Preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride

Abstract

The invention provides a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride, and the method comprises the following steps: (1) preparing an intermediate 2: dissolving N-benzyl glycine ethyl ester in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain N-benzyl glycine ethyl ester; (2) dissolving the intermediate 2 in anorganic solvent, reacting with alkali, adjusting the pH value to 7-8 after the reaction is finished, adding water for washing, adjusting the pH value of an organic layer to 1-2, and separating out crystals to obtain a crude product; and (3) dissolving the crude product in water, adding alkali to adjust the pH value to 7-8, adding an organic solvent to extract, washing, adjusting the pH value of anorganic layer to 1-2, and crystallizing to obtain the product. The method is simple in process operation, high in product yield, high in purity and easy for industrial production.

Description

technical field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride. Background technique

[0002] N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride is an important intermediate of a new generation of fluoroquinolone antibacterial drug baloxacin, and the current synthetic method (CN105622444B) is: a kind of N- The preparation method of ethyl benzylglycine comprises the steps of: dissolving benzylamine in an organic solvent, then adding ethyl 2-haloacetate, alkali, and quaternary ammonium salt, and reacting to obtain ethyl benzylglycine. Also disclosed is a preparation method of 1-benzyl-3-piperidone hydrochloride, the specific steps are: (1) preparing intermediate 1 (N-benzylglycine ethyl ester); (2) preparing intermediate 1 Dissolve in an organic solvent, then add ethyl 4-halobutyrate and a base to react to obtain intermed...

Examples

Embodiment 1

[0018] Embodiment 1: Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride

[0019] Follow the steps below:

[0020] (1) Preparation of intermediate 2

[0021] In a 20L four-necked reaction flask, add 6kg (31mol) of ethyl N-benzylglycine, add 6.65kg (34.1mol) of ethyl 4-bromobutyrate, add 6L of methanol, 3.6kg (34.1mol) of sodium carbonate, and heat to Reflux, heat preservation and reflux reaction for 10 hrs, after the basic reaction was detected by TLC, the reaction was stopped, the reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 29.41 kg of an intermediate with a yield of 98.6%.

[0022] (2) Preparation of crude product

[0023] Add the intermediate 2 prepared in the previous step into a 20L four-necked reaction flask, add 10L of ethyl acetate, add 1.84kg (34.1mol) of sodium methoxide, heat to reflux, keep warm and reflux for 4hrs, and stop the reaction after the basic reaction...

Embodiment 2

[0026] Embodiment 2: Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride

[0027] Follow the steps below:

[0028] (1) Preparation of intermediate 2

[0029] Add 6kg (31mol) of N-benzylglycine ethyl ester into a 20L four-necked reaction flask, add 7kg (46.5mol) of ethyl 4-chlorobutyrate, add 6L of toluene, 6.43kg (46.5mol) of potassium carbonate, and heat to reflux , heat-preserved and refluxed for 8 hours, after the basic reaction was detected by TLC, the reaction was stopped, the reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 29.46 kg of intermediate, with a yield of 99.1%.

[0030] (2) Preparation of crude product

[0031] Add the intermediate 2 prepared in the previous step into a 20L four-necked reaction flask, add 10L of toluene, add 5.22kg (46.5mol) of potassium tert-butoxide, heat to reflux, keep warm and reflux for 3hrs, and stop the reaction after the basic reaction ...

Embodiment 3

[0034] Embodiment 3: Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride

[0035] Follow the steps below:

[0036] (1) Preparation of Intermediate 2

[0037] Add 6kg (31mol) of N-benzylglycine ethyl ester into a 20L four-necked reaction flask, add 7.86kg (40.3mol) of ethyl 4-bromobutyrate, add 6L of ethanol, 1.61kg (40.3mol) of sodium hydroxide, and heat To reflux, keep warm and reflux for 12 hrs, after TLC detects that the basic reaction is complete, stop the reaction, cool the reaction solution to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain 9.4kg of intermediate 2 with a yield of 98.5%

[0038] (2) Preparation of crude product

[0039] Add the intermediate 2 prepared in the previous step into a 20L four-necked reaction flask, add 10L of tetrahydrofuran, add 2.74kg (40.3mol) of sodium ethoxide, heat to reflux, keep warm and reflux for 4hrs, and stop the reaction after TLC detects that the basic reaction is co...

technical field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride. Background technique

[0002] N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride is an important intermediate of a new generation of fluoroquinolone antibacterial drug baloxacin, and the current synthetic method (CN105622444B) is: a kind of N- The preparation method of ethyl benzylglycine comprises the steps of: dissolving benzylamine in an organic solvent, then adding ethyl 2-haloacetate, alkali, and quaternary ammonium salt, and reacting to obtain ethyl benzylglycine. Also disclosed is a preparation method of 1-benzyl-3-piperidone hydrochloride, the specific steps are: (1) preparing intermediate 1 (N-benzylglycine ethyl ester); (2) preparing intermediate 1 Dissolve in an organic solvent, then add ethyl 4-halobutyrate and a base to react to obtain intermed...

Examples

Embodiment 1

[0018] Embodiment 1: Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride

[0019] Follow the steps below:

[0020] (1) Preparation of intermediate 2

[0021] In a 20L four-necked reaction flask, add 6kg (31mol) of ethyl N-benzylglycine, add 6.65kg (34.1mol) of ethyl 4-bromobutyrate, add 6L of methanol, 3.6kg (34.1mol) of sodium carbonate, and heat to Reflux, heat preservation and reflux reaction for 10 hrs, after the basic reaction was detected by TLC, the reaction was stopped, the reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 29.41 kg of an intermediate with a yield of 98.6%.

[0022] (2) Preparation of crude product

[0023] Add the intermediate 2 prepared in the previous step into a 20L four-necked reaction flask, add 10L of ethyl acetate, add 1.84kg (34.1mol) of sodium methoxide, heat to reflux, keep warm and reflux for 4hrs, and stop the reaction after the basic reaction...

Embodiment 2

[0026] Embodiment 2: Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride

[0027] Follow the steps below:

[0028] (1) Preparation of intermediate 2

[0029] Add 6kg (31mol) of N-benzylglycine ethyl ester into a 20L four-necked reaction flask, add 7kg (46.5mol) of ethyl 4-chlorobutyrate, add 6L of toluene, 6.43kg (46.5mol) of potassium carbonate, and heat to reflux , heat-preserved and refluxed for 8 hours, after the basic reaction was detected by TLC, the reaction was stopped, the reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 29.46 kg of intermediate, with a yield of 99.1%.

[0030] (2) Preparation of crude product

[0031] Add the intermediate 2 prepared in the previous step into a 20L four-necked reaction flask, add 10L of toluene, add 5.22kg (46.5mol) of potassium tert-butoxide, heat to reflux, keep warm and reflux for 3hrs, and stop the reaction after the basic reaction ...

Embodiment 3

[0034] Embodiment 3: Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride

[0035] Follow the steps below:

[0036] (1) Preparation of Intermediate 2

[0037] Add 6kg (31mol) of N-benzylglycine ethyl ester into a 20L four-necked reaction flask, add 7.86kg (40.3mol) of ethyl 4-bromobutyrate, add 6L of ethanol, 1.61kg (40.3mol) of sodium hydroxide, and heat To reflux, keep warm and reflux for 12 hrs, after TLC detects that the basic reaction is complete, stop the reaction, cool the reaction solution to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain 9.4kg of intermediate 2 with a yield of 98.5%

[0038] (2) Preparation of crude product

[0039] Add the intermediate 2 prepared in the previous step into a 20L four-necked reaction flask, add 10L of tetrahydrofuran, add 2.74kg (40.3mol) of sodium ethoxide, heat to reflux, keep warm and reflux for 4hrs, and stop the reaction after TLC detects that the basic reaction is co...

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