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Intermediate of (1S,4S)-2,5-diazabicyclo[2,2,2]octane derivative and preparation method of intermediate

The technology of a compound, nitrobenzenesulfonyl, is applied in the field of heterocyclic organic chemical synthesis, which can solve the problems of high reaction temperature, elimination of side reactions, and reduced yield, and achieve safe synthesis process, easy scale-up production, and short route steps Effect

Active Publication Date: 2018-01-19
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] 3) Preparation of compound x: Sodium azide is required, which is highly toxic and explosive; the reaction temperature is high, which easily leads to the elimination of side reactions, resulting in a decrease in yield;
[0010] 4) Preparation of compound xi: azide and ester need to be reduced at the same time, and lithium aluminum tetrahydrogen is used in a large amount;
[0011] 5) Preparation of compound ix and compound xiii: using methanesulfonyl chloride twice, highly toxic and poor stability
[0015] This method uses compound xiv as a raw material to prepare compound i-2 through four steps of O protection, azide substitution, reductive amination and ring closure, with a total yield of 67.4%. However, sodium azide is required for its preparation. The compound is highly toxic and explosive, and the cis structure of the raw material xiv is difficult to separate, and the raw material is not easy to obtain; the compound xvii is very polar and difficult to separate, and step p produces a lot of waste solid and waste liquid of phosphine, which is not environmentally friendly. Tributylphosphine is highly toxic

Method used

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  • Intermediate of (1S,4S)-2,5-diazabicyclo[2,2,2]octane derivative and preparation method of intermediate
  • Intermediate of (1S,4S)-2,5-diazabicyclo[2,2,2]octane derivative and preparation method of intermediate
  • Intermediate of (1S,4S)-2,5-diazabicyclo[2,2,2]octane derivative and preparation method of intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072]

[0073] Compound VI-1 Preparation of Compound VII-1:

[0074] Add compound VI-1 (180.5g, 0.527mol, 1.0e.q.) and dichloromethane (1.5L) into the reaction flask, cool down to 0°C, add thionyl chloride (627.0g, 5.270mol, 10.0e.q.) dropwise, After dropping, the temperature was raised to reflux for 2 hours, and TLC showed that the reaction was complete. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, separated into layers, and the organic phase was washed once with water and once with saturated brine, and then washed with anhydrous sulfuric acid. After drying over sodium, the solvent was distilled off under reduced pressure to obtain 177.30 g of compound VII-1 as a gray solid, yield: 93.2%.

[0075] Compound VII-1 Preparation of Compound I-1:

[0076] Sodium methoxide (26.51g, 0.491mol, 1.0e.q.) and DMF (0.8L) were added to the reaction flask, and a DMF (0.6L) solution of compound VII-1 (177.30g, 0.491mol, 1.0e.q.) was added dropwise ...

Embodiment 2

[0078]

[0079] Compound VI-2 Preparation of Compound VII-2:

[0080] Add compound VI-2 (185.2g, 0.500mol, 1.0e.q.) and 1,2-dichloroethane (1.5L) into the reaction flask, cool down to -30°C, add phosphorus trichloride (68.7g, 0.500 mol, 0.5e.q.), after dropping, the temperature was raised to reflux for 1.5 hours, TLC showed that the reaction was complete, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution, layered and separated, the organic phase was washed once with water, and washed with saturated saline Once, dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure to obtain compound VII-2 as gray solid 185.5g, yield: 95.4%.

[0081] Compound VII-2 Preparation of Compound I-2:

[0082] Potassium tert-butoxide (160.6g, 1.431mol, 3.0e.q.) and DMF (1.5L) were added to the reaction flask, and the DMF of compound VII-2 (185.5g, 0.477mol, 1.0e.q.) was added dropwise at 0-10°C. (0.5L) solution, dropwise, heated to 90 °...

Embodiment 3

[0084]

[0085] Compound VI-3 Preparation of Compound VII-3:

[0086] Add compound VI-3 (146.1g, 0.380mol, 1.0e.q.) and dichloromethane (1.5L) into the reaction flask, cool down to 10°C, add N-chlorosuccinimide (60.9g, 0.456mol, 1.2e.q.) and triphenylphosphine (119.6g, 0.456mol, 1.2e.q.), the addition was completed, and the temperature was raised to 30°C for 18 hours. TLC showed that the reaction was complete, and the reaction mixture was poured into ice water, separated into layers, and water The phases were extracted with dichloromethane (1L×2), the organic phases were combined, washed 3 times with water, washed 1 time with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain 151.4 g of compound VII-3 as a gray solid. Rate: 98.9%.

[0087] Compound VII-3 Preparation of Compound I-3:

[0088] 60% NaH (18.0g, 0.451mol, 1.2e.q.) and DMF (1L) were added to the reaction flask, and DMF (0.5 L) solution, d...

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Abstract

The invention discloses an intermediate of a (1S,4S)-2,5-diazabicyclo[2,2,2]octane derivative and a preparation method of the intermediate. The preparation method comprises the following steps of: taking a compound II as a raw material, firstly performing an amidation reaction to protect amido groups of the compound II and obtain a compound III, and conducting a reduction reaction between the compound III and hydrogen in the presence of a catalyst to obtain a compound IV; carrying out an amidation reaction to protect nitrogen atoms in a piperidine ring to obtain a compound V, then conducting areaction of the compound V with a reducing agent to obtain a compound VI, and then conducting a reaction between the compound VI with a halogenating reagent to obtain a compound VII, wherein the compound VII can also be subjected to a ring-closure reaction in the presence of a base so as to obtain a compound I.

Description

technical field [0001] The invention relates to the field of heterocyclic organic chemical synthesis, in particular to an intermediate of (1S,4S)-2,5-diazabicyclo[2.2.2]octane derivatives and a preparation method thereof. Background technique [0002] A compound that selectively activates / stimulates α-7 nicotinic receptors in mammals has recently been discovered, which can treat or prevent diseases caused by dysfunction of nicotinic acetylcholine receptor transmission in mammals. , neurodegenerative diseases and / or memory and / or cognitive impairment disorders involving dysfunction of the cholinergic system have a significant effect, mainly including schizophrenia, anxiety disorders, mania, depression, manic depression, Touré Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficit, attention deficit, attention deficit disorder etc. These compounds are composed ...

Claims

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Application Information

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IPC IPC(8): C07D471/08C07D211/96
Inventor 祝兴勇王旭
Owner PHARMABLOCK SCIENCES (NANJING) INC
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