CN113429411A - Preparation method of 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound - Google Patents
Preparation method of 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound Download PDFInfo
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- CN113429411A CN113429411A CN202110885734.2A CN202110885734A CN113429411A CN 113429411 A CN113429411 A CN 113429411A CN 202110885734 A CN202110885734 A CN 202110885734A CN 113429411 A CN113429411 A CN 113429411A
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- C07—ORGANIC CHEMISTRY
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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
- C07D487/04—Ortho-condensed systems
Abstract
The invention belongs to the technical field of organic synthesis, and provides a preparation method of a 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound. The preparation method takes 2, 4-dichloropyrimidine-5-formaldehyde and alkyl hydrazine hydrochloride as raw materials, and compared with 6-chloropyrazolo [3,4-d ] pyrimidine, the cost is low; meanwhile, 2, 4-dichloropyrimidine-5-formaldehyde and alkyl hydrazine hydrochloride are used as raw materials, aldehyde in the 2, 4-dichloropyrimidine-5-formaldehyde and alkyl hydrazine form hydrazone first and then cyclize, so that the position of the alkyl is 1 position, no 2-position isomer is generated, and the yield is high; in addition, the solvent methanol has good solubility to the alkyl hydrazine hydrochloride, the reaction speed is high, and the yield is high. The data of the examples show that: the yield of the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound is 72.6-82.8%.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound.
Background
The 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound is a very important medical intermediate and is commonly used for preparing JAK3 inhibitor medicines. European patent applications WO2016/100349A2, WO2013/41605A1 and WO2020/132269A1 disclose that 6-chloropyrazolo [3,4-d ] pyrimidine and a halide are used as reaction raw materials and subjected to alkylation reaction to prepare a 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound; the raw material 6-chloropyrazolo [3,4-d ] pyrimidine is expensive, so that the cost is high; meanwhile, the yield of the final 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound is low due to the production of isomers.
Disclosure of Invention
In view of the above, the present invention is directed to a method for preparing a 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound. The preparation method provided by the invention has the advantages of low cost of raw materials and high yield of the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound, which comprises the following steps:
mixing 2, 4-dichloropyrimidine-5-formaldehyde, alkyl hydrazine hydrochloride, methanol and an acid-binding agent, and carrying out cyclization reaction to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound;
the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound has the structure shown in formula I:
in the formula I, R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or substituted phenyl.
Preferably, the hydrocarbyl hydrazine hydrochloride has the structure shown in formula II:
R-NHNH2HCl formula II;
in the formula II, R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or substituted phenyl.
Preferably, the molar ratio of the 2, 4-dichloropyrimidine-5-carbaldehyde to the hydrocarbyl hydrazine hydrochloride is 1: (1-2.5).
Preferably, the acid scavenger is triethylamine.
Preferably, the molar ratio of the 2, 4-dichloropyrimidine-5-formaldehyde to the acid-binding agent is 1: (3-3.5).
Preferably, the operation of mixing the 2, 4-dichloropyrimidine-5-formaldehyde, the alkyl hydrazine hydrochloride, the methanol and the acid-binding agent to carry out the cyclization reaction comprises the following steps:
mixing the alkyl hydrazine hydrochloride with methanol to obtain an alkyl hydrazine hydrochloride solution; dropwise adding part of an acid-binding agent into the alkyl hydrazine hydrochloride solution to perform acid-base neutralization reaction to obtain an acid-base neutralization reaction system;
and sequentially adding a2, 4-dichloropyrimidine-5-formaldehyde methanol solution and the balance acid-binding agent into the acid-base neutralization reaction system to perform cyclization reaction to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound.
Preferably, the molar ratio of the partial acid-binding agent to the rest acid-binding agent is (2.0-2.2): 1.
preferably, the temperature of the acid-base neutralization reaction is-5 ℃ and the time is 0.5-1 h.
Preferably, the temperature of the cyclization reaction is-15-5 ℃ and the time is 2 h.
Preferably, after the cyclization reaction, the method further comprises evaporating the obtained cyclization reaction liquid to dryness, and performing column chromatography to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound; the column chromatography reagent is ethyl acetate and petroleum ether with the volume ratio of 5: 95 of the composition.
The invention provides a preparation method of a 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound, which comprises the following steps: mixing 2, 4-dichloropyrimidine-5-formaldehyde, alkyl hydrazine hydrochloride, methanol and an acid-binding agent, and carrying out cyclization reaction to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound; the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound has a structure shown in formula I. The invention takes 2, 4-dichloropyrimidine-5-formaldehyde and alkyl hydrazine hydrochloride as raw materials, compared with 6-chloropyrazolo [3,4-d ] pyrimidine, the cost is low; meanwhile, 2, 4-dichloropyrimidine-5-formaldehyde and alkyl hydrazine hydrochloride are used as raw materials, aldehyde in the 2, 4-dichloropyrimidine-5-formaldehyde and alkyl hydrazine form hydrazone first and then cyclization is carried out, so that the position of the alkyl is 1, no 2-position isomer is generated, and the yield is high; in addition, the solvent methanol has good solubility to the alkyl hydrazine hydrochloride, the reaction speed is high, and the yield is high. The data of the examples show that: the yield of the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound is 72.6-82.8%.
Detailed Description
The invention provides a preparation method of a 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound, which comprises the following steps:
mixing 2, 4-dichloropyrimidine-5-formaldehyde, alkyl hydrazine hydrochloride, methanol and an acid-binding agent, and carrying out cyclization reaction to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound.
In the present invention, the starting materials used in the present invention are preferably commercially available products unless otherwise specified.
In the present invention, the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound has the structure shown in formula I:
in the formula I, R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or substituted phenyl, preferably methyl, cyclopropyl, cyclopropylmethyl, phenyl or isopropyl.
In the present invention, the hydrocarbyl hydrazine hydrochloride has the structure shown in formula II:
R-NHNH2HCl formula II;
in formula II, R is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group or a substituted phenyl group, and more preferably a methyl group, a cyclopropyl group, a cyclopropylmethyl group, a phenyl group or an isopropyl group.
In the present invention, the acid scavenger is preferably triethylamine.
In the invention, the molar ratio of the 2, 4-dichloropyrimidine-5-formaldehyde to the hydrocarbyl hydrazine hydrochloride is preferably 1: (1-2.5).
In the invention, the molar ratio of the 2, 4-dichloropyrimidine-5-formaldehyde to the acid-binding agent is preferably 1: (3 to 3.5), more preferably 1: 3.2.
in the present invention, the operation of mixing the 2, 4-dichloropyrimidine-5-carbaldehyde, the hydrocarbyl hydrazine hydrochloride, the methanol and the acid-binding agent to perform the cyclization reaction preferably comprises: mixing the alkyl hydrazine hydrochloride with methanol to obtain an alkyl hydrazine hydrochloride solution; dropwise adding part of an acid-binding agent into the alkyl hydrazine hydrochloride solution to perform acid-base neutralization reaction to obtain an acid-base neutralization reaction system; and sequentially adding a2, 4-dichloropyrimidine-5-formaldehyde methanol solution and the balance acid-binding agent into the acid-base neutralization reaction system to perform cyclization reaction to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound.
In the invention, the molar ratio of the partial acid-binding agent to the rest acid-binding agent is preferably (2.0-2.2): 1.
in the invention, the concentration of the alkyl hydrazine hydrochloride in the alkyl hydrazine hydrochloride solution is preferably 0.2-0.6 mol/L. In the invention, the dripping speed of the partial acid-binding agent is preferably 4-6 mL/min; the temperature of the dropwise adding part of the acid-binding agent is preferably-5 ℃; the dropwise addition of part of the acid-binding agent is preferably carried out under a protective atmosphere.
In the invention, the temperature of the acid-base neutralization reaction is preferably-5 ℃, and more preferably 0 ℃; the time is preferably 0.5 h; the time of the acid-base neutralization reaction is timed from the completion of dropwise adding of part of the acid-binding agent; the acid-base neutralization reaction is preferably carried out under stirring.
In the invention, the solvent of the methanol solution of the 2, 4-dichloropyrimidine-5-formaldehyde is preferably methanol; the concentration of the 2, 4-dichloropyrimidine-5-formaldehyde methanol solution is preferably 0.2-0.5 mol/L. In the invention, the 2, 4-dichloropyrimidine-5-formaldehyde methanol solution is preferably added dropwise; the dropping speed is preferably 5 mL/min; the addition temperature of the 2, 4-dichloropyrimidine-5-formaldehyde methanol solution is preferably-10 ℃. In the invention, the addition mode of the residual acid-binding agent is preferably dropwise adding; the dropping speed is preferably 5 mL/min; the adding temperature of the rest acid binding agent is preferably-10 ℃; the rest acid-binding agent is preferably added immediately after the 2, 4-dichloropyrimidine-5-formaldehyde methanol solution is added.
In the invention, the temperature of the cyclization reaction is preferably-15-5 ℃, more preferably-10-0 ℃, and the time is preferably 2 h; the time of the cyclization reaction is preferably timed from the completion of the addition of the rest of the acid-binding agent. In the present invention, the end point of the cyclization reaction is preferably detected by TLC.
After the cyclization reaction, evaporating the obtained cyclization reaction liquid to dryness, and carrying out column chromatography to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound.
The operation of evaporating to dryness is not particularly limited as long as the solvent can be removed.
In the invention, the reagent for column chromatography is preferably ethyl acetate and petroleum ether with a volume ratio of 5: 95 of the composition.
The following examples are provided to illustrate the preparation of the 1-hydrocarbyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compounds of the present invention in detail, but they should not be construed as limiting the scope of the invention.
Example 1
1- (cyclopropylmethyl) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (3b)
Adding 25mL of methanol, a compound 2b (1.70g, 13.85mmol, 1.1eq) and nitrogen into a 100mL three-necked flask, dropwise adding triethylamine (2.79g, 27.67mmol, 2.2eq) at the speed of 5mL/min at the temperature of 0 ℃ T, stirring for 0.5h after dropwise adding to perform acid-base neutralization reaction to obtain an acid-base neutralization reaction system, dropwise adding a 25mL methanol solution of a compound 1(2.23g, 12.58mmol, 1eq) at the speed of 5mL/min at the temperature of-10 ℃ in the acid-base neutralization reaction system, dropwise adding triethylamine (1.27g, 12.58mmol, 1eq) at the speed of 5mL/min after completing addition, keeping the temperature at-10-0 ℃ for cyclization reaction for 2h, completely performing TLC reaction, and spin-drying, wherein the volume ratio of ethyl acetate to petroleum ether is 5: column chromatography of 95 mixture afforded compound 3b (1.91g, 72.6% yield).
MS-ESI[M+1]+＝209.2，211.3。
1HNMR(300MHz，CDCl3): δ 9.00(s, 1H), 8.15(s, 1H), 4.32(d, 2H), 1.47-1.33(m, 1H), 0.63-0.54(m, 2H), 0.53-0.45(m, 2H); to illustrate the fact that the substance obtained in this example was 1- (cyclopropylmethyl) -6-chloro-1H-pyrazolo [3,4-d]A pyrimidine.
Example 2
1-isopropyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (3c)
Adding 25mL of methanol, a compound 2c (0.69g, 6.21mmol, 1.1eq) and nitrogen into a 100mL three-neck flask, dropwise adding triethylamine (1.26g, 12.43mmol, 2.2eq) at the speed of 5mL/min at the temperature of 0 ℃ T under the protection of nitrogen, and stirring for 0.5h after dropwise adding to perform acid-base neutralization reaction to obtain an acid-base neutralization reaction system; and (3) dropwise adding a 25mL methanol solution of the compound 1(1g, 5.65mmol, 1eq) at the speed of 5mL/min in the acid-base neutralization reaction system at the temperature of-10 ℃, dropwise adding triethylamine (0.63g, 6.21mmol, 1.1eq) at the speed of 5mL/min after the addition is finished, performing heat preservation and cyclization reaction at the temperature of-10-0 ℃ for 2h, completely performing TLC reaction, performing spin drying, and performing reaction by using ethyl acetate and petroleum ether at the volume ratio of 5: column chromatography of the mixture of 95 gave compound 3c (0.84g, yield 75.5%).
MS-ESI[M+1]+＝197.2，199.2。
1HNMR(300MHz，CDCl3): δ 9.00(s, 1H), 8.15(s, 1H), 5.26-5.16(m, 1H), 1.58(d, 6H); this example illustrates the preparation of 1-isopropyl-6-chloro-1H-pyrazolo [3,4-d]A pyrimidine.
Example 3
1-cyclopropyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (3d)
Adding 25mL of methanol, a compound 2d (0.68g, 6.21mmol, 1.1eq) and nitrogen into a 100mL three-neck flask, dropwise adding triethylamine (1.26g, 12.43mmol, 2.2eq) at the speed of 5mL/min at the temperature of 0 ℃ T under the protection of nitrogen, and stirring for 0.5h after dropwise adding to perform acid-base reaction neutralization reaction to obtain an acid-base neutralization reaction system; and (3) dropwise adding a 25mL methanol solution of the compound 1(1g, 5.65mmol, 1eq) at the speed of 5mL/min in the acid-base neutralization reaction system at the temperature of-10 ℃, dropwise adding triethylamine (0.63g, 6.21mmol, 1.1eq) at the speed of 5mL/min after the addition is finished, carrying out heat preservation reaction at the temperature of-10-0 ℃ for 2h, completely carrying out TLC reaction, carrying out spin drying, and adopting ethyl acetate and petroleum ether in a volume ratio of 5: column chromatography of the mixture of 95 gave compound 3d (0.87g, yield 79.1%).
MS-ESI[M+1]+＝195.2，197.2。
1HNMR(300MHz，CDCl3): δ 9.00(s, 1H), 8.08(s, 1H), 3.92-3.83(m, 1H), 1.38-1.28(m, 2H), 1.26-1.17(m, 2H); this example shows that 1-cyclopropyl-6-chloro-1H-pyrazolo [3,4-d]A pyrimidine.
Example 4
1-phenyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (3e)
Adding 25mL of methanol, a compound 2e (1.80g, 12.43mmol, 1.1eq), protecting with nitrogen, adding triethylamine (2.52g, 24.86mmol, 2.2eq) dropwise at the speed of 5mL/min at the temperature of 0 ℃ T, stirring for 0.5h, adding 25mL of a methanol solution of the compound 1(2g, 11.30mmol, 1eq) dropwise at the temperature of-10 ℃, adding triethylamine (1.26g, 12.43mmol, 1.1eq) dropwise, keeping the temperature at 10-0 ℃ for 2h, completely TLC reacting, spin-drying, and reacting with ethyl acetate and petroleum ether at a volume ratio of 5: column chromatography of the mixture of 95 gave compound 3e (2.16g, yield 82.8%).
MS-ESI[M+1]+＝230.1，232.1。
1HNMR(300MHz，CDCl3): δ 9.11(s, 1H), 8.32(s, 1H), 8.18(d, 2H), 7.56(t, 2H), 7.39(t, 1H); this example shows that 1-phenyl-6-chloro-1H-pyrazolo [3,4-d is obtained]A pyrimidine.
Example 5
1-methyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (3f)
Adding 25mL of methanol, a compound 2f (1.03g, 12.43mmol, 1.1eq) and nitrogen protection into a 100mL three-necked flask, stirring at the speed of 5mL/min and under the condition that T is 0 ℃, and carrying out acid-base neutralization reaction for 0.5h after dropwise addition, so as to obtain an acid-base neutralization reaction system, wherein the compound 2f (1.03g, 12.43mmol, 1.1eq) is added; and (3) dropwise adding a 25mL methanol solution of the compound 1(2g, 11.30mmol, 1eq) into the acid-base neutralization reaction system at the speed of 5mL/min, dropwise adding triethylamine (1.26g, 12.43mmol, 1.1eq) at the speed of 5mL/min after the addition is finished, carrying out heat preservation reaction at the temperature of-10-0 ℃ for 2h, completely carrying out TLC reaction, and carrying out spin drying, wherein the volume ratio of ethyl acetate to petroleum ether is 5: column chromatography of the mixture of 95 gave compound 3f (1.46g, yield 76.7%).
MS-ESI[M+1]+＝169.3，171.2。
1HNMR(300MHz，CDCl3): δ 9.02(s, 1H), 8.14(s, 1H), 4.11(s, 3H); this example shows that 1-methyl-6-chloro-1H-pyrazolo [3,4-d is obtained]A pyrimidine.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A process for the preparation of a 1-hydrocarbyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound comprising the steps of:
mixing 2, 4-dichloropyrimidine-5-formaldehyde, alkyl hydrazine hydrochloride, methanol and an acid-binding agent, and carrying out cyclization reaction to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound;
the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound has the structure shown in formula I:
in the formula I, R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or substituted phenyl.
2. The method of claim 1, wherein the hydrocarbyl hydrazine hydrochloride has the structure of formula II:
R-NHNH2HCl formula II;
in the formula II, R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or substituted phenyl.
3. The process according to claim 1 or 2, wherein the molar ratio of 2, 4-dichloropyrimidine-5-carbaldehyde to the hydrocarbyl hydrazine hydrochloride is 1: (1-2.5).
4. The method of claim 1, wherein the acid scavenger is triethylamine.
5. The process according to claim 1 or 4, wherein the molar ratio of the 2, 4-dichloropyrimidine-5-carbaldehyde to the acid-binding agent is 1: (3-3.5).
6. The method of claim 1, wherein the step of combining 2, 4-dichloropyrimidine-5-carbaldehyde, the hydrocarbyl hydrazine hydrochloride, methanol, and the acid-binding agent to perform a cyclization reaction comprises:
mixing the alkyl hydrazine hydrochloride with methanol to obtain an alkyl hydrazine hydrochloride solution; dropwise adding part of an acid-binding agent into the alkyl hydrazine hydrochloride solution to perform acid-base neutralization reaction to obtain an acid-base neutralization reaction system;
and sequentially adding a2, 4-dichloropyrimidine-5-formaldehyde methanol solution and the balance acid-binding agent into the acid-base neutralization reaction system to perform cyclization reaction to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound.
7. The preparation method according to claim 6, wherein the molar ratio of the partial acid-binding agent to the rest acid-binding agent is (2.0-2.2): 1.
8. the preparation method according to claim 6, wherein the temperature of the acid-base neutralization reaction is-5 to 5 ℃ and the time is 0.5 to 1 hour.
9. The method according to claim 1 or 6, wherein the cyclization reaction is carried out at a temperature of-15 to 5 ℃ for 2 hours.
10. The preparation method according to claim 1 or 6, characterized by further comprising, after the cyclization reaction, evaporating the obtained cyclization reaction solution to dryness, and then performing column chromatography to obtain the 1-alkyl-6-chloro-1H-pyrazolo [3,4-d ] pyrimidine compound; the column chromatography reagent is ethyl acetate and petroleum ether with the volume ratio of 5: 95 of the composition.
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| CN102115476A (en) * | 2011-03-23 | 2011-07-06 | 常州大学 | 2H-pyrazolo [3, 4-d] pyrimidine derivative and synthetic method thereof |
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| CN104557938A (en) * | 2013-10-28 | 2015-04-29 | 中山大学 | N-substituted pyrazolo[3,4-d]pyrimidinone compound and application thereof |
| CN110078736A (en) * | 2019-06-05 | 2019-08-02 | 广州白云山医药集团股份有限公司白云山制药总厂 | Pyrazolopyrimidine derivative, preparation method and its application |
| CN110862394A (en) * | 2018-08-28 | 2020-03-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | Preparation method of PDE9A inhibitor |
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| WO2011156698A2 (en) * | 2010-06-11 | 2011-12-15 | Abbott Laboratories | NOVEL PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS |
| CN102115476A (en) * | 2011-03-23 | 2011-07-06 | 常州大学 | 2H-pyrazolo [3, 4-d] pyrimidine derivative and synthetic method thereof |
| CN104557938A (en) * | 2013-10-28 | 2015-04-29 | 中山大学 | N-substituted pyrazolo[3,4-d]pyrimidinone compound and application thereof |
| CN110862394A (en) * | 2018-08-28 | 2020-03-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | Preparation method of PDE9A inhibitor |
| CN110078736A (en) * | 2019-06-05 | 2019-08-02 | 广州白云山医药集团股份有限公司白云山制药总厂 | Pyrazolopyrimidine derivative, preparation method and its application |
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