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Preparation method of (S)-2-methyl azetidine hydrochloride

A technology of methylazetidine and hydrochloride, applied in the direction of organic chemistry methods, chemical instruments and methods, organic racemization, etc., can solve the problems of unfavorable industrial production, high cost of raw materials, complicated operation, etc., and achieve simplification The effect of operation, low raw material price and high reaction yield

Pending Publication Date: 2022-04-12
苏州楚凯药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The disadvantage of this route is that: the starting chiral raw material D-acridine-2-carboxylic acid is more expensive, and the yield in the second step is only 19%, the cost is higher, and it is not conducive to industrial production
[0013] Several methods reported in the above literature have high cost of raw materials and complicated operation, so it is necessary to find a low-cost route suitable for industrialization

Method used

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  • Preparation method of (S)-2-methyl azetidine hydrochloride
  • Preparation method of (S)-2-methyl azetidine hydrochloride
  • Preparation method of (S)-2-methyl azetidine hydrochloride

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preparation example Construction

[0047] The preparation method comprises the following steps:

[0048] Step 1), the raw material 1,3-butanediol reacts with methanesulfonyl chloride in a reaction solvent in the presence of a base to obtain a compound of formula (I);

[0049] Step 2), the ring-closing reaction of the compound of formula (I) and S-phenethylamine to obtain a mixture of the compound of formula (II) and the compound of formula (III);

[0050] Step 3), the mixture of the compound of formula (II) and the compound of formula (III) is refined and resolved to obtain the compound of formula (II);

[0051] Step 4), the compound of formula (II) is dissolved in a solvent, and deprotected under the action of a catalyst to obtain the compound of formula (IV).

[0052] The synthetic route is as follows:

[0053]

Embodiment 1

[0055]

[0056] Add 1,3-butanediol (90 g, 1 mol), triethylamine (130 g, 1.3 mol) and DCM (1 L) into the reaction flask, and add methanesulfonyl chloride (350 g, 3 mol) dropwise at room temperature. After the dropwise addition was completed, the reaction was carried out at room temperature for 2h. After the reaction was completed, saturated sodium chloride solution was added to wash with water, extracted with DCM (3*500mL), the organic phase was dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and the crude product was passed through a column to obtain 220 g of the compound of formula (I) (yield 91%). 1 H NMR (CDCl 3)δ: 1.48-1.50 (d, 3H), 2.06-2.10 (m, 2H), 3.03-3.05 (s, 6H), 4.32-4.35 (t, 2H), 4.96-5.00 (m, 1H).

Embodiment 2

[0058]

[0059] Add S-phenylethylamine (1187g, 9.8mol) into the reaction flask, control the temperature below 45°C, add the compound of formula (I) (690g, 2.8mol) dropwise, stir at room temperature for 1h after the addition, then raise the temperature to 45°C for 10h ( A large amount of solids were precipitated), and the ratio of the diastereomer formula (II) compound and the formula (III) compound detected by LC was 91:9. After the reaction was completed, filter, combine the organic phases, wash and separate the liquids, add HCl / EA (1.5L) The solution was stirred to form a salt, filtered, MTBE recrystallized, filtered and dried to obtain 486 g of the compound of formula (II) (yield 82%).

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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an intermediate (S)-2-methyl azetidine hydrochloride of a hexanketokinase inhibitor, which comprises the following steps: esterifying 1, 3-butanediol and methanesulfonyl chloride to obtain a compound shown as a formula (I), cyclizing the compound shown as the formula (I) and S-phenylethylamine to obtain a mixture of a compound shown as a formula (II) and a compound shown as a formula (III), and carrying out recrystallization to obtain the (S)-2-methyl azetidine hydrochloride of the hexanketokinase inhibitor. Refining and splitting the mixture to obtain a compound shown as a formula (II), and deprotecting the compound shown as the formula (II) to obtain a compound shown as a formula (IV). The invention provides a simple and cost-reducing industrial production route for the intermediate of the hexanketokinase inhibitor, and has the advantages of low price of initial raw materials, simple and convenient reaction, high resolution yield, low cost and capability of realizing stable industrial production and preparation.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of an intermediate (S)-2-methylazetidine hydrochloride of a ketohexokinase inhibitor. Background technique [0002] Diabetes is a major public health concern due to its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. The two main forms of diabetes are type 1 and type 2. Type 1 diabetes (T1D) occurs when the body's immune system damages pancreatic beta cells. Type 2 diabetes (T2D) usually begins with insulin resistance or when insulin production is insufficient to maintain acceptable glucose levels. T2D is most commonly associated with hyperglycemia and insulin resistance. [0003] Current drug treatments for T2D vary in strategy to include agents that increase insulin secretion, affect insulin activity,...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B57/00C07D205/04
Inventor 张中剑刘现军郑行行余飞飞黄文飞
Owner 苏州楚凯药业有限公司
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