CN111943885B

CN111943885B - Synthesis method of Laratinib intermediate 2-amino-5-bromo-3-hydroxypyridine

Info

Publication number: CN111943885B
Application number: CN202010615870.5A
Authority: CN
Inventors: 刘家琴; 刘凯; 赖鑫悦; 陈国凤; 朱雨晗; 杨维清
Original assignee: Xihua University
Current assignee: Xihua University
Priority date: 2020-07-01
Filing date: 2020-07-01
Publication date: 2023-08-04
Anticipated expiration: 2040-07-01
Also published as: CN111943885A

Abstract

The invention relates to synthesis of an important intermediate 2-amino-5-bromo-3-hydroxypyridine of an antitumor drug Laratinib (Lorlatinib, PF-06463922). 2-amino-3-hydroxypyridine is taken as a starting material, and is finally synthesized into 2-amino-5-bromo-3-hydroxypyridine through 3 steps of ring closure, bromination, hydrolysis and the like, wherein the step of ring closure combines bis (trichloromethyl) carbonate (BTC) with N, N' -Carbonyl Diimidazole (CDI); the bromination step adopts 2-hydroxy-2-methyl-1-phenyl-1-acetone as a photoinitiator and adopts liquid bromine as a brominating agent, and compared with the prior art, the technology is more environment-friendly and economical.

Description

Synthesis method of Laratinib intermediate 2-amino-5-bromo-3-hydroxypyridine

Technical Field

The invention relates to synthesis of 2-amino-5-bromo-3-hydroxypyridine, in particular to a synthesis method of 2-amino-5-bromo-3-hydroxypyridine by adopting the steps of ring closure, photocatalysis bromination, hydrolysis and the like.

Background

Latifinib (Lorlatinib, PF-06463922), english is named: (R) -26-amino-55-fluoro-11,4,7-trimethyl-6-oxo-11H-3-oxa-7-za-2 (3, 5) -pyridina-1 (4, 3) -pyrazola-5 (1, 2) -benzocyclicotaphane-15-carbonifle, CAS number: 14548 46-35-5, molecular formula: c (C) ₂₁ H ₁₉ FN ₆ O ₂ Molecular weight: 406.4.lorlatinib is a third generation ALK (anaplastic lymphoma kinase) inhibitor. The first generation of ALK inhibitor Crizotinib (Crizotinib) is an ATP-competitive multi-target protein kinase inhibitor, and its approval by the U.S. FDA was in 2016 for the treatment of patients with advanced (metastatic) non-small cell lung cancer (NSCLC) carrying a mutation in the ROS-1 gene. Unfortunately, most patients develop resistance to Crizotinib within 12 months after treatment and acquired resistance mutations occur. In recent years, a number of second generation ALK inhibitors have been developed that are therapeutically effective and have low toxicity: ceritinib, alectinib, brigatinib. However, refractory tumors soon develop resistance to these new inhibitors. In the face of resistance to Crizotinib and second generation ALK inhibitors, scientists began to develop third generation ALK inhibitors, i.e., drugs that are useful for NSCLC patients resistant to Crizotinib and second generation ALK inhibitors and that develop central nervous system metastases, yet still have therapeutic effects. The third generation of ALK inhibitors is lorelatinib developed by the company pyroxene. 27, 2017, FDA granted the designation of the new generation ALK/ROS1 tyrosine kinase inhibitor lorelatinib "breakthrough drug" for the second line treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC).

The synthesis of Latification and its intermediates are reported in many literature, but the synthesis routes mainly include the following two routes. Scheme one (ref. JohnsonTW, richardsonPF, bailey S, et al Journal of Medicinal Chemistry, 2014, 57 (11): 4720-4744) compounds 1 (with 2-amino-5-bromo-3-hydroxypyridine as intermediate) and 2 were coupled via Suzuki-Miyaura to give compound 3, followed by hydrolysis of the ester to give carboxylic acid 4, followed by deprotection of the Boc to give compound 5, and finally by formation of a molecular lactam linkage, the macrocyclic compound, loretinib, was formed.

Reaction 1

Scheme II (ref: duan S, li B, dugger R W, et al Organic Process Research & Development, 2017, 21 (9)) is shown in scheme 2. Compound 6 (5-fluoro-3-methylisobenzofuran-1 (3H) -one) is amidated with pyrazole compound 7 to give compound 8, which is then reacted with an amino-protected, hydroxy-activated compound 9 (a derivative of 2-amino-5-bromo-3-hydroxypyridine) to afford the macrocyclic compound Lorlatinib in several steps. Wherein the compound 9 is essentially 2-amino-5-bromo-3-hydroxypyridine with both amino and hydroxyl groups protected (scheme 3).

Reaction 2

Reaction 3

Furthermore, the publication CN109232607 a, EP 3415518 A1,WO 2018137679 A1, etc. discloses a synthesis method of loratidine successively. However, in almost all publications reporting the synthesis method of loratidine, 2-amino-5-bromo-3-hydroxypyridine is one of important intermediates of loratidine, and thus, research on its synthesis is of great importance.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of an easy-to-operate and efficient Laratinib intermediate 2-amino-5-bromo-3-hydroxypyridine.

The invention is realized in the following way: 2-amino-5-bromo-3-hydroxypyridine is finally synthesized by taking 2-amino-3-hydroxypyridine as a starting material and performing 3-step reactions such as ring closure, bromination, hydrolysis and the like.

Reaction 4

First, the ring closure reaction step (equation 4): dissolving 2-amino-3-hydroxypyridine in Tetrahydrofuran (THF), stirring for a period of time, adding N, N' -Carbonyl Diimidazole (CDI), stirring for 1.5 hours at room temperature after the CDI solid is gradually dissolved and the solution is yellow brown and clear, cooling to 0 ℃ by an ice salt bath, adding bis-trichloromethyl carbonate (BTC) in batches, heating to reflux after the addition, heating for about 1 hour, filtering, washing the filter cake by water, and drying to obtain a light yellow powder 3H-oxazol [4,5-b ] pyridine-2-one crude product, wherein the crude product can be directly used in the next bromination reaction without purification, and the molar yield of the crude product is 92-98%.

Reaction 5

Second, photocatalytic bromination reaction step (equation 5): dissolving the crude product of the oxazol [4,5-b ] pyridine-2 (3H) -ketone obtained in the ring closing step in an anhydrous solvent N, N-Dimethylformamide (DMF), adding the anhydrous solvent N, N-Dimethylformamide (DMF) into a quartz glass three-necked bottle, adding a catalytic amount of photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone, irradiating a reaction bottle by adopting a 23W ultraviolet lamp with a standard lampshade, controlling the temperature of the reaction solution to be 0-5 ℃, slowly dropwise adding a DMF solution of bromine, and continuing the illumination reaction for 1-2 hours at the temperature of 0-5 ℃ after the dropwise adding; after the reaction is monitored to be complete by thin layer chromatography, pouring the reaction solution into a certain amount of ice-water mixture, stirring, filtering, washing a filter cake with water, and drying to obtain a yellow solid 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one crude product, wherein the crude product can be directly used in the next hydrolysis reaction without purification, and the molar yield of the photocatalytic bromination single-step reaction crude product is 85-97%.

Reaction 6

Third, hydrolysis reaction step (equation 6): adding the intermediate of the 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone obtained in the photocatalytic bromination reaction step into a three-necked bottle, adding 10 mass percent sodium hydroxide aqueous solution, and heating to reflux reaction. Monitoring the reaction process by thin layer chromatography, cooling to room temperature after the reaction raw material 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone is completely converted, dropwise adding 5% dilute hydrochloric acid to adjust the pH value of the solution to 6-7, extracting three times by using ethyl acetate, collecting an organic layer, adding anhydrous magnesium sulfate into the organic layer for drying, concentrating under reduced pressure to obtain an gray brown solid crude product of 2-amino-5-bromo-3-hydroxypyridine, hydrolyzing the crude product by a single step reaction with a molar yield of 88-95%, and obtaining a liquid chromatography with a relative content of 90-94%, wherein the product purity can be further improved by adopting column chromatography purification.

In the photocatalytic bromination reaction step method, the anhydrous solvent N, N-Dimethylformamide (DMF) can be any aprotic polar solvent such as dimethyl sulfoxide (DMSO), sulfolane, N-methylpyrrolidone (NMP), N-Dimethylacetamide (DMC) and the like.

In the photocatalytic bromination reaction step method, the amount of the photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone is 0.01-20% of the mass fraction of the raw material of the oxazole [4,5-b ] pyridine-2 (3H) -ketone in the reaction step, and the optimal dosage is 0.1-5%.

The invention has the technical characteristics that: the ring closing step combines the bis-trichloromethyl carbonate (BTC) and the N, N' -Carbonyl Diimidazole (CDI), thereby avoiding the defect that the conventional method needs to use highly toxic phosgene as a cyclization reagent and improving the reaction yield and the product quality.

The invention also has the technical characteristics that: in the step of photocatalysis bromination reaction, liquid bromine is used for replacing NBS which is conventionally used, so that the generation of byproduct succinimide is reduced, and the method has potential industrial application value.

The invention also has the technical characteristics that: 2-hydroxy-2-methyl-1-phenyl-1-acetone is adopted as a photoinitiator to catalyze the bromination reaction, so that the reaction selectivity is improved, the reaction can be performed at a lower temperature, the energy consumption is saved, and the method has potential industrial application value.

Therefore, the invention has good economic benefit and social benefit.

The invention is characterized in that: (1) avoiding the use of highly toxic phosgene as a cyclizing reagent; (2) The combined use of BTC and CDI significantly increases the rate of reaction compared to the use of BTC or CDI alone; (3) improving the reaction efficiency by adopting a photocatalysis method.

Detailed Description

Example 1: synthesis of 3H-oxazol [4,5-b ] pyridin-2-one

Dissolving 2-amino-3-hydroxypyridine (4.0 g,36.3 mmol) in THF (120 mL), stirring for a period of time, adding CDI (8.8 g,54.3 mmol) to gradually dissolve CDI solid, stirring at room temperature for 1.5 hr, adding BTC (6.5 g,21.9 mmol) in portions under ice bath condition, heating to reflux, reacting for 1 hr, filtering, washing the filter cake with water, and oven drying to obtain light yellow powder 3H-oxazole [4,5-b ]]4.75g of pyridin-2-one, 96.1% yield, was used in the next bromination reaction without purification. The intermediate structure identification needs to be further separated and purified by column chromatography, ¹ H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 8.04 (dd, J = 5.3, 1.2 Hz, 1H), 7.64 (dd, J = 7.9, 1.2 Hz, 1H), 7.11 (dd, J = 7.9, 5.3 Hz, 1H).

example 2: synthesis of 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one

Oxazole [4,5-b ] obtained by the above ring closing step]Pyridine-2 (3H) -ketone crude product (2.50 g,18.35 mmol) and 30 mL anhydrous N, N-Dimethylformamide (DMF) are sequentially added into a quartz glass three-necked bottle, then 25 mg photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone is added, a 23W ultraviolet lamp with a standard lampshade is adopted to irradiate a reaction bottle, the temperature of the reaction liquid is controlled to be 0-5 ℃, DMF solution containing bromine (2.94 g,18.35 mmol) is slowly added dropwise, and after the dropwise addition, the reaction liquid is continuously subjected to illumination reaction for 1.5 hours at 0-5 ℃; after the reaction is monitored to be complete by thin layer chromatography, pouring the reaction solution into a certain amount of ice-water mixture, stirring, filtering, washing a filter cake with water, and drying to obtain yellow solid 6-bromo-3H-oxazolo [4,5-b ]]3.93g of crude pyridin-2-one, 86.4 percent of photo-catalytic bromination single-step reaction crude product molar yield and 93.7 percent of liquid chromatography relative content. The crude product was used without purification in the next hydrolysis reaction. The intermediate structure identification needs to be further separated by adopting column chromatographyThe mixture is purified and then is processed, ¹ H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.17 (s, 1H), 8.00 (t, J = 16.4 Hz, 1H)。

example 3: synthesis of 2-amino-5-bromo-3-hydroxypyridine

The 6-bromo-3H-oxazolo [4,5-b ] prepared by the photocatalysis bromination reaction method]Pyridine-2-one intermediate (5.0 g,23.3 mmol) was added to a three-necked flask, followed by addition of 10% strength by mass aqueous sodium hydroxide solution 40-mL, and reflux reaction at elevated temperature for 14 hours. Monitoring the reaction process by thin layer chromatography, and waiting for the step of reaction, starting the raw material 6-bromo-3H-oxazolo [4,5-b ]]The pyridine-2-ketone is completely converted, the solution is cooled to room temperature, 5% dilute hydrochloric acid is dripped to adjust the pH value of the solution to 6-7, ethyl acetate is used for extraction for three times, an organic layer is collected, anhydrous magnesium sulfate is added into the organic layer for drying, decompression concentration is carried out, 3.96g of gray brown solid 2-amino-5-bromo-3-hydroxypyridine crude product is obtained, the single-step reaction molar yield of hydrolysis is 90%, the relative content of liquid chromatography is 94%, and the purification can be carried out by adopting column chromatography (eluent ethyl acetate: petroleum ether=3:1) to further improve the purity of the product. ¹ H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 7.47 (s, 1H), 6.92 (s, 1H), 5.74 (s, 2H)。

Example 4: synthesis of 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one

The crude product (2.50 g,18.35 mmol) of the oxazol [4,5-b ] pyridine-2 (3H) -ketone, 30 mL anhydrous N, N-Dimethylformamide (DMF) prepared by the method of example 1, are sequentially added into a quartz glass three-necked flask, then 0 mg photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone is added, a 23W ultraviolet lamp with a standard lampshade is adopted to irradiate the reaction flask, the temperature of the reaction solution is controlled to be 0-5 ℃, a DMF solution containing liquid bromine (2.94 g,18.35 mmol) is slowly added dropwise, and the reaction solution is continuously subjected to illumination reaction for 3 hours at the temperature of 0-5 ℃ after the dropwise addition; after the reaction is monitored to be complete by thin layer chromatography, the reaction solution is poured into a certain amount of ice-water mixture, stirred and filtered, a filter cake is washed by water, and 3.87g of yellow solid 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone crude product is obtained after drying, the molar yield of the photocatalytic bromination single-step reaction crude product is 85.1%, and the relative content of liquid chromatography is 76.2%. The crude product is low in purity, can not be directly used in the next hydrolysis reaction without purification, and adopts column chromatography (eluent ethyl acetate: petroleum ether=4:1) to obtain 2.51g of pale yellow solid 6-bromo-3H-oxazolo [4,5-b ] pyridin-2-one product, wherein the molar yield of the crude product obtained by the photocatalytic bromination single step reaction is 55.2%, and the relative content of liquid chromatography is 96.7%.

Claims

1. A synthesis method of 2-amino-5-bromo-3-hydroxypyridine is characterized in that 2-amino-3-hydroxypyridine is used as a starting material, and the 2-amino-5-bromo-3-hydroxypyridine is finally synthesized through 3 steps of reactions such as ring closure, photocatalytic bromination, hydrolysis and the like:

the specific experimental operation steps are as follows:

first, a ring closing reaction step: dissolving 2-amino-3-hydroxypyridine in tetrahydrofuran, adding N, N '-carbonyldiimidazole after stirring for a period of time, stirring for 1.5 hours at room temperature after the N, N' -carbonyldiimidazole is gradually dissolved, cooling to 0 ℃ in an ice salt bath, adding bis (trichloromethyl) carbonate in batches, heating to reflux after the addition, about 1 hour, filtering after the reaction is finished, washing a filter cake with water, and drying to obtain a light yellow powder 3H-oxazol [4,5-b ] pyridin-2-one crude product, wherein the crude product is directly used in the next bromination reaction without purification, and the molar yield of the crude product is 92-98%;

second, photocatalytic bromination reaction: sequentially adding the crude product of the oxazol [4,5-b ] pyridine-2 (3H) -ketone and an anhydrous solvent obtained in the ring closing step into a quartz glass three-necked bottle, then adding a catalytic amount of photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone, irradiating the reaction bottle by adopting a 23W ultraviolet lamp with a standard lampshade, controlling the temperature of the reaction solution to be 0-5 ℃, slowly dropwise adding DMF solution of bromine, and continuing the illumination reaction for 1-2 hours at the temperature of 0-5 ℃ after the dropwise adding of the reaction solution; after the reaction is monitored to be complete by thin layer chromatography, pouring the reaction solution into a certain amount of ice-water mixture, stirring, filtering, washing a filter cake by using water, and drying to obtain a yellow solid 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone crude product, wherein the crude product is directly used in the next hydrolysis reaction without purification, and the molar yield of the photocatalytic bromination single-step reaction crude product is 85-97%;

third, hydrolysis reaction step: adding the intermediate of the 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone obtained in the photocatalytic bromination reaction step into a three-necked bottle, adding 10 mass percent sodium hydroxide aqueous solution, and heating to reflux reaction. Monitoring the reaction process by thin layer chromatography, cooling to room temperature after the reaction raw material 6-bromo-3H-oxazolo [4,5-b ] pyridine-2-ketone is completely converted, dropwise adding 5% dilute hydrochloric acid to adjust the pH value of the solution to 6-7, extracting with ethyl acetate three times, collecting an organic layer, adding anhydrous magnesium sulfate into the organic layer for drying, concentrating under reduced pressure to obtain an off-brown solid crude product of 2-amino-5-bromo-3-hydroxypyridine, hydrolyzing the crude product by a single step reaction with a molar yield of 88-95%, and a relative content of 90-94% by liquid chromatography, purifying by column chromatography to further improve the product purity

。

2. The method of claim 1, wherein the anhydrous solvent is any one of N, N-dimethylformamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, and N, N-dimethylacetamide.

3. The synthesis method of claim 1, wherein the amount of the photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-propanone is 0.1-5% of the mass fraction of the reaction raw material oxazol [4,5-b ] pyridine-2 (3H) -ketone.