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Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride

A technology of diethyl azodicarboxylate and triphenylphosphine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of many by-products, difficulties in separation and purification, and low yield, and achieve improved reaction yield, simple experimental operation, The effect of high purity

Inactive Publication Date: 2020-06-02
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Aiming at problems such as many by-products, low yield and difficult separation and purification in the synthesis method of (1-fluorocyclopropyl)methylamine hydrochloride in the prior art, the invention provides a kind of (1-fluorocyclopropyl) The preparation method of methylamine hydrochloride

Method used

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  • Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride
  • Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride
  • Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation of formula III compound

[0028]

[0029] Dissolve the compound of formula II (30.00g, 0.23mol, 1.0eq.) in diethyl ether (200mL), add lithium aluminum hydride (8.90g, 0.25mol, 1.1eq.) in batches at 0°C, after the addition is complete, stir at 30°C 2h, 0°C, slowly add water (40mL) and 1N sodium hydroxide (10mL) dropwise, filter with suction, wash the filter cake with ether (200mL×3), dry the filtrate with anhydrous magnesium sulfate, concentrate under reduced pressure below 20°C, 21.00 g of a colorless liquid was obtained, and the yield was 100%. 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 3.85-3.79 (m, 2H), 2.88 (t, 1H), 0.70-0.68 (m, 4H).

[0030] The preparation of formula IV compound

[0031]

[0032] At 0°C, dissolve the compound of formula III (21.0g, 0.23mol, 1.0eq.) in tetrahydrofuran (400mL), add triphenylphosphine (91.56g, 0.35mol, 1.5eq.), add phthaloyl Imine (34.50g, 0.23mol, 1.0eq.), was added dropwise with a solution of diethyl azodicarboxyl...

Embodiment 2

[0038] The preparation of formula III compound

[0039]

[0040] The compound of formula II (30.00g, 0.23mol, 1.0eq.) was dissolved in tetrahydrofuran (200mL), and a 70% mass fraction of red aluminum toluene solution (128mL, 0.46mol, 2.0eq.) was added in batches at 0°C. After completion, stir at 30°C for 2h, then slowly add potassium carbonate aqueous solution dropwise at 0°C to quench, the filter cake is washed with tetrahydrofuran, the filtrate is dried with anhydrous magnesium sulfate, and the reaction solution is directly used in the next step. 1H NMR (400 MHz, CDCl3) δ (ppm): 3.85-3.79 (m, 2H), 2.88 (t, 1H), 0.70-0.68 (m, 4H).

[0041] The preparation of formula IV compound

[0042]

[0043] At 0°C, the compound of formula III (20.0g, 0.22mol, 1.0eq.) was dissolved in isopropyl ether (400mL), triphenylphosphine (57.7g, 0.22mol, 1.0eq.) was added, and phthalic di Formimide (32.4g, 0.22mol, 1.0eq.), was added dropwise with a solution of diisopropyl azodicarboxylate ...

Embodiment 3

[0049] The preparation of formula III compound

[0050]

[0051] Compound of formula II (30.00g, 0.23mol, 1.0eq.) and sodium borohydride (13.1g, 0.345mol, 1.5eq.) were dissolved in tetrahydrofuran (300mL) at 0°C, and trifluoride was added dropwise at -5°C Boron-ether complex (49g, 0.345mol, 1.5eq), after the addition was completed, stirred at 30°C for 16h, quenched by adding methanol at 0°C, and concentrated under reduced pressure below 20°C to obtain 20.5 g of a colorless liquid with a yield of 99.0 %. 1 HNMR (400MHz, CDCl 3 ) δ (ppm): 3.85-3.79 (m, 2H), 2.88 (t, 1H), 0.70-0.68 (m, 4H).

[0052] The preparation of formula IV compound

[0053]

[0054] At 0°C, dissolve the compound of formula III (20.5g, 0.23mol, 1.0eq.) in diethyl ether (400mL), add triphenylphosphine (91.56g, 0.35mol, 1.5eq.), add phthaloyl Imine (34.50g, 0.23mol, 1.0eq.), add diethyl azodicarboxylate (60.86g, 0.35mol, 1.5eq.) in diethyl ether (200mL) dropwise, stir at room temperature for 12h, add...

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Abstract

The invention provides a preparation method of (1-fluorocyclopropyl) methylamine hydrochloride, wherein (1-fluorocyclopropyl) methylamine hydrochloride is prepared by taking 1-fluorocyclopropane carboxylic acid as an initial raw material through the steps of reduction, ammoniation and the like. According to the method, the generation of fluoromethylation by-products in the preparation method in the prior art is avoided, the experimental operation is simple, the purity is high, the reaction yield is greatly improved compared with that of the existing method, the yield of the three-step reactioncan reach more than 60%, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of (1-fluorocyclopropyl)methylamine hydrochloride. Background technique [0002] Cyclopropylmethylamine is an intermediate widely used in the field of drug synthesis, especially plays an important role in the structural modification of drug lead compounds, and it has become common to introduce fluorine atoms into lead compounds to improve physical and chemical properties such as lipophilicity. means of structural modification. (1-Fluorocyclopropyl)methylamine hydrochloride has been used to synthesize compounds with GPR40 agonist activity in the international patent publication WO2015020184A1, such as: [0003] [0004] There are two main methods for the synthesis of (1-fluorocyclopropyl)methylamine hydrochloride. [0005] Route 1, as disclosed in the international patent publication WO2015020184A1, is prepared from ethylmagnesium bromide ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/44C07C211/17
CPCC07C209/44C07C29/147C07D209/48C07C2601/02C07C211/17C07C31/44
Inventor 巩沛王正江夏爱华
Owner PHARMABLOCK SCIENCES (NANJING) INC
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