CN104926712A - Telaprevir synthesis intermediate and preparation method thereof - Google Patents
Telaprevir synthesis intermediate and preparation method thereof Download PDFInfo
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- CN104926712A CN104926712A CN201410106516.4A CN201410106516A CN104926712A CN 104926712 A CN104926712 A CN 104926712A CN 201410106516 A CN201410106516 A CN 201410106516A CN 104926712 A CN104926712 A CN 104926712A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title abstract description 6
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 title description 2
- 229960002935 telaprevir Drugs 0.000 title description 2
- 108010017101 telaprevir Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims abstract description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims abstract description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 8
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 abstract description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 abstract description 4
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- KWRNCAUXSJOYQO-ACZMJKKPSA-N (3s,3as,6ar)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-2-ium-3-carboxylate Chemical compound C1CC[C@@H]2[C@@H](C(=O)O)NC[C@@H]21 KWRNCAUXSJOYQO-ACZMJKKPSA-N 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 239000007868 Raney catalyst Substances 0.000 abstract 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- 108050000761 Serpin Proteins 0.000 description 2
- 102000008847 Serpin Human genes 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 239000003001 serine protease inhibitor Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MOQCFMZWVKQBAP-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)benzoyl]-n-(4-chlorophenyl)piperidine-3-carboxamide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)N2CC(CCC2)C(=O)NC=2C=CC(Cl)=CC=2)=C1 MOQCFMZWVKQBAP-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- FAOSYNUKPVJLNZ-UHFFFAOYSA-N butylstannane Chemical compound CCCC[SnH3] FAOSYNUKPVJLNZ-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- NNHOUIKFCCIVCI-UHFFFAOYSA-N cyclopenta[c]pyrrole Chemical class N1=CC2=CC=CC2=C1 NNHOUIKFCCIVCI-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000012991 xanthate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Abstract
The present invention provides a (1S, 3aR, 6aS)-octahydro-cyclopenta [c] pyrrole-1-carboxylic acid synthesis intermediate-compound c and a preparation method thereof, the method is as follows: a compound b is reduced in an alcohol solvent in the presence of raney nickel to obtain the compound c; the reaction conditions are as follows: reaction temperature is 70-90 DEG C, the alcohol solvent is selected from one or a plurality of methanol, ethanol, propanol, n-butyl alcohol, isopropyl alcohol, and tertiary butyl alcohol, the route VI shown in the specification; R1 in the chemical formula is selected from benzyl oxy carbonyl acyl group or tert-butyl oxy carbonyl group, R2 in the chemical formula is selected from C1-C4 alkyl groups. Through use of the new compound b, use of dangerous reagent sodium-hydrogen, and poisonousreagent carbon disulfide and methyl iodide and the like can be avoided in the subsequent synthesis method of the compound 1, the raw materials are cheap and readily available, operation is easy, and the yield of the compound 1 prepared by the method is equal to the yield of the compound 1 prepared by the method reported in original patent document WO02 / 18369.
Description
Technical field
The invention belongs to medical synthesis field, be specifically related to intermediate synthesizing VX-960 and preparation method thereof.
Background technology
Hepatitis C virus (hepatitis C virus, referred to as HCV) cause chronic hepatitis and and then one of the main pathogens developing into liver cirrhosis and hepatocellular carcinoma, in human population worldwide, hepatitis C virus infection rate is 0.1% ~ 10%.Be 3.2% at the infection rate of Chinese HCV, i.e. about 3,800 ten thousand population hepatitis C virus carrier.In recent years, the diagnosis of Chinese hepatitis C is improving constantly and hepatitis C latest report case also continues to increase; After HCV infection, the state of an illness is hidden, and 50% ~ 80% can be transformed into chronic hepatitis, if do not taked rational therapy, wherein the patient of 10% ~ 30% developed into liver cirrhosis most probably after 10 ~ 20 years, and 1% ~ 3% can develop into primary hepatocarcinoma, thus serious harm patient health and even life.
Infect HIV (human immunodeficiency virus) (HIV, or be called AIDS virus of AIDS) and the patient Shang Ke of hepatitis B virus (HBV) have efabirenz to treat, and for HCV, still lack effective vaccine at present, and the methods for the treatment of of nearly 20 years is mainly the conbined usage of Interferon, rabbit (IFN-α) or polyethyleneglycol modified long-acting IFN-α and broad-spectrum antiviral medicament ribavirin, this therapy for gene II type and Ш type patient curative effect comparatively remarkable, but it is only effective to the I type patient of about 40%, in addition the serious adverse reaction such as fash also have impact on it and uses.Find the important directions that HCV particular target is HCV-Ab IgG research to antiviral therapy medicine, along with the inhibitor VX-960 (Telaprevir) being target with serine protease HCV NS3/4A and IFN-α and ribavirin combined utilization clinically, HCV NS3/4A serpin more and more becomes study hotspot.
Patent WO02/18369 discloses the proteinase inhibitor being used for the treatment of HCV infection, particularly serpin series compound and synthesize the intermediate of these compounds, wherein, (1S, aR, 6aS)-octahydro cyclopenta [c] pyrroles-1-carboxylic acid [(1S, 3aR, 6aS)-octahydrocyclopenta [c] pyrrole-carboxylic acid, compound 1] be the key intermediate synthesizing VX-960 and its analogue, disclosed in this section of patent there is multiple deficiency in preparation method: complex operation and employ hazardous agents explosive substance sodium hydrogen (NaH) in crucial preparation process, poisonous reagent dithiocarbonic anhydride and methyl iodide, with reference to route II.The compound 11 that obtains in route II can prepare the key intermediate 1 of VX-960 through sloughing N-carbobenzoxy-(Cbz) and carboxyester hydrolysis two-step reaction.
Initial feed racemize-octahydro cyclopenta [c] pyrroles (compound 2) reported in patent WO07/109023 for the preparation of compound 1 is synthesized by biological method, therefore prepares expensive.
For (1S, aR, 6aS)-octahydro cyclopenta [c] pyrroles-1-carboxylic acid (compound 1), it is as synthesis VX-960 and a key intermediate of its analogue, still wishes to obtain the preparation method meeting suitability for industrialized production of safer, high yield and low cost urgently.
Document J.Org.Chem, provides the syntheti c route of racemic compound 6 in Vol.59,2773-2778 page, using thiazole derivative 9 as starting raw material, can prepare compound 6 through three-step reaction.
Summary of the invention
The present invention aims to provide a kind of for the synthesis of (1S, aR, intermediate-compound c of 6aS)-octahydro cyclopenta [c] pyrroles-1-carboxylic acid (compound 1) and preparation method thereof, relatively easily can be synthesized by this intermediate and obtain compound 1, see route IV.
Compound a can prepare compound d (R with reference to the method for route III
2=Et is compound 6), by N-protected on compound d, can compound a be prepared, see route V.
The invention provides a kind of method preparing compound c, comprise and compound b reduction in alcoholic solvent and under Raney's nickel exists is obtained compound c; Reaction conditions is: temperature of reaction is 70-90 DEG C, and described alcoholic solvent is selected from one or more in methyl alcohol, ethanol, propyl alcohol, propyl carbinol, Virahol, the trimethyl carbinol; See route VI; Wherein R in chemical formula
1be selected from benzyloxy carbonyl acyl group or tertbutyloxycarbonyl, R
2be selected from the alkyl of C1-C4.
At above-mentioned reaction formula (route VI), R in chemical formula
1preferred benzyloxy carbonyl acyl group.
At above-mentioned reaction formula (route VI), R in chemical formula
2preferred Me, Et or Pr; More preferably Et.
In a preferred embodiment, described alcoholic solvent is the trimethyl carbinol.More preferably, the amount that solvent uses is 1g compound b employing 50-100mL solvent, preferred 90-100mL.
In a preferred embodiment, the appropriate mass of compound b/ Raney's nickel consumption is than being 1:100-1:150, preferred 1:120.
In a preferred embodiment, temperature of reaction is 70-90 DEG C, is preferably 75-80 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can arbitrary combination, thus obtains each preferably embodiment of the present invention.
Positive progress of the present invention is to carry out synthetic compound c by a class novel compounds b, this compounds c may be used for preparing (the 1S as VX-960 key intermediate, aR, 6aS)-octahydro cyclopenta [c] pyrroles-1-carboxylic acid (1S, 3aR, 6aS)-octahydrocyclopenta [c] pyrrole-carboxylic acid (compound 1).Utilization obtains compound c and avoids using hazardous agents sodium hydrogen, poisonous reagent dithiocarbonic anhydride, methyl iodide etc. in the method for follow-up synthetic compound 1, cheaper starting materials is easy to get, simple to operate, and it is suitable to prepare the method that compound 1 yield and former patent documentation WO02/18369 report.
Term
Except as otherwise noted, the abbreviation min used herein refers to minute, and h refers to hour, and MS refers to mass spectroscopy, and NMR refers to nuclear magnetic spectrum analysis.
By the following examples to illustrate the present invention further; It should be pointed out that for those skilled in the art, without departing from the inventive concept of the premise, can also make some improvements and modifications, these improvements and modifications also should be considered within the scope of protection of the present invention.
Embodiment
The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.The all commercially available acquisition of agents useful for same of the present invention and raw material.
Embodiment 1
4g (13.4mmol) racemize-2-(benzyloxy carbonyl acyl group)-4-(carbonyl) octahydro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester is added in four-hole bottle, 1.36g (14.7mmol) 1,2-dithioglycol, 3.8g (26.8mmol) boron trifluoride diethyl etherate, 40ml methylene dichloride, stirred at ambient temperature 30min stopped reaction, wash 2 times (40ml*2) with saturated sodium bicarbonate solution, wash 1 time (40ml*1), anhydrous magnesium sulfate drying organic phase, suction filtration, is spin-dried for, and obtains target compound 4g (yield 96%); MS (m/z): 407.12 [M+H]
+;
1hNMR (CDCl
3.400MHz) δ: 1.1-1.2 (t, 3H), 1.65-1.68 (m, 1H), 2.0-2.21 (m, 2H), 2.21-2.34 (m, 2H), 2.85-2.852 (m, 1H), 3.0-3.05 (m, 1H), 3.27-3.276 (m, 4H), 3.5-3.8 (m, 2H), 4.0-4.2 (m, 2H), 5.0-5.1 (m, 2H), 7.2-7.4 (m, 5H).
Embodiment 2
7.62g (18.7mmol) compound 12 is added in four-hole bottle; 76.2g (10 times of massfractions) Raney's nickel; the 700mL trimethyl carbinol; logical nitrogen protection; back flow reaction 8h stopped reaction; suction filtration, is spin-dried for and obtains 3.8g target compound (yield 65%), MS (m/z): 317.16 [M+H]
+.
Embodiment 3
10.4g(35mmol is added in four-hole bottle) racemize-2-(tert-butoxycarbonyl)-4-(carbonyl) octahydro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester, 3.5g (38.5mmol) 1,2-dithioglycol, 10g (70mmol) boron trifluoride diethyl etherate, 100mL methylene dichloride, stirred at ambient temperature 30min stopped reaction, wash 2 times (100ml*2) with saturated sodium bicarbonate solution, wash 1 time (100ml*1), anhydrous magnesium sulfate drying organic phase, is spin-dried for.Obtain target compound 9.1g (yield 95%) MS (m/z): 274.09 [M+H]
+;
1hNMR (CDCl
3.400MHz) δ: 1.1-1.2 (t, 3H), 1.65-1.68 (m, 1H), 2.0-2.21 (m, 2H), 2.21-2.34 (m, 2H), 2.85-2.852 (m, 1H), 3.0-3.05 (m, 1H), 3.27-3.276 (m, 4H), 3.5-3.8 (m, 2H), 4.0-4.2 (m, 2H), 8.1-8.12 (s, 1H, D
2o exchanges disappearance).
Comparative example
Embodiment 6
Add 12.18g (36.6mmol) compound 13,120mL ethanol in four-hole bottle, stir and make it dissolve, cryosel bath makes temperature drop to 0 DEG C, add 1.44g sodium borohydride in batches, add and slowly rise to room temperature, continue to stir 30min, add 4.5ml acetic acid termination reaction, ethanol is spin-dried for, adds 350ml ethyl acetate, respectively with saturated ammonium chloride solution and saturated sodium bicarbonate solution washing, drying, is spin-dried for.Obtain 11.5g compound 14 (yield 95%), MS (m/z): 333.14 [M+H]
+.
Embodiment 7
4.8 (14.4mmol) compound 14 is added in four-hole bottle, 120ml tetrahydrofuran (THF), be cooled to-5 DEG C, slowly add the sodium hydrogen of 1.17g (28.8mmol) 60%, add, slowly rise to room temperature, continue to stir 12h, add 29.7g (388.8mmol) dithiocarbonic anhydride, 13.2ml (17.3mmol) methyl iodide, room temperature for overnight.Be spin-dried for by tetrahydrofuran (THF), add 120ml methyl tertiary butyl ether, with saturated common salt water washing twice, dry organic phase, is spin-dried for, and the xanthate compound 12 obtained directly is cast single step reaction.
Embodiment 8
Crude product obtained in embodiment 4 is added in four-hole bottle; 0.237g (1.44mmol) Diisopropyl azodicarboxylate; 5.8ml (21.6mmol) three n-butyltin hydride; 120mL toluene; logical nitrogen protection, is heated to 90 DEG C of reaction 3h, toluene is spin-dried for the crude product obtaining 2.17g compound 11; crude yield is 60%, MS (m/z): 317.16 [M+H]
+.
Claims (9)
1. the preparation method of compound c, comprises and compound b reduction in alcoholic solvent and under Raney's nickel exists is obtained compound c; Reaction conditions is: temperature of reaction is 70-90 DEG C, and described alcoholic solvent is selected from one or more in methyl alcohol, ethanol, propyl alcohol, propyl carbinol, Virahol, the trimethyl carbinol; See route VI; R wherein in chemical formula
1be selected from benzyloxy carbonyl acyl group or tertbutyloxycarbonyl, R
2be selected from the alkyl of C1-C4,
2. preparation method according to claim 1, wherein R in chemical formula
1be selected from benzyloxy carbonyl acyl group.
3. preparation method according to claim 1, the R wherein in chemical formula
2be selected from Me, Et or Pr.
4. the preparation method according to claim 1-3 any one, wherein, described alcoholic solvent is the trimethyl carbinol.
5. the preparation method according to claim 1-3 any one, wherein, the amount that described alcoholic solvent uses is 1g compound b employing 60-100mL solvent.
6. preparation method according to claim 5, wherein, the amount that described alcoholic solvent uses is 1g compound b employing 50-100mL solvent.
7. the preparation method according to claim 1-3 any one, wherein, the appropriate mass of described compound b/ Raney's nickel consumption is than being 1:100-1:150.
8. preparation method according to claim 5, wherein, the appropriate mass of described compound b/ Raney's nickel consumption is than being 1:120.
9. preparation method according to claim 1, wherein, described temperature of reaction is 75-80 DEG C.
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