CN113149995A - Synthesis method and application of 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile - Google Patents
Synthesis method and application of 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile Download PDFInfo
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- CN113149995A CN113149995A CN202110344999.1A CN202110344999A CN113149995A CN 113149995 A CN113149995 A CN 113149995A CN 202110344999 A CN202110344999 A CN 202110344999A CN 113149995 A CN113149995 A CN 113149995A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method and application of 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile, which provides a synthesis method of 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile, aims at developing a brand-new synthesis method to overcome the defects of more reaction byproducts, low conversion rate, complex post-treatment operation, low product purity and the like in a preparation method of an intermediate synthetic compound of a drug for cardiovascular disorder, and develops a novel general, economic, efficient, green and environment-friendly synthesis method, so that a product synthesis principle that raw materials are easily available, the price is low, the operation is simple, and the pollution is low is achieved, the final preparation yield reaches more than 44%, and the purity reaches more than 99.6%.
Description
Technical Field
The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a synthesis method and application of 7-fluoro-pyrazolo [1,2-b ] pyrazine-4-carbonitrile.
Background
The present invention relates to novel active ingredient combinations which consist of other known active ingredients, known as pyridine-3-carbonitrile, as intermediate synthetic compounds for the production of medicaments, in particular for the production of medicaments for the treatment and/or prophylaxis of cardiovascular disorders.
CN201180042458.8 describes a process for the preparation of 5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carbonitrile of the formula which is useful for the synthesis of intermediate compounds for medicaments, in particular for the manufacture of medicaments for the treatment and/or prevention of cardiovascular disorders.
The active ingredients and active ingredient combinations described in the prior art have good activity but are in some cases not ideal at low application rates.
It is therefore an object of the present invention to provide a similar compound with improved activity.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of 7-fluoro-pyrazolo [1,2-b ] pyrazine-4-carbonitrile, aims to develop a brand-new synthesis method, overcomes the defects of more reaction byproducts, low conversion rate, complex post-treatment operation, low product purity and the like in the preparation method of an intermediate synthetic compound of a medicine for treating cardiovascular disorder, and develops a novel general, economic, efficient, green and environment-friendly synthesis method, so that the synthesis principle of products with easily available raw materials, low price, simple operation and less pollution is achieved, the final preparation yield is more than 44%, and the purity is more than 99.6%.
In order to realize the purpose, the invention adopts the technical scheme that: a synthesis method of 7-fluoro-pyrazolo [1,2-b ] pyrazine-4-carbonitrile is characterized in that the reaction formula is shown as the formula (I):
comprises the following steps:
the method comprises the following steps: reacting the compound 2
Dissolving in organic solvent, and reacting at room temperature to obtain compound 1
Dissolving in methanol, and adding dropwise into the solution; after stirring at room temperature for three days, the reaction mixture was concentrated in vacuo and filtered through silicaPurifying by gel column chromatography to obtain target compound 3
And a second reaction step: compound 3 was dissolved in a mixed solvent of acetonitrile and acetic acid at room temperature, and Selectfluor was then added to the reaction solution. Refluxing the reaction mixture, concentrating under vacuum, and purifying by silica gel column chromatography to obtain compound 4
Further, in the synthesis method, the organic solvent mixed solution in the step one is prepared by dropwise adding concentrated hydrochloric acid prepared in advance into a reaction system of methanol, and naturally raising the temperature for reaction overnight.
Further, in the synthesis method, the solvent used for silica gel column chromatography purification in the first step is a mixture of petroleum ether and ethyl acetate, and the molar ratio of the petroleum ether to the ethyl acetate is 5: 2.
Further, in the synthesis method, the solvent used for silica gel column chromatography purification in the second step is a mixture of petroleum ether and ethyl acetate, and the molar ratio of the petroleum ether to the ethyl acetate is 5: 1.
Further, the synthesis method comprises the steps of dissolving the crude compound 4 obtained in the step two in a solution of n-heptane and ethyl acetate in a ratio of 3:1, adding DCM for dissolution assistance, filtering the solution by silica gel until the material is washed clean by n-heptane and EA in a ratio of 3:1, concentrating eluent until a large amount of solid is separated out, cooling and filtering to obtain solid, concentrating the obtained mother liquor until a large amount of solid is separated out, filtering to obtain solid, continuously concentrating the secondary mother liquor until the solid is separated out, and filtering to obtain the solid compound 4.
Further, according to the synthesis method, the solid compound 3 obtained by suction filtration is obtained, the yield is 88%, and the chemical purity is 96.6%.
Furthermore, the synthesis method is characterized in that the solid compound 4 obtained by suction filtration has the yield of more than 44%, the chiral purity of more than 99.80%, the isomer of less than 0.10% and the chemical purity of more than 99.6%.
Use of 7-fluoro-pyrazolo [1,2-b ] pyrazine-4-carbonitrile in cardiovascular disorders for lowering blood pressure.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention is a two-step reaction, the yield is not lower than 44%, 7-fluoro-pyrazolo [1,2-b ] pyrazine-4-carbonitrile is synthesized for the first time, and meanwhile, the production procedures are reduced, and the cost is reduced.
(2) The method has the advantages of easily obtained raw materials and reagents, mild reaction conditions, easy operation of post-treatment and purification, and large-scale production.
Detailed Description
The description is to be construed as illustrative and explanatory only and is not intended to limit the scope of the present invention, as defined in the appended claims.
Example 1
7-fluoro-pyrazolo [1,2-b]The method for synthesizing pyrazine-4-carbonitrile is characterized in that the reaction formula is shown as the formula (I):
a first reaction step: compound 2(7.3g, 50mmol) was dissolved in 150mL of methanol and 4.2mL of concentrated hydrochloric acid, and after dissolving compound 1 (2.1g, 25mmol) in 10mL of methanol at room temperature, it was added dropwise to the above solution. After stirring at room temperature for three days, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate 5: 2) to give the title compound 3 (pale yellow solid, 3.15g, 88% yield). 1H NMR (400MHz, DMSO-d 6): δ 6.90(d, J ═ 2.4Hz, 1H), 8.44(d, J ═ 2.4Hz, 1H), 8.76(d, J ═ 4.0Hz, 1H), 9.96(dd, J1 ═ 1.4Hz, J2 ═ 2.0Hz, 1H), EI-MS: 144, 117, 90, 66, 52. m.p.: 194 ℃ and 196 ℃.
And a second reaction step: compound 3(1.25g, 10mmol) was dissolved in a mixed solvent of 75L acetonitrile and 75mL acetic acid at room temperature, followed by addition of Selectfluor (3.55g, 10mmol) to the reaction solution. The reaction mixture was refluxed for 5h, then concentrated under vacuum and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate 5: 1) to give compound 4 (light yellow solid, 0.7g, yield 44%). 1H NMR (400MHz, CDCl 3): δ 8.22(d, J ═ 3.2Hz, 1H), 8.50(d, J ═ 2.0Hz, 1H), 8.88(t, J ═ 1.6Hz, 1H), 13C NMR (100MHz, CDCl 3): δ 95.67, 113.91, 135.75, 135.88, 140.48, 147.29, 147.32.19F NMR (282MHz, CDCl 3): δ -179.12(s, 1F). EI-MS: 162, 135, 108, 84, 63, 51. m.p.: 154 ℃ and 156 ℃.
And dissolving the crude product compound 4 obtained in the step two in a solution of n-heptane and ethyl acetate in a ratio of 3:1, adding DCM for assisting dissolution, filtering the solution by using silica gel, washing the material by using n-heptane and FA in a ratio of 3:1 until the material is completely washed, concentrating eluent until a large amount of solid is separated out, cooling and filtering to obtain solid, concentrating the obtained mother liquor until a large amount of solid is separated out, filtering to obtain solid, continuously concentrating the secondary mother liquor until the solid is separated out, and filtering to obtain the purified solid compound 4.
Example 2
7-fluoro-pyrazolo [1,2-b]The method for synthesizing pyrazine-4-carbonitrile is characterized in that the reaction formula is shown as the formula (I):
a first reaction step: compound 2(4.77g, 34mmol) was dissolved in 100mL of methanol and 2.77mL of concentrated hydrochloric acid, and after dissolving compound 1(1.4g, 16.7mmol) in 6.7mL of methanol at room temperature, it was added dropwise to the above solution. After stirring at room temperature for three days, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate 5: 2) to give the title compound 3 (pale yellow solid, 3.62g, 92% yield). 1H NMR (400MHz, DMSO-d 6): δ 6.90(d, J ═ 2.4Hz, 1H), 8.44(d, J ═ 2.4Hz, 1H), 8.76(d, J ═ 4.0Hz, 1H), 9.96(dd, J1 ═ 1.4Hz, J2 ═ 2.0Hz, 1H), EI-MS: 144, 117, 90, 66, 52. m.p.: 194 ℃ and 196 ℃.
And a second reaction step: compound 3(0.83g, 6.67mmol) was dissolved in a mixed solvent of 50mL acetonitrile and 10mL acetic acid at room temperature, and Selectfluor (2.37g, 6.67mmol) was added to the reaction solution. After refluxing the reaction mixture for 5h, it was concentrated under vacuum and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate 5: 1) to give compound 4 (pale yellow solid, 0.82g, yield 52%): 7-fluoro-pyrazolo [1,2-b ] pyrazine-4-carbonitrile. 1H NMR (400MHz, CDCl 3): δ 8.22(d, J ═ 3.2Hz, 1H), 8.50(d, J ═ 2.0Hz, 1H), 8.88(t, J ═ 1.6Hz, 1H), 13C NMR (100MHz, CDCl 3): δ 95.67, 113.91, 135.75, 135.88, 140.48, 147.29, 147.32.19F NMR (282MHz, CDCl 3): δ -179.12(s, 1F). EI-MS: 162, 135, 108, 84, 63, 51. m.p.: 154 ℃ and 156 ℃.
Biological experiments
The test was carried out in hypertensive rats generated by chronic infusion of ouabain, and the procedure used to test the antihypertensive activity of this compound in the above model was as follows: systolic Blood Pressure (SBP) and Heart Rate (HR) were measured by indirect tail-cap (indiect tailcuff) method. The hypotensive effect of the compound 7-fluoro-pyrazolo [1,2-b ] pyrazine-4-carbonitrile of the present invention was detected in hypertensive ouabain-sensitive rats. The compound was suspended in 0.2% (w/v) methylcellulose and administered orally at a dose of 6. mu.g/kg/day for 3 weeks per day. SBP and HR were measured weekly 5 hours after treatment. For comparison, hypertensive ouabain-sensitive rats and non-hypertensive rats, both treated with methylcellulose only at 0.2% (w/v), were used. As shown in Table 1 below, the data were averaged and the blood pressure (180mmHg) of hypertensive ouabain-sensitive rats treated with the compound of the present invention was reduced almost to the level (145mmHg) of the control rats.
TABLE 1 systolic blood pressure drop in hypertensive ouabain-sensitive rats.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
The principles and embodiments of the present invention are explained herein using specific examples, which are presented only to assist in understanding the method and its core concepts of the present invention. The foregoing is only a preferred embodiment of the present invention, and it should be noted that there are objectively infinite specific structures due to the limited character expressions, and it will be apparent to those skilled in the art that a plurality of modifications, decorations or changes may be made without departing from the principle of the present invention, and the technical features described above may be combined in a suitable manner; such modifications, variations, combinations, or adaptations of the invention using its spirit and scope, as defined by the claims, may be directed to other uses and embodiments.
Claims (8)
1. A method for synthesizing 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile is characterized in that the reaction formula is shown as the formula (I):
comprises the following steps:
the method comprises the following steps: reacting the compound 2
Dissolving in organic solvent, and reacting at room temperature to obtain compound 1
Dissolving in methanol, and adding dropwise into the solution; after stirring at room temperature for three days, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography to give the target compound 3
And a second reaction step: dissolving the compound 3 in a mixed solvent of acetonitrile and acetic acid at room temperature, and then adding Selectfluor into the reaction solution; will be provided withRefluxing the reaction mixture, concentrating under vacuum, and purifying by silica gel column chromatography to obtain compound 4
2. The method for synthesizing 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile according to claim 1, characterized in that: the synthesis method comprises the step one of adding concentrated hydrochloric acid prepared in advance dropwise into a methanol reaction system, and naturally heating for reaction overnight.
3. The method for synthesizing 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile according to claim 1, characterized in that: according to the synthesis method, in the first step, a solvent used for silica gel column chromatography purification is a mixture of petroleum ether and ethyl acetate, and the molar ratio of the petroleum ether to the ethyl acetate is 5: 2.
4. The method for synthesizing 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile according to claim 1, characterized in that: according to the synthesis method, a solvent used for silica gel column chromatography purification in the step two is a mixture of petroleum ether and ethyl acetate, and the molar ratio of the petroleum ether to the ethyl acetate is 5: 1.
5. The method for synthesizing 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile according to claim 1, characterized in that: dissolving the crude compound 4 obtained in the step two in a solution of n-heptane and ethyl acetate 3:1, adding DCM for assisting dissolution, filtering the solution by silica gel, washing the materials by using n-heptane and EA 3:1 until the materials are completely washed, concentrating eluent until a large amount of solids are separated out, cooling and filtering to obtain solids, concentrating the obtained mother liquor until a large amount of solids are separated out, filtering to obtain solids, continuously concentrating the secondary mother liquor until the solids are separated out, and filtering to obtain the solid compound 4.
6. The method for synthesizing 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile according to claim 1, characterized in that: according to the synthesis method, the solid compound 3 obtained by suction filtration has the yield of 88% and the chemical purity of 96.6%.
7. The method for synthesizing 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile according to claim 1, characterized in that: according to the synthesis method, the solid compound 4 obtained by suction filtration has the yield of 44%, the chiral purity of more than 99.80%, the isomer of less than 0.10% and the chemical purity of more than 99.6%.
Use of 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile in cardiovascular disorders for lowering blood pressure.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108026099A (en) * | 2015-06-24 | 2018-05-11 | 百时美施贵宝公司 | The aminopyridine compounds substituted through heteroaryl |
| CN111704582A (en) * | 2020-06-23 | 2020-09-25 | 杭州煌森生物科技有限公司 | Preparation method of Favipiravir and derivatives thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108026099A (en) * | 2015-06-24 | 2018-05-11 | 百时美施贵宝公司 | The aminopyridine compounds substituted through heteroaryl |
| CN111704582A (en) * | 2020-06-23 | 2020-09-25 | 杭州煌森生物科技有限公司 | Preparation method of Favipiravir and derivatives thereof |
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