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Preparation method of dapoxetine impurity reference substance

A technology of impurity reference substance, dapoxetine, applied in the field of medicine

Pending Publication Date: 2021-12-31
南京卓康医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Its synthetic method has not been published yet

Method used

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  • Preparation method of dapoxetine impurity reference substance
  • Preparation method of dapoxetine impurity reference substance
  • Preparation method of dapoxetine impurity reference substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Preparation of compound 7 using p-methoxychlorbenzyl

[0057]

[0058]Compound 3 (200g, 0.718mol, 1eq.) was dissolved in dichloromethane (2000ml), triethylamine (181.6g, 248.8ml, 1.795mol, 2.5eq.) was added, and the reaction solution was cooled to below 10°C, Add p-methoxychlorbenzyl (134.9g, 0.862mol, 1.2eq) dropwise, after the reaction is over, add 10% potassium bisulfate solution (1000ml), stir and separate layers, collect the lower organic phase, add n-heptane (1000ml) , cooled to 5±5°C for crystallization, filtered, and vacuum-dried at 40±5°C to obtain 260.4 g of an off-white solid with a yield of 91%, which is compound 7.

[0059] ESI-MS(+):399.2[M+H] + .1H-NMR (400MHz, CDCl3): 8.31(d, J=5.5Hz, 1H), 8.08(d, J=5.5Hz, 1H), 7.62~7.59(m, 3H), 7.40~7.27(m, 6H ),6.98(d,J=5.5Hz,2H),6.91(d,J=5.5Hz,2H),6.42(d,J=5.0Hz,1H),4.71(s,2H),4.43(t,J =7.0Hz, 1H), 3.92(t, J=7.5Hz, 2H), 3.70(s, 3H), 2.17(t, J=7.5Hz, 2H).

Embodiment 2

[0060] Embodiment 2: use p-methoxybromide to prepare compound 7

[0061]

[0062] Compound 3 (200g, 0.718mol, 1eq.) was dissolved in dichloromethane (2000ml), triethylamine (181.6g, 248.8ml, 1.795mol, 2.5eq.) was added, and the reaction solution was cooled to below 10°C, Add p-methoxybromide (173.3g, 0.862mol, 1.2eq) dropwise, after the reaction, add 10% potassium bisulfate solution (1000ml), stir and separate layers, collect the lower organic phase, add n-heptane (1000ml) , cooled to 5±5°C for crystallization, filtered, and vacuum-dried at 40±5°C to obtain 262.7 g of an off-white solid with a yield of 91.8%, which is compound 7.

Embodiment 3

[0063] Embodiment 3: preparation compound 8

[0064]

[0065] Compound 7 (50g, 0.125mol) was dissolved in nitrobenzene (300ml), aluminum chloride (33.46g, 0.25mol, 2eq.) was added, and compound 1 (42.31g, 0.251mol, 2eq.) was dissolved in Nitrobenzene (200ml), the reaction system was heated to 100-110°C, and the solution of compound 1 was added dropwise, and the dropwise addition took 3 hours, and the resulting reaction mixture was stirred and reacted at 100-110°C for 2 hours. Monitor the reaction (TLC monitoring condition is GF254 silica gel plate, developing agent is ethyl acetate:petroleum ether (v / v)=1:20, observe with 254nm ultraviolet light) until compound 7 basically disappears, stop heating, and cool to below 20°C .

[0066] The reaction solution was added dropwise to 10% dilute hydrochloric acid solution (1000ml), the lower organic phase was separated, washed with saturated sodium chloride solution (300ml×3), the organic phase was concentrated to dryness under redu...

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Abstract

The invention discloses a preparation method of a dapoxetine impurity reference substance, which comprises the following steps: (1) reacting 3-(naphthalene-1-yloxy)-1-phenylpropan-1-ol with a p-methoxybenzyl reagent to obtain a compound 7; (2) reacting the compound 7 with 3-chloro-1-phenylpropyl-1-ketone to obtain a compound 8; (3) removing a p-methoxybenzyl protecting group in the compound 8 by using an oxidizing agent to obtain a compound 4; (4) reacting the compound 4 with alkyl sulfonyl chloride, and then reacting the compound with dimethylamine to obtain the dapoxetine impurity reference substance as shown in a formula 6. The dapoxetine impurity reference substance shown in the formula 6 is prepared for the first time.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of a dapoxetine impurity reference substance. Background technique [0002] Dapoxetine is a selective serotonin reuptake inhibitor used for the treatment of premature ejaculation in men. Its structural formula is as follows, which may contain impurities (Formula 6). [0003] [0004] In the synthetic process of dapoxetine, a kind of preparation method of intermediate (formula 3) is to use 3-chloro-1-phenylpropan-1-one (formula 1) to obtain 3-chloro-1-benzene Propan-1-alcohol (Formula 2), followed by an ether-forming reaction with 1-naphthol, yields an intermediate (Formula 3). [0005] [0006] Wherein, in the process of being reduced to the intermediate (formula 2) from 3-chloro-1-phenylpropan-1-one (formula 1), there will be a small amount of 1 that is not reduced, and in the subsequent reaction with 1-naphthol During the reaction process, it wil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C217/48
CPCC07C41/16C07C45/68C07C45/64C07C213/02C07C43/2055C07C49/84C07C217/48Y02P20/55
Inventor 李强刘子宁
Owner 南京卓康医药科技有限公司
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