CN111620868A - Preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde - Google Patents
Preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis, and discloses a preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde, which comprises the following steps: s1, reacting 2-fluoropyridine with 2, 2-dialkoxy acetate under the action of alkali to obtain 1- (2-fluoropyridine-3-yl) -2, 2-dialkoxy ethanone; s2, reacting 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol with hydrazine hydrate to obtain 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine; s3, hydrolyzing 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine under an acidic condition to obtain 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde; the method has the advantages of easily available raw materials, low cost, convenient and safe process operation, high total yield, no special equipment requirements such as ultra-high temperature reaction and the like, high production safety factor, environmental friendliness, suitability for industrial production and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde.
Background
1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde (cas number: 1010073-87-6) can be used as a medical intermediate of a PIM3 inhibitor for clinical treatment of pancreatic cancer, the synthesis method reported in the existing literature is very few at present, WO2008147822 reports that 2-chloronicotinaldehyde is adopted as a raw material, hydrazine hydrate is firstly subjected to ring closure to obtain 1H-pyrazolo [3,4-b ] pyridine, and after iodination, Grignard reaction is carried out to obtain a target product, and the synthetic route is as follows:
although the yield of the reaction is high, the production cost is high because the raw materials such as 2-chloronicotinaldehyde, Grignard reagent and N-piperidinecarboxaldehyde are expensive.
Therefore, a method for producing 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde which can reduce the cost is desired.
Disclosure of Invention
The invention aims to overcome the defects of high price of raw and auxiliary materials, use of a precious catalyst, harsh reaction conditions, high synthesis difficulty, low production efficiency or high production discharge capacity and the like in the prior art, and provides a preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde, so as to at least achieve the effects of low cost, cheap and easily available raw materials, simple reaction process, convenient and safe operation, high total yield and environmental friendliness.
The purpose of the invention is realized by the following technical scheme: a preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde comprises the following synthetic routes:
wherein R is selected from methyl or ethyl, R1Selected from methyl or ethyl;
the method comprises the following steps:
s1, reacting 2-fluoropyridine with 2, 2-dialkoxy acetate under the action of alkali to obtain 1- (2-fluoropyridine-3-yl) -2, 2-dialkoxy ethanone;
s2, reacting 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol with hydrazine hydrate to obtain 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine;
s3, hydrolyzing the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine under acidic conditions to obtain 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde.
By adopting the technical scheme, a brand-new route for preparing 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde is provided, 2-fluoropyridine, 2-dialkoxyacetic ester, hydrazine hydrate and the like are used as starting raw materials, 1- (2-fluoropyridine-3-yl) -2, 2-dialkoxyacetone, 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine and 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde are sequentially synthesized, only 3 steps of reaction are needed, and the effects of easy obtainment of raw materials, low cost, convenient and safe process operation, no relation to the requirements of special equipment such as ultra-high temperature reaction and the like, high production safety factor and environmental friendliness are achieved; meanwhile, the data obtained in the embodiment of the invention show that the product yield of the synthetic route reaches more than 89%, and the effects of high total yield and suitability for industrial production are achieved.
Further, step S1 specifically includes: dissolving 2-fluoropyridine in an organic solvent I, dropwise adding 2, 2-dialkoxy acetate at the temperature of-60 to-80 ℃ under the action of alkali, carrying out heat preservation reaction for 1 to 2 hours, and finally carrying out quenching reaction, separation and purification to obtain the 1- (2-fluoropyridine-3-yl) -2, 2-dialkoxy ethanone.
Further, the organic solvent I comprises one or two of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane and dichloroethane; the base comprises one or two of n-butyllithium, lithium diisopropylamide and tert-butyllithium, and is preferably lithium diisopropylamide which is only strongly basic but has no nucleophilicity.
Further, the mass ratio of the 2-fluoropyridine to the organic solvent I is 1: 5-15; the molar ratio of the 2-fluoropyridine to the alkali to the 2, 2-dialkoxy acetate is 1: 1.0-1.5.
Further, step S2 specifically includes: dissolving the 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol in an organic solvent II, dropwise adding hydrazine hydrate, heating to 50-60 ℃, reacting for 8-10H, and finally carrying out quenching reaction, separation and purification to obtain the 3- (diethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine.
Further, the organic solvent II comprises one or two of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane and dichloroethane, preferably tetrahydrofuran capable of stabilizing strong base; the mass ratio of the 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol to the organic solvent II is 1: 1-10, and the molar ratio of the 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol to hydrazine hydrate is 1: 1.0-3.0.
Further, step S3 specifically includes: dissolving the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine in an organic solvent III, adding acid, heating to 50-60 ℃, reacting for 2-3H, and finally carrying out quenching reaction, separation and purification to obtain the 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde.
Further, the organic solvent III comprises one or two of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, dichloroethane, acetone and acetonitrile, preferably tetrahydrofuran which can maximize the reaction efficiency and yield; the acid comprises one or two of hydrochloric acid, acetic acid, sulfuric acid and hydrogen chloride, and is preferably hydrochloric acid.
Further, the mass ratio of the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine to the organic solvent III is 1:1 to 10, and the molar ratio of the acid to the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine is 1 to 5:1.
Further, the quenching reaction is quenching with water.
The invention has the beneficial effects that:
the preparation method of the 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde provided by the invention takes 2-fluoropyridine, 2-dialkoxyacetic ester, hydrazine hydrate and the like as starting raw materials, can obtain the 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde only through 3-step reaction, and has the advantages of easily available raw materials, low cost, convenience in process operation, safety, high total yield, no relation to special equipment requirements such as ultrahigh temperature reaction and the like, high production safety coefficient, environmental friendliness, suitability for industrial production and the like.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Detailed Description
The technical solutions of the present invention are described in further detail below, but the scope of the present invention is not limited to the following.
Example 1
A preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde comprises the following synthetic routes:
the method comprises the following steps:
s1.1- (2-Fluoropyridin-3-yl) -2, 2-diethoxyethanol:
adding 2-fluoropyridine (50g, 0.51mol, 1.0eq) and tetrahydrofuran (500g) into a three-necked flask, dropwise adding a cyclohexane solution (330.0mL, 0.66mol, 1.3eq) containing 2.0mol/L lithium diisopropylamide at-60 to-80 ℃, and after dropwise adding, carrying out heat preservation reaction for 1 to 2 hours; and then at the temperature of between 60 ℃ below zero and 80 ℃ below zero, dropwise adding 2, 2-diethoxyacetic acid ethyl ester (134.8g, 0.76mol and 1.5eq), preserving the temperature and reacting for 1 to 2 hours, after the central control raw materials are reacted, quenching the reaction with water, separating the liquid and concentrating the organic phase to obtain 1- (2-fluoropyridin-3-yl) -2, 2-diethoxyacetone (99.5g, the yield is 85%).
S2.preparation of 3- (diethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine:
dissolving 1- (2-fluoropyridin-3-yl) -2, 2-diethoxyacetone (50g, 0.22mol, 1.0eq) in tetrahydrofuran (250g), slowly adding hydrazine hydrate (16.3g, 0.44mol, 2.0eq) dropwise, after the completion of the addition, heating to 50-60 ℃, reacting for 8-10H, quenching the reaction with water, adding methyl tert-butyl ether (500g) to extract an organic phase, concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE ═ 2:1) to obtain 3- (diethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine (43.8g, yield 90%).
Nuclear magnetic detection:1H NMR(400MHz,(CD3)2SO)：8.60(1H,d),7.78(1H,d),7.38(1H,t),5.78(1H,S),3.60(4H,q),1.16(6H,t)。
preparation of S3.1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde:
3- (diethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine (50g, 0.23mol, 1.0eq) was dissolved in tetrahydrofuran (500g) and hydrogen chloride (24.8g, 0.68mol, 3.0eq), the system temperature was raised to 50 ℃ to 60 ℃ until the reaction of the starting materials was completed, the reaction was quenched with water, extracted with methyl tert-butyl ether (500g), the organic phase was separated and concentrated to dryness, and column chromatography (PE: MTBE 1:1) gave 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde (29.9g, yield 90%).
Nuclear magnetic detection:1H NMR(400MHz,(CD3)2SO)：13.23(1H,S),9.75(1H,S),8.51(1H,d),8.39(1H,d),7.36(1H,t)。
example 2
A preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde comprises the following synthetic routes:
the method comprises the following steps:
s1.1- (2-Fluoropyridin-3-yl) -2, 2-diethoxyethanol:
adding 2-fluoropyridine (50g, 0.51mol, 1.0eq) and tetrahydrofuran (500g) into a three-necked flask, dropwise adding a cyclohexane solution (330mL, 0.66mol, 1.3eq) containing 2.0mol/L lithium diisopropylamide at-60 to-80 ℃, and after dropwise adding, carrying out heat preservation reaction for 1 to 2 hours; and then at the temperature of between 60 ℃ below zero and 80 ℃ below zero, dropwise adding 2, 2-dimethoxyacetic acid methyl ester (101.9g, 0.76mol and 1.5eq), preserving the temperature and reacting for 1 to 2 hours, after the control raw materials are reacted, quenching the reaction by using water, separating liquid and concentrating an organic phase to obtain 1- (2-fluoropyridin-3-yl) -2, 2-dimethoxyethanone (87.4g, the yield is 86%).
S2.preparation of 3- (dimethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine:
dissolving 1- (2-fluoropyridin-3-yl) -2, 2-dimethoxyethanone (50g, 0.25mol, 1.0eq) in tetrahydrofuran (250g), slowly adding hydrazine hydrate (16.3g, 0.50mol, 2.0eq) dropwise, after the addition is finished, heating to 50-60 ℃, reacting for 8-10H, quenching the reaction with water, adding methyl tert-butyl ether (500g), extracting an organic phase, concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE ═ 2:1) to obtain 3- (dimethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine (44.4g, yield 92%).
Nuclear magnetic detection:1H NMR(400MHz,(CD3)2SO)：8.51(1H,d),8.39(1H,d),7.36(1H,t)6.38(1H,S),3.3(6H,s)。
preparation of S3.1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde:
3- (dimethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine (50g, 0.26mol, 1.0eq) was dissolved in tetrahydrofuran (500g) and hydrogen chloride (24.8g, 0.68mol, 3.0eq), the temperature of the system was raised to 50 ℃ to 60 ℃ until the reaction of the starting materials was completed, the reaction was quenched with water, extracted with methyl tert-butyl ether (500g), the organic phase was separated and concentrated to dryness, and column chromatography (PE: MTBE 1:1) gave 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde (33.9g, yield 89%).
Nuclear magnetic detection:1H NMR(400MHz,(CD3)2SO)：13.23(1H,S),9.75(1H,S),8.51(1H,d),8.39(1H,d),7.36(1H,t)。
in conclusion, the preparation method of the 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde can achieve the effects of low cost, cheap and easily available raw materials, simple reaction process, convenience in operation, safety, high total yield and environmental friendliness.
The foregoing is illustrative of the preferred embodiments of this invention, and it is to be understood that the invention is not limited to the precise form disclosed herein and that various other combinations, modifications, and environments may be resorted to, falling within the scope of the concept as disclosed herein, either as described above or as apparent to those skilled in the relevant art. And that modifications and variations may be effected by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde is characterized in that the synthetic route is as follows:
wherein R is selected from methyl or ethyl, R1Selected from methyl or ethyl;
the method comprises the following steps:
s1, reacting 2-fluoropyridine with 2, 2-dialkoxy acetate under the action of alkali to obtain 1- (2-fluoropyridine-3-yl) -2, 2-dialkoxy ethanone;
s2, reacting 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol with hydrazine hydrate to obtain 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine;
s3, hydrolyzing the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine under acidic conditions to obtain 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde.
2. The preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde according to claim 1, wherein step S1 specifically comprises: dissolving 2-fluoropyridine in an organic solvent I, dropwise adding 2, 2-dialkoxy acetate at the temperature of-60 to-80 ℃ under the action of alkali, carrying out heat preservation reaction for 1 to 2 hours, and finally carrying out quenching reaction, separation and purification to obtain the 1- (2-fluoropyridine-3-yl) -2, 2-dialkoxy ethanone.
3. The process for preparing 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde according to claim 2, wherein the organic solvent I comprises one or two of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane and dichloroethane; the base comprises one or two of n-butyl lithium, lithium diisopropylamide and tert-butyl lithium.
4. The preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde according to claim 2, wherein the mass ratio of the 2-fluoropyridine to the organic solvent I is 1: 5-15; the molar ratio of the 2-fluoropyridine to the alkali to the 2, 2-dialkoxy acetate is 1: 1.0-1.5.
5. The preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde according to claim 1, wherein step S2 specifically comprises: dissolving the 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol in an organic solvent II, dropwise adding hydrazine hydrate, heating to 50-60 ℃, reacting for 8-10H, and finally carrying out quenching reaction, separation and purification to obtain the 3- (diethoxymethyl) -1H-pyrazolo [3,4-b ] pyridine.
6. The process according to claim 5, wherein the organic solvent II comprises one or two of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane and dichloroethane; the mass ratio of the 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol to the organic solvent II is 1: 1-10, and the molar ratio of the 1- (2-fluoropyridin-3-yl) -2, 2-dialkoxyethanol to hydrazine hydrate is 1: 1.0-3.0.
7. The preparation method of 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde according to claim 1, wherein step S3 specifically comprises: dissolving the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine in an organic solvent III, adding acid, heating to 50-60 ℃, reacting for 2-3H, and finally carrying out quenching reaction, separation and purification to obtain the 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde.
8. The process for preparing 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde according to claim 7, wherein the organic solvent III comprises one or two of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, dichloroethane, acetone and acetonitrile; the acid comprises one or two of hydrochloric acid, acetic acid, sulfuric acid and hydrogen chloride.
9. The method for preparing 1H-pyrazolo [3,4-b ] pyridine-3-formaldehyde according to claim 7, wherein the mass ratio of the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine to the organic solvent III is 1:1 to 10, and the molar ratio of the acid to the 3- (dialkoxymethyl) -1H-pyrazolo [3,4-b ] pyridine is 1 to 5:1.
10. The process for producing 1H-pyrazolo [3,4-b ] pyridine-3-carbaldehyde according to claim 2, 5 or 7, wherein the quenching reaction is quenching with water.
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| US20180311255A1 (en) * | 2017-05-01 | 2018-11-01 | Theravance Biopharma R&D Ip, Llc | Fused imidazo-piperidine jak inhibitor compound |
| WO2019143994A1 (en) * | 2018-01-18 | 2019-07-25 | Array Biopharma Inc. | Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors |
| US20200131178A1 (en) * | 2018-10-29 | 2020-04-30 | Theravance Biopharma R&D Ip, Llc | 2-azabicyclo hexane jak inhibitor compound |
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| WO2008147822A1 (en) * | 2007-05-22 | 2008-12-04 | Chemocentryx, Inc. | Azaindazole compounds and methods of use |
| CN105473590A (en) * | 2013-08-23 | 2016-04-06 | 加拉帕戈斯股份有限公司 | Derivatives of 1H-pyrazolo[3,4-B]pyridine and pharmaceutical compositions thereof for the treatment of proliferative disorders |
| WO2015122504A1 (en) * | 2014-02-13 | 2015-08-20 | 国立大学法人 東京大学 | Kinase inhibitor |
| US20180311255A1 (en) * | 2017-05-01 | 2018-11-01 | Theravance Biopharma R&D Ip, Llc | Fused imidazo-piperidine jak inhibitor compound |
| WO2019143994A1 (en) * | 2018-01-18 | 2019-07-25 | Array Biopharma Inc. | Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors |
| US20200131178A1 (en) * | 2018-10-29 | 2020-04-30 | Theravance Biopharma R&D Ip, Llc | 2-azabicyclo hexane jak inhibitor compound |
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