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Preparation method for synthesis of N-protected and non-protected 3-hydroxy-4,4-dimethylpiperidine

A methyl and ethyl technology, applied in the field of pharmaceutical intermediate synthesis, can solve the problems such as no literature report in the synthesis process

Active Publication Date: 2020-04-07
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there is no literature report on the synthesis process of N-protected and non-protected 3-hydroxyl-4,4-dimethylpiperidine, so the development of a raw material is easy to get, The operation is convenient, the reaction is easy to control, and a synthetic route with a suitable overall yield is necessary

Method used

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  • Preparation method for synthesis of N-protected and non-protected 3-hydroxy-4,4-dimethylpiperidine
  • Preparation method for synthesis of N-protected and non-protected 3-hydroxy-4,4-dimethylpiperidine
  • Preparation method for synthesis of N-protected and non-protected 3-hydroxy-4,4-dimethylpiperidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]

[0046] Preparation of Compound III-1

[0047] Compound II-1 (84.18g, 0.592mol, 1.0eq.) was dissolved in 800mL ether, and H 2 O (600mL), pyridine (50.00g, 0.651mol, 1.1eq.), K 2 OSo 4 .2H 2 O (10.90g, 0.0296mol, 0.05eq.), lower the temperature to below 10°C, add sodium periodate (380.0g, 1.776mol, 3.0eq.) in batches, and stir the reaction at 0-10°C for 10h, TLC Shows complete reaction. Suction filtration, the filter cake was washed with 600mL MTBE, the combined filtrates were separated, the organic phase was washed with saturated sodium sulfite, 10% citric acid aqueous solution, sodium bicarbonate aqueous solution, saturated NaCl aqueous solution, dried and suction filtered, and the filtrate was concentrated to obtain compound III -1 is 55.00 g of black oily matter, yield 65%. 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 9.75 (s, 1H), 3.71 (s, 3H), 2.67 (s, 2H), 1.31 (s, 6H).

[0048] Preparation of Compound V-1

[0049] Compound IV-1 (35.50g, 0.160mol, 1.05eq.) and co...

Embodiment 2

[0054]

[0055] Preparation of Compound III-2

[0056] Compound II-2 (92.50g, 0.592mol, 1.0eq.) was dissolved in 1000mL 1,4-dioxane, and H 2 O (600mL), 2,6-lutidine (126.87g, 1.184mol, 2.0eq.), osmium tetroxide (1.5g, 0.00592mol, 0.01eq.), lower the temperature to below 10°C, and add in batches Sodium iodate (380.0 g, 1.776 mol, 4.0 eq.) was added and stirred at room temperature for 20 h. TLC showed that the reaction was complete. Add 600mL water and 1800mL DCM, stir and separate the liquids, extract the water phase with DCM once, combine the organic phases, wash the organic phase with saturated sodium sulfite, 10% citric acid aqueous solution, sodium bicarbonate aqueous solution, saturated NaCl aqueous solution, and dry After suction filtration, the filtrate was concentrated to obtain 63.68 g of compound III-2 as a black oil, with a yield of 68%.

[0057] Preparation of Compound V-2

[0058] Compound IV-2 (28.67g, 0.160mol, 1.5eq.) and compound III-2 (16.87g, 0.106mol, ...

Embodiment 3

[0063]

[0064] Preparation of Compound III-3

[0065] Compound II-3 (20.01g, 0.117mol, 1.0eq.) was dissolved in 200mL DCM / MeOH mixed solvent, cooled to below -78°C, and passed O 3 Gas for 30 min, PPh3 (36.7 g, 0.14 mol, 1.2 eq.) was added at -78 ° C, and the reaction was stirred at room temperature for 3 h after the addition was completed. TLC showed that the reaction was complete. The reaction solution was concentrated and distilled under reduced pressure to obtain 14.1 g of compound III-3 as a yellow oil, with a yield of 70%.

[0066] Preparation of Compound V-3

[0067] Compound IV-3 (28.17g, 0.146mol, 1.8eq.) and compound III-3 (14.01g, 0.081mol, 1.0eq.) were dissolved in 200mL toluene, and NaBH was added in batches 3 After adding CN (19.17g, 0.146mol, 1.8eq.), the reaction was stirred at room temperature for 18h, and TLC showed that the reaction was complete. Slowly pour the reaction solution into 400mLNaHCO 3 Aqueous solution, stirred until no bubbles, extracted ...

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Abstract

The invention discloses a preparation method of 3-hydroxy-4,4-dimethylpiperidine and N-protected 3-hydroxy-4,4-dimethylpiperidine and an intermediate thereof, and mainly solves the technical problem of lack of N-protected and non-protected 3-hydroxy-4,4-dimethylpiperidine synthesis process; the preparation method comprises the following steps: with a compound II (2,2-dimethyl-4-pentenoic acid ester) as a raw material, oxidizing olefinic bonds to generate a compound III; carrying out aldehyde amine condensation reaction on the compound III and a compound IV to generate a compound V; carrying out ring closing reaction on the compound V to generate a compound VI; hydrolyzing and decarboxylating to generate a compound VII; removing a benzyl protecting group from N of a piperidine ring of the compound VII to obtain a compound VIII; adding other protecting groups to obtain a compound IX; and finally, carrying out carbonyl reduction on the compound IX, to obtain the compound I (3-hydroxy-4,4-dimethylpiperidine and N-protected 3-hydroxy-4,4-dimethylpiperidine).

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a method for synthesizing 3-hydroxy-4,4-dimethylpiperidine and N-protected 3-hydroxy-4,4-dimethylpiperidine and its intermediate Body preparation methods and applications. Background technique [0002] Piperidine is a non-aromatic, saturated six-membered nitrogen-heterocyclic compound, which is an important intermediate for the preparation of kinase inhibitors and a key component of drugs for the prevention and treatment of diabetes. Many natural or synthetic pharmaceutical compounds often contain one or more piperidine ring structures, especially 3-position substituted piperidine rings are particularly common. N-protected and unprotected 3-hydroxy-4,4-dimethylpiperidine is an important pharmaceutical intermediate, which can be used to synthesize new 3-(pyrazin-2-yl)-1H-indazole Derivatives (compound X) as Pan-Pim kinase inhibitors. [0003] [0004]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/74C07D211/42
CPCC07D211/74C07D211/42Y02P20/55
Inventor 徐军刘文博余善宝
Owner PHARMABLOCK SCIENCES (NANJING) INC
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