CN111808029A - Preparation method of PDE4 inhibitor clobiplane - Google Patents
Preparation method of PDE4 inhibitor clobiplane Download PDFInfo
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Abstract
The invention discloses a preparation method of PDE4 inhibitor clobiplane, which specifically comprises 6 synthetic steps, namely synthesis of A2, synthesis of ZXSM02, synthesis of ZXSM01, synthesis of ZX01, synthesis of ZX02 and synthesis of ZX-101. In the preparation method, the intermediate ZXSM01 obtained by coupling is solid, and pure ZXSM01 can be obtained by ethanol crystallization. And the product is directly used for the next step after reduction and chlorination without column chromatography purification, so the operation is simple and convenient, and the method is more suitable for realizing industrial mass production. The method has the advantages of high yield, easily obtained and cheap raw materials and mild reaction conditions, and provides a novel, efficient and feasible method for synthesizing the topiramate.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a PDE4 inhibitor clobiplane.
Background
The chlobiprant (Chlorobipram, ZX-101) serving as a novel PDE4 inhibitor has a good improvement effect on a rat model with scopolamine-induced learning and memory acquired impairment, also has a good anti-depression activity on a rat model with despair behavior of forced swimming and tail suspension, and is proved to have only weak or even no vomiting and nausea side effects by adopting beagle dogs.
In the prior art, the invention patent with publication number CN106632070A discloses a method for preparing PDE4 inhibitor clobiplane, and the proposed synthesis route is as follows:
in the synthesis route, the product obtained after the intermediate chlorobenzene boric acid and bromobenzyl alcohol are subjected to Suzuki reaction is liquid, column chromatography purification is required, and the yield is low, so that the preparation method is not suitable for industrial production.
Disclosure of Invention
The invention aims to solve the technical problem of providing the preparation method of the PDE4 inhibitor chloropipran, which is simple to operate, does not need column chromatography purification and is beneficial to industrial production.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a process for the preparation of the PDE4 inhibitor clobiplane, which process comprises the steps of:
1) heating a raw material compound A1 and 3, 6-dichloropyridazine in ethanol to reflux reaction to obtain a compound A2; further comprising:
2) mixing the prepared compound A2, acetate and acetic acid, stirring, heating to reflux reaction, filtering the reaction solution, and drying a filter cake to obtain a compound ZXSM 02;
3) adding 3-bromo-4-methoxybenzaldehyde, m-chlorobenzoic acid, alkali and urea into a solution composed of isopropanol and water, replacing with nitrogen, adding a palladium catalyst, heating for reaction, performing suction filtration, concentrating an organic phase, removing isopropanol, concentrating, transferring to a reaction kettle, adding water, pulping overnight, performing suction filtration, adding ethanol into a filter cake, pulping, filtering, pulping the filter cake with ethanol, filtering, and finally performing forced air drying on the filter cake to constant weight to obtain a compound ZXSM 01;
4) heating a compound ZXSM01, tetrahydrofuran and sodium borohydride for reaction, adding the mixture into a mixed solution consisting of water and hydrochloric acid for quenching after the reaction is completed, concentrating to remove tetrahydrofuran, adding DCM for extraction twice, combining organic phases, and concentrating the obtained organic phase under reduced pressure and spin-drying to constant weight to obtain a compound ZX 01;
5) adding a compound ZX01, tetrahydrofuran and thionyl chloride into a three-necked bottle for reaction, and after the reaction is completed, carrying out spin drying on the reaction liquid to obtain a compound ZX 02;
6) adding a compound ZXSM02, an alkali and a solvent into a four-mouth bottle, stirring, performing nitrogen replacement for three times, adding a compound ZX02 under the protection of nitrogen, heating, adding a trace amount of the alkali, cooling a reaction solution, adding water, performing suction filtration, dissolving and separating a solid by using dichloromethane, extracting, combining organic phases, concentrating the organic phases to a thick state, adding acetonitrile, stirring, performing suction filtration, and performing vacuum drying on the solid to obtain a crude product of the compound ZX-101; adding dichloromethane into solid obtained by crystallizing a crude product of the compound ZX-101 twice by using acetonitrile, heating, dissolving, adding n-heptane, stirring, carrying out suction filtration, drying a filter cake to obtain solid, adding the solid obtained by drying the filter cake into the acetonitrile, pulping, carrying out suction filtration, and drying the filter cake to obtain a compound ZX-101, namely the chloropicrin;
the synthesis route of the novel preparation method of the PDE4 inhibitor clobiplane is as follows:
in order to optimize the technical scheme, the specific measures adopted further comprise:
the acetate in the step 2) is preferably one of crystalline sodium acetate hydrate and potassium acetate hydrate; after the reaction is finished, pouring the reaction solution into water, stirring for 1.5 hours, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound ZXSM 02.
In the step 3), the mass ratio of the isopropanol to the water in the solution formed by the isopropanol and the water is 1: 0.1-10; heating the heating medium at 50-100 ℃, carrying out heating reaction for 7 hours, carrying out suction filtration, separating the filtrate, and concentrating the organic phase; and (3) drying the filter cake by air blowing at the temperature of 25-85 ℃ for 23 hours until the weight is constant. The palladium catalyst is preferably one of palladium acetate, palladium chloride, 5 percent of palladium-carbon, 10 percent of palladium-carbon and tetrakis (triphenylphosphine) palladium, and the dosage of the palladium catalyst is 0.1 to 80 percent of the mass of the 3-bromo-4-methoxybenzaldehyde; the alkali is preferably one of potassium carbonate, sodium hydroxide and potassium hydroxide, and the dosage of the alkali is 1-5 equivalents of 3-bromo-4-methoxybenzaldehyde; the amount of the urea is 0-2 equivalent of 3-bromo-4-methoxybenzaldehyde.
Adding the compound ZXSM01, tetrahydrofuran and sodium borohydride in the step 4) into a single-neck bottle, heating and reacting for 1 hour at the temperature of the heating medium of 40-70 ℃, and stopping heating; the amount of the sodium borohydride is 0.5-0.9 equivalent of ZXSM01, and the amount of the tetrahydrofuran is 2.6-6.2 times of the mass of ZXSM 01.
Adding the compound ZX01, tetrahydrofuran and thionyl chloride in the step 5) into a three-neck flask for reaction, wherein the reaction temperature is 30-70 ℃, and the reaction time is 2-6 hours; the amount of the tetrahydrofuran is 2.6-6.2 times of the amount of the ZX01 by mass, and the completion of the reaction is monitored by TLC.
The solvent added into the four-mouth bottle in the step 6) is one of DMF, DMAC, NMP and DMSO, and the alkali added into the four-mouth bottle is one of potassium carbonate, cesium carbonate, triethylamine and pyridine; the equivalent weight of the alkali is 0.5-2.0 equivalent weight of ZXSM02, the dosage of ZX02 is 1.0-1.2 equivalent weight of ZXSM02, and the dosage of the solvent is 2.5-3.5 times of the mass of ZXSM 02; replacing with nitrogen for three times, stirring for 30 minutes at 30-40 ℃, adding ZX02 under the protection of nitrogen, stirring for 30 minutes at the temperature, heating to 60-90 ℃, stirring for 23 hours, supplementing 0.01-0.5 equivalent of alkali ZXSM01, wherein the alkali is one of potassium carbonate, cesium carbonate, triethylamine and pyridine, and stirring for 1 hour at 60-90 ℃.
Slowly cooling the reaction liquid in the step 6) to room temperature, slowly adding water dropwise, filtering to obtain a crude ZX-101 product, adding the crude ZX-101 product into acetonitrile, heating to dissolve, stirring for 1 hour, cooling to 0-25 ℃, separating out a solid, stirring overnight, carrying out suction filtration, carrying out vacuum drying on a filter cake to obtain a solid, adding the solid obtained by vacuum drying into acetonitrile, heating to dissolve, stirring overnight, cooling, carrying out suction filtration, and drying the filter cake to obtain a solid after crystallization twice.
Compared with the prior art, the preparation method specifically comprises 6 synthesis steps, namely the synthesis of A2, the synthesis of ZXSM02, the synthesis of ZXSM01, the synthesis of ZX01, the synthesis of ZX02 and the synthesis of ZX-101. The method adopts coupling firstly to obtain an intermediate ZXSM01 which is solid, and then pure ZXSM01 can be obtained through ethanol crystallization, thereby being beneficial to quality control. And the product is directly used for the next step after reduction and chlorination without column chromatography purification, so the method is simple and convenient to operate and is more suitable for realizing industrial production.
Detailed Description
The following further description of the technical solutions of the present invention is provided by examples, and is not meant to limit the content of the present invention in any way.
The first embodiment is as follows:
the invention discloses a preparation method of PDE4 inhibitor clobiplane, which comprises the following steps:
1) heating a raw material compound A1 and 3, 6-dichloropyridazine in ethanol to reflux reaction to obtain a compound A2;
2) mixing the obtained compound A2 and MOAc2Mixing and stirring O and acetic acid, heating to reflux reaction, pouring the reaction solution into water, stirring for 1.5 hours, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound ZXSM 02;
3) adding 3-bromo-4-methoxybenzaldehyde, m-chlorobenzoic acid, potassium carbonate and urea into a solution formed by isopropanol and water, wherein the mass ratio of the isopropanol to the water in the solution is 1: 0.1-10; of course, 1:1 is most preferred; replacing nitrogen, adding a palladium catalyst accounting for 0.1-80% of the mass of the 3-bromo-4-methoxybenzaldehyde, and heating the mixture at a heating medium temperature of 50-100 ℃ for reaction for 7 hours; the optimal heating medium temperature is 68 ℃, then, the filtration is carried out, the filtrate is subjected to liquid separation, the organic phase is concentrated, the isopropanol is removed, the obtained product is transferred to a reaction kettle, water is added, the obtained product is pulped overnight, the filtration is carried out, the obtained filter cake is pulped with ethanol, the obtained product is filtered, the obtained filter cake is pulped with ethanol and is filtered, and finally, the temperature of the obtained filter cake ranges from 25 ℃ to 85 ℃, and the optimal selection temperature is 35 ℃; drying by blowing for 23 hours under the condition of constant weight to obtain a compound ZXSM 01; the palladium catalyst comprises palladium acetate, palladium chloride, 5 percent of palladium-carbon, 10 percent of palladium-carbon and tetrakis (triphenylphosphine) palladium;
4) adding a compound ZXSM01, tetrahydrofuran and sodium borohydride into a single-mouth bottle, heating and reacting for 1 hour under the condition that the temperature of a heating medium is 40-70 ℃ (optimally 55 ℃), stopping heating, adding the mixture into a mixed solution consisting of water and hydrochloric acid after the reaction is completed, quenching, concentrating to remove tetrahydrofuran, adding DCM for extraction twice, combining organic phases, and performing reduced pressure concentration and spin drying on the obtained organic phases to obtain a compound ZX 01; wherein: the using amount of the sodium borohydride is 0.5-0.9 equivalent of ZXSM01, and the using amount of the tetrahydrofuran is 2.6-6.2 times of the mass of ZXSM 01;
5) adding a compound ZX01, tetrahydrofuran and thionyl chloride into a three-necked bottle for reaction at the temperature of 30-70 ℃ for 2-6 hours, wherein the amount of the tetrahydrofuran is 2.6-6.2 times of the mass of ZX01, and after TLC detection reaction is completed, spin-drying reaction liquid to obtain a compound ZX 02;
6) compound ZXSM02, base and solvent were added to a four-necked flask. Wherein: the solvent is one of DMF, DMAC, NMP and DMSO. The base is one of potassium carbonate, cesium carbonate, triethylamine and pyridine. The equivalent weight of the base is 0.5-2.0 equivalent weight of ZXSM02, the dosage of ZX02 is 1.0-1.2 equivalent weight of ZXSM02, and the dosage of the solvent is 2.5-3.5 times of the mass of ZXSM 02. Adding ZXSM02, alkali and a solvent, stirring, replacing with nitrogen for three times, stirring for 30 minutes at 30-40 ℃, adding ZX02 under the protection of nitrogen, stirring for 30 minutes at the temperature, heating to 60-90 ℃, stirring for 23 hours, adding a trace amount of the same alkali, stirring for 1 hour at 60-90 ℃, slowly cooling the reaction liquid to room temperature, slowly dripping the reaction liquid into water, performing suction filtration, dissolving and separating the solid with dichloromethane, extracting, combining organic phases, concentrating the organic phases to be thick, adding acetonitrile, heating to dissolve, cooling, performing suction filtration to obtain the solid, and performing vacuum drying to obtain a crude product of the compound ZX-101. Adding dichloromethane into solid obtained by crystallizing a crude product of the compound ZX-101 twice by using acetonitrile, heating, dissolving, adding n-heptane, stirring, carrying out suction filtration, drying a filter cake to obtain solid, adding the solid obtained by drying the filter cake into the acetonitrile, pulping, carrying out suction filtration, and drying the filter cake to obtain a compound ZX-101, namely the chloropicrin;
the synthesis route of the novel preparation method of the PDE4 inhibitor clobiplane is as follows:
and the two times of crystallization are that the crude product of the compound ZX-101 is added into acetonitrile, heated to dissolve out, stirred for 1 hour, cooled to 13 ℃, solid is separated out, stirred overnight, filtered, filter cake is dried in vacuum to obtain solid, the solid obtained by vacuum drying is added into acetonitrile, heated to dissolve out, stirred overnight, cooled, filtered and dried to obtain solid after two times of crystallization.
Example two:
the preparation method specifically comprises 6 synthesis steps, namely the synthesis of A2, the synthesis of ZXSM02, the synthesis of ZXSM01, the synthesis of ZX01, the synthesis of ZX02 and the synthesis of ZX-101. Wherein:
synthesis of a 2: 31.2g of the compound A1 and 28.2g of the compound 3, 6-dichloropyridazine were added to ethanol, the mixture was heated to reflux, the reaction was monitored by TLC, after the reaction was completed, the mixture was concentrated under reduced pressure to dryness to obtain a crude product, which was crystallized to obtain a yellow solid compound A2 with a yield of 44g of 84.3%.
Synthesis of ZXSM 02: compound A21528 g, NaOAc.3H2Adding O1490 g and acetic acid 4.584L into a 10L four-mouth bottle, stirring and heating to reflux for about 26 hours, and pouring the reaction liquid into 45L water; the addition took about 45 minutes to complete, and was stirred for 1.5 hours, filtered, the filter cake was washed with water, and dried under vacuum to give compound ZXSM021216.2g.
ESI-MS:m/z 284.1002 (M+Na)+；1H NMR(400MHz，CDCl3) 3.44(q，2H)，3.73(s.3H)，4.07 (t，2H)，6.55(t，1H)，6.70(d，1H) ，6.85～7.00(m，4H)，7.04(d，1H)，11.76(s，1H)。
Synthesis of ZXSM 01: synthesis of ZXSM 01: adding 5kg of 3-bromo-4-methoxybenzaldehyde, 4.37kg of m-chlorobenzoic acid, 9.64kg of potassium carbonate and 41.93g of urea into 55L of isopropanol-water (1:1) solution, stirring, replacing with nitrogen, adding palladium acetate or palladium-carbon, and heating at a heating medium temperature of 55-85 ℃ for reaction for about 7 hours. And (3) post-treatment: and (2) carrying out suction filtration, separating the filtrate, concentrating the organic phase, removing 10L of isopropanol, transferring to a 100L reaction kettle after the concentration is finished, adding 10L of water, pulping overnight at 20 ℃, carrying out suction filtration to obtain 6-9 kg of filter cake, taking 300g of the filter cake, adding 250mL of 95% purity ethanol, pulping for 5 minutes, filtering, pulping the filter cake with 250mL of 95% purity ethanol, filtering, and carrying out forced air drying on the filter cake at 35 ℃ for about 23 hours to constant weight to obtain a compound ZXSM01186.5 g.
ESI-MS:m/z 269.0339 (M+Na)+；1H NMR(400MHz，CDCl3)3.91(s，3H)，7.09(d，1H)，7.31～7.41(m，3H)，7.52(s，1H)，7.82(d，1H)，7.88(dd，1H)，9.93(s，1H)。
Synthesis of ZX 01: adding the compound ZXSM 0180 g and THF 400mL tetrahydrofuran in a 1L single-neck bottle in sequence, stirring, and adding NaBH46.13g of sodium borohydride as a reducing agent, and the reaction is heated for about 1 hour at a heating medium temperature of 55 ℃. Heating was stopped, the reaction was completed by HPLC, and the mixture was quenched by adding 300 mL of a mixed solution of water and 1.5 mL of hydrochloric acid, stirred, concentrated to remove THF, extracted by adding organic solvent DCM (100 mL. times.2), the organic phases were combined, and the resulting organic phase was concentrated under reduced pressure and rotary-dried to constant weight to obtain ZX 0167.1 g.
ESI-MS:m/z 271.0496 (M+Na)+；1H NMR(400MHz，CDCl3)3.77(s，3H)，4.47(s，2H)， 5.14
(br，s)1H，7.09(d，1H)，7.26(d，1H)，7.32(dd，1H)，7.37～7.45(m，3H)，7.51(s，1H)。
Synthesis of ZX 02: a500 mL three-necked flask was charged with ZX 0143 g and tetrahydrofuran 215mL, stirred, and added with SOCl224.7g, about 1 hour, TLC monitoring has reacted to completion. The reaction solution was spin-dried to obtain ZX0246.0 g.
1H NMR(400MHz，CDCl3)3.793(s，3H)，4.776(s，2H)，7.134(d，1H)，7.402～7.415(m，1H)，7.428～7.469(m，4H)，7.513(s，1H)。
Synthesis of ZX-101: A1L four-necked flask was charged with compound ZXSM0288.8 g, cesium carbonate 132.9g, and DMAC266mL, stirred, purged with nitrogen three times, and stirred at 30 to 40 ℃ for 30 minutes. Under nitrogen, compound ZX 02109 g was added and stirred at this temperature for 30 minutes. Then the temperature is raised to 80 ℃ and stirred for 23 hours, 0.4 equivalent of cesium carbonate is added, and stirring is carried out for 1 hour at 80 ℃. The reaction mixture was slowly cooled to room temperature, then slowly added dropwise to 1.76L of water, filtered, the solid was dissolved with 880mL of dichloromethane until no solid was present, the solution was separated, the aqueous phase was extracted with dichloromethane (440 mL. times.2), the organic phases were combined and washed once with 440mL of water. Concentrating the organic phase to be thick, adding 880mL of acetonitrile for dissolving, heating to 50-60 ℃ to completely dissolve the product, cooling to 10 ℃, performing suction filtration, and performing vacuum drying on the solid overnight60.0g of crude ZX-101 was obtained. 48g of crude ZX-101 was added to 480 mL of acetonitrile, heated to dissolve the supernatant, and stirred for about 1 hour. Cooling to 13 ℃, separating out solid, stirring overnight, filtering, and drying the filter cake in vacuum to obtain 42 g of solid. And recrystallizing the solid again by using acetonitrile, adding the solid into 420 mL of acetonitrile, heating to dissolve the solid clearly, stirring the mixture overnight, cooling, performing suction filtration, and drying a filter cake to obtain 35.4 g of solid. Adding the solid into 35.4 mL of dichloromethane, heating to dissolve the solid, slowly adding 354 mL of n-heptane, stirring overnight, performing suction filtration, adding the solid into 5 volumes of acetonitrile, pulping for 1.5 hours, performing suction filtration, and drying a filter cake to obtain 27.5 g of a compound ZX-101, namely the clobiplane. ESI-MS: M/z 514.1501 (M + Na)+，1H NMR(500MHz，CDCl3)3.59(t, 2H), 3.75(s, 3H), 3.80(s, 3H), 4.12(t, 2H), 4.79(s, br, 1H), 5.13(s, 2H), 6.67(d, 1H), 6.75(d, 1H), 6.83-6.87 (m, 3H), 6.88(m, 1H), 6.93(m, 1H), 7.25(s, br, 1H), 7.27(m, 1H), 7.36(m, 1H), 7.38(m, 1H), 7.40(m, 1H), 7.48(s, br, 1H). While the preferred embodiments of the present invention have been illustrated, various changes and modifications may be made by one skilled in the art without departing from the scope of the invention.
Claims (7)
1. A preparation method of PDE4 inhibitor clobiplane is characterized in that: the method comprises the following steps:
1) heating a raw material compound A1 and 3, 6-dichloropyridazine in ethanol to reflux reaction to obtain a compound A2;
2) mixing and stirring the prepared compound A2, acetate hydrate and acetic acid, heating to reflux reaction, filtering reaction liquid, and drying a filter cake to obtain a compound ZXSM 02;
3) adding 3-bromo-4-methoxybenzaldehyde, m-chlorobenzoic acid, alkali and urea into a solution composed of isopropanol and water, replacing with nitrogen, adding a palladium catalyst, heating for reaction, performing suction filtration, concentrating an organic phase, removing isopropanol, concentrating, transferring to a reaction kettle, adding water, pulping overnight, performing suction filtration, adding ethanol into a filter cake, pulping, filtering, pulping the filter cake with ethanol, filtering, and finally performing forced air drying on the filter cake to constant weight to obtain a compound ZXSM 01;
4) heating a compound ZXSM01, tetrahydrofuran and sodium borohydride for reaction, adding the mixture into a mixed solution consisting of water and hydrochloric acid for quenching after the reaction is completed, concentrating to remove tetrahydrofuran, adding DCM for extraction twice, combining organic phases, and concentrating the obtained organic phases under reduced pressure and spin-drying the organic phases to obtain a compound ZX 01;
5) adding a compound ZX01, tetrahydrofuran and thionyl chloride into a three-necked bottle for reaction, and after the reaction is completed, carrying out spin drying on the reaction liquid to obtain a compound ZX 02;
6) adding a compound ZXSM02, an alkali and a solvent into a four-mouth bottle, stirring, performing nitrogen replacement for three times, adding a compound ZX02 under the protection of nitrogen, heating, adding the alkali, cooling a reaction solution, adding water, performing suction filtration, dissolving and separating a solid by using dichloromethane, extracting, combining organic phases, concentrating the organic phases to a thick state, adding acetonitrile for dissolving, performing suction filtration, and performing vacuum drying on the solid to obtain a crude compound ZX-101; adding dichloromethane into solid obtained by crystallizing a crude product of the compound ZX-101 twice by using acetonitrile, heating, dissolving, adding n-heptane, stirring, carrying out suction filtration, drying a filter cake to obtain solid, adding the solid obtained by drying the filter cake into the acetonitrile, pulping, carrying out suction filtration, and drying the filter cake to obtain a compound ZX-101, namely the chloropicrin;
the synthesis route of the novel preparation method of the PDE4 inhibitor clobiplane is as follows:
2. the process of claim 1 for the preparation of the inhibitor chloropipran of PDE4, which is characterized by: in the step 2), the acetate is preferably one of crystalline sodium acetate hydrate and potassium acetate hydrate; after the reaction is finished, pouring the reaction solution into water, stirring for 1.5 hours, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound ZXSM 02.
3. The process of claim 1 for the preparation of the inhibitor chloropipran of PDE4, which is characterized by: in the step 3), the mass ratio of the isopropanol to the water in the solution formed by the isopropanol and the water is 1: 0.1-10; heating the heating medium at 50-100 ℃, carrying out heating reaction for 7 hours, carrying out suction filtration, separating the filtrate, and concentrating the organic phase; drying the filter cake by air blast for 23 hours at the temperature of 25-85 ℃ to constant weight; the palladium catalyst is preferably one of palladium acetate, palladium chloride, 5 percent of palladium-carbon, 10 percent of palladium-carbon and tetrakis (triphenylphosphine) palladium, and the dosage of the palladium catalyst is 0.1 to 80 percent of the mass of the 3-bromo-4-methoxybenzaldehyde; the alkali is preferably one of potassium carbonate, sodium hydroxide and potassium hydroxide, and the using amount of the alkali is 1-5 equivalents of 3-bromo-4-methoxybenzaldehyde; the amount of urea is 0-2 equivalents of 3-bromo-4-methoxybenzaldehyde.
4. The process of claim 1 for the preparation of the inhibitor chloropipran of PDE4, which is characterized by: adding the compound ZXSM01, tetrahydrofuran and sodium borohydride in the step 4) into a single-neck bottle, heating and reacting for 1 hour at the temperature of the heating medium of 40-70 ℃, and stopping heating; the amount of the sodium borohydride is 0.5-0.9 equivalent of ZXSM01, and the amount of the tetrahydrofuran is 2.6-6.2 times of the mass of ZXSM 01.
5. The process of claim 1 for the preparation of the inhibitor chloropipran of PDE4, which is characterized by: adding the compound ZX01, tetrahydrofuran and thionyl chloride in the step 5) into a three-neck flask for reaction at the temperature of 30-70 ℃ for 2-6 hours; the amount of the tetrahydrofuran is 2.6-6.2 times of the amount of the ZX01 by mass, and the completion of the reaction is monitored by TLC.
6. The process of claim 1 for the preparation of the inhibitor chloropipran of PDE4, which is characterized by: the solvent added into the four-mouth bottle in the step 6) is one of DMF, DMAC, NMP and DMSO, and the alkali added into the four-mouth bottle is one of potassium carbonate, cesium carbonate, triethylamine and pyridine; the equivalent weight of the alkali is 0.5-2.0 equivalent weight of ZXSM02, the dosage of ZX02 is 1.0-1.2 equivalent weight of ZXSM02, and the dosage of the solvent is 2.5-3.5 times of the mass of ZXSM 02; replacing with nitrogen for three times, stirring for 30 minutes at 30-40 ℃, adding ZX02 under the protection of nitrogen, stirring for 30 minutes at the temperature, heating to 60-90 ℃, stirring for 23 hours, supplementing 0.01-0.5 equivalent of alkali ZXSM02, wherein the alkali is one of potassium carbonate, cesium carbonate, triethylamine and pyridine, and stirring for 1 hour at 60-90 ℃.
7. The process of claim 1 for the preparation of the inhibitor chloropipran of PDE4, which is characterized by: slowly cooling the reaction solution in the step 6) to room temperature, then slowly adding the reaction solution into water in a dropwise manner, adding a compound ZX-101 crude product into acetonitrile for two times of crystallization, heating to dissolve the crude product clearly, stirring for 1 hour, cooling to 0-25 ℃, separating out a solid, stirring overnight, performing suction filtration, performing vacuum drying on a filter cake to obtain a solid, adding the solid obtained by vacuum drying into acetonitrile, heating to dissolve the solid clearly, stirring overnight, cooling, performing suction filtration, and drying the filter cake to obtain a solid after two times of crystallization.
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| CN106632070A (en) * | 2016-12-16 | 2017-05-10 | 徐江平 | Preparation method for chlorbipram PDE4-inhibitor |
| CN108976107A (en) * | 2018-08-23 | 2018-12-11 | 南方医科大学 | 3- aryl -4- alkoxybenzyl amine derivative and its preparation method and application |
| CN108997122A (en) * | 2018-08-23 | 2018-12-14 | 南方医科大学 | 3- aryl -4- alkoxy benzyl oxide derivative and its preparation method and application |
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| CA2928242C (en) * | 2013-10-22 | 2022-03-15 | Chiesi Farmaceutici S.P.A. | Process for the preparation of a pde4 inhibitor |
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| CN106632070A (en) * | 2016-12-16 | 2017-05-10 | 徐江平 | Preparation method for chlorbipram PDE4-inhibitor |
| CN108976107A (en) * | 2018-08-23 | 2018-12-11 | 南方医科大学 | 3- aryl -4- alkoxybenzyl amine derivative and its preparation method and application |
| CN108997122A (en) * | 2018-08-23 | 2018-12-14 | 南方医科大学 | 3- aryl -4- alkoxy benzyl oxide derivative and its preparation method and application |
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| Title |
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| BISHWAJIT SAIKIA ，等: "Simple and efficient phosphine-free Pd(OAc)2 catalyzed urea accelerated Suzuki–Miyaura cross-coupling reactions in iPrOH–H2O at room temperature", 《TETRAHEDRON LETTERS》 * |
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