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A kind of preparation method and application of 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol

A technology of azetidine and hydroxyethyl, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of high price, difficulty in obtaining, and no literature report on the preparation of compound 7, and achieve simple process steps and easy operation Effect

Active Publication Date: 2020-03-06
SUZHOU GUOKUANG PHARMTECH CO LTD
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Problems solved by technology

[0008] But commercial 3-(piperidin-3-yl) azetidinyl-1-carboxylate tert-butyl ester (compound 7) is extremely difficult to obtain, even if it can be obtained, there is a significant problem of high price; The high procurement cost of raw materials (compound 7) will inevitably lead to a sharp increase in the production cost of final target products such as clinical drug compound 6
[0009] At the same time, there is no literature report on the preparation of compound 7
In the previous study, the applicant of this patent once explored the use of tert-butyl 3-(pyridine-3 base) azetidinyl-1 carboxylate (compound 2) in platinum / palladium catalyst such as PtO 2 ,Pd(PPh 3 ) 4 , Pd(OAC) 2 Catalytic hydrogenation with high pressure (80atm) and long time (60 hours) heating (80°C) under other conditions, but no reaction, the target product 3-(pyridine-3 base)azetidinyl-1 carboxylic acid could not be obtained tert-butyl ester (compound 7)

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  • A kind of preparation method and application of 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol
  • A kind of preparation method and application of 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol
  • A kind of preparation method and application of 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol

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preparation example Construction

[0041] The present invention provides a kind of preparation method of 2-(3-(azetidin-3-yl) piperidin-1-yl) ethyl-1-alcohol, described method comprises the following steps:

[0042] (1) Compound 2 is reacted with 2-halogenated ethanol in a solvent to obtain compound 3;

[0043] (2) Compound 3 is hydrogenated to obtain Compound 4 under the action of a catalyst;

[0044] (3) Compound 4 is under acidic conditions, removes the Boc protecting group and then removes the acid in vacuo or neutralizes with a base to obtain compound 1, namely 2-(3-(azetidin-3-yl)piperidine- 1-base) ethyl-1-alcohol, reaction synthetic route is:

[0045]

[0046] Wherein, X is a halogen atom.

[0047] In a preferred embodiment, the halogen atom X in the 2-haloethanol in step (1) is chlorine, bromine, iodine, preferably an iodine atom, and the molar ratio of compound 2 to 2-haloethanol is 1: 0.5-3, preferably 1:1-2, and the reaction temperature is 25-120°C, preferably 50-100°C.

[0048] In a preferred ...

Embodiment 1

[0061] The preparation of embodiment 1 compound 3

[0062]

[0063] 3-(Pyridin-3 yl)azetidinyl-1 carboxylate tert-butyl ester (compound 2) (1.0 g, 4.0 mmoL) and 2-iodoethanol (1.1 g, 6 mmoL) were added to acetonitrile (10.0 mL) in an oil bath at 80°C overnight. TLC detected that the reaction was complete, and the solvent was distilled off under reduced pressure. The residue was washed with a n-hexane / ethyl acetate=5 / 1 mixed system to remove excess 2-iodoethanol to obtain 1.62 g of brown oil with a yield of 100%.

[0064] 1 H NMR (CDCl 3 ,400MHz)δ=9.23(s,1H),9.04(d,J=8.0Hz,1H),8.53(d,J=8.0Hz,1H),8.13(dd,J 1 =4.0Hz,J 2 =8.0Hz,1H),4.96-4.94(m,2H),4.46(t,J=8.0Hz,2H),4.16-4.12(m,2H),4.05-4.01(m,2H),3.83(t, J=4.0Hz, 3H), 1.45(s, 9H).

Embodiment 2

[0065] The preparation of embodiment 2 compound 4

[0066]

[0067] Compound 3 (1.5g, 3.74mmoL) and PtO 2 (0.15g, 10%, w / w) was added into ethanol (10.0mL), and catalytic hydrogenation was carried out in an oil bath at 50°C under normal pressure overnight. TLC detects that the reaction is complete. The catalyst was removed by filtration, the catalyst was washed with ethanol, the solvent was evaporated from the filtrate under reduced pressure, and the residue was dried under high vacuum to obtain 980 mg of an oily substance with a yield of 92%. It was directly used in the next reaction without purification.

[0068] 1 H NMR (CDCl 3 ,400MHz)δ=3.98-3.93(m,2H),3.78-3.71(m,2H),3.69-3.65(m,3H),3.11-3.02(m,2H),2.76-2.73(m,2H), 2.30-1.77(m,8H),1.43(s,9H).ESI-MS:285.2[M+H] + .

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Abstract

The present invention provides a kind of preparation method of 2-(3-(azetidine-3-yl) piperidin-1-yl) ethyl-1-alcohol, it is characterized in that, described method comprises the following steps: (1) Compound 2 reacts with 2-halogenated ethanol in a solvent to obtain compound 3; (2) compound 3 obtains compound 4 through hydrogenation under the action of a catalyst; (3) compound 4 is removed under acidic conditions After the Boc protecting group, remove the acid in vacuo or neutralize with a base to obtain compound 1, i.e. 2-(3-(azetidine-3-yl) piperidin-1-yl) ethyl-1-alcohol, reaction synthesis The route is: wherein, X is a halogen atom. The method has cheap and easy-to-obtain raw materials, mild reaction conditions, simple operation and high yield.

Description

technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol, and Its application in the preparation of antitumor drugs. Background technique [0002] Regulatory T cells (T reg ) play an important role in tumor immunity. CCR4 (chemokine receptor 4) antagonists selectively inhibit T reg , and can produce a durable anti-tumor immune response, which is an important part of small molecule tumor immunity. ((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxyethyl)piperidin-3-yl)azacycle Butan-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile (compound 6) is an orally active CCR4 antagonist (WO2018 / 022922A1). In preclinical studies, compound 6 can effectively inhibit tumor growth when administered alone; compound 6 can significantly enhance immune checkpoint inhibitors such as PD-1 / PD-L1 and CTLA4, and immune stimulants such as Antitumor e...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00
CPCA61P35/00C07D487/04Y02P20/55
Inventor 梅德盛刘爱风孙靖汪奎孙高睿陈林瑞施佳
Owner SUZHOU GUOKUANG PHARMTECH CO LTD
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