CN101851207A - Antiviral compound intermediate 1-acyl-pyrazol-3-carboxylic acid and preparation method thereof - Google Patents
Antiviral compound intermediate 1-acyl-pyrazol-3-carboxylic acid and preparation method thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 19
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- -1 nitrogen-containing organic base Chemical class 0.000 claims abstract description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 20
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- 229910052763 palladium Inorganic materials 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
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- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
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- 238000001914 filtration Methods 0.000 claims description 8
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
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- 238000007445 Chromatographic isolation Methods 0.000 claims description 4
- 238000011097 chromatography purification Methods 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
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- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
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- 238000001035 drying Methods 0.000 claims description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
The invention relates to an antiviral compound intermediate 1-acyl-pyrazol-3-carboxylic acid and a preparation method thereof, in particular to a chemical synthesis method of compound. The method comprises the steps of: first, leading pyrazol-3-carboxylic acid benzyl ester to have reaction with acylation reagent and nitrogen-containing organic base, and generating 1-acylation derivative; and then, leading the 1-acylation derivative to have dehydrogenation for removing benzyl under the action of hydrogen atmosphere and palladium catalyst, and obtaining the 1-acyl-pyrazol-3-carboxylic acid. The antiviral compound intermediate 1-acyl-pyrazol-3-carboxylic acid can be used as intermediate for producing anti-hepatitis B virus medicines and antiviral pesticides, has the capability of combining with DNA and RNA in a specific way like other nucleoside compounds, has better pseudo modification performance, can block the activity of RNA polymerase, is better in the blockage of virus replication, has excellent anti-drug resistance, and is beneficial to long-term-usage.
Description
Technical field
The present invention relates to a kind of chemical synthesis process of compound, particularly have the intermediates preparation of antiviral compound, belong to the organic synthesis field.
Background technology
As the nucleoside compound of antiviral generally all with purine, guanine, pyrimidine with and analogue etc. be base, they usually have antiviral effect preferably in initial operational phase as antiviral, but increase along with administration time, can produce resistance in various degree, or occur the bounce-back of the state of an illness after the drug withdrawal.
Summary of the invention
The purpose of this invention is to provide and can be used as antiviral or a kind of low chemical sproof midbody compound---1-acyl-pyrazole-3-carboxylic acid of agricultural chemicals synthetic.
The molecular structural formula of 1-acyl-pyrazole-3-carboxylic acid of the present invention is:
In the formula, R is: the saturated or unsaturated alkyl of the straight or branched of C1-C20 or cyclic, the perhaps saturated or unsaturated-oxyl of the straight or branched of C1-C20 or cyclic.
Compound of the present invention can be used as the intermediate of anti-hepatic-B virus medicine and antiviral pesticide producing, and for example, it is agonist (Skinner, the P.J of the high affinity of niacin receptor GPR109a; BMCL; 17 (20); 5620; 2007), in addition dna fragmentation had special binding ability (Laemmli, Ulrich; US2002169296; 07/11/2001).Because the multiple choices of R group, The compounds of this invention can be used to introduce diversity in combinatorial chemistry; Have the drug molecule of acceleration metabolism because heterocyclic replaces, The compounds of this invention can be used to carry out the research of structure activity relationship in pharmaceutical chemistry.The same ability that has specific in conjunction with NDA and RNA of product of the present invention with other nucleoside compounds, and have better dis-guised, can block the activity of RNA polymerase, for the good blocking effect of having duplicated of virus, have good anti-drug resistance simultaneously, be beneficial to life-time service.
Another object of the present invention provides the preparation method of above-claimed cpd.
With pyrazoles-3-benzyl carboxylate and acylating reagent and nitrogenous organic bases reaction, generate the 1-acylated derivatives earlier, again hydrogenolysis is taken place under nitrogen atmosphere and palladium catalyst effect the 1-acylated derivatives and slough benzyl, obtain the 1-acyl-pyrazole-3-carboxylic acid.
The concrete operations step is:
1) pyrazoles-3-benzyl carboxylate is dissolved in solvent, adds nitrogenous organic bases, acylating reagent,, under the effect of N-lutidine, stir reaction down in 0 ℃ of temperature condition to solvent boiling point at catalyst n;
2) with after the above reaction solution washing, after drying, the filtration, obtain the 1-acylated derivatives, obtain the pure product of 1-acylated derivatives through recrystallization or column chromatographic isolation and purification;
3) the pure product of 1-acylated derivatives are dissolved in solvent, add palladium catalyst, nitrogen atmosphere and 22 ℃ to the temperature condition of solvent boiling point, stirring reaction;
4) with the reaction solution of step 3) after filtering, obtain the 1-acyl-pyrazole-3-carboxylic acid.
Wherein, the solvent of described step 1) is any in methylene dichloride, trichloromethane, tetrachloromethane, acetonitrile, tetrahydrofuran (THF), ether, methyltetrahydrofuran, t-butyl methyl ether, dioxane, ethyl acetate, benzene, the toluene.
Described acylating reagent is any among di-tert-butyl dicarbonic acid ester, acyl chlorides RCOCl and the chloro-formic ester RCOCl; R group among the described acyl chlorides RCOCl is the straight or branched of C1-C20 or cyclic is saturated or unsaturated alkyl; R group among the described chloro-formic ester RCOCl is straight or branched or the saturated or unsaturated-oxyl of cyclic of C1-C20.
Described nitrogenous organic bases is triethylamine, diisopropyl ethyl amine, Tributylamine, 1,8-diazacyclo [5,4,0] hendecene-7 (DBU), 1, any in 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN).
Described palladium catalyst is palladium carbon or palladium hydroxide carbon.
The solvent of described step 3) is any in ethyl acetate, tetrahydrofuran (THF), dioxane, methyl alcohol, ethanol, the Virahol.
The type (proton or aprotic solvent) of considering solvent is relevant with solubleness, and when the solvent of described dissolving pyrazoles-3-benzyl carboxylate was methylene dichloride, preferred acylating reagent was a chloro-formic ester.
In like manner, when the solvent of described dissolving pyrazoles-3-benzyl carboxylate was acetonitrile, preferred acylating reagent was a di-tert-butyl dicarbonic acid ester.
In order to save production cost, when feeding intake, the molar ratio of pyrazoles in the described step 1)-3-benzyl carboxylate and acylating reagent is 1: 1～1.5, and pyrazoles-3-benzyl carboxylate is 1: 1.2～2 with the molar ratio that contains organic bases.
To account for the mass percent of total reaction liquid be 1～15% to palladium catalyst in the described step 3).
Can regard a seed amino acid as from the parent pyrazoles-3-carboxylic acid of 1-acyl-pyrazole-3-carboxylic acid, but because its aromaticity, alkalescence and the nucleophilicity of 1-position N are weaker than common amido.Because the above-mentioned singularity of pyrazoles-3-carboxylic acid, and the existence of the carboxyl that dissociates in the molecule, pyrazoles-direct acidylate of 3-carboxylic acid can't obtain the 1-acyl-pyrazole-3-carboxylic acid.For example, protect amino acid whose method according to known technology, pyrazoles-3-carboxylic acid is handled with di-tert-butyl dicarbonic acid ester in the presence of alkali, can only reclaim raw material, detects the generation less than 1-tertbutyloxycarbonyl-pyrazoles-3-carboxylic acid.
By research; find the quadrature deprotection method of a kind of 1-acidylate-pyrazoles-3-carboxylicesters; be that carboxyl can highly selective be sloughed benzyl by the 1-acylated derivatives of pyrazoles-3-carboxylicesters acidylate generation of benzyl protection under the hydrogenolysis condition; obtain the free carboxy acid---1-acyl-pyrazole-3-carboxylic acid, the i.e. technical scheme of above preparation.The R group range that this preparation method is suitable for comprises: the saturated or unsaturated alkyl of C1-C20 straight chain, side chain or cyclic; And the saturated or unsaturated-oxyl of C1-C20 straight chain, side chain or cyclic, but do not comprise the group to the hydrogenolysis sensitivity such as benzyloxy.
The superiority of preparation process of the present invention and the superiority of product are embodied in:
From compound of the present invention, synthetic antiviral effective lead compound, synthesis step is short, and the operational condition gentleness is convenient, can set out by compound of the present invention simultaneously and synthesize such different active compounds, can be used for further synthetic.In addition, the preparation of this compound relates to the problem of quadrature hydrolysis conflict, and the present invention obtains the free carboxy acid by can highly selective sloughing benzyl under the hydrogenolysis condition---the 1-acyl-pyrazole-3-carboxylic acid.
Description of drawings
Fig. 1 is a two-step reaction step of the present invention.
Embodiment
One, the two-step reaction preparation method of 1-acyl-pyrazole-3-carboxylic acid of the present invention sees shown in Figure 1.
The step 1 concrete grammar:
1, pyrazoles-3-benzyl carboxylate (II) is dissolved in solvent, adds nitrogenous organic bases, acylating reagent,, under the effect of N-lutidine, stir reaction down in 0 ℃ of temperature condition to solvent boiling point at catalyst n.When feeding intake, the mol ratio of pyrazoles-3-benzyl carboxylate and acylating reagent is 1: 1～1.5, and pyrazoles-3-benzyl carboxylate is 1: 1.2～2 with the mol ratio that contains organic bases.
2, with after the above reaction solution washing, after drying, the filtration, obtain 1-acylated derivatives (III) crude product, obtain the pure product of 1-acylated derivatives (III) through recrystallization or column chromatographic isolation and purification.
The step 2 concrete grammar:
1, the pure product of 1-acylated derivatives (III) are dissolved in solvent, add palladium catalyst, nitrogen atmosphere and 22 ℃ to the temperature condition of solvent boiling point, stirring reaction.
2, after filtering, obtain the thick product of 1-acyl-pyrazole-3-carboxylic acid (I), obtain the pure product of product 1-acyl-pyrazole-3-carboxylic acid (I) through recrystallization or column chromatography for separation with the reaction solution that makes.
Embodiment:
1, preparation 1-tertbutyloxycarbonyl-pyrazoles-3-benzyl carboxylate (III)
0.142 gram pyrazoles-3-benzyl carboxylate is dissolved in 3 milliliters of acetonitriles; add the nitrogenous organic bases triethylamine of 0.07 gram, 0.229 gram acylating reagent di-tert-butyl dicarbonic acid ester and 0.009 gram catalyst n under the room temperature; the N-lutidine; stirring reaction 40 minutes; thin-layer chromatography shows that raw material disappears, and reaction finishes.
After above reaction solution is used diluted acid, diluted alkaline, water and salt water washing successively,, obtain the thick product of spissated 1-tertbutyloxycarbonyl-pyrazoles-3-benzyl carboxylate (III) again through super-dry, filtration.
Obtain to such an extent that product 1-tertbutyloxycarbonyl-pyrazoles-3-benzyl carboxylate pure product 0.204 restrain 96% productive rate, white crystal through recrystallization or column chromatographic isolation and purification the thick product of 1-tertbutyloxycarbonyl-pyrazoles-3-benzyl carboxylate (III).
Above product identifies that by nucleus magnetic hydrogen spectrum every index is:
1H?NMR(400MHz，CDCl
3)8.11(d，1H，J＝3.6Hz)，7.50-7.30(m，5H)，6.88(d，1H，J＝4.0Hz)，5.39(s，2H)，1.66(s，9H)。
Confirmed further to pass through pyrazoles-3-benzyl carboxylate (II) and acylating reagent and nitrogenous organic bases reaction have been generated the 1-acylated derivatives---1-tertbutyloxycarbonyl-pyrazoles-3-benzyl carboxylate.
With same method, adopt different nitrogenous organic bases, solvent and acylating reagent can prepare different 1-acylated derivatives (III), molecular structural formula is:
In the formula, R is: the saturated or unsaturated alkyl of the straight or branched of C1-C20 or cyclic, the perhaps saturated or unsaturated-oxyl of the straight or branched of C1-C20 or cyclic.
Nitrogenous organic bases can be selected for use and be triethylamine, diisopropyl ethyl amine, Tributylamine, 1,8-diazacyclo [5,4,0] hendecene-7 (DBU), 1, any of 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN).
The solvent of pyrazoles-3-benzyl carboxylate can use in methylene dichloride, trichloromethane, tetrachloromethane, tetrahydrofuran (THF), ether, methyltetrahydrofuran, t-butyl methyl ether, dioxane, ethyl acetate, benzene, the toluene any to substitute.
Acylating reagent can be among di-tert-butyl dicarbonic acid ester, acyl chlorides RCOCl and the chloro-formic ester RCOCl any.R group among the acyl chlorides RCOCl can for the straight or branched of C1-C20 or cyclic be saturated or unsaturated alkyl; R group among the chloro-formic ester RCOCl can be straight or branched or the saturated or unsaturated-oxyl of cyclic of C1-C20.
Another preferred version is: when solvent was methylene dichloride, acylating reagent adopted chloro-formic ester.
2, preparation 1-tertbutyloxycarbonyl-pyrazoles-3-carboxylic acid
0.199 gram 1-tertbutyloxycarbonyl-pyrazoles-3-benzyl carboxylate of above acquisition is dissolved in 6 ml methanol, 22 ℃ to 26 ℃ temperature condition adds 0.020 gram 10% palladium-carbon catalyst palladium carbon or palladium hydroxide carbon down, stirring reaction is 45 minutes under the normal pressure nitrogen atmosphere, thin-layer chromatography shows that raw material disappears, and reaction finishes.Wherein, when feeding intake, the mass percent that palladium catalyst accounts for total reaction liquid is 1～15%.
With the diatomite filtration reaction solution, make filtrate concentrating, again through recrystallization or column chromatography for separation, get product 1-tertbutyloxycarbonyl-pyrazoles-3-carboxylic acid 0.140 gram, 100% productive rate, white crystal.
With same method, any in employing ethyl acetate, tetrahydrofuran (THF), dioxane, methyl alcohol, ethanol, the Virahol can prepare different 1-acyl-pyrazole-3-carboxylic acids (I) as solvent.
Two, use:
Compound 1-tertbutyloxycarbonyl-pyrazoles-3-carboxylic acid can be used as the intermediate of medicine and pesticide producing, and for example, it is agonist (Skinner, the P.J of the high affinity of niacin receptor GPR109a; BMCL; 17 (20); 5620; 2007), in addition dna fragmentation had special binding ability (Laemmli, Ulrich; US2002169296; 07/11/2001), its derivative has the effect of anti-hepatitis C virus NS 5 B RNA polymerase, and its ID50 can reach 0.3um, has good antiviral activity (Deng, Yongqi; Shipps, Gerald W.; Wang, Tong; Popovici-Muller, Janeta; Rosner, Kristin E.; Siddiqui, M.Arshad; Duca, Jose; Cooper, Alan B.; Cable, Michael.Discovery of 4H-pyrazolo[1,5-a] pyrimidin-7-ones as potent inhibitors of hepatitis C virus polymerase.Bioorganic﹠amp; Medicinal Chemistry Letters (2009), 19 (18), 5363-5367.), (Paruch, Kamil; Guzi, Timothy J.; Dwyer, Michael P.; Shipps, Gerald W.Preparation of a novel class of pyrazolopyrimidines as inhibitors of protein and checkpoint kinases useful in treatment and prophylaxis of HCV infection and other diseases such as cancer. U.S.Pat.Appl.Publ. (2006), 240pp., Cont.-in-part of U.S.Ser.No.452,400), (Shipps, Gerald W., Jr.; Rosner, Kristin E.; Popovici-Muller, Janeta; Deng, Yongqi; Wang, Tong; Curran, Patrick J. Preparation of pyrazolo[1,5-a] pyrimidine compounds as antiviral agents against hepatitis C virus (HCV) infection.PCT Int.Appl. (2003), 249pp.CODEN:PIXXD2WO 2003101993A120031211).Using this compound fragment to be used in the active testing of hepatitis B virus resisting, also finding has good biological activity, and its resistance is low, is beneficial to life-time service.
Because the multiple choices of R group, Compound I can be used to introduce diversity in combinatorial chemistry; Have the drug molecule of acceleration metabolism because heterocyclic replaces, I can be used to carry out the research of structure activity relationship in pharmaceutical chemistry.
Claims (7)
1. antiviral compound intermediate 1-acyl-pyrazole-3-carboxylic acid, molecular structural formula is:
In the formula, R is: the saturated or unsaturated alkyl of the straight or branched of C1-C20 or cyclic, the perhaps saturated or unsaturated-oxyl of the straight or branched of C1-C20 or cyclic.
2. the preparation method of antiviral compound intermediate 1-acyl-pyrazole-3-carboxylic acid according to claim 1; it is characterized in that earlier with pyrazoles-3-benzyl carboxylate and acylating reagent and nitrogenous organic bases reaction; generate the 1-acylated derivatives; again hydrogenolysis is taken place in the 1-acylated derivatives under nitrogen atmosphere and palladium catalyst effect and slough benzyl, obtain the 1-acyl-pyrazole-3-carboxylic acid.
3. preparation method according to claim 2 is characterized in that may further comprise the steps:
1) pyrazoles-3-benzyl carboxylate is dissolved in solvent, adds nitrogenous organic bases, acylating reagent,, under the effect of N-lutidine, stir reaction down in 0 ℃ of temperature condition to solvent boiling point at catalyst n;
2) with after the above reaction solution washing, after drying, the filtration, obtain the 1-acylated derivatives, obtain the pure product of 1-acylated derivatives through recrystallization or column chromatographic isolation and purification;
3) the pure product of 1-acylated derivatives are dissolved in solvent, add palladium catalyst, nitrogen atmosphere and 22 ℃ to the temperature condition of solvent boiling point, stirring reaction;
4) with the reaction solution of step 3) after filtering, obtain the 1-acyl-pyrazole-3-carboxylic acid;
The solvent of described step 1) is any in methylene dichloride, trichloromethane, tetrachloromethane, acetonitrile, tetrahydrofuran (THF), ether, methyltetrahydrofuran, t-butyl methyl ether, dioxane, ethyl acetate, benzene, the toluene;
Described acylating reagent is any among di-tert-butyl dicarbonic acid ester, acyl chlorides RCOC1 and the chloro-formic ester RCOC1; R group among the described acyl chlorides RCOC1 is the straight or branched of C1-C20 or cyclic is saturated or unsaturated alkyl; R group among the described chloro-formic ester RCOC1 is straight or branched or the saturated or unsaturated-oxyl of cyclic of C1-C20;
Described nitrogenous organic bases is triethylamine, diisopropyl ethyl amine, Tributylamine, 1,8-diazacyclo [5,4,0] hendecene-7,1, in 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene any;
Described palladium catalyst is palladium carbon or palladium hydroxide carbon;
The solvent of described step 3) is any in ethyl acetate, tetrahydrofuran (THF), dioxane, methyl alcohol, ethanol, the Virahol.
4. preparation method according to claim 3 is characterized in that the solvent of described dissolving pyrazoles-3-benzyl carboxylate is a methylene dichloride, and described acylating reagent is a chloro-formic ester.
5. preparation method according to claim 3 is characterized in that the solvent of described dissolving pyrazoles-3-benzyl carboxylate is an acetonitrile, and described acylating reagent is a di-tert-butyl dicarbonic acid ester.
6. according to claim 2 or 3 or 4 or 5 described preparation methods, the molar ratio that it is characterized in that pyrazoles in the described step 1)-3-benzyl carboxylate and acylating reagent is 1: 1～1.5; Pyrazoles-3-benzyl carboxylate is 1: 1.2～2 with the molar ratio that contains organic bases.
7. according to claim 2 or 3 or 4 or 5 described preparation methods, it is characterized in that the mass percent that palladium catalyst in the described step 3) accounts for total reaction liquid is 1～15%.
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| US9951025B2 (en) | 2013-03-15 | 2018-04-24 | Verseon Corporation | Halogenopyrazoles as inhibitors of thrombin |
| US9963440B2 (en) | 2010-03-30 | 2018-05-08 | Verseon Corporation | Multisubstituted aromatic compounds as inhibitors of thrombin |
| US10058541B2 (en) | 2013-03-15 | 2018-08-28 | Verseon Corporation | Multisubstituted aromatic compounds as serine protease inhibitors |
| US10189810B2 (en) | 2014-09-17 | 2019-01-29 | Verseon Corporation | Pyrazolyl-substituted pyridone compounds as serine protease inhibitors |
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| CN118688370A (en) * | 2024-08-27 | 2024-09-24 | 天津辰欣药物研究有限公司 | A quality control method for new antiviral drug intermediates |
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| CN1960976A (en) * | 2004-03-26 | 2007-05-09 | 史密丝克莱恩比彻姆公司 | 4-carbox pyrazole derivates useful as anti-viral agents |
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| US9963440B2 (en) | 2010-03-30 | 2018-05-08 | Verseon Corporation | Multisubstituted aromatic compounds as inhibitors of thrombin |
| US10653674B2 (en) | 2010-03-30 | 2020-05-19 | Verseon Corporation | Multisubstituted aromatic compounds as inhibitors of thrombin |
| US9951025B2 (en) | 2013-03-15 | 2018-04-24 | Verseon Corporation | Halogenopyrazoles as inhibitors of thrombin |
| US10058541B2 (en) | 2013-03-15 | 2018-08-28 | Verseon Corporation | Multisubstituted aromatic compounds as serine protease inhibitors |
| US10251872B2 (en) | 2013-03-15 | 2019-04-09 | Verseon Corporation | Multisubstituted aromatic compounds as serine protease inhibitors |
| US10189810B2 (en) | 2014-09-17 | 2019-01-29 | Verseon Corporation | Pyrazolyl-substituted pyridone compounds as serine protease inhibitors |
| US10532995B2 (en) | 2015-02-27 | 2020-01-14 | Verseon Corporation | Substituted pyrazole compounds as serine protease inhibitors |
| CN118688370A (en) * | 2024-08-27 | 2024-09-24 | 天津辰欣药物研究有限公司 | A quality control method for new antiviral drug intermediates |
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