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3-amino-oxetane derivative as well as preparation method and application thereof

A technology of oxetane and its derivatives, which is applied in the field of 3-amino-oxetane derivatives and its preparation, can solve the problems of not easy to obtain raw materials, long synthetic route, high cost, etc., and achieve market supply Sufficient, short steps, the effect of increasing the success rate

Pending Publication Date: 2019-07-09
NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above three approaches all have the disadvantages that the raw materials are not easy to obtain, the cost is high, the synthetic route is long, and the disadvantages are uneconomical.

Method used

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  • 3-amino-oxetane derivative as well as preparation method and application thereof
  • 3-amino-oxetane derivative as well as preparation method and application thereof
  • 3-amino-oxetane derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076]

[0077] Preparation of Compound IV-1:

[0078] Dissolve diisopropylamine (56.0g, 0.55mol, 1.25eq.) in THF, cool to -78°C, add n-butyllithium (212mL, 0.53mol, 1.2eq.) dropwise, and react for 30min after the addition is complete , and the prepared LDA solution was set aside.

[0079] Compound II-1 (125.0g, 0.44mol, 1.0eq.) was dissolved in THF (2L), and the above-mentioned self-made LDA solution was added dropwise at -78°C. After the dropwise addition, the reaction was carried out for 30min, and acetone (31.0g, 0.53mol, 1.2eq.), reacted for 2h, poured into saturated ammonium chloride solution (1L), separated into layers, dried and concentrated the organic phase, added n-heptane (100mL), stirred in an ice-water bath, and solid precipitated out, filtered , the solid was dried to obtain 81.0 g of white solid, yield: 54.8%. 1 H-NMR (400MHz, CDCl 3 )δ (ppm) 7.25-7.41 (m, 10H), 4.30-4.44 (m, 2H), 4.23-4.28 (m, 2H), 3.41-3.47 (m, 3H), 3.15 (s, 1H), 1.46- 1.48 (m, 3H), 1....

Embodiment 2

[0085]

[0086] Preparation of Compound IV-2:

[0087] Compound II-2 (125.0g, 0.364mol, 1.0eq.) was dissolved in THF (2L), and a THF solution of 1M LiHMDS (364mL, 0.364mol, 1.0eq.) was added dropwise at -78°C. After the addition was complete, , reacted for 30min, and added compound III-2 (41.56g, 0.364mol, 1.0eq.) dropwise at -78°C. After the addition, the temperature was naturally raised to -5°C, and the reaction was stirred for 2h. LC-MS detection showed that the reaction of the raw materials was complete. The liquid was poured into saturated ammonium chloride solution (1L), separated into layers, the organic phase was dried and concentrated, added n-heptane (100mL), stirred in an ice-water bath, a solid precipitated out, filtered, and the solid was dried to obtain compound IV-2 as a white solid 111.2 g, yield: 64.8%.

[0088] Preparation of Compound V-2:

[0089] Compound IV-2 (80.0g, 0.170mol, 1.0eq.), was dissolved in 600mL of dioxane, under ice-cooling, NaBH was add...

Embodiment 3

[0093]

[0094] Preparation of compound IV-3:

[0095] Compound II-3 (37.70g, 0.14mol, 1.0eq.) was dissolved in dioxane, under the protection of nitrogen, the temperature was lowered to -80°C, and 1M 2,2,6,6-tetramethylpiperidine was added dropwise After the THF solution of lithium (420mL, 0.42mol, 3.0eq.) was added dropwise, the reaction was incubated for 30min, and compound III-3 (30.28g, 0.42mol, 3.0eq.) was added dropwise, and the reaction was stirred at -50°C for 2h. TLC showed that the raw material disappeared, the reaction solution was poured into 300mL of saturated ammonium chloride, separated, the organic phase was dried, and concentrated to obtain a yellow oil, which was added to 100mL of n-heptane and stirred to precipitate a solid, which was filtered to obtain compound IV-3 as white The solid was 28.68g, and the yield was 60%. 1 HNMR (400MHz, CDCl 3 )δ (ppm): 7.26-7.35 (m, 10H), 4.28-4.43 (m, 2H), 3.86-3.93 (m, 3H), 3.43-3.47 (d, 2H), 3.32-3.35 (d, 1H) , 2.13...

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Abstract

The invention discloses a 3-amino-oxetane derivative as well as a preparation method and application thereof. The preparation method comprises the following steps: by taking a compound II and a compound III as raw materials, preparing a compound IV in the presence of alkali 1, preparing a compound V from the compound IV under the action of a reducing agent, and reacting the compound V under the action of 30-98% sulfuric acid or alkali and a ring closing reagent to generate a compound VI: the 3-amino-oxetane derivative; and subjecting the compound VI to a reduction reaction in the presence of ahydrogen source, a hydrogen source / a catalyst or a hydrogen source / a deprotection reagent to obtain a compound I.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a 3-amino-oxetane derivative and its preparation method and application. Background technique [0002] 3-Amino-oxetane derivatives are a very important class of pharmaceutical intermediates that are widely used, such as the MGLUR1 receptor antagonist developed by Astellas Pharmaceuticals, and non-opioid analgesics include 3-Amino-oxetane fragment molecule. [0003] [0004] The PRMT5 receptor antagonist developed by GlaxoSmithKline also uses the 3-amino-oxetane fragment: [0005] [0006] Conventional methods for synthesizing 3-amino-oxetane generally have the following three types: [0007] 1. From the corresponding hydroxyl group through the sulfonate ester, and then react with sodium azide to obtain azide, and obtain it through reduction; [0008] 2. The oxime is made from the corresponding ketone and hydroxylamine hydrochloride, and then obtained through red...

Claims

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Application Information

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IPC IPC(8): C07D305/08C07D305/14C07D491/107C07D493/10C07D405/04C07D405/14C07D407/12
CPCC07D305/08C07D305/14C07D491/107C07D493/10C07D405/04C07D405/14C07D407/12Y02P20/55
Inventor 张雷亮徐峰刘贵华
Owner NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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