CN110862394A - Preparation method of PDE9A inhibitor - Google Patents
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a preparation method of a PDE9A inhibitor, which comprises the steps of dissolving 2,4, 6-trichloro-5-pyrimidine formaldehyde as a starting material, condensing with substituted hydrazine hydrochloride in the presence of alkali for ring closure, then carrying out hydrolysis reaction, reacting with chiral amine, and recrystallizing and purifying to obtain 1, 6-disubstituted-1, 5-dihydropyrazolo [3,4] -pyrimidine-2-ketone. The invention adopts the selected starting raw materials which are cheap and easy to obtain, has mild reaction conditions, simple process operation and less three wastes generated by the process, and is easy to realize industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis processes, and particularly relates to a synthesis process of a PDE9A inhibitor.
Background
Phosphodiesterases (PDEs) selectively degrade the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the human body. There are 11 families of PDEs that have been reported so far, among which PDEIX is capable of hydrolyzing cGMP with high specificity (J.Bio.chem.1998,273 (25); 15559) -15564). The PDEIX inhibitor can inhibit the enzymolysis of PDEIX on cGMP, so as to increase the cGMP level. Studies have shown that cGMP plays an important role in improving the cognitive ability of humans. Thus PDEIX is a new generation of targets for improving attention, cognition, learning and memory.
Chinese patent CN102786525 invents a novel PDEIX inhibitor, and the structural formula of an N-substituted pyrazolo [3,4-d ] pyrimidone compound is shown in formula (I), and the N-substituted pyrazolo [3,4-d ] pyrimidone compound has high selectivity on PDE9, and the highest IC50 can reach 15.0 nm. However, the synthesis method of the compounds reported in the patent document has the following disadvantages: (1) the laboratory is usually cooled by liquid nitrogen at low temperature (-78 ℃), special equipment is needed, the industrialization condition is not easy to achieve, and the energy consumption is high; (2) the tube sealing reaction is needed, high pressure is easily generated in the large-scale production process, and safety risk exists; (3) the method needs column chromatography separation, has low product yield and long period, generates a large amount of solid waste and has large environmental protection pressure. Due to the above-mentioned limitations, this method is only suitable for preparing gram-scale samples in laboratories, and cannot realize industrial scale-up.
N-substituted pyrazolo [3,4-d ] pyrimidinones of formula (I)
The invention content is as follows:
the invention aims to provide a novel preparation method of an N-substituted pyrazolo [3,4-d ] pyrimidone compound, which has the characteristics of environment-friendly reagents, mild conditions and low cost and can meet the requirements of industrial mass production.
The purpose of the invention is realized by the following technical scheme. The method of the invention comprises the following steps:
step S1: dissolving 2,4, 6-trichloro-5-pyrimidinecarbaldehyde (SM1) and a starting material hydrazine compound (SM2) in an organic solvent at the reaction temperature of-15-0 ℃, and reacting in the presence of an organic base to obtain a compound A of 1, 4-dichloro-1-substituted-pyrazolo [3,4-d ] pyrimidine;
step S2: dissolving the compound A obtained by the reaction in the step S1 in an organic solvent at the reaction temperature of 40-60 ℃, and reacting in the presence of an inorganic base to obtain a compound B of 6-chloro-1-substituted-1, 5-dihydropyrazolo [3,4] -pyrimidin-2-one;
and S3, dissolving the product B obtained in the step S2 in an organic solvent at the reaction temperature of 80-120 ℃, and reacting the product B with a α -phenylethylamine compound (SM3) for 6-20 hours in the presence of an organic base to obtain a compound C of the N-substituted pyrazolo [3,4-d ] pyrimidinone.
The process route for preparing the N-substituted pyrazolo [3,4-d ] pyrimidone compound is as follows:
wherein R1 is selected from isopropyl, cyclopentyl, cyclohexyl, isobutyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, o-chlorophenyl, pyridine-2-phenyl;
r2 is selected from hydrogen and chlorine.
The preparation method of the invention is divided into three steps, and the preparation process of each step is detailed as follows.
Step S1 process
2,4, 6-trichloropyrimidine formaldehyde and SM2 are used as starting materials, organic base is used as a reaction promoter, the reaction is carried out in an organic solvent at the temperature of-15 ℃ to 0 ℃, and after the reaction is finished, the compound A is obtained by filtering, and operations such as reduced pressure distillation, column chromatography purification and the like are not needed; the reaction temperature condition can be achieved by adopting a conventional ice salt water cooling system in industrialization, and a special cooling device is not needed.
In step S1, the organic solvent is a protic polar solvent, and is selected from one or more of methanol, ethanol, and isopropanol; the organic base is aliphatic amine containing 1-9 carbon atoms, and is selected from triethylamine and diethylamine.
In the step S1, the ratio of the 2,4, 6-trichloropyrimidine formaldehyde to the SM2 to the organic base is 1: 1-1.2: 2-2.5; the concentration of the 2,4, 6-trichloropyrimidine formaldehyde is 0.05-1.0 mol/L.
The reaction formula in step S1 is as follows.
Step S2
Dissolving a compound A in an organic solvent, dropwise adding an inorganic alkaline aqueous solution, and heating to 40-60 ℃ for reaction; and (4) carrying out suction filtration, adjusting the pH value of the filtrate to 5.0, filtering, and pulping the filter cake with an organic solvent to obtain a compound B.
In step S2, the organic solvent is an aprotic polar solvent, and is one or more selected from acetonitrile, N-dimethylformamide, and dimethylsulfoxide.
In step S2, the inorganic base is hydroxide of alkali metal selected from one or more of NaOH, KOH, CsOH. The concentration of the inorganic base is 0.2-2mol per liter, and the dosage is 1-15 times of the mol number of the 1, 4-dichloro-1-substituted-pyrazolo [3,4-d ] pyrimidine.
In step S2, the PH adjusting acid is formic acid, acetic acid, or diluted hydrochloric acid.
The organic solvent used for the beating in step S2 is selected from ethyl acetate, methanol, ethanol, toluene, acetonitrile.
The concentration of the compound A in the reaction solvent in the step S2 is 0.05-1.0 mol/L; the concentration of the inorganic alkaline water solution is 0.2-2 mol/L.
The reaction formula in step S2 is as follows.
Step S3
Dissolving the compound B in an organic solvent, adding SM3, dropwise adding an organic base, heating to 80-120 ℃, reacting for 6-20 hours, filtering, and spin-drying the filtrate. Dissolving the obtained solid with water and ethyl acetate, adjusting pH to 6-7, and extracting. Adding anhydrous sodium sulfate into the organic phase, drying, filtering, adding active carbon, stirring, decolorizing, filtering, distilling under reduced pressure to remove solvent, and recrystallizing to obtain target compound C.
The organic solvent described in step S3 is an aprotic solvent, and is one or more selected from toluene, xylene, N-dimethylformamide, dimethyl sulfoxide, and dioxane, and is mixed in any ratio.
The organic base is an aliphatic amine having 1 to 15 carbon atoms or an aromatic amine having 4 to 15 carbon atoms in step S3. Wherein the aliphatic amine having 1 to 15 carbon atoms is selected from triethylamine or diisopropylethylamine; the aromatic amine having 4 to 15 carbon atoms is pyridine.
The concentration of compound B in the aprotic solvent in step S3 is 0.05-1.0 mol/L.
The reaction formula in step S3 is as follows.
More specifically, the preparation method comprises the following steps:
step S1: dissolving 2,4, 6-trichloro-5-pyrimidinecarbaldehyde in an organic solvent at the temperature of-15-0 ℃, dropwise adding a solution of SM2 in a polar solvent, dropwise adding a triethylamine solution, stirring, precipitating a solid, filtering, and washing with water to obtain a compound A;
step S2: dissolving the compound A obtained in the step S1 in an organic solvent, dropwise adding an inorganic alkaline aqueous solution, heating to 40-60 ℃, reacting, adjusting the pH to 5.0, filtering, and pulping the solid with the organic solvent to obtain a compound B;
step S3: dissolving the compound B obtained in the step S2 in an aprotic solvent, adding SM3, dropwise adding an organic base, heating to the temperature of 80-120 ℃, reacting for 6-20 hours, cooling, decompressing, spin-drying, dissolving with ethyl acetate and water, adjusting the pH to be neutral, decoloring an organic phase with activated carbon, drying with anhydrous sodium sulfate, decompressing, distilling, removing the solvent, and recrystallizing to obtain the compound C.
Compared with the existing preparation method, the preparation method has the advantages of low cost, mild reaction conditions, simple post-treatment and easy amplification production. Compared with the subzero reaction condition of-78 ℃ required in the method of the patent CN102786525, the preparation method of the invention adopts the reaction temperature of-15-0 ℃, can be realized by adopting a conventional refrigerant system in production, does not need special equipment and devices, and reduces the hardware investment. In the preparation method, the reaction products obtained in the steps S1 and S2 are washed by slurry, and the reaction product obtained in the step S3 is recrystallized, so that the purity can meet the requirement. The post-treatment is simple, column chromatography purification is not needed, the production flow operation is less, the production period is shortened, the production cost is low, the discharge of solid waste is greatly reduced, and the environmental protection pressure is reduced.
The specific implementation mode is as follows:
the following is a further description of the invention and is not intended to be limiting:
example 1: synthesis of Compound A1
Dissolving 2,4, 6-trichloropyrimidinecarbaldehyde (100g, 473mmol) in 750mL of methanol, cooling to about-10 ℃, stirring, dissolving cyclohexylhydrazine hydrochloride (56.7g, 497mmol) in 250mL of methanol, dropwise adding the solution, dissolving triethylamine (98.1g, 970mmol) in 50mL of methanol, slowly dropwise adding the solution to the reaction solution, stirring at about-10 ℃ for about 1 hour, and performing suction filtration to obtain a compound A1(101g, 79%).
MS(ESI+):m/z:271([M+H]+)；1H NMR(400MHz，CDCl3)δ8.12(s,1H)，4.81–4.70(m，1H)，2.05–1.90(m，6H)，1.81–1.72(m，1H)，1.58–1.46(m，2H)，1.38–1.26(m，1H)。
Example 2: synthesis of Compound B1
Compound A1(80g, 295mmol) was dispersed in 300mL acetonitrile, heated to about 50 ℃ and stirred to dissolve completely. Slowly dropwise adding 1000L of 1N NaOH solution, stirring at about 50 ℃ for about 4 hours, carrying out suction filtration, cooling the filtrate to about 15 ℃, adjusting the pH to 5.0 by using glacial acetic acid, carrying out suction filtration, pulping the filter cake by using 800mL of ethyl acetate, and carrying out suction filtration to obtain a compound B1(59g, 79%).
MS(ESI-):m/z:251([M-H]-)；1H NMR(400MHz，DMSO)δ13.13(brs，1H)，8.06(s，1H)，4.55-4.39(m，1H)，1.91-1.79(m，6H)，1.68(d，J＝12.6Hz，1H)，1.53-1.38(m，2H)，1.24(ddd，J＝12.8，9.5，3.2Hz，1H)。
Example 3: synthesis of Compound C1
Dissolving the compound B1(50g, 198mmol) in example 2 in 500mL of toluene, adding triethylamine (22.3g, 218mmol) and 4- (chlorophenyl) ethylamine under stirring, heating to about 100 ℃ for reflux reaction for about 8 hours, drying under reduced pressure, adding 1000mL of ethyl acetate and 300mL of water, stirring for 30 minutes, adjusting pH to 6-7 with glacial acetic acid, cooling to room temperature under stirring, separating the organic phase, adding 50g of anhydrous sodium sulfate, drying, filtering, adding 5g of activated carbon, stirring at about 40 ℃ for decolorizing for about 1 hour, filtering, and removing the solvent from the filtrate under reduced pressure. Recrystallization afforded compound C1(58g, 82%) as a white solid.
MS(ESI-):m/z:356([M-H]-)；1H NMR(400MHz，CDCl3)δ11.04(brs，1H)，7.52(s，1H)，7.31(q，J＝8.5Hz，4H)，6.87(brs，1H)，4.62(d，J＝4.4Hz，2H)，4.46–4.36(m，1H)，1.97–1.69(m，7H)，1.49-1.27(m,3H)。
Example 4 Synthesis of Compound A2
Dissolving 2,4, 6-trichloropyrimidine formaldehyde (100g, 473mmol) in 750mL of isopropanol, cooling to about-10 ℃, stirring, dissolving isopropylhydrazine hydrochloride (55g, 497mmol) in 250mL of isopropanol, dropwise adding the solution, dissolving triethylamine (98.1g, 970mmol) in 50mL of isopropanol, slowly dropwise adding the solution to the reaction solution, stirring at about-10 ℃ for about 1 hour, and performing suction filtration to obtain a compound A1(99g, 90%).
MS(ESI+):m/z:231([M+H]+)；1H NMR(400MHz，CDCl3)δ8.13(s，1H)，5.16(hept，J＝6.8Hz，1H)，1.57(d，J＝6.7Hz，6H)。
EXAMPLE 5 Synthesis of Compound B2
Compound A2(80g,346mmol) was dispersed in 300mL of dimethyl sulfoxide, and heated to about 50 ℃ and stirred to completely dissolve. Slowly dropwise adding 1000L of 1N KOH solution, stirring at 50 ℃ for about 4 hours, carrying out suction filtration, cooling the filtrate to 15 +/-5 ℃, adjusting the pH to 5.0 by using glacial acetic acid, carrying out suction filtration, pulping the filter cake by using 800mL of toluene, and carrying out suction filtration to obtain a compound B2(58g, 79%).
MS(ESI-):m/z:211([M-H]-)，1H NMR(400MHz，CDCl3)δ8.12(s，1H)，5.01(hept，J＝6.7Hz，1H)，1.54(d，J＝6.7Hz，6H)。
EXAMPLE 6 Synthesis of Compound C2
Dissolving the compound B2(50g, 235mmol) in example 2 in 500mL of dimethylformamide, adding triethylamine (26.4g, 259mmol) and 2, 4-dichlorophenyl ethylamine (45.5g, 258mmol) under stirring, heating to about 100 ℃ for reflux reaction for about 8 hours, drying under reduced pressure, adding 1000mL of ethyl acetate and 300mL of water, stirring for 30 minutes, adjusting pH to 6-7 with glacial acetic acid, separating the organic phase, adding 50g of anhydrous sodium sulfate, drying, filtering, adding 5g of activated carbon, stirring at about 40 ℃ for about 1 hour for decolorization, filtering, and removing the solvent from the filtrate under reduced pressure. Recrystallization afforded compound C1(58g, 82%) as a white solid.
MS(ESI-):m/z:350([M-H]-)；1H NMR(400MHz，CDCl3)δ11.03(brs，1H)，7.70(s，1H)，7.43(d，J＝8.2Hz，1H)，7.39(d，J＝2.0Hz,1H)，7.19(dd，J＝8.2，1.9Hz，1H)，6.97(brs，1H)，4.86(dt，J＝13.3，6.7Hz，1H)，4.70(d，J＝4.0Hz，2H)，1.49(d，J＝6.7Hz，6H)。
EXAMPLE 7 Synthesis of Compound A3
Dissolving 2,4, 6-trichloropyrimidine formaldehyde (100g, 473mmol) in 750mL of methanol, cooling to about-10 ℃, stirring, dissolving cyclohexylhydrazine hydrochloride (67.8g, 497mmol) in a mixed solvent of 200mL of water and 50mL of methanol, dropwise adding the solution, dissolving diethylamine (70.9g, 970mmol) in 150mL of methanol, slowly dropwise adding the solution into the reaction solution, stirring for about 1 hour at about-10 ℃, and performing suction filtration to obtain a compound A3(100g, 82.1%).
EXAMPLE 8 Synthesis of Compound B3
Compound A3(80g, 338mmol) was dispersed in 300mL of N, N-dimethylformamide and heated to about 50 ℃ and stirred to dissolve completely. Slowly dropwise adding 1000L of 1N NaOH solution, controlling the temperature to be about 50 ℃, stirring for about 4 hours, carrying out suction filtration, cooling the filtrate to be about 15 ℃, adjusting the pH to be 5.0 by using glacial acetic acid, carrying out suction filtration, pulping the filter cake by using 800mL of ethyl acetate, and carrying out suction filtration to obtain a compound B3(61g, 82%).
EXAMPLE 9 Synthesis of Compound C3
Dissolving the compound B2(50g, 211mmol) in example 2 in 500mL of dimethyl sulfoxide, adding 1- (4-dichlorophenyl) ethylamine (36.1g, 232mmol) under stirring, heating to about 100 ℃, refluxing for about 8 hours, drying under reduced pressure, cooling to room temperature, adding 1000mL of ethyl acetate and 300mL of water, stirring for 30 minutes, adjusting pH to 6-7 with glacial acetic acid, separating an organic phase, adding 50g of anhydrous sodium sulfate, drying, filtering, adding 5g of activated carbon, stirring at about 40 ℃ for about 1 hour for decolorization, filtering, and removing the solvent from the filtrate under reduced pressure. Recrystallization afforded compound C1(59g, 78%).
MS(ESI-):m/z:322([M-H]-)；1H NMR(400MHz,CDCl3)δ10.70(brs，1H)，7.58(s，1H)，7.45-7.39(m，2H)，7.34(t，J＝7.4Hz，2H)，7.29-7.24(m，1H)，7.13(d，J＝7.0Hz，1H)，5.25(p，J＝6.8Hz，1H)，4.96(p，J＝7.6Hz，1H)，2.12–2.05(m，2H)，2.05–1.98(m，2H)，1.97–1.88(m，2H)，1.75–1.67(m，2H)，1.65(d，J＝6.9Hz，3H)。
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents and are included in the scope of the present invention.
Claims (10)
1. A method for preparing a PDE9A inhibitor, comprising the steps of:
step S1: dissolving 2,4, 6-trichloro-5-pyrimidinecarbaldehyde (SM1) and a starting material hydrazine compound (SM2) in an organic solvent at the reaction temperature of-15-0 ℃, and reacting in the presence of an organic base to obtain a compound A of 1, 4-dichloro-1-substituted-pyrazolo [3,4-d ] pyrimidine;
step S2: dissolving the compound A obtained by the reaction in the step S1 in an organic solvent at the reaction temperature of 40-60 ℃, and reacting in the presence of an inorganic base to obtain a compound B of 6-chloro-1-substituted-1, 5-dihydropyrazolo [3,4] -pyrimidin-2-one;
step S3, dissolving the product B obtained in the step S2 in an organic solvent at the reaction temperature of 80-120 ℃, and reacting the product B with a α -phenylethylamine compound (SM3) for 6-20 hours in the presence of an organic base to obtain a compound C of N-substituted pyrazolo [3,4-d ] pyrimidinone;
the reaction formula of the N-substituted pyrazolo [3,4-d ] pyrimidone compound is as follows:
wherein R1 is selected from isopropyl, cyclopentyl, cyclohexyl, isobutyl, phenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, o-chlorophenyl, pyridine-2-phenyl;
r2 is selected from hydrogen and chlorine.
2. The method according to claim 1, wherein the organic solvent in step S1 is a protic polar solvent, and the organic base is an aliphatic amine having 1 to 9 carbon atoms.
3. The method according to claim 1, wherein the organic solvent in step S2 is an aprotic polar solvent and the inorganic base is an alkali metal hydroxide.
4. The method according to claim 1, wherein the organic solvent in step S3 is an aprotic solvent; the organic base in step S3 is an aliphatic amine having 1 to 15 carbon atoms or an aromatic amine having 4 to 15 carbon atoms.
5. The method according to claim 2, wherein the protic polar solvent in step S1 is selected from one or more of methanol, ethanol, and isopropanol, and the aliphatic amine containing 1-9 carbon atoms is selected from triethylamine and diethylamine.
6. The method according to claim 3, wherein the aprotic polar solvent is selected from one or more of acetonitrile, N-dimethylformamide, and dimethylsulfoxide, and the hydroxide of alkali metal is selected from one or more of NaOH, KOH, and CsOH in step S2.
7. The method according to claim 4, wherein the aprotic solvent in step S3 is one or more selected from toluene, xylene, N-dimethylformamide, dimethyl sulfoxide, and dioxane, the aliphatic amine containing 1 to 15 carbon atoms is selected from triethylamine or diisopropylethylamine, and the aromatic amine containing 4 to 15 carbon atoms is pyridine.
8. The process according to any one of claims 1, 3 or 6, wherein the inorganic base used in step S2 has a concentration of 0.2 to 2 moles per liter and is used in an amount of 1 to 15 times the number of moles of 1, 4-dichloro-1-substituted-pyrazolo [3,4-d ] pyrimidine.
9. The method of claim 1, comprising the steps of:
step S1: dissolving 2,4, 6-trichloro-5-pyrimidinecarbaldehyde in an organic solvent at the temperature of-15-0 ℃, dropwise adding a solution of SM2 in a polar solvent, dropwise adding a triethylamine solution, stirring, precipitating a solid, filtering, and washing with water to obtain a compound A;
step S2: dissolving the compound A obtained in the step S1 in an organic solvent, dropwise adding an inorganic alkaline aqueous solution, heating to 40-60 ℃, reacting, adjusting the pH to 5.0, filtering, and pulping the solid with the organic solvent to obtain a compound B;
step S3: dissolving the compound B obtained in the step S2 in an aprotic solvent, adding SM3, dropwise adding an organic base, heating to the temperature of 80-120 ℃, reacting for 6-20 hours, cooling, decompressing, spin-drying, dissolving with ethyl acetate and water, adjusting the pH to be neutral, decoloring an organic phase with activated carbon, drying with anhydrous sodium sulfate, decompressing, distilling, removing the solvent, and recrystallizing to obtain the compound C.
10. The method according to claim 9, wherein the organic solvent used for the beating in step S2 is selected from the group consisting of ethyl acetate, methanol, ethanol, toluene, and acetonitrile.
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| CN113429411A (en) * | 2021-08-03 | 2021-09-24 | 韶远科技（上海)有限公司 | Preparation method of 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound |
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| EP1120120A1 (en) * | 1998-10-05 | 2001-08-01 | Eisai Co., Ltd. | Tablets immediately disintegrating in the oral cavity |
| CN102260266A (en) * | 2011-05-03 | 2011-11-30 | 中山大学 | Pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of phosphodiesterase IX inhibitor |
| CN102786525A (en) * | 2012-08-08 | 2012-11-21 | 中山大学 | N-substituted pyrazolo [3, 4-d] pyrimidine ketone compound and preparation method and application thereof |
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| EP1120120A1 (en) * | 1998-10-05 | 2001-08-01 | Eisai Co., Ltd. | Tablets immediately disintegrating in the oral cavity |
| CN102260266A (en) * | 2011-05-03 | 2011-11-30 | 中山大学 | Pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of phosphodiesterase IX inhibitor |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113429411A (en) * | 2021-08-03 | 2021-09-24 | 韶远科技（上海)有限公司 | Preparation method of 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound |
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