CN102898449A - Method for synthesizing Crizotinib intermediate - Google Patents

Abstract

The present invention belongs to the technical field of drug synthesis, and specifically relates to a method for synthesizing an intermediate of Crizotinib . ) as raw material, react with 4- nitropyrazole to prepare compound 3 ; b ) use hydrazine hydrate to reduce the nitro group to obtain amino compound 4 ; In the presence of benzoyl oxide , react with boronate compound 5 to prepare Crizotinib intermediate ( 1 ). Compared with the existing synthetic method, the inventive method has the following advantages: use the diazotization method to synthesize the boric acid ester product, compared with the existing method, that is, the Pd- catalyzed Miyaura boronation method, this method avoids the use of expensive palladium Catalyst and ligand, and has the advantages of mild reaction conditions, high yield, simple operation, cheap and easy to obtain raw materials, short reaction cycle, etc., and is very easy for industrialized large-scale production.

Description

A kind of method of synthetic crizotinib intermediate

technical field

The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing a crizotinib intermediate (compound 1).

Background technique

Crizotinib is a new drug (WO 2006021881, EP 1784396, CN 1010187800) developed by Pfizer for the treatment of non-small cell lung cancer (accounting for 80-85% of the total lung cancer). Approved by the US FDA for marketing. English product name is Xalko, Chinese chemical name: 3-[( 1R)-1-( 2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-( 4-piperidinyl) -1H-pyrazol-4-yl]-2-pyridinamine; English chemical name: (R)-3-[1-(2,6-dichloro-3-fluorophenyl)–ethoxy-5-(1-piperidin- 4-yl-1H–pyrazol -4-yl)-pyridin-2-ylamine. the

The molecular structural formula is as follows:

Crizotinib

Crizotinib is mainly used for the treatment of anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (non-small-cell lung cancer, NSCLC). Drugs to treat this disease. Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (c-Met, HGFR) and tyrosine kinase receptor (RON), by inhibiting ALK and c- Met phosphorylation blocks tumor cell growth and survival, and is used for ALK-positive advanced NSCLC patients (Helen Y Z, et al . Cancer Res., 2007 , 67(9) , 4408-4417), and crizotinib is the first in the world Oral ALK inhibitors.

Anaplastic lymphoma kinase (ALK) was first discovered in anaplastic large cell lymphoma (ALCL), and it is an important molecular marker of anaplastic large cell lymphoma. In recent years, researchers have also discovered that ALK gene is involved in the occurrence and development of tumors play an important role in. Crizotinib acts as a small-molecule ATP-competitive inhibitor of the hepatocyte growth factor receptor c-Met protein, ALK, and their oncogenic variants. In vitro studies have confirmed that Crizotinib can not only inhibit c-Met and ALK in tumor cells, but also have a strong inhibitory effect on tumor cells with ALK gene translocation or inversion; clinical studies have shown that: it can inhibit ALK-positive The survival of patients with non-small cell lung cancer (NSCLC) has been significantly improved, and more than 90% of patients have shown tumor shrinkage, and it is well tolerated and safe. Therefore, the launch of Crizotinib is of great significance for the treatment of patients with non-small cell lung cancer.

The synthesis method of Crizotinib is generally realized according to the following reaction scheme (Pieter D K, et al. Org. Process Res. Dev., 2011 , 15 , 1018-1026):

It can be found from the above synthetic route that compound 1 is a key intermediate for the synthesis of Crizotinib , and its molecular structural formula is as follows:

Compound 1

The important intermediate of Crizotinib , that is, the synthesis method of compound 1 can generally be prepared by the following route (WO 2009036404):

1

Existing methods all utilize the Miyaura boronation method to synthesize boroester compound 1 , need to use expensive palladium catalyst and ligand in the reaction, and the preparation cost of reaction substrate iodide is also higher; Reaction under anaerobic conditions, the cost is high and the operation is cumbersome, so this route is difficult to apply to industrial production.

Contents of the invention

The purpose of the present invention is to provide a new method for synthesizing the intermediate (compound 1) of crizotinib (Crizotinib) easily and at low cost in industry.

The method for the synthesis of crizotinib (Crizotinib) intermediate (compound 1) proposed by the present invention, its synthetic route is as follows:

Wherein: ^R in the borate ester represents a hydrogen atom, any alkoxy group or borate ester with a carbon number of 1 to 20; ^R represents a hydrogen atom, any alkyl or aryl group with a carbon number of 1 to 20 ; R ³ represents a hydrogen atom, and the number of carbon atoms is any alkyl or aryl group with 1 to 20 carbon atoms. Among them, double pinacol borate is preferred.

Specific steps are as follows:

(1) Use tert-butyl 4-methanesulfonate piperidine-1-carboxylate (compound 2 ) as raw material, react with 4-nitropyrazole in a solvent in the presence of a base, and the reaction temperature is -5°C To the solvent reflux temperature, the reaction time is 1-24 hours, generating tert-butyl 4-[4-amino-1H-pyrazol-1-yl]piperidine-1-carboxylate (compound 3 ); wherein: base and 4- The molar ratio of tert-butyl mesylate piperidine-1-carboxylate is 1:1-3:1; The molar ratio is 1:1-1.5:1;

(2) In a solvent, under the condition of a reducing agent, 4-[4-amino-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (compound 3) is reduced to 4-[4 -Amino-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (compound 4 ); wherein: reducing agent and 4-[4-amino-1H-pyrazol-1-yl]piperidine- The molar ratio of 1-tert-butyl formate is 1:1-5:1; the reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is 1-24 hours;

(3) In a solvent, under the action of a diazotization reagent and an initiator, react with a borate (compound 5 ) to obtain a crizotinib intermediate (compound 1 ); wherein: the diazotization reagent The molar ratio to 4-[4-amino-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester is 1:1-3:1, the initiator and 4-[4-amino-1H- The molar ratio of pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester is 0.1:1-0.01:1; borate and 4-[4-amino-1H-pyrazol-1-yl]piperidine - The molar ratio of 1-tert-butyl formate is 1:1-1.5:1; the reaction temperature is from -5°C to the solvent reflux temperature, and the reaction time is 1-24 hours.

In the present invention, the alkali described in step (1) is selected from any one of sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or sodium ethoxide, wherein sodium hydride is preferably .

In the present invention, the solvent described in step (1) is selected from any one of dimethyl sulfoxide, N,N-dimethylformamide, toluene or xylene, wherein N,N-dimethylformamide is preferred.

In the present invention, the molar ratio of base to tert-butyl 4-methanesulfonate piperidine-1-carboxylate in step (1) is 1.5:1-1.7:1.

In the present invention, the reaction temperature in step (1) is 100° C.; the reaction time is 8-10 h.

In the present invention, the reducing agent described in the step (2) is selected from any one of hydrazine hydrate, hydrogen/palladium carbon, stannous chloride, iron powder/concentrated hydrochloric acid, zinc powder/acetic acid or hydrochloric acid, wherein preferably hydrated Hydrazine.

In the present invention, the solvent in step (2) is selected from ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol or ethyl acetate, wherein methanol is preferred.

In the present invention, the molar ratio of the reducing agent to 4-[4-amino-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester in step (2) is 2:1-3:1 .

In the present invention, the reaction temperature in step (2) is 60-65°C; the reaction time is 2-4h.

In the present invention, the diazotization reagent described in step (3) is selected from sodium nitrite or alkyl nitrite; the alkyl group in the alkyl nitrite is generally a straight chain or a straight chain with 3 to 6 carbon atoms. A branched chain alkyl group, preferably an alkyl group with 4 to 5 carbon atoms, such as tert-butyl nitrate, n-pentyl nitrite, isoamyl nitrite, among which tert-butyl nitrite is preferred.

In the present invention, the solvent in step (3) is selected from any one of ethyl acetate, dichloromethane, 1,2-dichloroethane or acetonitrile, wherein acetonitrile is preferred.

In the present invention, the initiator described in step (3) is selected from any one of benzoyl peroxide, benzoyl tert-butyl peroxide or azobisisobutyronitrile, wherein benzoyl peroxide is preferred.

In the present invention, the molar ratio of the diazotization reagent described in step (3) to 4-[4-amino-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester is 1.3:1-1.5 :1; the molar ratio of initiator and 4-[4-amino-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester is 0.02:1, borate and 4-[4-amino- The molar ratio of tert-butyl 1H-pyrazol-1-yl]piperidine-1-carboxylate is 1:1.

In the present invention, the reaction temperature in step (3) is 20°C, and the reaction time is 2-3h.

Compared with the prior art, the present invention has the advantages that: the present invention adopts a brand-new synthetic route, taking 4-methylsulfonate piperidine-1-formic acid tert-butyl as raw material to react with 4-nitropyrazole, and then After reduction, diazotization and borate reaction, the intermediate of Crizotinib (Compound 1 ) was obtained. This method not only can easily synthesize the crizotinib (Crizotinib) intermediate (compound 1 ), but also the raw material amino substrate (compound 4 ) is cheaper to prepare than the previous iodo substrate, and because it avoids the use of The expensive palladium catalyst further reduces the preparation cost. At the same time, because the reaction involved in this route does not require strict anhydrous and oxygen-free conditions, it can be carried out smoothly under mild conditions, so it is very convenient for industrial production and application.

Detailed ways

The present invention is further illustrated by the following examples, but the content of the present invention can not be limited.

Example 1:

Add 4-nitropyrazole (3.73 g, 0.033 mol) and 80 mL of N,N-dimethylformamide into the reactor. Cool in an ice bath to 0°C, stir, add sodium hydride (0.93 g, 0.038 mol) in batches, stir at the same temperature for 1 h after addition, add compound 2 (10.0 g, 0.036 mol) to the reaction solution, heat up to 100°C, and react for 12 h . Cool, add 400 mL of water, extract with 400 mL of ethyl acetate three times, dry over anhydrous sodium sulfate, filter and spin dry to obtain the crude product, and recrystallize from ethyl acetate petroleum ether to obtain compound 3 (7.8 g, yield 80%).

Example 2:

Add 4-nitropyrazole (3.73 g, 0.033 mol) and 100 mL of dimethyl sulfoxide to the reactor. Cool in an ice bath to 0°C, stir, add potassium hydroxide (0.93 g, 0.038 mol) in batches, stir at the same temperature for 1 h after addition, add compound 2 (10 g, 0.036 mol) to the reaction solution, raise the temperature to 80°C, and react 18 h. Cool, add 400 mL of water, extract three times with 400 mL of ethyl acetate, dry over anhydrous sodium sulfate, filter and spin dry to obtain the crude product, recrystallize from ethyl acetate petroleum ether to obtain compound 3 (7.1 g, yield 72%).

Example 3:

Add 4-nitropyrazole (3.73 g, 0.033 mol) and 80 mL of toluene into the reactor. Cool in an ice bath to 5 °C, stir, add potassium tert-butoxide (0.93 g, 0.038 mol) in batches, stir at the same temperature for 1 h after addition, add compound 2 (10 g, 0.036 mol) to the reaction solution, heat up to 108 °C, and react 10 h. Cooled, added 400 mL of water, separated, extracted three times with 400 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product, recrystallized from ethyl acetate/petroleum ether to obtain compound 3 (7.4 g, yield 76% ).

Example 4:

Add compound 3 (6.7 g, 0.023 mol), 67 mL of methanol, 2.2 g of carbon powder, 0.3 g of ferric chloride to the reactor, stir and raise the temperature to reflux, add hydrazine hydrate (3.67 g, 0.069 mol), and stir at the same temperature after adding 2 h. Cool, filter with suction, wash the filter cake with methanol, and spin dry to obtain the crude compound 4 (6 g), which can be directly used in the next reaction without purification.

Example 5:

At room temperature, compound 3 (6.7 g, 0.023 mol), 67 mL of ethyl acetate, 10% palladium on carbon were added to the reactor, replaced by hydrogen, and stirred at the same temperature for 2.5 h after addition. After suction filtration, the filter cake was washed with ethyl acetate, and spin-dried to obtain crude compound 4 (6.1 g), which was directly used in the next reaction without further purification.

Embodiment 6:

At room temperature, compound 3 (70 g, 0.24 mol) and 670 mL of acetic acid were added to the reactor, and zinc powder (75 g, 1.15 mol) was added in batches, and stirred at the same temperature for 2 h after addition. Add ammonia water to adjust pH=9, filter with suction, wash the filter cake with 100 mL ethyl acetate, extract twice with 1200 mL ethyl acetate, dry over anhydrous sodium sulfate, filter, and spin dry to obtain the crude compound 4 (65 g), which can be obtained without purification. used directly in the next reaction.

Embodiment 7:

At room temperature, compound 3 (70 g, 0.24 mol) and 670 mL of hydrochloric acid were added to the reactor, and iron powder (134.4 g, 2.4 mol) was added in batches. After the addition, the temperature was raised to 50 °C and stirred for 5 h. Add sodium hydroxide to adjust pH=9, filter with suction, wash the filter cake with 100 mL ethyl acetate, extract twice with 1200 mL ethyl acetate, dry over anhydrous sodium sulfate, filter, and spin dry to obtain the crude compound 4 (60 g), It can be directly used in the next reaction without purification.

Embodiment 8:

At room temperature, 34 mL of ethyl acetate, bis-pinacol borate (0.32 g, 0.0013 mol), 7 mg of azobisisobutyronitrile, compound 4 (0.34 g, 0.0013 mol), Stir, add tert-butyl nitrite (0.1 g, 0.002 mol) dropwise, stir at 20°C for 2 h, spin to dry the solvent, column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 1 (0.38 g, 79 %).

Embodiment 9:

At room temperature, add 34 mL of dichloromethane, pinacol borate (6.5 g, 0.052 mol), 0.14 g of benzoyl peroxide, and compound 4 (6.9 g, 0.026 mol) into the reaction flask in sequence, stir and drop Add n-amyl nitrite (2 g, 0.02 mol), stir at 40°C for 1.5 h, spin to dry the solvent, and obtain compound 1 (8 g, 80%) by column chromatography (petroleum ether: ethyl acetate = 1:2).

Example 10:

At room temperature, 34 mL of 1,2-dichloroethane, diethyl borate (2.65 g, 0.026 mol), 0.14 g of benzoyl peroxide, compound 4 (6.9 g, 0.026 mol), Stir, add isoamyl nitrite (2 g, 0.02 mol) dropwise, stir at 25°C for 2.0 h, spin to dry the solvent, column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 1 (7.5 g, 82 %).

Example 11:

At room temperature, 34 mL of acetonitrile, double-linked pinacol borate (6.5 g, 0.026 mol), 0.12 g of benzoyl tert-butyl peroxide, compound 4 (6.9 g, 0.026 mol), Stir, add sodium nitrite (2.8 g, 0.04 mol), stir at 20°C for 12 h, spin to dry the solvent, column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 1 (4 g, 40%).

Product NMR: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.85(s, 1H), 7.73 (s, 1H), 4.30 (m, 3H), 2.92 (m, 2H), 2.16(m, 2H), 1.93 (m, 2H), 1.51 (s, 9H), 1.35 (s, 12H); MS: m/z 378.1 [M+H] ⁺ .

Claims (10)

1. the method for a synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate is characterized in that synthetic route is as follows:

Wherein: the R in boric acid ester ¹mean any alkoxyl group or boric acid ester that hydrogen atom, carbonatoms are 1 ~ 20; R ²mean any alkyl or aryl that hydrogen atom, carbonatoms are 1 ~ 20; R ³mean that hydrogen atom, carbonatoms are 1 ~ 20 any alkyl or aryl;

Concrete steps are as follows:

(1) take 4-methanesulfonates piperidines-1-t-butyl formate is raw material, under the existence of alkali, with the 4-nitropyrazole, in solvent, reacted, temperature of reaction be-5 ℃ to the solvent refluxing temperature, the reaction times is 1-24 hour, generates 4-[4-amino-1H-pyrazol-1-yl] piperidines-1-t-butyl formate; Wherein: alkali is 1:1-3:1 with the ratio of the molar weight of 4-methanesulfonates piperidines-1-t-butyl formate; The mol ratio of 4-nitropyrazole and 4-methanesulfonates piperidines-1-t-butyl formate is 1:1-1.5:1;

(2) in solvent, under the condition of reductive agent, by 4-[4-amino-1H-pyrazol-1-yl] piperidines-1-t-butyl formate is reduced to 4-[4-amino-1H-pyrazol-1-yl] piperidines-1-t-butyl formate; Wherein: reductive agent and 4-[4-amino-1H-pyrazol-1-yl] mol ratio of piperidines-1-t-butyl formate is 1:1-5:1; Temperature of reaction be room temperature to the solvent refluxing temperature, the reaction times is 1-24 hour;

(3) in solvent, under diazo reagent and initiator effect, with boric acid ester, react, obtain the (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate; Wherein: diazo reagent and 4-[4-amino-1H-pyrazol-1-yl] mol ratio of piperidines-1-t-butyl formate is 1:1-3:1, initiator and 4-[4-amino-1H-pyrazol-1-yl] mol ratio of piperidines-1-t-butyl formate is 0.1:1-0.01:1; Boric acid ester and 4-[4-amino-1H-pyrazol-1-yl] mol ratio of piperidines-1-t-butyl formate is 1:1-1.5:1; Temperature of reaction is at-5 ℃ to the solvent refluxing temperature, and the reaction times is 1-24 hour.

2. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that alkali described in step (1) is selected from sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate or sodium ethylate any; Described solvent is selected from dimethyl sulfoxide (DMSO), DMF, toluene or dimethylbenzene any.

3. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that the mol ratio of alkali described in step (1) and 4-methanesulfonates piperidines-1-t-butyl formate is 1.5:1-1.7:1.

4. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that in step (1), temperature of reaction is 100 ℃; Reaction times is 8-10h.

5. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that reductive agent described in step (2) is selected from hydrazine hydrate, hydrogen/palladium carbon, tin protochloride, iron powder/concentrated hydrochloric acid, zinc powder/acetic acid or vat powder any; Described solvent is selected from ethyl acetate, methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol or ethyl acetate.

6. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that reductive agent described in step (2) and 4-[4-amino-1H-pyrazol-1-yl] mol ratio of piperidines-1-t-butyl formate is 2:1-3:1.

7. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that described in step (2), temperature of reaction is 60-65 ℃; Reaction times is 2-4h.

8. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that described in step (3), diazo reagent is selected from Sodium Nitrite or alkyl nitriteester; Alkyl in described alkyl nitriteester is the straight or branched alkyl of 3 ~ 6 carbon atoms; Described solvent is selected from ethyl acetate, methylene dichloride, 1, in 2-ethylene dichloride or acetonitrile any; Described initiator is selected from benzoyl peroxide, the benzoyl peroxide tert-butyl ester or Diisopropyl azodicarboxylate any.

9. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that diazo reagent and 4-[4-amino-1H-pyrazol-1-yl in step (3)] mol ratio of piperidines-1-t-butyl formate is 1.3:1-1.5:1; Initiator and 4-[4-amino-1H-pyrazol-1-yl] mol ratio of piperidines-1-t-butyl formate is 0.02:1, boric acid ester and 4-[4-amino-1H-pyrazol-1-yl] mol ratio of piperidines-1-t-butyl formate is 1:1.

10. the method for synthetic (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine intermediate according to claim 1, is characterized in that described in described step (3), temperature of reaction is 20 ℃, and the reaction times is 2-3h.