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Fasudil impurity I preparation method

A technology of fasudil and impurity, which is applied in the field of preparation of fasudil impurity Ⅰ, which can solve the problems of scarce suppliers, high sales price, difficulty in obtaining fasudil impurity Ⅰ, etc.

Inactive Publication Date: 2018-05-04
深圳市祥根生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] It is difficult to obtain Fasudil impurity Ⅰ, and the best yield of this patent is only 14%
[0008] In addition, the impurity is expensive in the market, and there are few optional suppliers
[0009] It can be seen that designing a specialized preparation method, reducing the generation of by-products, increasing product yield, and reducing costs are the key to the research of the entire preparation process for commercial production and batch supply, but the existing technology cannot meet

Method used

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  • Fasudil impurity I preparation method

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Experimental program
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Effect test

Embodiment 1

[0029] The preparation of embodiment 1 acyl hydroxylamine

[0030] Fasudil (2.91g, 10mmol, 1.0eq), dipotassium hydrogen phosphate (2.91g, 12mmol, 1.2eq) and anhydrous DMF (30mL) were added to a 100mL single-necked bottle, and the reaction was stirred at 25°C for 3 hours. TLC monitoring fasudil reaction is complete. Add 60mL of water to the reaction flask, then extract with 50mL of ethyl acetate, and separate the layers. The aqueous phase was extracted twice more with 30 mL of ethyl acetate. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a white solid with a purity of 98%, which was acyl hydroxylamine, which was directly used in the next reaction.

[0031] MS(m / z): 411.9(M+H)+

[0032] 1H NMR (400MHz, CDCl3): δ9.37(s, 1H), 8.71(d, J=6.12Hz, 1H), 8.46(d, J=6.16Hz, 1H), 8.38(dd, J=7.4Hz, 1Hz, 1H), 8.21(d, J=8.16Hz, 1H), 7.95(d, J=7.2Hz, 2H), 7.71(t, J=7.76Hz, 1H), 7.57(t, J=7.44Hz...

Embodiment 2

[0033] The preparation of embodiment 2 fasudil impurity I

[0034] Add tetrahydrofuran (40mL) to the spin-dried bottle of acylhydroxylamine above, stir to dissolve, control the reaction temperature at 0-10°C, add dropwise a solution of lithium hydroxide (264mg, 1.1mmol, 1.1eq) dissolved in water (8mL), After the dropwise addition was completed, the reaction was carried out overnight, and the reaction solution was concentrated to dryness. The crude product was purified by column chromatography to obtain 2.80 g of a white solid with a purity of 99% and a yield of 91%, which was Fasudil Impurity I.

[0035] MS(m / z): 308(M+H)+

[0036] 1H NMR (400MHz, DMSO-d6): δ9.50(s, 1H), 8.71(d, J=6.12Hz, 1H), 8.47(d, J=8.24Hz, 1H), 8.35(d, J=6.12 Hz, 1H), 8.33(dd, J=7.36, 1Hz, 1H), 8.08(s, 1H), 7.85(t, J=7.56Hz, 1H), 3.49-3.50(m, 2H), 3.42(t, J=6.24Hz, 2H), 2.87-2.91(m, 4H), 2.03-1.91(m, 2H).

Embodiment 3

[0037] The HPLC detection of embodiment 3 fasudil impurity I

[0038] The HPLC detection method of Fashur impurity Ⅰ is as follows:

[0039] Chromatographic column: InertSustain C18 4.6X250mm 5μm

[0040] mobile phase:

[0041] A: methanol: 60% B: 1.4g / L disodium hydrogen phosphate

[0042] Mobile phase ratio: A:B=70:30

[0043] Column temperature: 35°C

[0044] Detection wavelength: 230nm

[0045] Flow rate: 1.2mL / min

[0046] Time: 16.00min

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Abstract

The invention discloses a fasudil impurity I preparation method. A fasudil impurity I (shown in a formula I) is an oxidization product of fasudil, is one of important impurities for fasudil medicine or preparations of the fasudil medicine, can be applied to toxicological and pharmacological researches for absorption, metabolism and the like of the fasudil in the body and also can be applied to researches for aspects of stability, quality control and the like of the fasudil preparations. The invention discloses a method which can be used for preparing the fasudil impurity I in high efficiency.According to the method, the fasudil or salt of the fasudil reacts with acyl peroxide under the alkali action, and generated intermediates are hydrolyzed to prepare the fasudil impurity I. According to the fasudil impurity I preparation method disclosed by the invention, cheap reactants and a dedicated reaction method are utilized, and a total yield of products can be improved to 90% or more.The formula I is shown in the description.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for preparing fasudil impurity I. Background technique [0002] Fasudil (fasudil hydrochloride) is also known as hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazepine hydrochloride, its structure is: [0003] [0004] It is the only Rho kinase inhibitor currently on the market. It can relax vascular smooth muscle and dilate blood vessels by inhibiting the phosphorylation of myosin light chain in the final stage of smooth muscle contraction. It is clinically suitable for improving and preventing cerebral spasm after subarachnoid hemorrhage and the symptoms of cerebral ischemia caused by it. [0005] Studies have found that fasudil or its salts are unstable in solution or in the air, and are easily oxidized to generate a more polar impurity. Patent CN102250066A discloses the structure and preparation method of Fasudil Impurity I (Formula I) for the first time. In...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 彭锦安李方林肖海新
Owner 深圳市祥根生物科技有限公司
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