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Synthetic method of 3-fluoro-azetidine derivative

A technology for the synthesis of azetidine, which is applied in the direction of organic chemistry, can solve the problems of high risk, low total yield, and high equipment requirements, and achieve the effects of high reaction yield, simple operation, and mild reaction conditions

Active Publication Date: 2016-03-09
NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The method of this report has the following disadvantages: the total yield is relatively low, 51.6%, the second step uses fluorine on NFSI and needs to be reacted at -78°C, which requires high equipment requirements; the preparation of raw materials requires 3 steps of reaction, and the third step Need to use high-pressure hydrogenation, the risk of large-scale preparation is greater

Method used

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  • Synthetic method of 3-fluoro-azetidine derivative
  • Synthetic method of 3-fluoro-azetidine derivative
  • Synthetic method of 3-fluoro-azetidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Synthesis of Compound II:

[0028]

[0029] Add raw material I (17.1g, 0.1mol, 1.0eq.), THF (100mL) and trimethylsilyl cyanide (10.4g, 0.105mol, 1.05eq.) into a 250mL four-neck flask, heat up to 65°C for 5h, TLC Shows complete reaction. Concentrate to obtain 27.0 g of off-white solid, theoretically 27.0 g, yield: 100%. 1 H-NMR (400MHz, CDCl3) δ (ppm) 4.41-4.33 (d, J = 9.8Hz, 2H), 4.10-3.99 (d, J = 9.8Hz, 2H), 1.52-1.39 (s, 9H), 0.32 -0.22(s,9H).

[0030] Synthesis of Compound III:

[0031]

[0032] Add intermediate II (27.0g, 0.1mol, 1.0eq.) and methanol (100mL) to a 250mL four-neck flask, add thionyl chloride (11.9g, 0.1mol, 1.0eq.) dropwise, reflux at 65°C for 3h, and LC - MS showed complete reaction. Concentrate to obtain 16.8 g of off-white solid, theoretically 16.76 g, yield: 100%. directly into the next reaction. 1 H-NMR (400MHz,D 2 O) δ (ppm) 4.55-4.41 (d, J = 12.5Hz, 2H), 4.21-4.05 (d, J = 12.5Hz, 2H), 3.90-3.78 (s, 3H).

[0033] Synthesis of Comp...

Embodiment 2

[0046] Synthesis of Compound II:

[0047]

[0048] Add raw material I (17.1g, 0.10mol, 1.0eq.), toluene (100mL) and trimethylsilyl cyanide (11.9g, 0.12mol, 1.2eq.) into a 250mL four-necked flask, reflux at 110°C for 3h, TLC shows the reaction completely. Concentrate to obtain 27.0 g of off-white solid, theoretically 27.0 g, yield: 100%. 1 H-NMR (400MHz, CDCl 3 )δ (ppm) 4.41-4.33 (d, J = 9.8Hz, 2H), 4.10-3.99 (d, J = 9.8Hz, 2H), 1.52-1.39 (s, 9H), 0.32-0.22 (s, 9H) .

[0049] Synthesis of compound VII:

[0050]

[0051] In a 500mL four-neck flask, add intermediate II (14.7g, 0.054mol, 1.0eq.), then add tetrahydrofuran (100mL) to dissolve, add tetraethylammonium fluoride trihydrate (12.2g, 0.060mol, 1.1eq. ), incubated at 40°C for 2h, and TLC detected that the reaction was complete. Add water (200mL), separate the layers, extract the aqueous layer with EA (100mL, 50mL) once respectively, combine the organic phases, wash with saturated aqueous sodium chloride solution...

Embodiment 3

[0065] Synthesis of Compound II:

[0066]

[0067] In a 2L four-neck flask, add intermediate I (200.0g, 1.168mol, 1.0eq.), dissolve it with EA (1.2L), add trimethylsilyl cyanide (173.8g, 1.752mol, 1.5eq.), 20 After reacting at ℃ for 4 hours, the reaction was complete as detected by TLC, and the solvent was removed by rotary evaporation to obtain 359.0 g of a yellow oil, the theoretical yield: 315.8 g, and the yield of the crude product was 100%. 1 H-NMR (400MHz, CDCl 3 )δ (ppm) 4.41-4.33 (d, J = 9.8Hz, 2H), 4.10-3.99 (d, J = 9.8Hz, 2H), 1.52-1.39 (s, 9H), 0.32-0.22 (s, 9H) .

[0068] Synthesis of Compound III:

[0069]

[0070] Add intermediate II (27.0g, 0.1mol, 1.0eq.) and MeOH (100mL) to a 250mL four-neck flask, add thionyl chloride (23.8g, 0.2mol, 2.0eq.) dropwise, react at 40°C for 4h, LC - MS showed complete reaction. Concentrate to obtain 16.8 g of off-white solid, theoretically 16.8 g, yield: 100%. directly into the next reaction. 1 H-NMR (400MHz,D 2 O) δ...

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Abstract

The invention provides a synthetic method of a 3-fluoro-azetidine derivative. The synthetic method takes a compound I as the raw material, the compound I is reacted with trimethylsilyl cyanide to obtain a compound II, and a compound VI is obtained through esterification, N-protection and fluoronation or through hydrolysis, fluoro, esterification and N-protection. The synthetic method is mild in reaction condition and easy to operate, the yield of a reaction of each step is high, and the total recovery can reach 85 percent.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of 3-fluoro-azetidine derivatives. Background technique [0002] Fluorine-substituted azetidines are widely used in the field of drug research and development due to their unique physical and chemical properties and in vivo metabolism characteristics, such as dipeptidyl peptidase IV inhibitors, cannabinoid receptor modulators and other structures that contain fluorine substitution Fragments of Azetidine. The synthesis of these active compounds is mainly connected with 3-fluoro-substituted azetidine through different substituents, therefore, 3-fluoro-azetidine derivatives will be a drug intermediate with great market potential body. [0003] For the synthesis of 3-fluoro-azetidine derivatives, the route reported in the patent ZL201210236105.8 is as follows: [0004] [0005] Reagents and yields: (a) (Boc) 2 O, NaHCO 3 , EA, water, ...

Claims

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Application Information

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IPC IPC(8): C07D205/04
CPCC07D205/04
Inventor 张雷亮李磊方锐刘贵华杨民民
Owner NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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