CN109053727B - Preparation method of ABT-199 intermediate - Google Patents

Abstract

The invention discloses a preparation method of an ABT-199 intermediate, namely a preparation method of 5-bromo-7-azaindole. Specifically, 2-amino-3-methyl-5-bromopyridine is used as an initial raw material to finally synthesize the 5-bromo-7-azaindole in three steps. The preparation method has mild reaction conditions, is easy to operate, does not need anhydrous and anaerobic operation, does not need high temperature and high pressure, and has high safety; the yield of the reaction steps is high; the raw materials are easy to obtain, and the cost is low; the catalytic reaction is carried out without adopting heavy metal; the production process can realize industrialization and can carry out hundred-kilogram production.

Description

Preparation method of ABT-199 intermediate

Technical Field

The invention relates to the technical field of medicines, in particular to a preparation method of an ABT-199 intermediate.

Background

Ebervix announced in 2015 that a new drug developed for treating chronic lymphocytic leukemia, venetocalax (ABT-199), obtained breakthrough drug certification by FDA. The drug is an experimental B cell lymphoma factor-2 (BCL-2) inhibitor. ABT-199/venetocalax showed high response rates as single drug in refractory/relapsed CLL. In particular, high CR rates were shown in refractory/relapsed CLL (29% as single agent combined with rituximab 39%). ABT-199 is therefore prone to a broad spectrum of new hematological malignancies either as an effective single agent or in combination with other drugs. 5-bromo-7-azaindole is a key intermediate for synthesizing a novel drug venetoclax (ABT-199).

In the prior art, e.g. WO2004/78757,2004, A2; CN106045995,2016, a; U.S. Pat. No. 5,2011, 28511,2011,A1 describes processes for the preparation of venetocalax (ABT-199) and intermediates thereof. However, there are generally 3 main processes for the preparation of 5-bromo-7-azaindole: 1. the method is an oxidation reaction, and 5-bromo-2, 3-dihydro-1H-pyrrolyl [2,3-B ] pyridine is oxidized into 5-bromo-7-azaindole, so that the method has the advantages of long oxidation reaction period, generally 5-7 days, easiness in incomplete reaction, low yield, large amount of wastewater generated in the oxidation process and great pressure on environmental protection; 2. the 5-bromo-7-azaoxindole is used for reduction synthesis, a reducing agent such as borane or metal hydride is needed in the reduction reaction, the reaction is not easy to control, and the method is not suitable for industrial production; 3. the pyridine alkynyl compound is subjected to intramolecular ring closure, firstly, the synthesis of the pyridine alkynyl compound adopts metal catalytic reaction and has heavy metal pollution, secondly, the ring closure usually adopts high-pressure autoclave pressurization to promote the production of products, and the high-pressure reaction and related operation have high risk and are not beneficial to industrial production.

Disclosure of Invention

The invention aims to provide a simple, safe and easily-amplified preparation method of an ABT-199 intermediate, namely 5-bromo-7-azaindole.

The invention provides a preparation method of an ABT-199 intermediate, wherein the ABT-199 intermediate is 5-bromo-7-azaindole, and the preparation method comprises the following steps:

(1) synthesis of ethyl (E) -N- (5-bromo-3-methylpyridin-2-yl) carboxylate, the reaction scheme is as follows:

(2) synthesis of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-formimino phenyl ester, reaction formula:

(3) the synthesis of 5-bromo-7-azaindole has the following reaction formula:

alternatively, the process for preparing the ABT-199 intermediate comprises the steps of:

(1) adding 2-amino-3-methyl-5-bromopyridine, trimethyl orthoformate, an acidic catalyst and a first solvent into a reaction kettle, heating and stirring until reflux, reacting for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove the organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formiate;

(2) adding (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formiate, N-methylaniline and a second solvent into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water for stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove the organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-ethyl formiate phenyl ester;

(3) adding (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformiate and a third solvent into a reaction kettle, cooling to 10 ℃, stirring, adding a strong base, controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water and stirring after the reaction of the raw materials is finished, separating liquid, drying an organic phase, evaporating the organic solvent, and recrystallizing to obtain 5-bromo-7-azaindole;

wherein the acidic catalyst is p-toluenesulfonic acid, acetic acid, sulfuric acid or phosphoric acid; the first solvent is 1, 2-dichloromethane, dioxane, tetrahydrofuran or acetonitrile; the second solvent is toluene, xylene or chlorobenzene; the third solvent is ethylene glycol dimethyl ether, dioxane or tetrahydrofuran; the strong base is sodium amide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.

Alternatively, in step (1), the molar ratio of the 2-amino-3-methyl-5-bromopyridine to the trimethyl orthoformate to the acidic catalyst is 1: (0.001-0.003): (2-4).

Alternatively, in step (2), the molar ratio of the (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) carboxylate to N-methylaniline is 1: (1-2).

Alternatively, in step (3), the molar ratio of the phenyl (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-carboxylate to the strong base is 1: (1-1.2).

Alternatively, the process for preparing the ABT-199 intermediate comprises the steps of:

(1) adding 1000mol of 2-amino-3-methyl-5-bromopyridine, 2mol of p-toluenesulfonic acid, 3000mol of trimethyl orthoformate and 950L of 1, 2-dichloromethane into a reaction kettle, heating and stirring until reflux, reacting for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formate;

(2) adding 500mol (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) formate imine, 750mol N-methylaniline and 750L toluene into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformate imine;

(3) adding 100mol of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylimino formate and 300L of ethylene glycol dimethyl ether into a reaction kettle, cooling to 10 ℃, stirring, adding 110mol of sodium amide, controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water and stirring after the reaction of the raw materials is finished, separating liquid, drying an organic phase, evaporating to remove the organic solvent, and recrystallizing to obtain the 5-bromo-7-azaindole.

The invention has the following beneficial effects:

(1) the method has mild reaction conditions, is easy to operate, does not need anhydrous and anaerobic operation, does not need high temperature and high pressure, and has high safety;

(2) the yield of the reaction steps is high;

(3) the invention has the advantages of easily obtained reaction raw materials and low cost;

(4) the reaction of the invention does not need to adopt heavy metal to carry out catalytic reaction;

(5) the production process can realize industrialization and can carry out hundred-kilogram production.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The synthetic route of the ABT-199 intermediate, namely 5-bromo-7-azaindole provided by the invention is as follows

Example 1

(1) Synthesis of ethyl (E) -N- (5-bromo-3-methylpyridin-2-yl) carboxylate

Adding 2-amino-3-methyl-5-bromopyridine (185kg, 1000mol), p-toluenesulfonic acid (3.44kg, 2mol), trimethyl orthoformate (318kg, 3000mol) and 1, 2-dichloromethane (950L) into a reaction kettle, heating and stirring until refluxing are carried out, reacting for 16 hours, adding water and stirring after the raw materials are reacted, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formiate (205.4kg, 84.4mol) with the yield of 84.4%.

(2) Synthesis of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-formimino phenyl ester

Adding (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) formiminium formate (121kg, 500mol), N-methylaniline (160.5kg, 750mol) and toluene (750L) into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-formiminium phenyl ester (1331.5kg, 438mol) with the yield of 87.6%.

(3) Synthesis of 5-bromo-7-azaindole

Adding (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylimino formate (30.4kg, 100mol) and ethylene glycol dimethyl ether (300L) into a reaction kettle, cooling to 10 ℃, stirring, adding sodium amide (4.29kg, 110mol), controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water, stirring, separating, drying an organic phase, evaporating an organic solvent, and recrystallizing to obtain the 5-bromo-7-azaindole (16.5kg, 83.7mol) with the yield of 87.6%.

1H NMR(CDCl3,400MHz)δ6.46(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),8.09(s,1H),8.34(s,1H),10.85(bs,1H).

13C NMR(CDCl3,100MHz)δ100.5,111.4,122.3,126.8,131.4,142.3,146.3.IR(KBr,cm-1)3132,2862,1558,1282,884,740.

In addition to the above examples, the acidic catalyst may be acetic acid, sulfuric acid or phosphoric acid in addition to p-toluenesulfonic acid. The first solvent may be dioxane, tetrahydrofuran or acetonitrile in addition to 1, 2-dichloromethane. The second solvent may be xylene or chlorobenzene, in addition to toluene. The third solvent may be dioxane or tetrahydrofuran in addition to ethylene glycol dimethyl ether. The strong base can be sodium hydride, sodium tert-butoxide or potassium tert-butoxide besides sodium amide, and is used for ring closure after hydrogen is removed.

In addition, in the step (1), the molar ratio of the 2-amino-3-methyl-5-bromopyridine to the trimethyl orthoformate to the acidic catalyst is 1: (0.001-0.003): (2-4). In the step (2), the molar ratio of (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl iminecarboxylate to N-methylaniline is 1: (1-2). In the step (3), the molar ratio of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformiate to strong base is 1: (1-1.2).

Under the conditions, the ABT-199 intermediate, namely 5-bromo-7-azaindole can be prepared, and the yield is higher than 80%.

The preparation method has the advantages of few reaction steps, easy operation and high yield of the reaction steps; the reaction condition is mild, no anhydrous and anaerobic operation is needed, high temperature and high pressure are not needed, the safety is high, the production process can realize industrialization, hundred-kilogram-level production can be carried out, and higher product yield is ensured.

The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure herein. This invention is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims (1)

1. A preparation method of an ABT-199 intermediate is characterized by comprising the following steps:

(1) adding 1000mol of 2-amino-3-methyl-5-bromopyridine, 2mol of p-toluenesulfonic acid, 3000mol of triethyl orthoformate and 950L of 1, 2-dichloromethane into a reaction kettle, heating and stirring until reflux, reacting for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formate;

(2) adding 500mol (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) formate imine, 750mol N-methylaniline and 750L toluene into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformate imine;

(3) adding 100mol of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylimino formate and 300L of ethylene glycol dimethyl ether into a reaction kettle, cooling to 10 ℃, stirring, adding 110mol of sodium amide, controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water and stirring after the reaction of the raw materials is finished, separating liquid, drying an organic phase, evaporating to remove the organic solvent, and recrystallizing to obtain the 5-bromo-7-azaindole.