CN108752274B - Preparation method of 5-isoquinoline sulfonyl chloride - Google Patents
Preparation method of 5-isoquinoline sulfonyl chloride Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of an important intermediate 5-isoquinoline sulfonyl chloride of fasudil hydrochloride. The preparation method of the 5-isoquinoline sulfonyl chloride comprises the following steps: 1) performing alkylation reaction on 5-bromoisoquinoline serving as a raw material and thiourea to obtain a product, and performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, and then recrystallizing and drying to obtain S-isoquinoline isothiourea salt; 2) dissolving the S-isoquinoline isothiourea salt obtained in the step 1) in dilute hydrochloric acid to prepare a solution, then carrying out oxidative chlorosulfonyl acylation reaction on the solution and an oxidant, and carrying out suction filtration, washing and drying after the reaction is finished to obtain the 5-isoquinoline sulfonyl chloride. The 5-isoquinoline sulfonyl chloride prepared by the invention has the advantages of simple synthetic route, short reaction time and convenient operation; does not use reagents with strong corrosivity, strong irritation and toxicity, and the synthetic route is environment-friendly.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of an important intermediate 5-isoquinoline sulfonyl chloride of fasudil hydrochloride.
Background
Fasudil hydrochloride is a novel isoquinoline sulfonamide derivative which is cooperatively developed by Asahi Kasei K.K. and Minggu university, and is an RHO kinase inhibitor and novel intracellular Ca2+The antagonist can expand blood vessels, reduce tension of endothelial cells, improve microcirculation of brain tissues, protect ischemic brain tissues, antagonize inflammatory factors, protect nerves from apoptosis and promote nerve regeneration by increasing activity of myosin light chain phosphatase.
The 5-isoquinoline sulfonyl chloride is an important intermediate for synthesizing fasudil hydrochloride, and in the traditional synthesis mode, isoquinoline is used as a raw material, is salified with concentrated sulfuric acid, then reacts with fuming sulfuric acid to generate 5-isoquinoline sulfonic acid, then reacts with thionyl chloride to generate 5-isoquinoline sulfonyl chloride hydrochloride, and finally is neutralized with a sodium bicarbonate solution to generate the 5-isoquinoline sulfonyl chloride. The synthesis equation is as follows:
however, the synthesis method has many steps and complicated post-treatment, fuming sulfuric acid and thionyl chloride used in the reaction process belong to acidic substances with strong corrosivity and strong irritation, and are expensive, and more waste acid generated after the reaction pollutes the environment, so the synthesis method is not suitable for industrial production.
Chinese patent application publication No. CN103724263A discloses a preparation method of isoquinoline-5-sulfonyl chloride, which comprises the steps of carrying out diazotization reaction on 5-aminoisoquinoline serving as a raw material, sodium nitrite and concentrated hydrochloric acid, and carrying out sulfonyl chlorination on the obtained diazotization solution and sulfur dioxide in an acetic acid solvent to obtain 5-isoquinoline sulfonyl chloride. The synthesis equation is as follows:
although the synthetic route is shortened, the yield of the 5-isoquinoline sulfonyl chloride depends on the stability of the diazonium salt, and a toxic reagent sodium nitrite is used in the reaction process.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a method for synthesizing an important intermediate 5-isoquinoline sulfonyl chloride of fasudil hydrochloride, which has the advantages of short synthetic route, simple and convenient operation and high yield.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a preparation method of 5-isoquinoline sulfonyl chloride comprises the following steps:
1) synthesis of S-isoquinoline isothiourea salt
Taking 5-bromoisoquinoline as a raw material, adding a solvent to perform alkylation reaction with thiourea, adding water to obtain a precipitate after the reaction is finished, performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, then recrystallizing and drying to obtain the S-isoquinoline isothiourea salt, wherein the reaction route is as follows:
2) synthesis of 5-isoquinoline sulfonyl chloride
Dissolving the S-isoquinoline isothiourea salt obtained in the step 1) in dilute hydrochloric acid to prepare a solution, then carrying out oxidative chlorosulfonation reaction on the solution and an oxidant, carrying out suction filtration after the reaction is finished, and sequentially using NaHSO with the mass concentration of 5% as a product after the suction filtration3The solution was washed with a 15% strength by mass dilute hydrochloric acid solution (NaHSO)3The solution can be reacted with an oxidizing agent to remove excess oxidizing agent, and the dilute hydrochloric acid solution can be used for removing excess NaHSO3Solution) and drying to obtain 5-isoquinoline sulfonyl chloride, wherein the reaction route is as follows:
preferably, the molar ratio of the 5-bromoisoquinoline to the thiourea in the step 1) is 1 (1-1.4), and the solvent is one of methanol, ethanol or N, N-Dimethylformamide (DMF).
Preferably, in the step 1), the 5-bromoisoquinoline and the thiourea react for 2-6 h under the reflux of the solvent.
Preferably, the molar ratio of the S-isoquinoline isothiourea salt to the oxidant in the step 2) is 1 (1-4), and the oxidant is H2O2、KMnO4、NCS、KClO3One or more of them.
Specifically, the mass concentration of the dilute hydrochloric acid solution for dissolving the S-isoquinoline isothiourea salt in the step 2) is 15%, and further, the dilute hydrochloric acid solution for dissolving the S-isoquinoline isothiourea salt is dropwise added, and the dropwise adding time is controlled within 1 hour.
Preferably, the reaction temperature in the step 2) is 10-25 ℃, and the reaction time is 1-5 h.
Compared with the prior art, the invention has the beneficial effects that:
1. the 5-isoquinoline sulfonyl chloride prepared by the invention is subjected to two-step reaction, and has the advantages of simple synthetic route, short reaction time and convenient operation;
2. the scheme takes 5-bromoisoquinoline and thiourea as raw materials to synthesize S-isoquinoline isothiourea salt, and then the product is obtained through oxidative chlorosulfonyl acylation reaction, and the used raw materials are simple and easy to obtain and do not have strong corrosivity and strong irritation;
3. the yield of the 5-isoquinoline sulfonyl chloride prepared by the scheme is high, and the maximum yield is 95.9% through orthogonal test optimization, and does not depend on the stability of an intermediate;
4. the reaction condition is mild, and the method is non-toxic and environment-friendly, and is convenient for realizing industrial production.
Detailed Description
The technical scheme of the invention is further explained by the following embodiments, wherein the mass concentration of the dilute hydrochloric acid solution mentioned in the embodiments is 15%, and the NaHSO is3The mass concentration of the solution is 5%, but the present invention is not limited thereto.
Example 1
The preparation method of 5-isoquinoline sulfonyl chloride described in the embodiment comprises the following steps:
1) synthesis of S-isoquinoline isothiourea salt
Adding 2mol of 5-bromoisoquinoline and 2mol of finely ground (screened by a No. 6 sieve) thiourea into a round-bottom flask, adding 50ml of methanol, stirring, heating and refluxing for 2 hours, cooling, adding 50ml of water, separating out a large amount of white solid, performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, recrystallizing with 50ml of ethanol, and drying to obtain the S-isoquinoline isothiourea salt, wherein the calculated yield is 20.1%.
2) Synthesis of 5-isoquinoline sulfonyl chloride
1mol of H with the mass concentration of 30 percent2O2Adding 25ml of water into a round-bottom flask, dropwise adding 25ml of dilute hydrochloric acid solution dissolved with 1mol of S-isoquinoline isothiourea salt under the cooling of ice-water bath, controlling the dropwise adding time within 1h, stirring and reacting at 10 ℃ for 1h after the dropwise adding is finished, performing suction filtration after the reaction is finished, and respectively using 100ml of NaHSO to obtain solids3Washing the solution and 100ml of dilute hydrochloric acid solution for 1 time, and drying to obtain the 5-isoquinoline sulfonyl chloride, wherein the calculated yield is 20.3 percent, and the purity is 99.0 percent.
Example 2
The preparation method of 5-isoquinoline sulfonyl chloride described in the embodiment comprises the following steps:
1) synthesis of S-isoquinoline isothiourea salt
Adding 2mol of 5-bromoisoquinoline and 2.8mol of ground (screened by a No. 6 sieve) thiourea into a round-bottom flask, adding 100ml of ethanol, stirring, heating for reflux reaction for 6 hours, cooling, adding 200ml of water, precipitating a large amount of white solid, performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, recrystallizing with 50ml of ethanol, and drying to obtain the S-isoquinoline isothiourea salt, wherein the calculated yield is 57.3%.
2) Synthesis of 5-isoquinoline sulfonyl chloride
4mol of KMnO4Adding 100ml of water into a round-bottom flask, dropwise adding 25ml of dilute hydrochloric acid solution dissolved with 1mol of S-isoquinoline isothiourea salt under the cooling of ice-water bath, controlling the dropwise adding time within 1h, stirring and reacting at 25 ℃ for 5h after the dropwise adding is finished, performing suction filtration after the reaction is finished, and respectively using 100ml of NaHSO to obtain solids3Washing the solution with 100ml of dilute hydrochloric acid solution for 3 times, and drying to obtain the 5-isoquinoline sulfonyl chloride, wherein the calculated yield is 38.1 percent, and the purity is 99.1 percent.
Example 3
The preparation method of 5-isoquinoline sulfonyl chloride described in the embodiment comprises the following steps:
1) synthesis of S-isoquinoline isothiourea salt
Adding 2mol of 5-bromoisoquinoline and 2.4mol of finely ground (screened by a No. 6 sieve) thiourea into a round-bottom flask, adding 80ml of DMF, stirring, heating for reflux reaction for 4 hours, cooling, adding 100ml of water, precipitating a large amount of white solid, performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, recrystallizing with 50ml of ethanol, and drying to obtain the S-isoquinoline isothiourea salt, wherein the calculated yield is 99.3%.
2) Synthesis of 5-isoquinoline sulfonyl chloride
Adding 3mol NCS and 50ml water into a round-bottom flask, dropwise adding 25ml of dilute hydrochloric acid solution dissolved with 1mol S-isoquinoline isothiourea salt under the cooling of ice-water bath, controlling the dropwise adding time within 1h, stirring and reacting at 15 ℃ for 2h after the dropwise adding is finished, carrying out suction filtration after the reaction is finished, and respectively using 50ml NaHSO to obtain solid3Washing the solution with 50ml of dilute hydrochloric acid solution for 3 times, and drying to obtain the 5-isoquinoline sulfonyl chloride, wherein the calculated yield is 95.9 percent, and the purity is 99.5 percent.
Example 4
The preparation method of 5-isoquinoline sulfonyl chloride described in the embodiment comprises the following steps:
1) synthesis of S-isoquinoline isothiourea salt
Adding 2mol of 5-bromoisoquinoline and 2.4mol of ground (screened by a No. 6 sieve) thiourea into a round-bottom flask, adding 70ml of methanol, stirring, heating for reflux reaction for 5 hours, cooling, adding 150ml of water, precipitating a large amount of white solid, performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, recrystallizing with 50ml of ethanol, and drying to obtain the S-isoquinoline isothiourea salt, wherein the calculated yield is 74.6%.
2) Synthesis of 5-isoquinoline sulfonyl chloride
3mol of KClO3Adding 75ml of water into a round-bottom flask, dropwise adding 25ml of dilute hydrochloric acid solution dissolved with 1mol of S-isoquinoline isothiourea salt under the cooling of ice-water bath, controlling the dropwise adding time within 1h, stirring and reacting at 15 ℃ for 2h after the dropwise adding is finished, performing suction filtration after the reaction is finished, and respectively using 50ml of NaHSO to obtain solids3Washing the solution with 50ml of dilute hydrochloric acid solution for 2 times, and drying to obtain the 5-isoquinoline sulfonyl chloride, wherein the calculated yield is 82.5 percent, and the purity is 99.2 percent.
Example 5
The preparation method of 5-isoquinoline sulfonyl chloride described in the embodiment comprises the following steps:
1) synthesis of S-isoquinoline isothiourea salt
Adding 2mol of 5-bromoisoquinoline and 2.4mol of finely ground (screened by a No. 6 sieve) thiourea into a round-bottom flask, adding 50ml of DMF, stirring, heating for reflux reaction for 4h, cooling, adding 150ml of water, precipitating a large amount of white solid, performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, recrystallizing with 50ml of ethanol, and drying to obtain the S-isoquinoline isothiourea salt, wherein the calculated yield is 99.0%.
2) Synthesis of 5-isoquinoline sulfonyl chloride
Adding 2mol NCS and 50ml water into a round-bottom flask, dropwise adding 25ml of dilute hydrochloric acid solution dissolved with 1mol S-isoquinoline isothiourea salt under the cooling of ice-water bath, controlling the dropwise adding time within 1h, stirring and reacting at 20 ℃ for 3h after the dropwise adding is finished, carrying out suction filtration after the reaction is finished, and respectively using 50ml NaHSO to obtain solid3Washing the solution with 50ml of dilute hydrochloric acid solution for 2 times, and drying to obtain 5Isoquinoline sulfonyl chloride, calculated yield 83.2%, purity 99.0%.
Example 6
The preparation method of 5-isoquinoline sulfonyl chloride described in the embodiment comprises the following steps:
1) synthesis of S-isoquinoline isothiourea salt
Adding 2mol of 5-bromoisoquinoline and 2.4mol of finely ground (screened by a No. 6 sieve) thiourea into a round-bottom flask, adding 50ml of DMF, stirring, heating for reflux reaction for 4h, cooling, adding 150ml of water, precipitating a large amount of white solid, performing suction filtration to obtain a crude product of S-isoquinoline isothiourea salt, recrystallizing with 50ml of ethanol, and drying to obtain the S-isoquinoline isothiourea salt, wherein the calculated yield is 99.0%.
2) Synthesis of 5-isoquinoline sulfonyl chloride
2mol of H with the mass concentration of 30 percent2O2、2mol KMnO4Adding 50ml of water into a round-bottom flask, dropwise adding 25ml of dilute hydrochloric acid solution dissolved with 1mol of S-isoquinoline isothiourea salt under the cooling of ice-water bath, controlling the dropwise adding time within 1h, stirring and reacting at 15 ℃ for 3h after the dropwise adding is finished, performing suction filtration after the reaction is finished, and respectively using 50ml of NaHSO to obtain solids3Washing the solution with 50ml of dilute hydrochloric acid solution for 2 times, and drying to obtain the 5-isoquinoline sulfonyl chloride, wherein the calculated yield is 50.6 percent, and the purity is 99.2 percent.
In order to obtain the optimal preparation conditions of the S-isoquinoline isothiourea salt, a solvent (A), a molar ratio (B) of 5-bromoisoquinoline to thiourea and reaction time (C) are respectively selected as influencing factors to carry out orthogonal experiments, and the levels of the orthogonal experiment factors are shown in Table 1. According to the design principle of orthogonal experiments, the yield (%) of S-isoquinoline isothiourea salt is taken as a survey index to determine the optimal conditions, the design of orthogonal test schemes and test results are shown in table 2, the analysis of extremely poor results of orthogonal tests is shown in table 3, and the analysis of variance results of orthogonal tests is shown in table 4.
TABLE 1 orthogonal test factor horizon
TABLE 2 orthogonal test scheme design and test results table
TABLE 3 analysis of range results of orthogonal tests
TABLE 4 analysis of variance results of orthogonal tests
As can be seen from the analysis in table 4, the A, B, C factors are significant; table 3 shows that the main and sub-sequence of the A, B, C factors is A according to the magnitude of the range>B>C, obtaining the optimal combination A according to the mean value3B2C2Namely, the optimal reaction conditions in the step (1) of the invention are that DMF is selected as a solvent, the molar ratio of 5-bromoisoquinoline to thiourea is 1:1.2, and the reaction time is 4 h.
In order to obtain the optimal preparation conditions of the 5-isoquinoline sulfonyl chloride, an orthogonal experiment is carried out by respectively selecting an oxidant (A), the using amount of water (B), the molar ratio of S-isoquinoline isothiourea salt to the oxidant (C) and the reaction temperature (D) as influencing factors, and the levels of the orthogonal experiment factors are shown in a table 5. According to the design principle of the orthogonal experiment, the yield (%) of 5-isoquinoline sulfonyl chloride is taken as a survey index to determine the optimal conditions, the design of the orthogonal experiment scheme and the experiment result are shown in table 6, the analysis of the extremely poor result of the orthogonal experiment is shown in table 7, and the analysis of the variance result of the orthogonal experiment is shown in table 8.
TABLE 5 orthogonal test factor horizon
TABLE 6 orthogonal test scheme design and test results table
TABLE 7 analysis of range results of orthogonal tests
TABLE 8 analysis of variance results of orthogonal tests
From the analysis of table 8, A, C are significant; table 7 shows that the main and sub-sequence of A, B, C, D four factors is A according to the magnitude of the range>C>B>D, obtaining the optimal combination A according to the mean value3B2C3D2That is, in the step (2) of the present invention, the optimum reaction conditions are that NCS is used as the oxidant, the amount of water is 50mL (1 mol of NCS is dissolved in 50mL of water), the molar ratio of S-isoquinoline isothiourea salt to the oxidant is 1:3, and the reaction temperature is 15 ℃.
In summary, example 3 for optimal reaction conditions for the preparation of 5-isoquinolinesulfonyl chloride (including step 1) and step 2) of the present invention), nuclear magnetic characterization of the 5-isoquinolinesulfonyl chloride prepared in example 3 was performed: m.p.175-180 ℃;1H NMR（DMSO-d 6，300 MHZ）δ:9.25（1H），8.52（1H）,8.45（1H）,8.25（1H）,7.84（1H）,7.63（1H）；13C NMR（DMSO-d 6，100 MHZ）δ:152.5（1C）,143.4（1C）,141.8（1C）,134.8（1C）,133.8（1C）,130.1（1C）,128.4（2C）,120.9（1C）。
according to the preparation method of the 5-isoquinoline sulfonyl chloride, the yield of the S-isoquinoline isothiourea salt is 99.3% and the yield of the 5-isoquinoline sulfonyl chloride is 95.9% under the optimal reaction condition through orthogonal experimental design. The method has the advantages of simple scheme, high yield and convenient industrial popularization.
The above description is only an exemplary embodiment of the present invention, and is not intended to limit the scope of the present invention. Any equivalent changes and modifications that can be made by one skilled in the art without departing from the principle and spirit of the invention shall fall within the protection scope of the invention.
Claims (1)
1. A preparation method for improving the yield and the purity of 5-isoquinoline sulfonyl chloride is characterized by comprising the following steps:
1) synthesis of 5-isoquinoline isothiourea salt
Adding 2mol of 5-bromoisoquinoline and 2.4mol of thiourea which is ground and sieved by a No. 6 sieve into a round-bottom flask, adding 80ml of DMF, stirring, heating and refluxing for 4h, cooling, adding 100ml of water, separating out a white solid, performing suction filtration to obtain a crude product of 5-isoquinoline isothiourea salt, recrystallizing by using 50ml of ethanol, and drying to obtain 5-isoquinoline isothiourea salt with the yield of 99.3%;
2) synthesis of 5-isoquinoline sulfonyl chloride
Adding 3mol NCS and 50ml water into a round-bottom flask, dropwise adding 25ml of dilute hydrochloric acid solution dissolved with 1mol 5-isoquinoline isothiourea salt under the cooling of ice-water bath, controlling the dropwise adding time within 1h, stirring and reacting at 15 ℃ for 2h after the dropwise adding is finished, carrying out suction filtration after the reaction is finished, and respectively using 50ml NaHSO to obtain solid3Washing the solution with 50ml of dilute hydrochloric acid solution for 3 times, and drying to obtain 5-isoquinoline sulfonyl chloride with the yield of 95.9 percent and the purity of 99.5 percent;
wherein, NaHSO3The mass concentration of the solution is 5 percent, and the mass concentration of the dilute hydrochloric acid solution is 15 percent.
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