H) -ones (R 1 =chloro, R 2 =cyclopentyl, R 3 Methyl group =
2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] were each introduced into a 25mL reaction tube]Pyrimidin-7 (8H) -one (1.0 mmol,263 mg), pyruvic acid (2.0 mmol,176 mg), silver carbonate (0.4 mmol,66 mg), K 2 S 2 O 8 (2 mmol,540 mg) and 5mL of acetonitrile and 5mL of aqueous solution were reacted in an oil bath at 70℃for 6 hours, and detected by TLC. Filtering with diatomite, extracting with water and ethyl acetate, collecting organic phase, concentrating under reduced pressure, using petroleum ether as recrystallization solvent, cooling, crystallizing, separating and purifying to obtain white solid product 6-acetyl-2-chloro-8-ring with purity of more than 99%Amyl-5-methylpyrido [2,3-d ]]Pyrimidin-7 (8H) -one 238.49mg, 78% yield.
Structural identification of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one:
1 H NMR(400MHz,Chloroform-d)δ8.89(s,1H),5.94–5.83(m,1H),2.58(s,3H),2.43(s,3H),2.24(dt,J＝14.1,7.0Hz,2H),2.19–2.11(m,2H),1.96(dt,J＝9.9,4.9Hz,2H),1.75–1.68(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ201.60,160.45,157.18,155.36,140.01,135.15,113.06,31.32,28.75,26.10,14.23。
analysis results show that the obtained target product is correct.
Example 6
6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Preparation of pyrimidin-7 (8H) -ones (R 1 =chloro, R 2 =cyclopentyl, R 3 Methyl group =
2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] were each introduced into a 25mL reaction tube]Pyrimidin-7 (8H) -one (1.0 mmol,263 mg), pyruvic acid (2.0 mmol,176 mg), silver carbonate (0.2 mmol,66 mg), K 2 S 2 O 8 (2 mmol,540 mg) and 6mL of acetonitrile and 3mL of aqueous solution were reacted in an oil bath at 70℃for 6 hours, and detected by TLC. After the reaction is finished, filtering by diatomite, extracting by water and ethyl acetate, collecting an organic phase, concentrating under reduced pressure, using petroleum ether as a recrystallization solvent, cooling, crystallizing, separating and purifying to obtain a white solid product 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] with the purity of more than 99 percent]Pyrimidin-7 (8H) -one 189.57mg with 62% yield.
Structural identification of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidin-7 (8H) -one:
1 H NMR(400MHz,Chloroform-d)δ8.89(s,1H),5.94–5.83(m,1H),2.58(s,3H),2.43(s,3H),2.24(dt,J＝14.1,7.0Hz,2H),2.19–2.11(m,2H),1.96(dt,J＝9.9,4.9Hz,2H),1.75–1.68(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ201.60,160.45,157.18,155.36,140.01,135.15,113.06,31.32,28.75,26.10,14.23。
analysis results show that the obtained target product is correct.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.

Claims (4)

1. A process for the preparation of formula (I-3), characterized by the steps of:
(1) 2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ]]Adding pyrimidine-7 (8H) -ketone, pyruvic acid, an oxidant and a silver catalyst into a reaction vessel, adding a solvent, and placing the reaction vessel into an oil bath kettle for reaction; the silver catalyst is one of silver carbonate, silver nitrate and silver acetate, and the oxidant is K 2 S 2 O 8 The solvent is acetonitrile water solution, wherein the mass ratio of acetonitrile to water is 1: 0.5-1;
(2) After the reaction is finished, filtering, extracting, concentrating, separating and purifying to obtain a product of the formula (I-3);
。
2. the method of manufacturing according to claim 1, characterized in that: and (5) recycling the superfluous silver salt after the reaction.
3. The method of manufacturing according to claim 1, characterized in that: the reaction temperature in the step (1) is 60-80 ℃.
4. The method of manufacturing according to claim 1, characterized in that: the molar ratio of the 2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d ] pyrimidine-7 (8H) -ketone to the pyruvic acid to the oxidant to the silver catalyst is 1:2:2:0.2 to 0.4.
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