CN102633779B - Fasudil acetate as well as preparation method and application thereof - Google Patents
Fasudil acetate as well as preparation method and application thereof Download PDFInfo
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- CN102633779B CN102633779B CN201210125285.2A CN201210125285A CN102633779B CN 102633779 B CN102633779 B CN 102633779B CN 201210125285 A CN201210125285 A CN 201210125285A CN 102633779 B CN102633779 B CN 102633779B
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Abstract
The invention relates to fasudil acetate as well as a preparation method and application thereof, belonging to the technical field of medicines and chemicals. According to the method, fasudil acetate is prepared through reaction between fasudil and acetic acid, and fasudil hydrochloride with high purity is prepared from fasudil acetate, therefore, the column chromatography operation is effectively avoided, the problems of need of column chromatography, high toxicity and long separation period existing in a fasudil hydrochloride preparation process are solved, and therefore, the process is more suitable for industrial production.
Description
Technical field
The present invention relates to a kind of new compound fasudil acetate and its preparation method and application, belong to pharmaceutical chemistry technical field.
Background technology
Fasudil is isoquinoline 99.9 sulfamido material; chemical name is six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1H-1; 4-diazepine; English name fasudil; by Japanese Asahi Kasei Corporation (Asahi Kasei Pharma), researched and developed; there is the effect of powerful vasodilative effect and protection ischemic tissue of brain, belong to Rho-kinase inhibitor.Fasudil went on the market in Japan in nineteen ninety-five, and marketed drug is its mono-hydrochloric salts form at present, for the symptoms of cerebral ischemia of improving the cerebral vasospasm after subarachnoid hemorrhage and causing thereupon.New indication-the acute cerebral thrombosis of this medicine also waits for ratification in Japan at present.
In the preparation method of the Fasudil Hydrochloride of having reported, the main 5-isoquinoline 99.9 SULPHURYL CHLORIDE that adopts is reacted the crude product that obtains fasudil with homopiperazine, this crude product makes fasudil through column chromatographic isolation and purification, and last and hydrochloric acid salify makes target product Fasudil Hydrochloride.
In the prior art, the major impurity in fasudil crude product is the two acylates shown in formula (II), for removing two acylates and other impurity in fasudil crude product, obtains the fasudil of better purity, the general column chromatography method that adopts in technique.But the silica gel consumption of the method is large, need chloroform that toxicity is higher or methylene dichloride as elutriant, solvent is volatile; loss is large, and the separation and purification cycle is long, and cost is high; the more important thing is that the method has limited process scale greatly, is not suitable for the industrial production of mass-producing.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of new midbody compound, six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1H-1,4-diazepine acetate, i.e. fasudil acetate, structural formula as shown in the formula (I):
N=1 or 2 wherein.
The preparation method of this fasudil acetate is: in organic solvent, fasudil is reacted and made in 0-60 ℃ with glacial acetic acid, reaction equation is as follows:
React complete, slow cooling is to crystallization 6-8 hour within the scope of 2-8 ℃, suction filtration, washing, the dry fasudil acetate that to obtain.
Wherein, described organic solvent is selected from methyl alcohol, ethanol, Virahol, acetone, methylene dichloride, trichloromethane, acetonitrile, DMF, N,N-dimethylacetamide, one or more in tetrahydrofuran (THF).
In preparation process, because glacial acetic acid is weak organic acid, can with fasudil free alkali salify, but two acylates that can not be weak with alkalescence react salify.Fasudil in fasudil crude product by with glacial acetic acid salify after pass through crystallization; and two acidylate impurity is not because continuing to stay in mother liquor with glacial acetic acid salify; therefore; this salification process can effectively be removed the two acylates in fasudil crude product, obtains highly purified fasudil acetate.In order to guarantee that fasudil crude product can fully dissolve, react salify with glacial acetic acid abundant, temperature of reaction is controlled at 0-60 ℃, preferably 40-60 ℃.Generally, in order to prevent the excessive exothermic effect with occurring of topical agent, glacial acetic acid adopts the mode dripping.In addition, in this preparation process, fasudil is different from the mol ratio of glacial acetic acid, and the acetate of the fasudil obtaining is not identical yet: when the mol ratio of glacial acetic acid and fasudil is 1-1.1:1, obtain fasudil Monoacetate; When the mol ratio of glacial acetic acid and fasudil is 2-4:1, obtain fasudil diacetate.
In the present invention, the molecular formula of fasudil acetate and molecular weight thereof are as listed in table 1:
Molecular formula and the molecular weight thereof of table 1 fasudil acetate
| Title | Molecular formula | Molecular weight |
| Fasudil Monoacetate (n=1) | C 14H 17N 3O 2S·CH 3COOH | 351.42 |
| Fasudil diacetate (n=2) | C 14H 17N 3O 2S·2CH 3COOH | 411.47 |
In addition, the present invention also provides the method for preparing highly purified Fasudil Hydrochloride by fasudil acetate.Adopt fasudil acetate to prepare Fasudil Hydrochloride and can effectively avoid column chromatography operation, solved the problem that column chromatography, toxicity are large, separation cycle is long that needs existing in Fasudil Hydrochloride preparation technology, make technique more be applicable to suitability for industrialized production, comprise the steps:
(1) in the organic solvent of fasudil acetate, add inorganic base aqueous solution, regulate reacting liquid pH value 9-11, guarantee that fasudil fully dissociates out, separate organic phase, washing, dry, filter, concentrating under reduced pressure obtains highly purified fasudil;
(2) highly purified fasudil is dissolved in methyl alcohol, adds hydrochloric acid reaction, regulate reacting liquid pH value 4-5, guarantee the abundant salify of fasudil, be cooled to-5-5 ℃ crystallization, obtains highly purified Fasudil Hydrochloride.Wherein, the excessive salify that causes of pH value is insufficient; PH value is too small, in product, can produce dihydrochloride, causes the yield of target product fasudil mono-hydrochloric salts to reduce.
Described in the preparation process of above-mentioned high-purity hydrochloric acid fasudil, organic solvent is selected from methylene dichloride, trichloromethane, one or more in ethyl acetate; Described mineral alkali is selected from one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.
In sum, the invention provides a kind of fasudil acetate and preparation method thereof, and utilize this fasudil acetate to make highly purified Fasudil Hydrochloride, through high performance liquid chromatography (HPLC) method, detect, Fasudil Hydrochloride purity is higher than 99.8%, effectively avoid column chromatography operation, solved in Fasudil Hydrochloride preparation technology, exist need column chromatography, toxicity is large, separation cycle is long problem, make technique more be applicable to suitability for industrialized production.
Embodiment
The embodiment of form, is described in further detail foregoing of the present invention by the following examples.Protection scope of the present invention includes but not limited to the description of following examples.In following examples, fasudil crude product all adopts the method preparation of patent CN1183782A report, wherein the two acylate content 3.66% of impurity.
Embodiment 1
Take fasudil crude product 50.8g(0.174mol), add 50ml dehydrated alcohol, in 55-60 ℃, drip glacial acetic acid 11ml (0.174mol); dropwise, slow cooling is to 5-8 ℃ of crystallization 7 hours, suction filtration; cold ethanol filter wash cake; must be white to off-white color solid, dry, obtain product 41.8g; productive rate 68.4%; through high performance liquid chromatography (HPLC) method, detect, purity is 99.92%, and the two acylates of impurity do not detect.Product is fasudil Monoacetate.
Ultimate analysis: (C
14h
17n
3o
2sCH
3cOOH): C, 54.70; H, 5.99; N, 11.97; S, 9.11;
Theoretical value: C, 54.68; H, 6.02; N, 11.96; S, 9.12.
1H-NMR(600?MHz,?DMSO-d6)
：9.70(s,?2H)?,?9.52(s,?1H),?8.73(d,?J?=?6Hz,?1H),?8.46(d,?J?=?6.0Hz,?1H),?8.35(d,?J?=?7.2Hz,?1H),?8.19(d,?J?=?8.4Hz,?1H),?7.69(t,?J?=?7.8Hz,?1H),?3.51(t,?J?=?6.0Hz,?2H),?3.46(t,?J?=?5.4Hz,?2H),?3.00(t,?J?=?4.8Hz,?2H),?2.95(t,?J?=?6.0Hz,?2H),?2.09(s,?3H)?,?1.85(m,?2H)。
MS(ESI,?m/z?),?292.1[M-CH
3COO]
+?,?314.3[M-CH
3COOH+Na]
+。
IR(KBr)cm
-1:3433，3392，2950，1647，1619，1563，1404，1308，1130，1015，899，812，716，599。
Embodiment 2
Take fasudil crude product 50.8g(0.174mol), add 150ml anhydrous methanol, in 30-35 ℃, drip glacial acetic acid 12ml (0.19mol); dropwise, slow cooling is to 2-5 ℃ of crystallization 6 hours, suction filtration; cold methanol filter wash cake; must be white to off-white color solid, dry, obtain product 36.6g; productive rate 59.9%; through high performance liquid chromatography (HPLC) method, detect, purity is 99.94%, and the two acylates of impurity do not detect.Product is the Monoacetate of fasudil.
Embodiment 3
Take fasudil crude product 50.8g(0.174mol), add 100ml methylene dichloride, in 40-45 ℃, drip glacial acetic acid 12ml (0.19mol); dropwise, slow cooling is to 4-6 ℃ of crystallization 6 hours, suction filtration; cold methylene dichloride filter wash cake; must be white to off-white color solid, dry, obtain product 40.2g; productive rate 65.8%; through high performance liquid chromatography (HPLC) method, detect, purity is 99.95%, and the two acylates of impurity do not detect.Product is fasudil Monoacetate.
Embodiment 4
Take fasudil crude product 50.8g(0.174mol), add 120ml acetone, in 0-20 ℃, drip glacial acetic acid 11ml (0.174mol); dropwise, slow cooling is to 6-8 ℃ of crystallization 8 hours, suction filtration; cold acetone filter wash cake; must be white to off-white color solid, dry, obtain product 41.8g; productive rate 68.4%; through high performance liquid chromatography (HPLC) method, detect, purity is 99.92%, and the two acylates of impurity do not detect.Product is fasudil Monoacetate.
Embodiment 5
Take fasudil crude product 200g(0.69mol), add 300ml dehydrated alcohol, in 30-40 ℃, drip glacial acetic acid 86.4ml (1.51mol); dropwise; slow cooling is to 2-3 ℃ of crystallization 6 hours, suction filtration, cold ethanol filter wash cake; obtain white to off-white color solid; dry, obtain product 192.4g, productive rate 68.2%; (HPLC) purity is 99.97%, and the two acylates of impurity do not detect.Product is the diacetate of fasudil.
Ultimate analysis: (C
14h
17n
3o
2s2CH
3cOOH): C, 52.58; H, 5.09; N, 10.23; S, 7.78;
Theoretical value: C, 52.54; H, 6.12; N, 10.21; S, 7.79.
1H-NMR(600?MHz,?DMSO-d6)
：10.12(s,?1H),?9.65(s,?2H),?9.53(s,?1H),?8.81(d,?J?=?6Hz,?1H),?8.51(d,?J?=?6.0Hz,?1H),?8.37(d,?J?=?7.2Hz,?1H),?8.22(d,?J?=?8.4Hz,?1H),?7.73(t,?J?=?7.8Hz,?1H),?3.51(t,?J?=?6.0Hz,?2H),?3.49(t,?J?=?5.4Hz,?2H),?3.11(t,?J?=?4.8Hz,?2H),?2.97(t,?J?=?6.0Hz,?2H),?2.11(s,?6H)?,?1.87(m,?2H)。
MS(ESI,?m/z?),?292.1[M-2CH
3COOH+H]
+?,?314.3[M-2CH
3COOH+Na]
+。
IR(KBr)cm
-1:3430，3393，2950，1690，1646，1620，1564，1403，1333，1130，1014，894，713，596。
Embodiment 6
Take fasudil crude product 200g(0.69mol), add 600ml anhydrous methanol, in 10-20 ℃, drip glacial acetic acid 158ml (2.76mol); dropwise,, slow cooling was to 6-8 ℃ of crystallization 8 hours; suction filtration, a small amount of cold methanol filter wash cake, obtains white to off-white color solid; dry; obtain product 172.1g, productive rate 61%, detects through high performance liquid chromatography (HPLC) method; purity is 99.96%, and the two acylates of impurity do not detect.Product is the diacetate of fasudil.
Embodiment 7:
(1) take the fasudil Monoacetate 35.1g(0.1mol that embodiment 1 makes, purity 99.92%), add 200ml methylene dichloride, under stirring, adding the pH of the sodium hydroxide solution adjusting water of 2mol/L is 9, separate organic phase, washing, dry, filter, concentrating under reduced pressure obtains white to off-white color solid 28.4g, be fasudil, through high performance liquid chromatography (HPLC) method, detect, purity is 99.7%.
(2) gained fasudil is joined in 110ml methyl alcohol, the hydrochloric acid soln that adds 4mol/L after stirring and dissolving, the pH to 4 of regulator solution, and at-5-0 ℃ stirring and crystallizing 4 hours, suction filtration, methyl alcohol filter wash cake, gained filter cake obtains after drying white solid and is Fasudil Hydrochloride, amount to 29.4g, yield 89.7%; Through high performance liquid chromatography (HPLC) method, detect, purity is 99.96%, and the two acylates of impurity do not detect.
Embodiment 8:
(1) take embodiment 5 fasudil diacetate 41.1g(0.1mol, purity 99.97%), add 240ml methylene dichloride, under stirring, adding the pH of the sodium hydroxide solution adjusting water of 2mol/L is 11, separate organic phase, washing, dry, filter, concentrating under reduced pressure obtains white to off-white color solid 27.2g, be fasudil, through high performance liquid chromatography (HPLC) method, detect, purity is 99.7%.
(2) gained fasudil is joined in 100ml methyl alcohol, the hydrochloric acid soln that adds 4mol/L after stirring and dissolving, regulate reaction solution pH to 5, and at 0-5 ℃ stirring and crystallizing 6 hours, suction filtration, a small amount of methanol wash filter cake, gained filter cake obtains after drying white solid and is Fasudil Hydrochloride, amount to 27.5g, yield 83.9%; Through high performance liquid chromatography (HPLC) method, detect, purity is 99.98%, and the two acylates of impurity do not detect.
Embodiment 9:
(1) take the fasudil Monoacetate 35.1g(0.1mol that embodiment 3 makes, purity 99.95%), add 150ml ethyl acetate, under stirring, adding the pH of the potassium hydroxide solution adjusting water of 2mol/L is 9, separate organic phase, washing, dry, filter, concentrating under reduced pressure obtains white to off-white color solid 29.2g, be fasudil, through high performance liquid chromatography (HPLC) method, detect, purity is 99.7%.
(2) gained fasudil is joined in 110ml methyl alcohol, the hydrochloric acid soln that adds 4mol/L after stirring and dissolving, the pH to 5 of regulator solution, and at-5-0 ℃ stirring and crystallizing 4 hours, suction filtration, methyl alcohol filter wash cake, gained filter cake obtains after drying white solid and is Fasudil Hydrochloride, amount to 28.8g, yield 87.9%; Through high performance liquid chromatography (HPLC) method, detect, purity is 99.98%, and the two acylates of impurity do not detect.
Claims (2)
1. application fasudil acetate is prepared the method for high-purity hydrochloric acid fasudil, it is characterized in that: comprise the steps:
(1) in the organic solvent of fasudil acetate, add inorganic base aqueous solution, regulate reacting liquid pH value 9-11, separate organic phase, washing, dry, filter, concentrating under reduced pressure obtains highly purified fasudil;
(2) the highly purified fasudil upper step being obtained is dissolved in methyl alcohol, adds hydrochloric acid reaction, regulates reacting liquid pH value 4-5, and be cooled to-5-5 ℃ crystallization, obtains highly purified Fasudil Hydrochloride;
Wherein said fasudil acetate has the structure shown in formula (I):
N=1 or 2 wherein.
2. the method for preparing high-purity hydrochloric acid fasudil according to claim 1, is characterized in that: described organic solvent is selected from methylene dichloride trichloromethane, one or more in ethyl acetate; Described mineral alkali is selected from one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.
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| CN109761958B (en) * | 2019-03-04 | 2020-04-28 | 中国药科大学 | Fasudil composite salt and preparation method and application thereof |
| CN109705096B (en) * | 2019-03-07 | 2023-06-09 | 山东新华制药股份有限公司 | Refining method of fasudil hydrochloride |
| CN112010805B (en) * | 2020-08-26 | 2023-12-05 | 山东威高药业股份有限公司 | Refining method of fasudil hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0187371A2 (en) * | 1984-12-27 | 1986-07-16 | Asahi Kasei Kogyo Kabushiki Kaisha | Substituted isoquinolinesulfonyl compounds |
| CN101341122A (en) * | 2005-12-20 | 2009-01-07 | 吉瑞工厂 | Novel process for production of highly pure polymorph (I) donepezil hydrochloride |
| CN102120739A (en) * | 2010-01-07 | 2011-07-13 | 成都欣捷高新技术开发有限公司 | Preparation method of fasudil hydrochloride |
-
2012
- 2012-04-26 CN CN201210125285.2A patent/CN102633779B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0187371A2 (en) * | 1984-12-27 | 1986-07-16 | Asahi Kasei Kogyo Kabushiki Kaisha | Substituted isoquinolinesulfonyl compounds |
| CN101341122A (en) * | 2005-12-20 | 2009-01-07 | 吉瑞工厂 | Novel process for production of highly pure polymorph (I) donepezil hydrochloride |
| CN102120739A (en) * | 2010-01-07 | 2011-07-13 | 成都欣捷高新技术开发有限公司 | Preparation method of fasudil hydrochloride |
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Effective date of registration: 20201026 Address after: 570314 -A, Nanhai Avenue, national hi tech Development Zone, Hainan, Haikou, 273 Patentee after: QILU PHARMACEUTICAL (HAINAN) Co.,Ltd. Patentee after: Qilu Pharmaceutical Co.,Ltd. Address before: 250100 No. 243 industrial North Road, Shandong, Ji'nan Patentee before: Qilu Pharmaceutical Co.,Ltd. |