CN103936818A - Midbody I for anti-hepatitis C medicine Boceprevir as well as preparing method and application thereof - Google Patents
Midbody I for anti-hepatitis C medicine Boceprevir as well as preparing method and application thereof Download PDFInfo
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- CN103936818A CN103936818A CN201310019983.9A CN201310019983A CN103936818A CN 103936818 A CN103936818 A CN 103936818A CN 201310019983 A CN201310019983 A CN 201310019983A CN 103936818 A CN103936818 A CN 103936818A
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- 0 C[C@]1(C*)[C@@]2C1[C@@](C(N1)=C(CCCC3)CC3CC1=C)NC2 Chemical compound C[C@]1(C*)[C@@]2C1[C@@](C(N1)=C(CCCC3)CC3CC1=C)NC2 0.000 description 5
- PWUSDWABIMTJLA-VIFPVBQESA-N CC(C)(C)[C@H](CCC(O)=O)NC(NC(C)(C)C)=O Chemical compound CC(C)(C)[C@H](CCC(O)=O)NC(NC(C)(C)C)=O PWUSDWABIMTJLA-VIFPVBQESA-N 0.000 description 1
- HLOFVEFPLZCEGV-OUPQRBNQSA-N CC(COCC(N)=O)/C=C\C=C/C Chemical compound CC(COCC(N)=O)/C=C\C=C/C HLOFVEFPLZCEGV-OUPQRBNQSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the technical field of a preparing method of an anti-hepatitis C medicine Boceprevir. A compound 1 provided by the invention has a structural formula shown as the attached drawing. The operation of the compound preparation is simple and convenient, and the yield is higher. The compound can be used for synthesizing the anti-hepatitis C medicine Boceprevir, and a new thought and method can be provided for synthesis of the anti-hepatitis C medicine Boceprevir. In addition, ultraviolet chromophoric groups are contained in molecules of the compound, the detection is more convenient than that of an ordinary synthesis method, and side reaction caused by oxhydryl nucleophilicity in a condensation step is avoided through the introduction of benzyls onto oxhydryls. Compared with the synthesis method in the prior art, the preparing method provided by the invention has certain advantages.
Description
Technical field
The present invention relates to the preparation method's technical field for anti-the third liver medicine Boceprevir, be specifically related to a class (1R, 2S, 5S)-N-[3-amino-1-(cyclobutylmethyl)-2-substituted hydroxy-3-oxopropyl]-3-((2S)-2-[[[(1,1-dimethyl ethyl)-amino] carbonyl] amino]-3,3-dimethyl-1-oxo butyl]-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-Carbox amide and preparation method thereof.
Background technology
In global range, the infection rate of hepatitis C virus (hepatitis C virus, HCV) is about 3%, and the total number of persons of infection is about 200,000,000.Because the high infection rate of HCV also can cause potential complication as serious in liver cirrhosis, liver cancer etc., thereby HCV is a serious threat of human life's health.According to Simmonds naming system, it is I-VI that HCV can be divided into 6 oligogene types, various several hypotypes (as Ia, Ib, IIa, IIb, IIIa, IIIb etc.) that can be divided into again.HCV the infected of China approximately 4,000 ten thousand, and wherein 69% is I type infection (taking Ib type as main).The method for the treatment of chronic hepatitis C is mainly polyoxyethylene glycol Interferon, rabbit (PEG-IFN α) and ribavirin (RBV) drug combination at present, this kind of therapy patient of approximately 50% in HCV I type patient can not produce lasting virological response, and there is untoward reaction, thereby need the effective medicine of exploitation badly.Due to this needs, anti-HCV new drug development is very active, has at present more than 50 planting anti-HCV drug candidate or grantedly carrying out clinical trial.In these medicines, Victrelis (boceprevir) is treated adult's chronic hepatitis C on May 13rd, 2011 by U.S. FDA approval and polyoxyethylene glycol Interferon, rabbit and ribavirin coupling.
Boceprevir(structure is as above) be the chronic hepatitis C curative by the exploitation of Schering Plough company of the U.S., it is a kind of orally active HCV NS3 proteinase inhibitor, that the high NS3 of a kind of tool is suppressed to amino-acid residue on active 11 peptides carries out systemic brachymemma and modification and the micromolecular inhibitor found, can catch the Serine of NS3 reactive site, on its keto-amide carbonyl carbon therewith Serine in conjunction with forming covalency adducts, thereby cause NS3 inactivation.A research that is published in " New England Journal of Medicine " shows, for untreated chronic hcv genotype I type infected patient of the past, on polyoxyethylene glycol Interferon, rabbit-ribavirin standard care basis, add with Boceprevir, compared with simple standard care, can significantly increase the virological response rate that continues.
The synthesis strategy of Boceprevir mainly contains two kinds, patent WO02/08244A2 and J.Med.Chem.2026, and 49,6074-6086 has reported that three fragments are once hydrolyzed last oxidation pendant hydroxyl group and obtain the synthesis strategy of Boceprevir through twice condensation.Specific as follows:
Patent WO2008/079216 has reported the initial oxidation pendant hydroxyl group synthesis strategy of the Boceprevir of condensation again, specific as follows:
The patent that other are relevant or document are all the optimize and improves (specifically can be referring to US2004/018914, US2006/043950, US2007/025804 etc.) that carry out on the basis of above two kinds of synthesis strategies.But all there is a same problem in existing synthetic method: owing to all not existing obvious chromophoric group event reaction detection and intermediate control comparatively to bother in the structure of each intermediate.In a tactful condensation step, there is exposed hydroxyl in addition, will inevitably cause side reaction occur, in the process of actually operating also just so.The present inventor replaces by introducing in a certain intermediate or unsubstituted benzyl has successfully solved the problem of detection difficult and condensation step side reaction, consider the importance of hepatitis C virus (" HCV ") proteinase inhibitor, the intermediate of novel this inhibitor of preparation is interesting all the time simultaneously.
Summary of the invention
Object of the present invention is exactly to solve the problem existing in above-mentioned existing synthetic Boceprevir method, and a kind of new midbody compound is provided, preparation Boceprevir or this compounds that can simple and effective.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
Following general formula compound 1:
R is the optional position substituting group of phenyl ring, and R is hydrogen, alkyl or alkoxyl group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
Above-mentioned new general formula compound 1, its chemical name is (1R, 2S, 5S)-N-[3-amino-1-(cyclobutylmethyl)-2-substituted hydroxy-3-oxopropyl]-3-((2S)-2-[[[(1,1-dimethyl ethyl)-amino] carbonyl] amino]-3,3-dimethyl-1-oxo butyl]-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-Carbox amide.Can be for the preparation of hepatitis C (HCV) the proteinase inhibitor Boceprevir with following structure
The compound of formula 1 can make Boceprevir through reaction path below
Formula 1 compound can conveniently be prepared into formula 2 compounds through hydro-reduction, can be referring to patent US2006/043950, WO02/08244A2 by the method for formula (2) compound preparation formula (3) compound, J.Med.Chem.2006,49,6074-6086, US8188137B2.
The preparation method of above-mentioned general formula 1 compound, comprises the steps:
Method one:
A), in organic solvent, under alkali and condensing agent existence condition, make compound F 17-hydroxy-corticosterone and compound G-1 condensation obtain formula 1 compound
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group, and A is acid group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
According to the preferred embodiment of the present invention, alkali can be selected from triethylamine, pyridine, N-methylmorpholine, DIPEA, DMAP described in step a).Preferably N-methylmorpholine and DIPEA.With respect to compound F 17-hydroxy-corticosterone, alkali conventionally can 2 molar equivalent to 8 molar equivalents, preferably 2 molar equivalent to 5 molar equivalents, and more preferably 2 molar equivalent to 4 molar equivalents use.
According to the preferred embodiment of the present invention, described condensing agent can be selected from 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl (PyBOP), N, N'-carbonyl dimidazoles (CDI), 2-(7-azo benzotriazole)-N, N, N', N '-tetramethyl-urea phosphofluoric acid ester (HATU), 2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid ester (HATU), >=99.5% (HPLC) (HBTU), N, N'-dicyclohexylcarbodiimide (DCC) etc., preferably EDCI, BOP, PyBOP, HATU, more preferably EDCI and HATU.With respect to compound F 17-hydroxy-corticosterone, condensing agent conventionally can approximately 1 molar equivalent to approximately 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalent, more preferably from about 1 molar equivalent to 2 molar equivalent uses.
According to the preferred embodiment of the present invention, above-mentioned reaction can also add additive, described additive can be 1-hydroxyl-7-azo benzotriazole (HOAT), I-hydroxybenzotriazole (HOBT), >=99% (HPLC) etc.With respect to compound F 17-hydroxy-corticosterone, additive conventionally can approximately 0 molar equivalent to approximately 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalent, more preferably from about 1 molar equivalent to 2 molar equivalent uses.
With respect to compound F 17-hydroxy-corticosterone, compound G-1 consumption approximately 1 molar equivalent to 2 molar equivalent, preferably 1 molar equivalent to 1.5 molar equivalent, more preferably from about 1 molar equivalent to 1.2 molar equivalent uses.
Available solvent comprises ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans, dioxane etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; Esters solvent, such as ethyl acetate etc., and other solvents, such as DMF, DMSO, acetonitrile etc. or its suitable mixture.Preferred solvent is other solvents, more preferably DMF and acetonitrile.
Reaction can be at-25 DEG C～50 DEG C, preferably-10 DEG C～25 DEG C, carry out approximately 24 hours or until react completely at the temperature of more preferably 0 DEG C～25 DEG C.
Method two:
A), in organic solvent, under alkali and condensing agent existence condition, make compound F 17-hydroxy-corticosterone and compound G-2 condensation obtain compound F 17-hydroxy-corticosterone-1
B) in organic solvent, under acidic conditions, make compound F 17-hydroxy-corticosterone-1 deprotection base, obtain compound F 17-hydroxy-corticosterone-2
C), in organic solvent, under alkali and condensing agent existence condition, make compound F 17-hydroxy-corticosterone-2 and compound G-3 condensation obtain formula 1 compound
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group, and A is acid group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
Step a) can with alkali comprise triethylamine, DIPEA, pyridine and N-methylmorpholine, preferably N-methylmorpholine and DIPEA.With respect to compound F 17-hydroxy-corticosterone, the consumption of alkali can be 2 molar equivalent to 8 molar equivalents, preferably 2 molar equivalent to 5 molar equivalents, and more preferably 2 molar equivalent to 4 molar equivalents use.Available condensing agent comprises EDCI, BOP, PyBOP, CDI, HATU, HBTU and DCC, preferably EDCI, BOP, PyBOP and HATU, more preferably EDCI and HATU.With respect to compound F 17-hydroxy-corticosterone, condensing agent consumption can be 1 molar equivalent to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 2 molar equivalent uses.Step a) also can add additive, and additive comprises HOBT and HOAT etc.With respect to compound F 17-hydroxy-corticosterone, additive amount can be 0 to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably from about 1 molar equivalent to 2 molar equivalent uses.With respect to compound F 17-hydroxy-corticosterone, compound G-2 conventionally can approximately 1 molar equivalent to approximately 2 molar equivalents, preferably 1 molar equivalent to 1.5 molar equivalent, more preferably 1 molar equivalent to 1.2 molar equivalent uses.Available solvent comprises ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans, dioxane etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; Esters solvent, such as ethyl acetate etc., and other solvents, such as DMF, DMSO, acetonitrile etc. or its suitable mixture.Preferred solvent is other solvents, more preferably DMF and acetonitrile.Reaction can, at-25 DEG C～50 DEG C, preferably-10 DEG C～25 DEG C, be carried out at the temperature of more preferably 0 DEG C～25 DEG C approximately 24 hours or until react completely.
The acid that step b) is used comprises hydrochloric acid, sulfuric acid, trifluoroacetic acid, preferably hydrochloric acid.With respect to compound F 17-hydroxy-corticosterone-1, sour that consumption can be 1 molar equivalent to 20 molar equivalent, preferably 1 molar equivalent to 10 molar equivalent, more preferably 1 molar equivalent to 5 molar equivalent uses.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP, dioxane etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc. or its suitable mixture.Preferred solvent is ether solvent, more preferably dioxane.Reaction can, at-25 DEG C～50 DEG C, preferably-10 DEG C～25 DEG C, be carried out at the temperature of more preferably 0 DEG C～25 DEG C approximately 1 hour or until react completely.
Step c) can with alkali comprise triethylamine, DIPEA, pyridine, N-methylmorpholine, preferably N-methylmorpholine and DIPEA.With respect to compound F 17-hydroxy-corticosterone-2, the consumption of alkali can be at 2 molar equivalent to 8 molar equivalents, preferably 2 molar equivalent to 5 molar equivalents, and more preferably 2 molar equivalent to 4 molar equivalents use.Available condensing agent comprises EDCI, BOP, PyBOP, CDI, HATU, HBTU, DCC, preferably EDCI, BOP, PyBOP, HATU, more preferably EDCI and HATU.With respect to compound F 17-hydroxy-corticosterone-2, the consumption of condensing agent can be at 1 molar equivalent to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 2 molar equivalent uses.For promoting reaction to carry out, can also add additive, available additive comprises HOBT, HOAT.With respect to compound F 17-hydroxy-corticosterone-1, the consumption of additive is at 0 to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 2 molar equivalent uses.With respect to compound F 17-hydroxy-corticosterone-2, the consumption of compound G-3 can be at 1 molar equivalent to 2 molar equivalent, preferably 1 molar equivalent to 1.5 molar equivalent, and more preferably 1 molar equivalent to 1.2 molar equivalent uses.Available solvent comprises ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans, dioxane etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; Esters solvent, such as ethyl acetate etc., and other solvents, such as DMF, DMSO, acetonitrile etc. or its suitable mixture.Preferred solvent is other solvents, more preferably DMF and acetonitrile.
Compound F 17-hydroxy-corticosterone, can be by compd E in organic solvent, and under acidic conditions, deprotection base obtains:
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
Available acid comprises hydrochloric acid, sulfuric acid, trifluoroacetic acid, preferably hydrochloric acid.With respect to compd E, sour that consumption can be at 1 molar equivalent to 20 molar equivalent, preferably 1 molar equivalent to 10 molar equivalent, more preferably 1 molar equivalent to 5 molar equivalent uses.Available solvent comprises ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans, dioxane etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc. or its suitable mixture.Preferred solvent is ether solvent, more preferably dioxane.Reaction can be at-25 DEG C～50 DEG C, preferably-10 DEG C～25 DEG C, more preferably at the temperature of 0～25 DEG C, carry out approximately 1 hour or until react completely.
Compd E, the Compound D of available following formula, in organic solvent, under alkali existence condition, directly with strong aqua is reacted is obtained after reacting with Vinyl chloroformate
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
The available alkali of above-mentioned reaction comprises triethylamine, DIPEA, pyridine, N-methylmorpholine, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably triethylamine, DIPEA and N-methylmorpholine, more preferably triethylamine.With respect to Compound D, the consumption of alkali is recommended as 1 molar equivalent to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 2.5 molar equivalent uses.With respect to Compound D, the consumption of Vinyl chloroformate can be extremely approximately 5 molar equivalents of 1 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 2.5 molar equivalent uses.With respect to Compound D, strong aqua consumption can be 1 molar equivalent to 8 molar equivalent, preferably 1 molar equivalent to 5 molar equivalent, and more preferably 1 molar equivalent to 3 molar equivalent uses.Available solvent comprises ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc. or its suitable mixture.Preferred solvent is ether solvent, more preferably tetrahydrofuran (THF).Reaction can be at-25 DEG C～50 DEG C, preferably-10 DEG C～25 DEG C, carry out approximately 2 hours or until react completely at the temperature of more preferably 0 DEG C～25 DEG C.
Compound D, can be in organic solvent, under alkali effect, Compound C hydrolysis is obtained:
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
Said hydrolyzed reaction, available alkali comprises potassium hydroxide, sodium hydroxide, lithium hydroxide, preferably sodium hydroxide and lithium hydroxide, more preferably lithium hydroxide.With respect to Compound C, the consumption of alkali can be 1 molar equivalent to 10 molar equivalent, preferably 1 molar equivalent to 5 molar equivalent, and more preferably 1 molar equivalent to 4 molar equivalent uses.Available solvent comprises ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc.; Protonic solvent, such as methyl alcohol, ethanol, water etc. or its suitable mixture.Preferred solvent is mixed solvent, more preferably tetrahydrofuran (THF)/methanol mixed solvent.This reaction can be at 0 DEG C～60 DEG C, preferably 0～40 DEG C, carry out approximately 4 hours or until react completely at the temperature of more preferably 10 DEG C～25 DEG C.
Compound C can, by the compd B of following formula, in organic solvent, under catalyst action, through hydrazine hydrate effect obtain after reacting with tert-Butyl dicarbonate again:
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
Available catalyzer can be DMAP, triethylamine, butyllithium, sodium hydroxide etc., preferably DMAP and triethylamine, more preferably DMAP.With respect to compd B, the consumption of catalyzer conventionally can be at 0.2 molar equivalent to 3 molar equivalent, preferably 0.2 molar equivalent to 1 molar equivalent, and more preferably 0.2 molar equivalent to 0.5 molar equivalent uses.With respect to compd B, the consumption of tert-Butyl dicarbonate conventionally can be at 1 molar equivalent to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 2 molar equivalent uses.With respect to compd B, the consumption of hydrazine hydrate conventionally can be at 2 molar equivalent to 10 molar equivalents, preferably 2 molar equivalent to 5 molar equivalents, and more preferably 2 molar equivalent to 4 molar equivalents use.With tert-Butyl dicarbonate be used as the used time can solvent comprise ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc. or its suitable mixture.Preferred solvent is ether solvent, more preferably tetrahydrofuran (THF).When hydrazinolysis can with solvent comprise ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans etc.; Halohydrocarbon, for example, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; Protonic solvent, such as methyl alcohol, ethanol, water etc. or its suitable mixture.Preferred solvent is mixed solvent, more preferably the mixed solvent of tetrahydrofuran (THF)/methyl alcohol.Compd B can be under 25 DEG C～reflux temperature with reacting of tert-Butyl dicarbonate, and preferably 50 DEG C～reflux temperature, more preferably carries out under reflux temperature, approximately 8 hours or until react completely; Hydrazinolysis reaction can be at-25 DEG C～50 DEG C, preferably-10 DEG C～approximately 25 DEG C, carry out approximately 4 hours or until react completely at the temperature of more preferably 10 DEG C～25 DEG C.
Compd B can, by the compd A of following formula, in organic solvent, under alkali existence condition, react and obtain with replacement or unsubstituted benzyl halide:
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.Preferably R is in contraposition; Preferably R is the alkyl of hydrogen or C1-C3, more preferably hydrogen.
In above-mentioned replacement or unsubstituted benzyl halide, X can be chlorine or bromine, and preferably X is bromine; R can be hydrogen, C1-C6 alkyl or C1-C6 alkoxyl group, and preferably R is hydrogen or C1-C3 alkyl; R can be at phenyl ring the position of substitution not arbitrarily, and preferably R is in contraposition.With respect to compd A, the consumption of replacement or unsubstituted benzyl halide conventionally can be at 1 molar equivalent to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 1.3 molar equivalent uses.Available alkali comprises potassium tert.-butoxide, sodium hydride, potassium hydride KH, two (trimethyl silicon based) Lithamide, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) potassium amide, lithium diisopropylamine, butyllithium, preferably potassium tert.-butoxide, sodium hydride, two (trimethyl silicon based) Lithamide, more preferably sodium hydride.With respect to compd A, alkali conventionally can be at 1 molar equivalent to 5 molar equivalent, preferably 1 molar equivalent to 3 molar equivalent, and more preferably 1 molar equivalent to 1.5 molar equivalent uses.Available solvent comprises ether solvent, as ether, tetrahydrofuran (THF), methyl tertiary butyl ether, tetrahydropyrans etc.; Aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; And esters solvent, such as ethyl acetate etc. or its suitable mixture.Preferred solvent is ether solvent, more preferably tetrahydrofuran (THF).Reaction can be at-25 DEG C～25 DEG C, preferably-10 DEG C～10 DEG C, carry out approximately 2 hours or until react completely at the temperature of more preferably-5 DEG C～0 DEG C.
Compd A of the present invention can be prepared by means known in the art, in detail referring to Chinese patent application 201210200429.6.
The invention provides a kind of new (1R, 2S, 5S)-N-[3-amino-1-(cyclobutylmethyl)-2-substituted hydroxy-3-oxopropyl]-3-((2S)-2-[[[(1,1-dimethyl ethyl)-amino] carbonyl] amino]-3,3-dimethyl-1-oxo butyl]-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-Carbox amide 1, the preparation of this compounds, operation is easy, and yield is higher.Use this compounds to can be used for the synthetic of anti-the third liver medicine Boceprevir, this is that anti-the third liver medicine Boceprevir synthetic provides new thinking and method.And convenient with the more original synthetic method detection of ultraviolet chromophoric group in such compound molecule, on hydroxyl, the side reaction causing because of hydroxyl nucleophilicity in condensation step has been avoided in the introducing of benzyl in addition, has certain advantage compared with existing synthetic method.
Embodiment
The reactions steps below relating to for the preferred embodiment of the present invention, outside indicating, chemical and solvent that the present invention is all obtain from commercial channel, use front without being further purified.
Embodiment 1-9:R is the preparation of formula 1 compound of hydrogen
Embodiment 1: the preparation of compd B
Compd A (5g, 20.6mmol) is dissolved in 40ml DMF and is added in there-necked flask, is cooled to-5 DEG C, add NaH (60% in batches, 1.1g, 26.8mmol), stir 1h, at-5 DEG C, drip 40ml BnBr (4.2g, DMF solution 24.7mmo), dropwise at this temperature and stir 2h, add frozen water cancellation reaction, extract with ethyl acetate, on a small quantity repeatedly, merge organic phase, desolventize and obtain yellow oil with anhydrous sodium sulfate drying after saturated common salt water washing steaming, it is white solid that column chromatography obtains 6.2g compd B, yield 90.4%, m/z (MH+) 334.16, 1H NMR (400MHz, CDCl3) δ 1.31 (t, 3H), 1.41-1.57 (m, 4H), 1.64-1.74 (m, 2H), 1.77 (s, 3H), 1.96-2.06 (m, 2H), 2.25-2.29 (m, 1H), 3.95 (d, 1H), 4.19-4.25 (m, 3H), 4.28 (d, 1H), 4.81 (d, 1H), 5.63 (d, 1H), 7.30-7.35 (m, 5H).
Embodiment 2: the preparation of Compound C
Compd B (5g, 15mmol), DMAP (0.37g, 3mmol) are dissolved in 60ml THF, add (Boc)
2o (6.88ml, 30mmol), be warming up to backflow, reflux and be down to room temperature after about 8h and add 60ml methyl alcohol and hydrazine hydrate (3g, 60mmol) after stirring 4h, add the dilution of 200ml methylene dichloride, reaction solution is successively with 1N HCl, copper-bath, saturated sodium bicarbonate solution and saturated common salt water washing, after anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oil, it is white solid that column chromatography obtains 4.4g Compound C, yield 75.0%, m/z (MNa+) 414.06, 1H NMR (400MHz, CDCl3) δ 1.32 (t, 3H), 1.44 (s, 9H), 1.48-1.68 (m, 4H), 1.78-1.87 (m, 2H), 2.02-2.11 (m, 2H), 2.33-2.37 (m, 1H), 3.98 (m, 1H), 4.20-4.32 (m, 3H), 4.43 (d, 1H), 4.65 (d, 1H), 4.81 (d, 1H), 7.30-7.37 (m, 5H).
Embodiment 3: the preparation of Compound D
Compound C (2g, 5mmol) be dissolved in 20ml MeOH/THF (v/v1:1) solution, add 20ml1MLiOH solution, stirring at room temperature 4h, adds 1M potassium hydrogen sulfate solution to regulate PH to 2, with dichloromethane extraction, merge organic phase, organic phase is used saturated sodium bicarbonate and saturated common salt water washing successively, and after anhydrous sodium sulfate drying steaming desolventize, obtaining Compound D is white solid 1.91g, yield 100%, m/z (MNa+) 386.13.
Embodiment 4: the preparation of compd E
Compound D (1.91g, 5mmol) be dissolved in the anhydrous THF of 30ml and be cooled to 0 DEG C, add triethylamine (1.9ml, 12.5mmol), add Vinyl chloroformate (1.2ml, 11mmol), stir 15min at 0 DEG C after, add 30% ammoniacal liquor (2ml, 13.5mmol) and at 0 DEG C stir 30min, after adding ethyl acetate 50ml, stir 20min, suction filtration is removed solid, filtrate is successively with 1M sal enixum, saturated sodium bicarbonate and saturated common salt solution washing, anhydrous sodium sulfate drying, after desolventizing, steaming obtains white solid, it is a white solid that column chromatography obtains 3.30g compd E, yield 71.2%.m/z(MNa+)385.16,1H?NMR(400MHz,CDCl3)δ1.44(s,9H),1.61-1.70(m,4H),1.76-1.90(m,2H),2.03-2.10(m,2H),2.34-2.40(m,1H),3.80-3.98(m,1H),4.47(s,1H),4.60-4.67(m,2H),5.50(s,1H),6.46(s,1H),7.28-7.41(m,5H)。
Embodiment 5: the preparation of compound F 17-hydroxy-corticosterone
By compd E (422mg, 1.12mmol) be dissolved in 5ml4N HCl/dioxane and stir 1h, concentrated by adding 10ml methylene dichloride to continue after the volatile matter evaporate to dryness of above-mentioned reaction solution, repeating to obtain 350mg compound F 17-hydroxy-corticosterone for 4 times is a white solid, yield 100%, m/z (MH+) 263.13.
Embodiment 6: the preparation of formula 1 compound
G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) be dissolved in 8ml DMF, ice-water bath is cooling, add NMM (0.23mml, 1.56mmol), stir 30min, compound F 17-hydroxy-corticosterone (117mg, 0.37mmol) be added in 8ml DMF, this solution is added in the reaction soln of G-1, 0 DEG C is stirred 2 days, in reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 177mg formula 1 compound, it is a white solid, yield 78.0%, m/z (MNa+) 634.34, 1HNMR (400MHz, DMSO-d) δ 0.89 (m, 9H), 0.82-1.00 (m, 6H), 1.17 (s, 9H), 1.26 (m, 1H), 1.43 (m, 1H), 1.65-1.74 (m, 4H), 1.78-1.94 (m, 2H), 2.01-2.08 (m, 2H), 2.36-2.40 (m, 1H), 3.74-3.76 (m, 2H), 3.92-3.97 (m, 1H), 4.11 (d, 1H), 4.26 (s, 1H), 4.47 (s, 1H), 4.60-4.67 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 7.28-7.46 (m, 5H), 7.76-8.04 (br, 2H), 8.20-8.30 (s, 1H).
Embodiment 7: the preparation of compound F 17-hydroxy-corticosterone-1
G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) be dissolved in 8ml DMF, ice-water bath is cooling, adds NMM (0.23mml, 1.56mmol), stir 30min, compound F 17-hydroxy-corticosterone (120mg, 0.37mmol) is added in 8ml DMF, this solution is added in the reaction soln of G-2, and 0 DEG C is stirred 2 days, in reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 146mg compound F 17-hydroxy-corticosterone-1, it is a white solid, yield 79.2%, m/z (MNa+) 522.30, 1H NMR (400MHz, DMSO-d) δ 0.92-1.03 (m, 6H), 1.23-1.26 (m, 1H), 1.44 (s, 9H), 1.46-1.50 (m, 1H), 1.64-1.74 (m, 4H), 1.75-1.92 (m, 2H), 2.03-2.08 (m, 2H), 2.38-2.44 (m, 1H), 3.54-3.72 (m, 2H), 3.91-3.97 (m, 1H), 4.13 (d, 1H), 4.49 (s, 1H), 4.60-4.69 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 7.25-7.49 (m, 5H).
Embodiment 8: compound F 17-hydroxy-corticosterone-2 synthetic
By compound F 17-hydroxy-corticosterone-1 (140mg, 0.28mmol) be dissolved in 3ml4N HCl/dioxane and stir 1h, concentrated by adding 10ml methylene dichloride to continue after the volatile matter evaporate to dryness of above-mentioned reaction solution, repeating to obtain 120mg compound F 17-hydroxy-corticosterone-2 for 4 times is a white solid, yield 100%, m/z (MH+) 400.30.
Embodiment 9: the preparation of formula 1 compound
G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) are dissolved in 8ml DMF, and ice-water bath is cooling, add DIEA (0.18mml, 1.00mmol), stir 30min; In compound F 17-hydroxy-corticosterone-2 (120mg, 0.28mmol), be added in 8ml DMF, this solution be added in the reaction soln of G-2,0 DEG C of stirring is spent the night; In reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, and column chromatography obtains 118mg formula 1 compound, be a white solid, yield 68.7%.
Embodiment 10-18:R is methyl and the R preparation at formula 1 compound of contraposition
Embodiment 10: the preparation of compd B
Compd A (2g, 8.23mmol) be dissolved in 10ml DMF and be added in there-necked flask, be cooled to-5 DEG C, add NaH (60% in batches, 0.43g, 10.70mmol), stir 1h, at-5 DEG C, drip 10ml to methyl bromobenzyl (1.83g, DMF solution 9.88mmo), dropwise at this temperature and stir 2h, add frozen water cancellation reaction, extract with ethyl acetate, on a small quantity repeatedly, merge organic phase, with anhydrous sodium sulfate drying after saturated common salt water washing, steaming desolventizes and obtains yellow oil, it is white solid that column chromatography obtains 2.4g compd B, yield 82.5%, 1H NMR (400MHz, CDCl3) δ 1.31 (t, 3H), 1.43-1.64 (m, 4H), 1.74-1.78 (m, 2H), 1.83 (s, 3H), 1.97-2.05 (m, 2H), 2.25-2.29 (m, 1H), 2.34 (s, 3H), 4.00 (d, 2H), 4.17-4.33 (m, 4H), 4.77 (d, 1H), 5.58 (d, 1H), 7.16 (d, 2H), 7.23 (d, 2H).
Embodiment 11: the preparation of Compound C
Compd B (1.8g, 5.19mmol), DMAP (0.13g, 1.04mmol) are dissolved in 20ml THF, add (Boc)
2o (2.4ml, 10.38mmol), be warming up to backflow, reflux and be down to room temperature after about 8h and add 20ml methyl alcohol and hydrazine hydrate (1.04g, 20.76mmol) after stirring 4h, add the dilution of 100ml methylene dichloride, reaction solution is successively with 1N HCl, copper-bath, saturated sodium bicarbonate solution and saturated common salt water washing, after anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oil, it is white solid that column chromatography obtains 1.34g Compound C, yield 63.7%, m/z (MNa+) 428.06, 1HNMR (400MHz, CDCl3) δ 1.32 (t, 3H), 1.43 (s, 9H), 1.50-1.67 (m, 4H), 1.76-1.91 (m, 2H), 2.00-2.10 (m, 2H), 2.30-2.33 (m, 1H), 2.35 (s, 3H), 3.94-3.98 (m, 1H), 4.00 (d, 1H), 4.17-4.38 (m, 3H), 4.64 (d, 1H), 4.79 (d, 1H), 7.17 (d, 2H), 7.27 (d, 2H).
Embodiment 12: the preparation of Compound D
Compound C (1.2g, 2.96mmol) is dissolved in 20ml MeOH/THF (v/v1:1) solution, adds 20ml1MLiOH solution, stirring at room temperature 4h, add 1M potassium hydrogen sulfate solution to regulate PH to 2, with dichloromethane extraction, merge organic phase, organic phase is used saturated sodium bicarbonate and saturated common salt water washing successively, anhydrous sodium sulfate drying steams and removes, and obtains Compound D 1.2g after solvent, is white solid, yield 100%, m/z (MNa+) 400.13.
Embodiment 13: the preparation of compd E
Compound D (1.2g, 3.19mmol) be dissolved in the anhydrous THF of 20ml and be cooled to 0 DEG C, add triethylamine (1.1ml, 7.98mmol), add Vinyl chloroformate (0.7ml, 7.02mmol), stir 15min at 0 DEG C after, add 30% ammoniacal liquor (1ml, 8.61mmol) and at 0 DEG C stir 30min, after adding ethyl acetate 50ml, stir 20min, suction filtration is removed solid, filtrate is successively with 1M sal enixum, saturated sodium bicarbonate and saturated common salt solution washing, anhydrous sodium sulfate drying, after desolventizing, steaming obtains white solid, column chromatography obtains 831mg compd E, it is a white solid, yield 69.3%, m/z (MNa+) 399.16, 1H NMR (400MHz, CDCl3) δ 1.43 (s, 9H), 1.60-1.71 (m, 4H), 1.77-1.93 (m, 2H), 2.00-2.10 (m, 2H), 2.35 (s, 3H), 2.36-2.40 (m, 1H), 3.83-3.98 (m, 1H), 4.50 (s, 1H), 4.62-4.69 (m, 2H), 5.50 (s, 1H), 6.47 (s, 1H), 7.18 (d, 2H), 7.25 (d, 2H).
Embodiment 14: the preparation of compound F 17-hydroxy-corticosterone
By compd E (400mg, 1.06mmol) be dissolved in 5ml4N HCl/dioxane and stir 1h, concentrated by adding 10ml methylene dichloride to continue after the volatile matter evaporate to dryness of above-mentioned reaction solution, repeating to obtain 330mg compound F 17-hydroxy-corticosterone for 4 times is a white solid, yield 100%, m/z (MH+) 277.13.
Embodiment 15: the preparation of compound 1
G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) be dissolved in 8ml DMF, ice-water bath is cooling, add NMM (0.23mml, 1.56mmol), stir 30min, compound F 17-hydroxy-corticosterone (120mg, 0.38mmol) be added in 8ml DMF, this solution is added in the reaction soln of G-1, 0 DEG C is stirred 2 days, in reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 173mg formula 1 compound, it is a white solid, yield 72.7%, m/z (MNa+) 648.34, 1H NMR (400MHz, DMSO-d) δ 0.88-0.92 (m, 9H), 0.81-1.02 (m, 6H), 1.18 (s, 9H), 1.27 (m, 1H), 1.45 (m, 1H), 1.68-1.75 (m, 4H), 1.81-1.94 (m, 2H), 2.03-2.09 (m, 2H), 2.33-2.41 (m, 1H), 2.35 (s, 3H), 3.75-3.77 (m, 2H), 3.92-3.97 (m, 1H), 4.13 (d, 1H), 4.25 (s, 1H), 4.44 (s, 1H), 4.61-4.67 (m, 2H), 5.48 (s, 1H), 6.42 (s, 1H), 7.17 (d, 2H), 7.23 (d, 2H), 7.77-8.04 (br, 2H), 8.20-8.28 (s, 1H).
Embodiment 16: the preparation of compound F 17-hydroxy-corticosterone-1
G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) be dissolved in 8ml DMF, ice-water bath is cooling, add NMM (0.23mml, 1.56mmol), stir 30min, compound F 17-hydroxy-corticosterone (120mg, 0.38mmol) be added in 8ml DMF, this solution is added in the reaction soln of G-2, 0 DEG C is stirred 2 days, in reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 139mg compound F 17-hydroxy-corticosterone-1, it is a white solid, yield 73.1%, m/z (MNa+) 536.30, 1H NMR (400MHz, DMSO-d) δ 0.90-1.03 (m, 6H), 1.22-1.26 (m, 1H), 1.44 (s, 9H), 1.48-1.51 (m, 1H), 1.62-1.71 (m, 4H), 1.75-1.92 (m, 2H), 2.03-2.08 (m, 2H), 2.34 (s, 3H), 2.37-2.44 (m, 1H), 3.54-3.70 (m, 2H), 3.90-3.97 (m, 1H), 4.13 (d, 1H), 4.52 (s, 1H), 4.60-4.69 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 7.18 (d, 2H), 7.23 (d, 2H).
Embodiment 17: compound F 17-hydroxy-corticosterone-2 synthetic
By compound F 17-hydroxy-corticosterone-1 (139mg, 0.27mmol) be dissolved in 3ml4N HCl/dioxane and stir 1h, concentrated by adding 10ml methylene dichloride to continue after the volatile matter evaporate to dryness of above-mentioned reaction solution, repeating to obtain 120mg compound F 17-hydroxy-corticosterone-2 for 4 times is a white solid, yield 100%, m/z (MH+) 414.30.
Embodiment 18: the preparation of formula 1 compound
G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) be dissolved in 8ml DMF, ice-water bath is cooling, add DIEA (0.18mml, 1.00mmol), stir 30min, compound F 17-hydroxy-corticosterone-2 (120mg, 0.27mmol) be added in 8ml DMF, this solution is added in the reaction soln of G-3, 0 DEG C of stirring is spent the night, in reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 102mg formula 1 compound, it is a white solid, yield 60.2%.
Embodiment 19-27:R is methoxyl group and the R preparation at formula 1 compound of contraposition
Embodiment 19: the preparation of compd B
Compd A (4g, 16.46mmol) is dissolved in 10ml DMF and is added in there-necked flask, is cooled to-5 DEG C; After adding NaH (60%, 0.86g, 21.40mmol), stir 1h in batches; At-5 DEG C, drip the DMF solution of 10ml to methoxyl group benzyl chloride (3.08g, 19.75mmol), dropwise at this temperature and stir 2h; Add frozen water cancellation reaction, with ethyl acetate extraction, on a small quantity repeatedly, merge organic phase, desolventize and obtain yellow oil with anhydrous sodium sulfate drying steaming after saturated common salt water washing; It is white solid that column chromatography obtains 2.3g compd B, yield 37.9%, m/z (MH+) 364.16
Embodiment 20: the preparation of Compound C
Compd B (2.0g, 5.51mmol), DMAP (134mg, 1.10mmol) are dissolved in 20ml THF, add (Boc)
2o (2.5ml, 11.02mmol), be warming up to backflow, reflux and be down to room temperature after about 8h and add 20ml methyl alcohol and hydrazine hydrate (1.10g, 22.04mmol) after stirring 4h, add the dilution of 100ml methylene dichloride, reaction solution is successively with 1N HCl, copper-bath, saturated sodium bicarbonate solution and saturated common salt water washing, after anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oil, it is white solid that column chromatography obtains 1.51g Compound C, yield 65.3%, (MNa+) 444.06.
Embodiment 21: the preparation of Compound D
Compound C (1g, 2.57mmol) be dissolved in 20ml MeOH/THF (v/v1:1) solution, add 20ml1MLiOH solution, stirring at room temperature 4h, adds 1M potassium hydrogen sulfate solution to regulate PH to 2, with dichloromethane extraction, merge organic phase, organic phase is used saturated sodium bicarbonate and saturated common salt water washing successively, and it is white solid that anhydrous sodium sulfate drying obtains Compound D 950mg after steaming and desolventizing, yield 100%, m/z (MNa+) 416.13.
Embodiment 22: the preparation of compd E
Compound D (900mg, 2.29mmol) be dissolved in the anhydrous THF of 20ml and be cooled to 0 DEG C, add triethylamine (0.8ml, 5.73mmol), add Vinyl chloroformate (0.5ml, 5.04mmol), stir 15min at 0 DEG C after, add 30% ammoniacal liquor (0.7ml, 8.61mmol) and at 0 DEG C stir 30min, after adding ethyl acetate 50ml, stir 20min, suction filtration is removed solid, filtrate is successively with 1M sal enixum, saturated sodium bicarbonate and saturated common salt solution washing, anhydrous sodium sulfate drying, after desolventizing, steaming obtains white solid, it is a white solid that column chromatography obtains 587mg compd E, yield 65.4%, m/z (MNa+) 415.16.
Embodiment 23: the preparation of compound F 17-hydroxy-corticosterone
By compd E (950mg, 2.42mmol) be dissolved in 5ml4N HCl/dioxane and stir 1h, concentrated by adding 10ml methylene dichloride to continue after the volatile matter evaporate to dryness of above-mentioned reaction solution, repeating to obtain 795mg compound F 17-hydroxy-corticosterone for 4 times is a white solid, yield 100%, m/z (MH+) 293.13.
Embodiment 24: the preparation of compound 1
G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) be dissolved in 8ml DMF, ice-water bath is cooling, add NMM (0.23mml, 1.56mmol), stir 30min, compound F 17-hydroxy-corticosterone (120mg, 0.37mmol) be added in 8ml DMF, this solution is added in the reaction soln of G-1, 0 DEG C is stirred 2 days, in reaction solution, add 50ml water, with dichloromethane extraction reaction solution, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 145mg formula 1 compound, it is a white solid, yield 61.3%, m/z (MNa+) 664.34, 1H NMR (400MHz, DMSO-d) δ 0.87-0.92 (m, 9H), 0.82-1.02 (m, 6H), 1.18 (s, 9H), 1.28 (m, 1H), 1.44 (m, 1H), 1.66-1.75 (m, 4H), 1.82-1.94 (m, 2H), 2.03-2.09 (m, 2H), 2.33-2.41 (m, 1H), 3.75-3.77 (m, 2H), 3.83 (s, 3H), 3.92-3.97 (m, 1H), 4.13 (d, 1H), 4.25 (s, 1H), 4.44 (s, 1H), 4.61-4.67 (m, 2H), 5.48 (s, 1H), 6.42 (s, 1H), 6.90 (d, 2H), 6.99 (d, 2H), 7.77-8.04 (br, 2H), 8.20-8.28 (s, 1H).
Embodiment 25: the preparation of compound F 17-hydroxy-corticosterone-1
G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) be dissolved in 8ml DMF, ice-water bath is cooling, add NMM (0.23mml, 1.56mmol), stir 30min, compound F 17-hydroxy-corticosterone (120mg, 0.37mmol) be added in 8ml DMF, this solution is added in the reaction soln of G-2, 0 DEG C is stirred 2 days, in reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 126mg compound F 17-hydroxy-corticosterone-1, it is a white solid, yield 64.6%, m/z (MNa+) 552.30, 1H NMR (400MHz, DMSO-d) δ 0.91-1.03 (m, 6H), 1.20-1.26 (m, 1H), 1.44 (s, 9H), 1.48-1.51 (m, 1H), 1.62-1.71 (m, 4H), 1.75-1.92 (m, 2H), 2.03-2.08 (m, 2H), 2.38-2.44 (m, 1H), 3.54-3.70 (m, 2H), 3.84 (s, 3H), 3.91-3.97 (m, 1H), 4.11 (d, 1H), 4.52 (s, 1H), 4.63-4.70 (m, 2H), 5.52 (s, 1H), 6.44 (s, 1H), 6.91 (d, 2H), 7.02 (d, 2H).
Embodiment 26: compound F 17-hydroxy-corticosterone-2 synthetic
By compound F 17-hydroxy-corticosterone-1 (120mg, 0.23mmol) be dissolved in 3ml4N HCl/dioxane and stir 1h, concentrated by adding 10ml methylene dichloride to continue after the volatile matter evaporate to dryness of above-mentioned reaction solution, repeating to obtain 105mg compound F 17-hydroxy-corticosterone-2 for 4 times is a white solid, yield 100%, m/z (MH+) 430.30.
Embodiment 27: the preparation of formula 1 compound
G-3 (30mg, 0.13mmol), HATU (50mg, 0.13mmol) be dissolved in 8ml DMF, ice-water bath is cooling, add DIEA (0.1ml, 0.57mmol), stir 30min, compound F 17-hydroxy-corticosterone-2 (50mg, 0.11mmol) be added in 8ml DMF, this solution is added in the reaction soln of G-2, 0 DEG C of stirring is spent the night, in reaction solution, add 50ml water, with ethyl acetate extractive reaction liquid, organic phase is successively with 1N hydrochloric acid and saturated sodium bicarbonate solution washing, again with saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes and obtains yellow oily matter, column chromatography obtains 40mg formula 1 compound, it is a white solid, yield 57.2%
Embodiment 28: formula 1 compound preparation formula 2 compounds taking R as hydrogen
By formula 1 compound (50mg, 0.08mmol) be dissolved in 20ml methyl alcohol, add the palladium carbon of 10mg10%, be placed on 40 DEG C, in the hydrogen atmosphere of 0.7MP, stir and spend the night, with diatomite filtering palladium carbon, after gained filtrate is concentrated, obtaining formula (2) compound 39mg, is a white solid, yield 92.3%, m/z (MNa+) 544.42, HPLC shows that purity is 91.2%.
Embodiment 5
Embodiment 29: taking R as methyl and R at formula 1 compound preparation formula 2 compounds of contraposition
By formula 1 compound (50mg, 0.08mmol) be dissolved in 20ml methyl alcohol, add the palladium carbon of 10mg10%, be placed on 40 DEG C, in the hydrogen atmosphere of 0.7MP, stir and spend the night, after concentrating with diatomite filtering palladium carbon gained filtrate, obtain formula (2) compound 37mg, it is a white solid, yield 89.5%, m/z (MNa+) 544.42, HPLC shows that purity is 90.3%.
Claims (31)
1. following general formula compound 1:
R is the optional position substituting group of phenyl ring, and R is hydrogen, alkyl or alkoxyl group.
2. general formula compound 1 as claimed in claim 1, is characterized in that: R is in contraposition.
3. general formula compound 1 as claimed in claim 1 or 2, is characterized in that: R is the alkyl of hydrogen or C1-C3.
4. general formula compound 1 as claimed in claim 3, is characterized in that: R is hydrogen.
5. the application of any described compound 1 of claim 1-4, is characterized in that: for the preparation of the compound 2 of following formula
6. the application of compound 1 as claimed in claim 5, is characterized in that: compound 2 is by obtaining compound 1 hydro-reduction:
7. the preparation method of any described compound 1 of claim 1-4, the method is, in organic solvent, under alkali and condensing agent existence condition, following formula: compound F and compound G-1 condensation to be obtained:
8. the preparation method of compound 1 as claimed in claim 7, is characterized in that: described alkali is selected from triethylamine, pyridine, N-methylmorpholine, DIPEA, DMAP.
9. the preparation method of compound 1 as claimed in claim 8, is characterized in that: described alkali is N-methylmorpholine or DIPEA.
10. the preparation method of compound 1 as claimed in claim 7, is characterized in that: described condensing agent is selected from EDCI, BOP, PyBOP, CDI, HATU and HBTU and DCC.
11. preparation methods of compound 1 as claimed in claim 10, is characterized in that: described condensing agent is EDCI, BOP, PyBOP or HATU.
12. preparation methods of compound 1 as claimed in claim 7, is characterized in that: add additive HOBt or HOAT.
13. as claim 1-4 arbitrarily as described in the preparation method of compound 1, comprise the steps:
A), in organic solvent, under alkali and condensing agent existence condition, make compound F 17-hydroxy-corticosterone and compound G-2 condensation obtain compound F 17-hydroxy-corticosterone-1
B) in organic solvent, under acidic conditions, make compound F 17-hydroxy-corticosterone-1 deprotection base, obtain compound F 17-hydroxy-corticosterone-2
C), in organic solvent, under alkali and condensing agent existence condition, make compound F 17-hydroxy-corticosterone-2 and compound G-3 condensation obtain formula 1 compound
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group, and A is acid group.
14. preparation methods of compound 1 as claimed in claim 13, is characterized in that: the alkali that step a) is used comprises triethylamine, DIPEA, pyridine and N-methylmorpholine.
15. preparation methods of compound 1 as claimed in claim 13, is characterized in that: the condensing agent that step a) is used comprises EDCI, BOP, PyBOP, CDI, HATU, HBTU and DCC.
16. preparation methods of compound 1 as claimed in claim 13, is characterized in that: step a) adds additive HOBT or HOAT.
17. preparation methods of compound 1 as claimed in claim 13, is characterized in that: the acid that step b) is used comprises hydrochloric acid, sulfuric acid and trifluoroacetic acid.
18. preparation methods of compound 1 as claimed in claim 13, is characterized in that: the alkali that step c) is used comprises triethylamine, DIPEA, pyridine and N-methylmorpholine.
19. preparation methods of compound 1 as claimed in claim 13, is characterized in that: the condensing agent that step c) is used comprises EDCI, BOP, PyBOP, CDI, HATU, HBTU and DCC.
20. preparation methods of compound 1 as claimed in claim 13, is characterized in that: step c) adds additive HOBT or HOAT.
21. as the preparation method of the compound 1 of claim 7-13 as described in arbitrarily, it is characterized in that: compound F 17-hydroxy-corticosterone is by compd E in organic solvent, and under acidic conditions, deprotection base obtains
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.
The preparation method of 22. compounds 1 as claimed in claim 21, is characterized in that: said acid comprises hydrochloric acid, sulfuric acid and trifluoroacetic acid.
The preparation method of 23. compounds 1 as claimed in claim 21, is characterized in that: compd E be Compound D in organic solvent, under alkali existence condition, directly react and obtain with strong aqua after reacting with Vinyl chloroformate
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.
The preparation method of 24. compounds 1 as claimed in claim 23, is characterized in that: said alkali comprises triethylamine, DIPEA, pyridine, N-methylmorpholine, lithium hydroxide, sodium hydroxide and potassium hydroxide.
The preparation method of 25. compounds 1 as claimed in claim 23, is characterized in that: said strong aqua mass concentration is 28-35%.
The preparation method of 26. compounds 1 as claimed in claim 23, is characterized in that: Compound D is in organic solvent, under alkali effect, Compound C hydrolysis is obtained
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.
The preparation method of 27. compounds 1 as claimed in claim 26, is characterized in that: said alkali comprises potassium hydroxide, sodium hydroxide and lithium hydroxide.
The preparation method of 28. compounds 1 as claimed in claim 26, is characterized in that: Compound C, by the compd B of following formula, in organic solvent, under catalyst action, through hydrazine hydrate effect obtains after reacting with tert-Butyl dicarbonate again
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group.
The preparation method of 29. compounds 1 as claimed in claim 28, is characterized in that: said catalyzer is DMAP, triethylamine, butyllithium or sodium hydroxide.
The preparation method of 30. compounds 1 as claimed in claim 28, is characterized in that: compd B, by the compd A of following formula, in organic solvent, under alkali existence condition, reacts and obtains with replacement or unsubstituted benzyl halide
Wherein R is the substituting group of phenyl ring optional position, and R is hydrogen, alkyl or alkoxyl group, and X is chlorine or bromine.
The preparation method of 31. compounds 1 as claimed in claim 28, is characterized in that: said alkali comprises potassium tert.-butoxide, sodium hydride, potassium hydride KH, two (trimethyl silicon based) Lithamide, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) potassium amide, lithium diisopropylamine and butyllithium.
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| CN114405063A (en) * | 2021-11-12 | 2022-04-29 | 河北大学 | Method for enriching and purifying diosmetin in dandelion on line |
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| CN1805920A (en) * | 2003-06-17 | 2006-07-19 | 先灵公司 | Process and intermediates for the preparation of 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide or salts thereof |
| WO2008079216A1 (en) * | 2006-12-20 | 2008-07-03 | Schering Corporation | Process for preparing (1r,2s,5s)-n-[(1s)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2s)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide |
| CN102206247A (en) * | 2000-07-21 | 2011-10-05 | 先灵公司 | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
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| CN102206247A (en) * | 2000-07-21 | 2011-10-05 | 先灵公司 | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
| CN1805920A (en) * | 2003-06-17 | 2006-07-19 | 先灵公司 | Process and intermediates for the preparation of 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide or salts thereof |
| WO2008079216A1 (en) * | 2006-12-20 | 2008-07-03 | Schering Corporation | Process for preparing (1r,2s,5s)-n-[(1s)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2s)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114405063A (en) * | 2021-11-12 | 2022-04-29 | 河北大学 | Method for enriching and purifying diosmetin in dandelion on line |
| CN114405063B (en) * | 2021-11-12 | 2023-02-24 | 河北大学 | Method for enriching and purifying diosmetin from dandelion on line |
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