CN104292146A - Telaprevir intermediate and preparation method thereof - Google Patents
Telaprevir intermediate and preparation method thereof Download PDFInfo
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- CN104292146A CN104292146A CN201310254217.0A CN201310254217A CN104292146A CN 104292146 A CN104292146 A CN 104292146A CN 201310254217 A CN201310254217 A CN 201310254217A CN 104292146 A CN104292146 A CN 104292146A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a telaprevir intermediate and a preparation method thereof. The telaprevir intermediate is a compound represented by 1. The preparation method of a telaprevir intermediate compound 2 comprises the following steps: in an organic solvent, under the effect of a desulfurization reagent, the compound 1 is subjected to a desulfurization reaction, such that the compound 2 can be prepared. R1 is C1-C6 straight-chain or branched-chain alkyl; n is 0, 1 or 2; Z is an amino protecting group. The telaprevir intermediate preparation method provided by the invention is simple and feasible.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly relate to Telaprevir intermediate 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.Due to HCV high infection rate and potential complication as serious in liver cirrhosis, liver cancer etc. can be caused, thus HCV is the threat that of human life's health is serious.According to Simmonds naming system, HCV can be divided into 6 main genotypes and I-VI, variously can be divided into again several hypotypes (as Ia, Ib, IIa, IIb, IIIa, IIIb etc.).The HCV infection person about 4,000 ten thousand of China, wherein 69% is I type infection (based on Ib type).Method mainly Peg-IFN alpha-2b (PEG-IFN α) and ribavirin (RBV) drug combination of current treatment chronic hepatitis C, this kind of therapy in HCV I type patient about 50% patient can not produce continued viral response, and have untoward reaction, thus need the effective medicine of exploitation badly.Due to this needs, HCV-Ab IgG new drug development is very active, has more than 50 planting HCV-Ab IgG drug candidate or grantedly carry out clinical trial at present.In these medicines, VX-960 (Incivek (Telaprevir)) is used for the treatment of Adult chronic hepatitis C by U.S. FDA (food and drug administration) approval with Peg-IFN alpha-2b and ribavirin combination on May 23rd, 2011.
VX-960
VX-960 (Telaprevir) is by the U.S.'s not chronic hepatitis C curative of developing of Turks Co., Ltd (Vertex pharmaceutical), it is a kind of orally active HCV NS3 proteinase inhibitor, that systemic brachymemma and modification are carried out and the micromolecular inhibitor found to the amino-acid residue on a kind of 11 peptides with high NS3 inhibit activities, the Serine of NS3 reactive site can be caught, carbonyl carbon Serine combination formation covalent adduct therewith on its keto-amide, thus cause NS3 inactivation.The research be published on " New England Journal of Medicine " shows, to the past untreated chronic hcv genotype Ⅰ infected patient, Peg-IFN alpha-2b-ribavirin standard therapy basis add with Telaprevir, compared with simple standard care, can significantly increase continued viral response rate.
Following three key intermediates are related in the synthetic method of Telaprevir disclosed in the original chemical patent WO02/18369A2 of Telaprevir:
Key intermediate 1 key intermediate 2 key intermediate 3
What wherein the primary synthetic methods of key intermediate 1 was reported has following three kinds:
(1) report with (1S in former compound patent WO02/18369A2,3aR, 6aS)-1-ethyl-2-(phenyl methyl)-4-oxo six hydrogen pentamethylene also [c] pyrroles-1,2 (1H)-dicarboxylic esters are that starting raw material obtains key intermediate 1 through 4 steps, and synthetic route is as follows.
Key intermediate 1
(2) patent US2007/0087973A1 report with (3aR, 6aS)-seven hydrogen pentamethylene also [c] pyrroles be that starting raw material obtains the oxalate of key intermediate 1 through 4 steps, synthetic route is as follows.
The oxalate of key intermediate 1
(3) patent WO2010/008828A2 report with (3aR, 6aS)-seven hydrogen pentamethylene also [c] pyrroles for starting raw material, through enzymatic oxidation etc. totally 5 steps be obtained by reacting key intermediate 1, synthetic route is as follows.
Key intermediate 1
Consider the importance of hepatitis C virus (" HCV ") proteinase inhibitor, the intermediate of novel this inhibitor of preparation is interesting all the time.
Summary of the invention
Technical problem solved by the invention is to there is provided a kind of and the diverse Telaprevir intermediate of prior art and preparation method thereof.The preparation method of Telaprevir intermediate of the present invention is simple.
The present invention solves the problems of the technologies described above by the following technical programs:
The invention provides a kind of preparation method of Telaprevir intermediate compound 2, it comprises the steps: in organic solvent, under the effect of desulfuration reagent, compound 1 is carried out desulphurization reaction, can obtain compound 2;
Wherein, R
1for C
1-C
6straight or branched alkyl, n be 0,1 or 2, Z be amino protecting group.
In the present invention, described R
1be preferably C
1-C
4straight or branched alkyl.
In the present invention, described Z is preferably tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or benzyl, is more preferably tertbutyloxycarbonyl or carbobenzoxy-(Cbz).
Wherein, the method for described desulphurization reaction and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following condition particularly preferably:
Described desulfuration reagent is preferably Raney's nickel.
The mass ratio of described desulfuration reagent and compound 1 is preferably (5:1 ~ 20:1), is more preferably (5:1 ~ 15:1) be (5:1 ~ 10:1) best.
Described organic solvent is preferably ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, alcoholic solvent, acetonitrile, DMF(N, dinethylformamide) and DMSO(dimethyl sulfoxide (DMSO)) in one or more, be more preferably alcoholic solvent.Described ether solvent is preferably one or more in ether, tetrahydrofuran (THF), methyl tertiary butyl ether and tetrahydropyrans (THP).Described halogenated hydrocarbon solvent is preferably one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.Described aromatic hydrocarbon solvent is preferably one or more in toluene, benzene, dimethylbenzene, Three methyl Benzene and chlorobenzene.Described alcoholic solvent is preferably one or more in methyl alcohol, ethanol and Virahol, is more preferably ethanol.
The volume mass of described organic solvent and compound 1 is 5 ~ 20ml/g than preferably.
The temperature of described desulphurization reaction is preferably 20 ~ 120 DEG C, is more preferably 40 ~ 100 DEG C, is 60 ~ 80 DEG C best.
The process of described desulphurization reaction is monitored by this area conventional means (as TLC or HPLC), and as the terminal of reaction when generally disappearing using compound 1, the time of described desulphurization reaction is preferably 4 ~ 8 hours.
In the present invention, described compound 1 can be obtained by following method: in solvent, under the effect of catalyzer, compd E and thiol reagent F is reacted, can obtain compound 1;
Wherein, the method for described reaction and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following condition particularly preferably:
Described catalyzer is preferably Lewis acid, and being more preferably one or more in boron trifluoride diethyl etherate, aluminum chloride and trifluoroacetic acid, is boron trifluoride diethyl etherate best.
Described catalyzer and the mol ratio of compd E are preferably (0.1:1 ~ 1:1), are more preferably (0.1:1 ~ 0.5:1), are (0.1:1 ~ 0.3:1) best.
Described preferred solvents ground is ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, esters solvent, acetonitrile, DMF(N, dinethylformamide) and DMSO(dimethyl sulfoxide (DMSO)) in one or more, be more preferably halogenated hydrocarbon solvent.Described ether solvent is preferably one or more in ether, tetrahydrofuran (THF), methyl tertiary butyl ether and tetrahydropyrans (THP).Described halogenated solvent hydrocarbon is preferably one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride, is more preferably methylene dichloride.Described aromatic hydrocarbon solvent is preferably one or more in toluene, benzene, dimethylbenzene, Three methyl Benzene and chlorobenzene.Described esters solvent is preferably ethyl acetate.
The volume mass of described solvent and compd E is 5 ~ 20ml/g than preferably.
Described thiol reagent F and the mol ratio of compd E are preferably (1:1 ~ 5:1), are more preferably (1:1 ~ 3:1), are (1:1 ~ 1.5:1) best.
The temperature of described reaction is preferably 0 ~ 80 DEG C, is more preferably 20 ~ 60 DEG C, is 20 ~ 30 DEG C best.
The process of described reaction is monitored by this area conventional means (as TLC or HPLC), and as the terminal of reaction when generally disappearing using compd E, the time of described reaction is preferably 0.5 ~ 4 hour.
In the present invention, described compd E can by document J.Org.Chem., Vol.59, No.10, the method preparation in 1994, and its syntheti c route is as follows:
1. step comprises the steps: that compd A and bromacetate react obtained compd B in organic solvent, relative to compd A, bromacetate can use to about 3 molar equivalents by about 1 molar equivalent, preferably 1 molar equivalent to 2 molar equivalent uses, more preferably 1.2 molar equivalents use, available bromacetate comprises methyl bromoacetate, ethyl bromoacetate etc., preferred ethyl bromoacetate.Available solvent comprises aromatic solvent, such as toluene, benzene, dimethylbenzene, Three methyl Benzene, chlorobenzene etc.; Esters solvent, such as ethyl acetate etc.; Alcoholic solvent, as methyl alcohol, ethanol, Virahol etc.; Preferred solvent is alcoholic solvent, more preferably ethanol.Step reaction 1. can at 20 DEG C ~ 120 DEG C, preferably 40 DEG C ~ 90 DEG C, carry out 3 ~ 6h or until react completely at the temperature of more preferably 70 DEG C ~ 90 DEG C.
2. step comprises the steps: in organic solvent, and under the effect of organic bases, compd B and 2-cyclopentenone obtain Compound C through 1,3-dipole-diople interaction.Relative to compd B, 2-cyclopentenone can use by about 2 molar equivalent ~ 8 molar equivalents, preferably 2 molar equivalent ~ 4 molar equivalents, and more preferably 3 molar equivalent ~ 4 molar equivalents use.Relative to compd B, organic bases can use by about 1 molar equivalent ~ about 4 molar equivalents, preferably 1 molar equivalent ~ 3 molar equivalent, and more preferably from about 1 molar equivalent ~ about 2 molar equivalents use.Available organic bases comprises triethylamine, DIPEA (DIEA), tripropyl amine etc., preferred triethylamine.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Halogenated hydrocarbon solvent, such as, 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.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is other solvents, more preferably acetonitrile.Step reaction 2. at about-20 DEG C ~ about 80 DEG C, preferably 0 DEG C ~ 50 DEG C, can be carried out about 24 ~ 26h or until reacts completely at the temperature of more preferably from about 10 DEG C ~ 30 DEG C.
3. step comprises the steps: in organic solvent, under the effect of catalyzer and three n-butyltin hydride, Compound C obtains Compound D through free radical reaction and with hydrochloric acid salt-forming reaction, wherein in this step of free radical reaction, relative to Compound C, three n-butyltin hydride can use by about 1 molar equivalent ~ 5 molar equivalent usually, preferably 1 molar equivalent ~ 3 molar equivalent, and more preferably from about 1 molar equivalent ~ 1.3 molar equivalent uses; Relative to Compound C, catalyzer can use by about 0.01 molar equivalent ~ about 0.5 molar equivalent usually, preferably 0.05 ~ 0.3 molar equivalent, and more preferably from about 0.1 molar equivalent ~ about 0.15 molar equivalent uses.Available catalyzer comprises AIBN.Available organic solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Halogenated hydrocarbon solvent, such as, 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.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is aromatic solvent, more preferably toluene.In this step of free radical reaction, reaction can at about 25 DEG C ~ about 150 DEG C, preferably 50 DEG C ~ 120 DEG C, carry out about 8h or until react completely at more preferably from about 80 DEG C ~ 100 DEG C temperature.Wherein with this single step reaction of hydrochloric acid salify, relative to Compound C, hydrochloric acid can use by about 1 molar equivalent ~ about 5 molar equivalents usually, preferably 1 molar equivalent ~ 3 molar equivalent, and more preferably from about 1 molar equivalent ~ about 1.5 molar equivalents use.Available solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Halogenated hydrocarbon solvent, such as, 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.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred solvent is esters solvent, more preferably ethyl acetate.Can at about 0 DEG C ~ about 80 DEG C with this single step reaction of hydrochloric acid salify, preferably 20 DEG C ~ 60 DEG C, more preferably from about 20 DEG C ~ about 30 DEG C reactions are carried out about 14h or until react completely.
4. step comprises the steps: in organic solvent; under the effect of alkali; Compound D and amino protecting group reagent react obtain compd E; relative to Compound D; amino protecting group reagent usually can about 1 molar equivalent ~ about 5 molar equivalents, preferably 1 molar equivalent ~ 3 molar equivalent, and more preferably from about 1 molar equivalent ~ about 1.5 molar equivalents use; available amino protecting group comprises carbobenzoxy-(Cbz), tertbutyloxycarbonyl, benzyl etc., preferred carbobenzoxy-(Cbz) and tertbutyloxycarbonyl.Relative to Compound D, alkali can use by about 1 molar equivalent ~ about 5 molar equivalents usually, preferably 1 molar equivalent ~ 3 molar equivalent, and more preferably from about 1 molar equivalent ~ about 1.5 molar equivalents use.Available alkali comprises sodium carbonate, sodium bicarbonate, sodium hydroxide, preferred sodium hydroxide.Available organic solvent comprises ether solvent, as ether, THF, methyl tertiary butyl ether, THP etc.; Halogenated hydrocarbon solvent, such as 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.; With other solvents, such as acetonitrile, DMF, DMSO etc. or its suitable mixture.Preferred esters solvent, more preferably ethyl acetate.Step reaction 4. about about-20 DEG C ~ about 80 DEG C, preferably-10 DEG C ~ 50 DEG C, can be carried out 4 ~ 6h at the temperature of more preferably from about 0 DEG C ~ about 30 DEG C or until reacts completely.
Present invention also offers a kind of Telaprevir intermediate as shown in Equation 1,
Wherein, R
1for C
1-C
6straight or branched alkyl, n be 0,1 or 2, Z be amino protecting group.
In the present invention, described R
1be preferably C
1-C
4straight or branched alkyl.
In the present invention, described Z is preferably tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or benzyl, is more preferably tertbutyloxycarbonyl or carbobenzoxy-(Cbz).
Present invention also offers a kind of preparation method of Telaprevir intermediate compound 1, it comprises the steps: in solvent, under the effect of catalyzer, compd E and thiol reagent F is reacted, can obtain compound 1;
Wherein, the method for described reaction and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following condition particularly preferably:
Described catalyzer is preferably Lewis acid, and being more preferably one or more in boron trifluoride diethyl etherate, aluminum chloride and trifluoroacetic acid, is boron trifluoride diethyl etherate best.
Described catalyzer and the mol ratio of compd E are preferably (0.1:1 ~ 1:1), are more preferably (0.1:1 ~ 0.5:1), are (0.1:1 ~ 0.3:1) best.
Described preferred solvents ground is ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, esters solvent, acetonitrile, DMF(N, dinethylformamide) and DMSO(dimethyl sulfoxide (DMSO)) in one or more, be more preferably halogenated hydrocarbon solvent.Described ether solvent is preferably one or more in ether, tetrahydrofuran (THF), methyl tertiary butyl ether and tetrahydropyrans (THP).Described halogenated hydrocarbon solvent is preferably one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride, is more preferably methylene dichloride.Described aromatic hydrocarbon solvent is preferably one or more in toluene, benzene, dimethylbenzene, Three methyl Benzene and chlorobenzene.Described esters solvent is preferably ethyl acetate.
The volume mass of described solvent and compd E is 5 ~ 20ml/g than preferably.
Described thiol reagent F and the mol ratio of compd E are preferably (1:1 ~ 5:1), are more preferably (1:1 ~ 3:1), are (1:1 ~ 1.5:1) best.
The temperature of described reaction is preferably 0 ~ 80 DEG C, is more preferably 20 ~ 60 DEG C, is 20 ~ 30 DEG C best.
The process of described reaction is monitored by this area conventional means (as TLC or HPLC), and as the terminal of reaction when generally disappearing using compd E, the time of described reaction is preferably 0.5 ~ 4 hour.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: the preparation method of Telaprevir intermediate of the present invention is simple.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
2-cyclopentenone is purchased from the Shanghai chemical Science and Technology Ltd. of special uncle, and 4-methyl-5-hydroxy ethylthiazole, 1，2-ethandithiol, Raney's nickel are purchased from Shanghai Da Rui Fine Chemical Co., Ltd, and Raney's nickel model is RTH-3110.Three n-butyltin hydride, Diisopropyl azodicarboxylate is purchased from lark waffle, and all the other reagent and solvent are all purchased from Chemical Reagent Co., Ltd., Sinopharm Group.Anhydrous methylene chloride distills gained after being refluxed by methylene dichloride and Vanadium Pentoxide in FLAKES.
Embodiment 1
The preparation (by document J.Org.Chem., Vol.59, No.10, the method in 1994) of Compound C:
At 20 DEG C, in there-necked flask, add 4-methyl-5-hydroxy ethylthiazole (40g, 0.27mol), ethyl bromoacetate (37.1ml, 0.33mol), EtOH400ml, be warming up to backflow, stir 3 hours, stop heating, revolve and steam except desolventizing.Use CH
2cl
250g white solid B is obtained with Diethyl ether recrystallization.
At N
2under protection, by compd B (20g, 64.5mmol), 2-cyclopentenone (25g; 304.5mmol) add in reaction flask with anhydrous acetonitrile, at 25 DEG C, in suspension, slowly drip triethylamine (7.17g; 70.9mmol), dropwise, room temperature reaction 24h under nitrogen protection.In reaction solution, add 100ml shrend to go out reaction, use extracted with diethyl ether aqueous phase, merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, steam and desolventize to obtain 17.9g brown oil.Column chromatography obtains 13.6g C-1 and 2.0gC-2.
When Z is carbobenzoxy-(Cbz), the preparation (by document J.Org.Chem., Vol.59, No.10, the method in 1994) of compd E:
At 20 DEG C, in there-necked flask, add C-1 and C-2(3.5g, 11.25mmol), AIBN(278mg, 1.69mmol), three n-butyltin hydride (3.9ml, 14.63mmol) and dry toluene (35ml), at N
2protection under, be warming up to backflow, stir 8h, revolve and steam except desolventizing, obtain residue.By residue, 1N HCl(15ml, 14.3mmol) and ether (15ml) add in reaction flask, stirring at room temperature 14h, is extracted with ethyl acetate aqueous phase, fetch water congenial next step reaction.
At 20 DEG C, in there-necked flask, add previous step aqueous phase, ethyl acetate (30ml) and chloroformic acid benzyl ester (1.7ml, 12.4mmol), two phase liquid is cooled to 0 DEG C.In solution, slowly drip the 2NNaOH aqueous solution (15.8ml, 31.5mmol), dropwise, keep 0 DEG C to stir 1h, rise to 20 DEG C of reaction 3h.Be extracted with ethyl acetate aqueous phase, merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, revolve and steam except desolventizing, obtain yellow oil 2.8g, column chromatography obtains 2.4g white solid (compd E).
Embodiment 2
N is 0, R
1for ethyl, when Z is carbobenzoxy-(Cbz), the preparation of compound 1:
At N
2under protection, in there-necked flask, add compd E (2g, 6.04mmol), 1; 2-dithioglycol (0.8ml, 9.05mmol) and anhydrous methylene chloride (20ml), slowly drip boron trifluoride diethyl etherate (0.5ml in 20 DEG C of downhill reaction liquid; 3.13mmol), dropwise, stir 0.5h; add saturated sodium bicarbonate cancellation reaction, use dichloromethane extraction aqueous phase, merge organic phase; organic phase saturated common salt water washing; anhydrous sodium sulfate drying, is spin-dried for, and obtains 2.6g pale yellow oil.Column chromatography obtains 2.3g compound 1 for colorless oil, and yield is 92%.m/z(M+Na
+)430.01,
1H?NMR(400MHz,CDCl
3)δ1.16-1.27(m,3H),1.69(s,1H),2.15-2.35(m,3H),2.81-2.86(m,1H),3.01-3.06(m,1H),3.28(s,4H),3.51-3.59(m,1H),3.75-3.82(m,1H),4.07-4.30(m,3H)5.04-5.16(m,2H),7.26-7.36(m,5H)。
Embodiment 3
N is 1, R
1for ethyl, when Z is carbobenzoxy-(Cbz), the preparation of compound 1:
At N
2under protection; compd E (0.5g is added in there-necked flask; 1.51mmol), 1; 3-dimercaptopropane (0.25ml; 2.26mmol) with anhydrous methylene chloride (8ml); slowly drip boron trifluoride diethyl etherate (0.2ml, 1.25mmol) in 20 DEG C of downhill reaction liquid, dropwise; stir 0.5h; add saturated sodium bicarbonate (20ml) cancellation reaction, use dichloromethane extraction aqueous phase, merge organic phase; organic phase saturated common salt water washing; anhydrous sodium sulfate drying, is spin-dried for, and obtains 0.6g pale yellow oil.Through purification by silica gel column chromatography, obtain 0.5g compound 1 for colorless oil, yield is 93%.m/z(M+Na
+)444.01,
1HNMR(400MHz,CDCl
3)δ1.16-1.27(m,3H),1.69(s,1H),1.88-1.97(m,1H),2.11-2.13(m,3H),2.31-2.41(m,1H),2.72-2.91(m,3H),2.92-3.01(m,2H),3.26-3.32(m,1H),3.62-3.79(m,2H),4.07-4.09(m,1H),4.11-4.20(m,2H),5.03-5.29(m,2H),7.26-7.36(m,5H)。
Embodiment 4
Z is the preparation (preparation of Compound D is with embodiment 1) of the compd E of tertbutyloxycarbonyl:
At 20 DEG C, in there-necked flask, add the aqueous phase, tetrahydrofuran (THF) (30ml) and the tert-Butyl dicarbonate (2.8ml, 12.4mmol) that contain D compound in embodiment example 1, two phase liquid is cooled to 0 DEG C.In solution, slowly drip the 2N NaOH aqueous solution (15.8ml, 31.5mmol), dropwise, keep 0 DEG C to stir 1h, rise to 20 DEG C of reaction 3h.Be extracted with ethyl acetate aqueous phase, merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, revolve and steam except desolventizing, obtain yellow oil 2.4g, column chromatography obtains 2.0g colorless oil (compd E).
Embodiment 5
N is 0, R
1for ethyl, when Z is tertbutyloxycarbonyl, the preparation of compound 1:
At N
2under protection; compd E (0.5g is added in there-necked flask; 2.13mmol), 1; 2-dimercaptopropane (0.27ml; 3.19mmol) with anhydrous methylene chloride (8ml); slowly drip boron trifluoride diethyl etherate (0.2ml, 1.25mmol) in 20 DEG C of downhill reaction liquid, dropwise; stir 0.5h; add saturated sodium bicarbonate cancellation reaction, by methylene dichloride (20ml × 3) aqueous phase extracted, merge organic phase; organic phase saturated common salt water washing; anhydrous sodium sulfate drying, is spin-dried for, and obtains 0.6g pale yellow oil.Column chromatography obtains 0.5g compound 1 for colorless oil, and yield is 93%.m/z(MH
+)312.01
1H?NMR(400MHz,CDCl
3)δ1.17-1.28(m,3H),1.45(s,9H)1.70(s,1H),2.13-2.34(m,3H),2.83-2.86(m,1H),3.03-3.08(m,1H),3.28(s,4H),3.51-3.59(m,1H),3.75-3.82(m,1H),4.07-4.30(m,3H)。
Embodiment 6
N is 1, R
1for ethyl, when Z is tertbutyloxycarbonyl, the preparation of compound 1:
At N
2under protection, in there-necked flask, add compd E (0.5g, 2.13mmol), 1; 3-succinimide mercaptans (0.34ml, 3.19mmol) and anhydrous methylene chloride (8ml), slowly drip boron trifluoride diethyl etherate (0.2ml in 20 DEG C of downhill reaction liquid; 1.25mmol), dropwise, stir 0.5h; add saturated sodium bicarbonate cancellation reaction, use dichloromethane extraction aqueous phase, merge organic phase; organic phase saturated common salt water washing; anhydrous sodium sulfate drying, is spin-dried for, and obtains 0.6g pale yellow oil.Column chromatography obtains 0.5g compound 1 for colorless oil, and yield is 93%.m/z(MH
+)326.01
1H?NMR(400MHz,CDCl
3)δ1.16-1.27(m,3H),1.45(s,9H)1.69(s,1H),1.88-1.97(m,1H),2.11-2.13(m,3H),2.31-2.41(m,1H),2.72-2.91(m,3H),2.92-3.01(m,2H),3.26-3.32(m,1H),3.62-3.79(m,2H),4.07-4.09(m,1H),4.11-4.20(m,2H)。
Embodiment 7
N is 0, R
1for ethyl, when Z is carbobenzoxy-(Cbz), prepare compound 2 by compound 1:
At N
2under protection, in there-necked flask, add compound 1(2g, 4.91mmol), dehydrated alcohol (20ml), Raney's nickel (20g) stirs, and heat up (80 DEG C) are to backflow.After reaction 4h, filter, get filtrate, revolve and steam except desolventizing obtains 1.4g colourless liquid, obtain 1.0g compound 2 for colorless oil through silica gel column chromatography, yield is 64%.
Embodiment 8
N is 0, R
1for ethyl, when Z is tert.-butoxy, prepare compound 2 by compound 1:
At N
2under protection, in there-necked flask, add compound 1(2g, 6.43mmol), dehydrated alcohol (20ml), Raney's nickel (20g) stirs, and heat up (80 DEG C) are to backflow.After reaction 4h, filter, get filtrate, revolve and steam except desolventizing obtains 1.2g colourless liquid, obtain 0.86g compound 2 for colorless oil through silica gel column chromatography, yield is 61%.
Claims (14)
1. a preparation method for Telaprevir intermediate compound 2, is characterized in that, it comprises the steps: in organic solvent, under the effect of desulfuration reagent, compound 1 is carried out desulphurization reaction, can obtain compound 2;
Wherein, R
1for C
1-C
6straight or branched alkyl, n be 0,1 or 2, Z be amino protecting group.
2. preparation method as claimed in claim 1, is characterized in that, described R
1for C
1-C
4straight or branched alkyl; Described Z is tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or benzyl.
3. preparation method as claimed in claim 1, it is characterized in that, described desulfuration reagent is Raney's nickel; The mass ratio of described desulfuration reagent and compound 1 is (5:1 ~ 20:1), is preferably (5:1 ~ 15:1), is more preferably (5:1 ~ 10:1).
4. preparation method as claimed in claim 1, is characterized in that, described organic solvent is one or more in ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, alcoholic solvent, acetonitrile, DMF and DMSO.
5. preparation method as claimed in claim 4, is characterized in that, described ether solvent is one or more in ether, tetrahydrofuran (THF), methyl tertiary butyl ether and tetrahydropyrans; Described halogenated hydrocarbon solvent is one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride; Described aromatic hydrocarbon solvent is one or more in toluene, benzene, dimethylbenzene, Three methyl Benzene and chlorobenzene; Described alcoholic solvent is one or more in methyl alcohol, ethanol and Virahol.
6. preparation method as claimed in claim 1, it is characterized in that, the temperature of described desulphurization reaction is 20 ~ 120 DEG C, is preferably 40 ~ 100 DEG C, is more preferably 60 ~ 80 DEG C.
7. preparation method as claimed in claim 1, it is characterized in that, described compound 1 is obtained by following method: in solvent, under the effect of catalyzer, compd E and thiol reagent F is reacted, can obtain compound 1;
Then, according to the method for claim 1, compound 2 can be obtained.
8. preparation method as claimed in claim 7, it is characterized in that, described catalyzer is Lewis acid, is preferably one or more in boron trifluoride diethyl etherate, aluminum chloride and trifluoroacetic acid, is more preferably boron trifluoride diethyl etherate; Described catalyzer and the mol ratio of compd E are (0.1:1 ~ 1:1), are preferably (0.1:1 ~ 0.5:1), are more preferably (0.1:1 ~ 0.3:1).
9. preparation method as claimed in claim 7, is characterized in that, described solvent is one or more in ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, esters solvent, acetonitrile, DMF and DMSO.
10. preparation method as claimed in claim 9, is characterized in that, described ether solvent is one or more in ether, tetrahydrofuran (THF), methyl tertiary butyl ether and tetrahydropyrans; Described halogenated hydrocarbon solvent is one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride; Described aromatic hydrocarbon solvent is one or more in toluene, benzene, dimethylbenzene, Three methyl Benzene and chlorobenzene; Described esters solvent is ethyl acetate.
11. preparation methods as claimed in claim 7, is characterized in that, described thiol reagent F and the mol ratio of compd E are (1:1 ~ 5:1), are preferably (1:1 ~ 3:1), are more preferably (1:1 ~ 1.5:1).
12. preparation methods as claimed in claim 7, is characterized in that, the temperature of described reaction is 0 ~ 80 DEG C, is preferably 20 ~ 60 DEG C, is more preferably 20 ~ 30 DEG C.
13. 1 kinds of Telaprevir intermediate as shown in Equation 1,
Wherein, R
1, n and Z be as claimed in claim 1 or 2.
The preparation method of 14. 1 kinds of Telaprevir intermediate 1 as claimed in claim 13, is characterized in that, it comprises the steps: in solvent, under the effect of catalyzer, compd E and thiol reagent F is reacted, can obtain compound 1;
Wherein, each reaction conditions is according to any one of claim 7 ~ 12.
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| CN104926712A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN104926831A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
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| CN1451014A (en) * | 2000-08-31 | 2003-10-22 | 伊莱利利公司 | Peptidomimetic protease inhibitors |
| US20070087973A1 (en) * | 2005-08-19 | 2007-04-19 | Tanoury Gerald J | Processes and intermediates |
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| CN104926712A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN104926831A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN104926712B (en) * | 2014-03-20 | 2018-03-23 | 上海医药工业研究院 | Synthesize intermediate of VX-960 and preparation method thereof |
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