CN101851207B - 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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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 along with the increase of 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 according to the 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 according to the invention can be used as the midbody 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 variety 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 of product of the present invention with specific combination NDA and RNA 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, filtration, obtain the 1-acylated derivatives, obtain the pure article of 1-acylated derivatives through recrystallization or column chromatographic isolation and purification;
3) the pure article 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 said step 1) is any in methylene dichloride, trichloromethane, tetrachloromethane, acetonitrile, THF, ether, methyltetrahydrofuran, t-butyl methyl ether, dioxane, ETHYLE ACETATE, benzene, the toluene.
Said acylating reagent is any among di-tert-butyl dicarbonic acid ester, acyl chlorides RCOCl and the chloro-formic ester RCOCl; R group among the said acyl chlorides RCOCl is the straight or branched of C1-C20 or cyclic is saturated or unsaturated alkyl; R group among the said chloro-formic ester RCOCl is straight or branched or the saturated or unsaturated-oxyl of cyclic of C1-C20.
Said 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).
Said palladium catalyst is palladium carbon or palladium hydroxide carbon.
The solvent of said step 3) is any in ETHYLE ACETATE, 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 said dissolving pyrazoles-3-benzyl carboxylate was methylene dichloride, preferred acylating reagent was a chloro-formic ester.
In like manner, when the solvent of said 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 said 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 said 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.
Through 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 that benzyloxy etc. is responsive to hydrogenolysis.
The present invention prepares the meliority of process and the meliority of product is 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 through 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 through can under the hydrogenolysis condition, highly selective sloughing benzyl---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, filtration, obtain 1-acylated derivatives (III) bullion, obtain the pure article of 1-acylated derivatives (III) through recrystallization or column chromatographic isolation and purification.
The step 2 concrete grammar:
1, the pure article 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 article 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 show that raw material disappears, and reaction finishes.
After above reaction solution is used diluted acid, diluted alkaline, water and brine wash 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 article 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 through nucleus magnetic hydrogen spectrum each item 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 have generated the 1-acylated derivatives through pyrazoles-3-benzyl carboxylate (II) and acylating reagent and nitrogenous organic bases are reacted---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, THF, ether, methyltetrahydrofuran, t-butyl methyl ether, dioxane, ETHYLE 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 filtrating 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 ETHYLE ACETATE, 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 midbody 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 verivate 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&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 variety 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 a tertiary butyl oxygen base.
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-carboxylic acid tert-butyl ester and acylating reagent and nitrogenous organic bases reaction; Generate the 1-acylated derivatives; Again the 1-acylated derivatives is sloughed the tertiary butyl under the effect of acid, 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-carboxylic acid tert-butyl ester is dissolved in solvent, adds nitrogenous organic bases, acylating reagent and catalyst n, the N-lutidine, 0 ℃ to the temperature condition of solvent boiling point, the 1-N-acylation reaction takes place generate the 1-acylated derivatives;
2) 0 ℃ to the condition of solvent boiling point temperature, deprotection reaction is taken place in 1-acylated derivatives and acid, generate the 1-acyl-pyrazole-3-carboxylic acid;
3) with step 2) pH of reaction solution is adjusted to 2～4, gets organic phase, successively through water and brine wash, again through dry, filter, obtain the 1-acyl-pyrazole-3-carboxylic acid;
Said acylating reagent is acyl chlorides RCOCl or chloro-formic ester RCOCl; R group among the said acyl chlorides RCOCl is a tertiary butyl oxygen base; R group among the said chloro-formic ester RCOCl is a tertiary butyl oxygen base;
Said nitrogenous organic bases is triethylamine, diisopropyl ethyl amine, Tributylamine, 1,8-diazacyclo [5,4,0] hendecene-7 or 1, in 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene any;
The solvent of said dissolving pyrazoles-3-carboxylic acid tert-butyl ester is any in methylene dichloride, trichloromethane, tetrachloromethane, acetonitrile, THF, ether, methyltetrahydrofuran, t-butyl methyl ether, dioxane, ETHYLE ACETATE, benzene, the toluene;
Said acid is that 1～12M hydrochloric acid, 0.5～6M sulfuric acid or percent by volume are any in 50～100% the trifluoroacetic acid aqueous solution.
4. preparation method according to claim 3, the solvent that it is characterized in that dissolving pyrazoles-3-carboxylic acid tert-butyl ester is a methylene dichloride.
5. preparation method according to claim 3 is characterized in that through super-dry, filtration, obtaining the pure article of 1-acylated derivatives with after the washing of 1-acylated derivatives, again deprotection reaction is taken place for pure article of 1-acylated derivatives and acid.
6. preparation method according to claim 3, the molar ratio that it is characterized in that pyrazoles in said step 1)-3-carboxylic acid tert-butyl ester and acylating reagent is 1: 1～1.5; The molar ratio of pyrazoles-3-carboxylic acid tert-butyl ester and nitrogenous organic bases is 1: 1.2～2.
7. preparation method according to claim 3 is characterized in that in said step 2) in the 1-acylated derivatives with acid molar ratio be 1: 1.5～10.
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