Method for preparing medicine Lu-AE-58054 for resisting alzheimer's disease

A compound and solvent technology, applied in the field of preparation of anti-Alzheimer's drug Lu-AE-58054, can solve the problems of high energy consumption and high price of 3-hydroxybenzaldehyde

Active Publication Date: 2015-03-18
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The price of raw material 3-hydroxybenzaldehyde is relatively high in the above-mentioned reaction route, and intermedi...

Method used

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  • Method for preparing medicine Lu-AE-58054 for resisting alzheimer's disease
  • Method for preparing medicine Lu-AE-58054 for resisting alzheimer's disease
  • Method for preparing medicine Lu-AE-58054 for resisting alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1 2,2,3,3-tetrafluoropropoxy-4-methylbenzenesulfonate

[0081] 2,2,3,3-Tetrafluoro-1-propanol (3.0 g, 22.7 mmol) and triethylamine (6.4 mL, 45.4 mmol) were dissolved in dichloromethane (20 mL), and then slowly added in portions to Toluenesulfonyl chloride (2.87g, 15.0mmol), after reacting at room temperature for 6 hours, dichloromethane (50ml) was added to dilute, washed with saturated sodium chloride solution (50mL), and the organic phase was dried with anhydrous sodium sulfate after separation. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=20 / 1) to obtain the title compound as a colorless liquid (3.67 g, 85%).

[0082] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.83 (d, J = 8.2Hz, 2H), 7.41 (d, J = 8.1Hz, 2H), 5.88 (tt, J = 52.9, 4.1Hz, 1H), 4.36 (t, J = 12.0Hz, 2H), 2.50(s, 3H).

Embodiment 2

[0083] Example 2 1-methyl-3-(2,2,3,3-tetrafluoropropoxy)benzene

[0084] 2,2,3,3-Tetrafluoropropoxy-4-methylbenzenesulfonate (572 mg, 2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate was added thereto (276mg, 2mmol) and m-cresol (432mg, 4mmol), heated to 100°C for reaction, monitored by TLC. After the reaction was complete, saturated brine (30 mL) was added, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=100 / 1) to obtain the title compound as white Solid (328 mg, 74%).

[0085] 1 H NMR (400MHz, CDCl 3 )δ (ppm): 7.23 (t, J = 7.8Hz, 1H), 6.89 (d, J = 7.5Hz, 1H), 6.78 (s, 1H), 6.75 (d, J = 8.2Hz, 1H), 6.08 (tt, J=53.1, 5.0Hz, 1H), 4.35(t, J=11.9Hz, 2H), 2.37(s, 3H).

Embodiment 3

[0086] Example 3 1-(bromomethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzene

[0087] 1-Methyl-3-(2,2,3,3-tetrafluoropropoxy)benzene (444 mg, 2 mmol) was dissolved in carbon tetrachloride (10 mL), and azobisisobutyronitrile was added thereto (10mg, 0.06mmol) and N-bromosuccinimide (356mg, 2mmol), heated to 80°C for reaction, monitored by TLC. After the reaction was completed, it was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=50 / 1) to obtain the title compound as a white solid (450 mg, 75%).

[0088] 1 H NMR (400MHz, CDCl 3 )δ (ppm): 7.22 (t, J = 7.9Hz, 1H), 7.00 (d, J = 7.5Hz, 1H), 6.90 (s, 1H), 6.79 (dd, J = 8.2, 2.0Hz, 1H) , 5.99 (tt, J=52.8, 4.9Hz, 1H), 4.38(s, 2H), 4.28 (t, J=11.8Hz, 2H).

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Abstract

The invention discloses a novel method for preparing a medicine Lu-AE-58054 for resisting an alzheimer's disease. The novel method comprises the following steps: firstly, reacting 2,2,3,3-tetrafluoromethane-1-propyl alcohol with paratoluensulfonyl chloride, so as to obtain 2,2,3,3-teflon propoxy-4-methyl benzene sulfonate; reacting 2,2,3,3-tetrafluoropropoxy-4-methyl benzene sulfonate with m-cresol, and generating 1-methyl-3-(2,2,3,3-tetrafluoropropoxy) benzene; and obtaining 1-(halogen methyl)-3-(2,2,3,3-tetrafluoropropoxy) benzene by halogenating reaction, and carrying out nucleophilic reaction together with a segment 6-fluorotryptamine, so as to obtain 2-(6-fluorin-1H-indolyl-3-yl)-N-(3-(2,2,3,3-tetrafluoropropoxy) benzyl) ethylamine, namely Lu-AE-58054. According to the preparation method disclosed by the invention, the raw materials are cheap and available, for example, the price of the cresol is only one half of the sodium borohydride; the price of NBS is one half of that of sodium borohydride; and the method is relatively mild in reaction condition, safe, controllable, relatively high in total yield, and especially suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of an improved anti-Alzheimer's drug Lu-AE-58054. Background technique [0002] Lu-AE-58054, chemical name 2-(6-fluoro-1H-indolyl-3-yl)-N-(3-(2,2,3,3-tetrafluoropropoxy)benzyl) Ethylamine, a 5-HT 6 Novel anti-Alzheimer's drug of receptor antagonist. The drug is jointly developed by Lundbeck and Otsuka, and is currently in the clinical phase III, mainly for the treatment of Alzheimer's disease (Alzheimer's disease, AD). [0003] The structural formula of Lu-AE-58054 is as follows: [0004] [0005] At present, the disclosed preparation methods at home and abroad are mainly the following methods: [0006] (1) The preparation method using 3-(2,2,3,3-tetrafluoropropoxyl) benzaldehyde as an intermediate [0007] This is the early published Lu-AE-58054 preparation method, which is found in the compound patent EP 1379239B1 (WO 02078693). The patent mentio...

Claims

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Application Information

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IPC IPC(8): C07D209/14C07C43/225C07C41/22C07C41/16
CPCC07C41/16C07C41/22C07D209/14C07C43/225
Inventor 张英俊金传飞钟文和
Owner SUNSHINE LAKE PHARM CO LTD
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