Preparation method of pyridine derivative

Abstract

The invention belongs to the field of medicine synthesis, relates to a preparation method of a pyridine derivative, and in particular, relates to a preparation method of a formula III, wherein the preparation method comprises the steps: in the presence of alkali and a solvent, taking an N-heterocyclic carbene palladium (II) (Pd (II)-NHC) complex as a catalyst, and reacting a compound represented by a formula I with a compound represented by a formula II to obtain the compound represented by the formula III. The compound represented by the formula III generates a mixture containing a compound represented by the formula IV in the presence of a solvent and NBS, and then the compound represented by the formula IV is obtained through recrystallization. In addition, the invention also provides a preparation method of the compound represented by the formula I. In the presence of inorganic alkali and methanol, 2,4-dichloropyridine reacts to generate 2-chloro-4-methoxypyridine, then the 2-chloro-4-methoxypyridine and acid form salt, and then the salt is converted into high-purity 2-chloro-4-methoxypyridine. The N-heterocyclic carbene palladium (II) complex is used as the catalyst, so that the yield is remarkably improved, and the dosage of the catalyst is remarkably reduced; and the method overcomes the problems of large dosage (2%) of palladium catalysts and ligands, low atom utilization rate, high cost, high reaction temperature, long reaction time, low yield and the like in the prior art, and is more suitable for industrial production.

Description

technical field

[0001] The invention belongs to the field of medicine synthesis, in particular to a preparation method of (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. Background technique

[0002] (S)-4-(5-Bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester is a synthetic anaplastic lymphoma kinase (ALK) inhibitor An important intermediate of the agent.

[0003] 2-chloro-4-methoxypyridine, as an important intermediate of pharmaceutical chemicals, is known in the prior art and can be prepared according to various methods, such as Organic Process Research & Development Volume 15, Issue 5, Pages1138-1148, 2011, published In order to use 2,4-dichloropyridine as a starting material, in the presence of toluene and sodium methoxide, the reaction temperature is 105-110° C., and the reaction time is as long as 21 hours. JACS, Volume 133 Issue 5 Pages 1251-1253, 2011, also discloses the synthesis method of 2-...

Examples

Embodiment 1

[0047] The preparation of embodiment 1 formula I compound

[0048]

[0049] Step 1: Add 101.4kg of 2,4-dichloropyridine, 305L of methanol and 142kg of potassium carbonate (powder) into the enamel reaction tank, heat up and reflux for more than 20 hours (monitored by HPLC to less than 3% of 2,6-dichloropyridine). After the reaction is completed, cool down to 10±3°C, stir and crystallize for 30 minutes, and filter. The temperature of the filtrate was controlled below 35°C, and 40kg of HCl gas was slowly introduced. After passing through, stir the reaction for more than 30 minutes, and concentrate under reduced pressure at 30-35°C. Concentrate until no obvious liquid flows out, add 60L ethyl acetate and continue to concentrate for 1.5h. After concentration, add 345L of ethyl acetate, stir for 30min, cool down to 0-5°C and continue to stir for 2.5h, shake off and dry to obtain the hydrochloride of the compound of formula Ⅰ-1 with a wet weight of 112.24kg, vacuum at 40-50°C D...

Embodiment 2

[0062]

[0063] Step 1: Add 1400.9g of 2-chloro-4-methoxypyridine, 1691.8g of (S)-3-methyl-1-tert-butoxycarbonylpiperazine, 16L of dry toluene and tert-butanol to the reactor Potassium 1904.9g, after stirring evenly, add Pd 2 (dba) 3 155.5g, BINAP212.2g, nitrogen replacement 3 times, under nitrogen atmosphere, reflux for 10h, TLC showed that the reaction of raw materials was complete. Add 10L of purified water, separate the layers, extract the aqueous layer twice with ethyl acetate 10L*2, combine the organic layers, wash twice with 20L of saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure until viscous. used directly in the next reaction.

[0064] Step 2: In the reaction kettle, add (S)-4-(4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester in acetonitrile solution, cool down to 0°C 1290.9 g of bromosuccinimide was added in batches with stirring. After adding, warm up to room temperature a...

technical field

[0001] The invention belongs to the field of medicine synthesis, in particular to a preparation method of (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. Background technique

[0002] (S)-4-(5-Bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester is a synthetic anaplastic lymphoma kinase (ALK) inhibitor An important intermediate of the agent.

[0003] 2-chloro-4-methoxypyridine, as an important intermediate of pharmaceutical chemicals, is known in the prior art and can be prepared according to various methods, such as Organic Process Research & Development Volume 15, Issue 5, Pages1138-1148, 2011, published In order to use 2,4-dichloropyridine as a starting material, in the presence of toluene and sodium methoxide, the reaction temperature is 105-110° C., and the reaction time is as long as 21 hours. JACS, Volume 133 Issue 5 Pages 1251-1253, 2011, also discloses the synthesis method of 2-...

Examples

Embodiment 1

[0047] The preparation of embodiment 1 formula I compound

[0048]

[0049] Step 1: Add 101.4kg of 2,4-dichloropyridine, 305L of methanol and 142kg of potassium carbonate (powder) into the enamel reaction tank, heat up and reflux for more than 20 hours (monitored by HPLC to less than 3% of 2,6-dichloropyridine). After the reaction is completed, cool down to 10±3°C, stir and crystallize for 30 minutes, and filter. The temperature of the filtrate was controlled below 35°C, and 40kg of HCl gas was slowly introduced. After passing through, stir the reaction for more than 30 minutes, and concentrate under reduced pressure at 30-35°C. Concentrate until no obvious liquid flows out, add 60L ethyl acetate and continue to concentrate for 1.5h. After concentration, add 345L of ethyl acetate, stir for 30min, cool down to 0-5°C and continue to stir for 2.5h, shake off and dry to obtain the hydrochloride of the compound of formula Ⅰ-1 with a wet weight of 112.24kg, vacuum at 40-50°C D...

Embodiment 2

[0062]

[0063] Step 1: Add 1400.9g of 2-chloro-4-methoxypyridine, 1691.8g of (S)-3-methyl-1-tert-butoxycarbonylpiperazine, 16L of dry toluene and tert-butanol to the reactor Potassium 1904.9g, after stirring evenly, add Pd 2 (dba) 3 155.5g, BINAP212.2g, nitrogen replacement 3 times, under nitrogen atmosphere, reflux for 10h, TLC showed that the reaction of raw materials was complete. Add 10L of purified water, separate the layers, extract the aqueous layer twice with ethyl acetate 10L*2, combine the organic layers, wash twice with 20L of saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure until viscous. used directly in the next reaction.

[0064] Step 2: In the reaction kettle, add (S)-4-(4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester in acetonitrile solution, cool down to 0°C 1290.9 g of bromosuccinimide was added in batches with stirring. After adding, warm up to room temperature a...

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