- Unconventional Synthetic Process of Fasudil Hydrochloride: Costly Homopiperazine Was Avoided
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An efficient, robust, and cost-effective synthetic process of fasudil hydrochloride 1 was developed. Starting from readily available ethylenediamine and 5-isoquinoline sulfonyl chloride, the target product 1 was prepared through a six-step reaction, including sulfonamidation, protection, nucleophilic substitution, deprotection, cyclization, and salification. The process afforded 1 in 67.1% overall yield (based on 5-isoquinoline sulfonyl chloride) with 99.94% purity. Compared to the earlier published methodologies, the use of homopiperazine or its derivatives as intermediates was avoided. The salient features of this environmentally friendly synthetic route include easily available starting materials and operational simplicity, which could be suitable for large-scale industrial production.
- Niu, Jinming,Wang, Dingding,Wu, Weiting,Yang, Wu-Lin,Zhao, Jianhong
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- Preparation method of compound fasudil hydrochloride
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The invention relates to a novel efficient and economical method for synthesizing fasudil hydrochloride. The method comprises the following steps: carrying outsulfonamide and Boc protection on cheap and easily available ethylenediamine serving as a starting raw material in a synthesis route to obtain an intermediate tert-butyl-(N-(2-aminoethyl)-5-isoquinoline sulfonamide) carbamate (5), and carrying out collapse condensation to obtain fasudil hydrochloride. The method comprises four steps of nucleophilic substitution, deprotection, cyclization and salification. The total yield of the fasudil hydrochloride (1) is 67.1%, and the purity of the fasudil hydrochloride (1) is as high as 99.94%. Compared with a traditional process, high-price homopiperazine and derivatives thereof are prevented from being used as synthesis intermediates in the route, so the method has the advantages that raw materials are cheap and easy to obtain, operation is easy, cost is low, and the process is environmentally friendly and suitable for industrial production.
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- Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chlorination system
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The invention discloses a method for preparing an isoquinoline hydrochloride intermediate and an Rho kinase inhibitor by using a BTC/Ph3PO chlorination system, which comprises the following steps: putting an isoquinoline 5-sulfonic acid compound, BTC and a catalytic amount of Ph3PO into a reaction bottle, adding an organic solvent A, uniformly mixing all the components, and heating the mixture toreact; after the reaction is finished, carrying out suction filtration and drying to obtain a white solid isoquinoline hydrochloride intermediate, which is the isoquinoline 5-sulfonylchloride hydrochloride compound; concentrating a mother liquor part of the filtrate for separating out Ph3PO at a low temperature, and washing Ph3PO with a low-polarity solvent for recycling use. The method has the advantages of few side reactions, high product quality, less three-waste pollution, high atom economy and the like, the invention also provides a method for further preparing the Rho kinase inhibitor byutilizing the prepared isoquinoline hydrochloride intermediate; the impurities in the Rho kinase inhibitor prepared by the method are obviously lower than those in medicines obtained by a traditionalmethod.
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Paragraph 0112-0127
(2020/11/23)
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- Preparation method of fasudil hydrochloride
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The invention belongs to the technical field of medicines, and relates to a preparation method of fasudil hydrochloride. The specific process of the method comprises the following steps: firstly reacting isoquinoline-5-sulfonic acid with 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine in an organic solvent under the action of organic alkali, then reacting the obtained reaction product with homopiperazine, washing the obtained reaction product with water, washing the obtained reaction product with alkali, and salifying and recrystallizing the obtained reaction product to obtain the high-purity fasudilhydrochloride. The impurity content of the fasudil hydrochloride prepared by the method is lower than 0.1%, and the purity of the fasudil hydrochloride reaches 99.5% or above. The preparation methodcompletely avoids the problem of product pigments caused by acyl chloride corrosion and hydrolysis, has the advantages of safety, environmental protection, low production cost, high product quality, convenience in operation and the like, and is suitable for industrial production.
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Paragraph 0032-0049
(2020/07/13)
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- Method for purifying fasudil hydrochloride
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The invention provides a method for purifying fasudil hydrochloride. According to the method, diffluent fasudil hydrochloride is converted into slightly soluble fasudil dihydrogen phosphate in a water-methanol solution, so that high-content piperazine impurities, most pigment and other water-soluble impurities which are easily dissolved in water and methanol are removed. The method has controllable process parameters, convenient operation and a mild reaction.
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Page/Page column 4-6
(2019/05/15)
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- Preparation method of Fasudil hydrochloride
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The invention belongs to the technical field of preparation of heterocyclic compounds, and particularly relates to a preparation method of Fasudil hydrochloride. The preparation method includes the following steps: 1) reacting isoquinoline-5-sulfonyl chloride hydrochloride, homopiperazine and liquid ammonia in an organic solvent at the temperature of 10-15 DEG C for 2-4 hours, subjecting a reactedreaction system to water extraction separation, and concentrating an oil-phase separation product to obtain an intermediate; 2) subjecting the intermediate obtained in the step 1) and hydrochloric acid to a salt formation reaction to obtain the Fasudil hydrochloride. The preparation method has the advantages that the isoquinoline-5-sulfonyl chloride hydrochloride as a raw material directly reactswith the homopiperazine to obtain the intermediate, so that the operation steps are reduced and the preparation process is simple.
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- FASUDIL-CONTAINING PREPARATION AND METHOD OF IMPROVING STABILITY THEREOF
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Fasudil-containing preparations that despite the use of a container excelling in the visibility of contents without particularly blocking of light, exhibit high stability against light; and a method of improving the stability of the preparations against light, or storing the same. By regulating the pH value of aqueous solution of fasudil charged in a colorless transparent container to ≦ 5.5, there can be provided fasudil-containing preparations excelling in stability against light; and can be provided a method of improving the stability of the aqueous solution of fasudil against light, or storing the same.
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Page/Page column 5
(2008/06/13)
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- 5-Isoquinolinesulfonamide derivatives. III. Synthesis and vasodilatory activity of 1-(5-isoquinolinesulfonyl)piperazine derivatives
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On the basis of a hypothesis that cyclization and alkylation of the diamine part in formula 1 may give highly active compounds, a new series of 5-isoquinolinesulfonamide derivatives, shown as formula 2, were prepared from cyclic diamines. Their vasodilatory effects were subsequently evaluated in vivo according to the increase in arterial blood flow after the formulas were injected locally to the femoral and/or vertebral arteries of dogs. Cyclization of the diamine structure in formula 1 gave very potent vasodilators: 6 and 14. Acylation and sulfonylation of terminal amino nitrogen afforded much less potent compounds. In contrast to the hypothesis, alkylation on the ring carbon and the terminal nitrogen of the cyclic amine afforded less active compounds except for compound 11. The most active compounds, 6, 11 and 14, showed more potent vasodilatory effects and more selective activity to the vertebral artery than either trapidil or diltiazem.
- Morikawa,Sone,Asano
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p. 770 - 773
(2007/10/02)
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- Substituted isoquinolinesulfonyl compounds
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An isoquinolinesulfonyl compound represented by the formula (I): STR1 wherein R1 : H, Cl, OH A : unsubstituted or substituted ethylene or alkylene R2, R3 : H, alkyl, jointly forming unsubstituted or substituted ethylene or trimethylene R4 : H, alkyl, amidino or an acid salt thereof. They can be prepared, for example, by converting 1-R1 substituted-5-isoquinolinesulfonic acid to the corresponding sulfonyl chloride and subsequently reacting the chloride with a compound of formula STR2 They can be advantageously utilized as vasodilator, cerebral circulation ameliorator, antihypertensive agent and drugs for prevention and treatment of various circulatory organ diseases.
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