CN103113288B - Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative - Google Patents
Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative Download PDFInfo
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Abstract
The invention relates to a synthesis method of a telaprevir intermediate octahydro-cyclopenta[c]pyrrole carboxylic acid derivative, which belongs to the technical field of pharmaceutical synthesis. The synthesis method comprises the following steps: dissolving a compound shown in formula (I) in a solvent, and adding a reducing agent for reducing ketonic groups to hydroxyl, thereby obtaining a compound shown in formula (II); dissolving the compound shown in formula (II) in a solvent, and under the action of organic alkali and a dehydrating agent, forming a carbon-carbon double bond, thereby obtaining a compound shown in formula (III); dissolving the compound shown in formula (III) in an organic solvent, carrying out hydrogenation reduction on the obtained object under the action of a catalyst so as to obtain a compound shown in formula (IV), and the synthetic route is described in the specification, wherein PG refers to protecting groups over N, and the protecting groups include benzyl, p-methoxybenzyl, benzyloxycarbonyl, triphenylmethyl, t-butyloxycarboryl, acetyl and fluorenl methoxy carbonyl; and R refers to hydrogen, alkyl or cycloalkyl with the carbon atom numbers of less than or equal to 6, halogenated alkyl, aryl or heteroaryl. The method is short in synthetic route, and suitable for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, particularly relate to a kind of synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative, belong to technical field of medicine synthesis.
Background technology
VX-960 (telaprevir) is the treatment hepatitis C new drug being developed listing by Vertex drugmaker, get permission and Peg-IFN alpha-2b α and ribavirin coupling, treat the patient of the anti-infectives treatment based on without Interferon, rabbit or the patient not good to this type of therapeutic response.Chemistry (the 1S by name of VX-960,3aR, 6aS)-(2S)-2-Cyclohexyl-N-(pyrainylcarbonyl) glycyl-3-methyl-L-valyl-N-((1S)-1-((cyclopropylamino) oxoacetyl) butyl) octahydrocyclopenta [c] pyrrole-1-carboxamide, the CAS number of logining: 402957-28-2, its chemical structural formula is:
Octahydro cyclopenta [c] pyrrole carboxylic acid derivative is a kind of important intermediate of synthesis VX-960, and its structural formula is:
chinese patent application file (publication number: CN101633636A) and Chinese patent application file (publication number: CN101696232A) disclose a kind of synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative, and synthetic route is as follows:
But need in this reaction scheme to use ignition control compound sodium hydride, dithiocarbonic anhydride and highly toxic product methyl iodide, there is potential safety hazard, be not suitable for large-scale industrial production.
The synthetic method of another octahydro cyclopenta [C] pyrrole carboxylic acid derivative is then disclosed in Chinese patent application file (publication number: CN102167680A).Octahydro cyclopenta [C] pyrroles that the method is protected with N, for raw material, with the one in tetrahydrofuran (THF), methyl tertiary butyl ether, dioxane for solvent, adds chiral organic ligand.-50 DEG C ~-78 DEG C time and lithium alkylide reaction 2 ~ 3 hours, then with carbon dioxide or Vinyl chloroformate reaction, obtain octahydro cyclopenta [c] pyrrole carboxylic acid derivative.The synthetic route of the method is as follows:
Although the method can a step complete, synthetic route is short, its severe reaction conditions, need react, be also difficult to applicable large-scale industrial production under the condition of very low temperature and anhydrous and oxygen-free.
Summary of the invention
The object of the invention is to for exist in prior art deficiency, a kind of synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative of applicable large-scale industrial production is provided.
Above-mentioned purpose of the present invention can be realized by following technical proposal: a kind of synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative, and this synthetic method comprises the following steps:
S1, ketone group reduction react: formula (I) compound is dissolved in solvent, and adds reductive agent in this solvent, make the ketone group reduction in formula (I) compound become hydroxyl to obtain formula (II) compound, the structural formula of its Chinese style (I) and formula (II) compound is as follows:
S2, eliminative reaction: formula (II) compound obtained in step S1 is dissolved in solvent, under the effect of organic bases and dewatering agent, formula (II) compound dehydration closed-loop forms carbon-carbon double bond, and obtain formula (III) compound, the structural formula of its Chinese style (III) compound is as follows:
S3, hydrogenation reduction: formula (III) compound obtained in step S2 is dissolved in organic solvent, carbon-carbon double bond under the effect of catalyzer in hydrogenating reduction formula (III) compound closed loop, obtain formula (IV) compound, the structural formula of its Chinese style (IV) compound is as follows:
wherein, PG is the protecting group on N, comprises benzyl, to methoxy-benzyl, carbobenzoxy-(Cbz), trityl, tertbutyloxycarbonyl, ethanoyl, fluorenylmethyloxycarbonyl; R is hydrogen, carbon atom number be less than or equal to 6 alkyl or cycloalkyl, haloalkyl, one or more in aryl or heteroaryl.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, in step sl, described solvent is one or both mixtures in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, ethylene glycol, the trimethyl carbinol, dioxane, tetrahydrofuran (THF), DMF, methyl-sulphoxide and water.
As preferably, solvent described is in step sl methyl alcohol, ethanol, Virahol.Methyl alcohol, ethanol, Virahol and other solvent phase ratios, process simple convenient operation in the reaction, and the intermediate yield that reduction obtains is high, purity is high.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, in step sl, described reductive agent is one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, zinc borohydride, tetrahydrochysene lithium aluminium.The mol ratio of described reductive agent and formula (I) compound is (1 ~ 2): 1.
As preferably, reductive agent described is in step sl sodium borohydride, POTASSIUM BOROHYDRIDE.Compared with other reductive agents, sodium borohydride, POTASSIUM BOROHYDRIDE are cheap and easy to get, good stability, convenient storage and use.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, described step S1 specifically comprises the steps: formula (I) compound to be dissolved in solvent forming reactions liquid, first reaction solution is cooled to-5 ~ 5 DEG C, then adds reductive agent in batches.After having fed in raw material, reaction solution is risen to room temperature and continue stirring 1 ~ 3 hour.After formula (I) compound is completely reduced, concentrated except desolventizing.Resistates is poured into water, concentrates to obtain formula (II) compound with after organic solvent extraction product.
As preferably, described step S1 comprises the steps: (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester to be dissolved in ethanol forming reactions liquid further, first reaction solution is cooled to 0 DEG C, then adds sodium borohydride in batches.Reaction solution is risen to stirring at room temperature 2 hours after having fed in raw material.After treating that (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester is completely reduced, concentrated removing ethanol.Resistates is poured into water, is extracted with ethyl acetate this reaction solution and obtains extraction liquid three times.Merging, concentrated extract obtain formula (II) compound.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, in step s 2, described organic bases is one or more in triethylamine, diisopropylethylamine, DMAP.The mol ratio of described organic bases and formula (II) compound is (2 ~ 4): 1.
As preferably, organic bases described is in step s 2 triethylamine, diisopropylethylamine.Compared with other organic basess, triethylamine and diisopropylethylamine reaction yield is in the present reaction high.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, in step s 2, described solvent is one or more in methylene dichloride, trichloromethane, 1,2-ethylene dichloride, chlorobenzene, acetonitrile, toluene, tetrahydrofuran (THF), methyl tertiary butyl ether, ether.
As preferably, solvent described is in step s 2 methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrahydrofuran (THF).Solvent preferably and other solvent phase ratios, can make reaction yield higher.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, in step s 2, described dewatering agent is one or more in formic anhydride, diacetyl oxide, trifluoroacetic anhydride.The mol ratio of described dewatering agent and formula (II) compound is (2 ~ 4): 1.
As preferably, dewatering agent described is in step s 2 trifluoroacetic anhydride, diacetyl oxide.Trifluoroacetic anhydride, diacetyl oxide, compared with other dewatering agents, have the reaction times short, yield advantages of higher.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, described step S2 specifically comprises the steps: formula (II) compound obtained in step S1 and organic bases to add solvent successively, is stirred to forming reactions liquid after all dissolving.First reaction solution is cooled to-5 ~ 5 DEG C, then dewatering agent is added reaction solution, stirring 1 ~ 3 is little forms carbon-carbon double bond up to formula (II) compound dehydration closed-loop.Then wash described reaction solution with weak alkaline aqueous solution, organic phase drying is concentrated to obtain formula (III) compound afterwards.
As preferably, described step S2 comprises the steps: (1S obtained in step S1 further, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester and triethylamine add methylene dichloride successively, are stirred to forming reactions liquid after all dissolving.First reaction solution is cooled to 0 DEG C, then trifluoroacetic anhydride is added in reaction solution.Reaction solution continues stirring 2 after rising to room temperature little of (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester dehydration closed-loop formation carbon-carbon double bond.Then saturated sodium bicarbonate aqueous solution washing reaction liquid twice is used, organic phase uses saturated common salt water washing once again, with anhydrous sodium sulfate drying, concentrate to obtain (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-3,3a, 6,6a-tetrahydro cyclopentyl alkene is [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester also.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, in step s3, described organic solvent is one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, ethylene glycol, ethyl acetate, tetrahydrofuran (THF).
As preferably, organic solvent described is in step s3 methyl alcohol, ethanol, propyl alcohol, Virahol.Described preferably after organic solvent the reaction times can be made short, yield is high.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, in step s3, described catalyzer is Raney's nickel, and the mass ratio of described catalyzer and formula (III) compound is (0.08 ~ 0.12): 1.
In the synthetic method of described octahydro cyclopenta [c] pyrrole carboxylic acid derivative, described step S3 specifically comprises the steps: formula (III) compound, organic solvent and catalyzer obtained in step S2 to add autoclave forming reactions liquid successively, after having fed in raw material, the air in autoclave is first used nitrogen replacement three times, then pass into the hydrogen of 0.5 ~ 2.0MPa.Stir 5 ~ 7 little carbon-carbon double bonds in formula (III) compound to be at ambient temperature completely reduced.Then reacting liquid filtering is obtained filtrate and filter cake, reclaim the catalyzer in filter cake, concentrated filtrate obtains formula (IV) compound, is octahydro cyclopenta [c] pyrrole carboxylic acid derivative.The catalyzer that recovery obtains is capable of circulation to be applied mechanically, cost-saving.
As preferably, described step S3 comprises the steps: (1S obtained in step S2 further, 3aR, 6aS)-2-tertbutyloxycarbonyl-3,3a, 6,6a-tetrahydro cyclopentyl alkene also [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester, ethanol and Raney's nickel add autoclave forming reactions liquid successively, fed in raw material rear first with nitrogen by the air displacement in autoclave three times, then pass into 1.0MPa hydrogen.Stir 6 little carbon-carbon double bonds in (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-3,3a, 6,6a-tetrahydro cyclopentyl alkene also [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester to be at ambient temperature completely reduced.Then reacting liquid filtering is obtained filtrate and filter cake, reclaim the catalyzer in filter cake, concentrated filtrate obtains (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-octahydro cyclopenta [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester.
The chemical equation of synthetic method of the present invention is as follows:
In sum, the present invention has the following advantages:
1, the raw material used in synthetic method of the present invention is cheap and easy to get, environmental protection, does not use poisonous to go back original reagent and catalyzer, there is not potential safety hazard, and the recyclable recycled of catalyzer.
2, the synthetic route in synthetic method of the present invention is short, and reaction conditions is simple, and production process is simple and direct, is convenient to large-scale industrial production.
3, hydrogenation reduction mild condition in synthetic method of the present invention, transformation efficiency is high, generate by product few, product octahydro cyclopenta [c] the pyrrole carboxylic acid derivative yield finally obtained and purity high, good product quality, can as the high-quality intermediate of synthesis VX-960.
Accompanying drawing explanation
Fig. 1 is the liquid chromatogram of (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-octahydro cyclopenta [c] pyrroles-1,2 (the 1H)-1-carboxylic acid, ethyl ester adopting synthetic method of the present invention to prepare.
Embodiment
Be below specific embodiments of the invention and by reference to the accompanying drawings, technical scheme of the present invention is further described, but the present invention be not limited to these embodiments.
Embodiment 1
(1S, 3aR, 6aS) the preparation of-2-tertbutyloxycarbonyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester: add 10g(1S in reaction flask, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester is dissolved in 100ml ethanol forming reactions liquid.First reaction solution is cooled to 0 DEG C, then 1.89g sodium borohydride is joined in reaction solution in batches.Reaction solution is risen to stirring at room temperature 2 hours after having fed in raw material.After treating that (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester is completely reduced, concentrated removing ethanol.Poured into by resistates in 50ml water, be extracted with ethyl acetate three times to obtain extraction liquid, merging, concentrated extract obtain 10g (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester.
(1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-3,3a, 6,6a-tetrahydro cyclopentyl alkene also [c] pyrroles-1, the preparation of 2 (1H)-1-carboxylic acid, ethyl ester: by described obtained 10g (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester and 10.1g triethylamine add reaction flask successively and be dissolved in 100ml methylene dichloride, is stirred to forming reactions liquid after all dissolving.Question response liquid is cooled to 0 DEG C, is slowly added in reaction solution by 13.9g trifluoroacetic anhydride.Reaction solution continues stirring 2 after rising to room temperature little of (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid, ethyl ester dehydration closed-loop formation carbon-carbon double bond.Then saturated sodium bicarbonate aqueous solution washing reaction liquid twice is used, organic phase uses saturated common salt water washing once again, with anhydrous sodium sulfate drying, concentrate to obtain 7.5g (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-3,3a, 6,6a-tetrahydro cyclopentyl alkene is [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester also.
(1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-octahydro cyclopenta [c] pyrroles-1, the preparation of 2 (1H)-1-carboxylic acid, ethyl ester: by described obtained 6g (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-3,3a, 6,6a-tetrahydro cyclopentyl alkene also [c] pyrroles-1,2(1H)-1-carboxylic acid, ethyl ester, 60ml ethanol and 0.6g Raney's nickel add forming reactions liquid in autoclave successively, fed in raw material rear first with nitrogen by the air displacement in autoclave three times, then by 1.0MPa hydrogen.Stir 6 little carbon-carbon double bonds in (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-3,3a, 6,6a-tetrahydro cyclopentyl alkene also [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester to be at ambient temperature completely reduced.Then reacting liquid filtering is obtained filtrate and filter cake, reclaim the catalyzer in filter cake, concentrated filtrate obtains 6g (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-octahydro cyclopenta [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester.
Embodiment 2
(1S, 3aR, 6aS) the preparation of-2-trityl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylate methyl ester: add 17g (1S in reaction flask, 3aR, 6aS)-2-trityl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylate methyl ester is dissolved in 120ml the formation of methanol reaction solution.First reaction solution is cooled to 2 DEG C, then 3.28g POTASSIUM BOROHYDRIDE is joined in reaction solution in batches.Reaction solution is risen to stirring at room temperature 3 hours after having fed in raw material.After treating that (1S, 3aR, 6aS)-2-trityl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylate methyl ester is completely reduced, concentrated removing methyl alcohol.Poured into by resistates in 60ml water, be extracted with ethyl acetate three times to obtain extraction liquid, merging, concentrated extract obtain 17g (1S, 3aR, 6aS)-2-trityl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylate methyl ester.
(1S, 3aR, 6aS)-2-trityl-1,2,3,3a, the preparation of 6,6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylate methyl ester: by described obtained 17g (1S, 3aR, 6aS)-2-trityl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylate methyl ester and 15.4g diisopropylethylamine add reaction flask successively and are dissolved in 150ml methylene dichloride, are stirred to forming reactions liquid after all dissolving.Question response liquid is cooled to 2 DEG C, is slowly added in reaction solution by 6.0g diacetyl oxide.Reaction solution continues stirring 3 after rising to room temperature little of (1S, 3aR, 6aS)-2-trityl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylate methyl ester dehydration closed-loop formation carbon-carbon double bond.Then use saturated sodium bicarbonate aqueous solution washing reaction liquid twice, organic phase uses saturated common salt water washing once again, with anhydrous sodium sulfate drying, concentrates to obtain 13.3g(1S, 3aR, 6aS)-2-trityl-1,2,3,3a, 6,6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylate methyl ester.
(1S, 3aR, 6aS) preparation of-2-trityl-octahydro cyclopenta [c] pyrroles-1-carboxylate methyl ester: by described obtained 10g(1S, 3aR, 6aS)-2-trityl-1,2,3,3a, 6,6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylate methyl ester, 100ml methyl alcohol and 0.9 Raney's nickel add autoclave forming reactions liquid successively, fed in raw material rear first with nitrogen by the air displacement in autoclave three times, then pass into 1.0MPa hydrogen.Stirring 7 is little is at ambient temperature completely reduced up to (1S, 3aR, 6aS)-2-trityl-1,2,3,3a, 6,6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylate methyl ester.Then reacting liquid filtering is obtained filtrate and filter cake, reclaim the catalyzer in filter cake, concentrated filtrate obtains 10g (1S, 3aR, 6aS)-2-trityl-octahydro cyclopenta [c] pyrroles-1-carboxylate methyl ester.
Embodiment 3
(1S; 3aR; 6aS) the preparation of-2-ethanoyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid: add 9g (1S in reaction flask; 3aR, 6aS)-2-ethanoyl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylic acid is dissolved in 100ml Virahol forming reactions liquid.First reaction solution is cooled to-1 DEG C, then 2.0g sodium borohydride is joined in reaction solution in batches.Reaction solution is risen to stirring at room temperature 1 hour after having fed in raw material.After treating that (1S, 3aR, 6aS)-2-ethanoyl-4-oxo octahydro cyclopenta [c] pyrroles-1-carboxylic acid is completely reduced, concentrated removing Virahol.Poured into by resistates in 50ml water, be extracted with ethyl acetate three times to obtain extraction liquid, merging, concentrated extract obtain 9g (1S, 3aR, 6aS)-2-ethanoyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid.
(1S; 3aR; 6aS)-2-ethanoyl-1,2,3; 3a; the preparation of 6,6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylic acid: by described obtained 9g (1S, 3aR; 6aS)-2-ethanoyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid and 12.7g triethylamine add reaction flask successively and are dissolved in 100ml methylene dichloride, are stirred to forming reactions liquid after all dissolving.Question response liquid is cooled to-1 DEG C, is slowly added in reaction solution by 7.2g diacetyl oxide.Reaction solution continues stirring 1 after rising to room temperature little of (1S, 3aR, 6aS)-2-ethanoyl-4-hvdroxv-octahvdro cyclopenta [c] pyrroles-1-carboxylic acid dehydration closed-loop formation carbon-carbon double bond.Then use saturated sodium bicarbonate aqueous solution washing reaction liquid twice, organic phase uses saturated common salt water washing once again, with anhydrous sodium sulfate drying, concentrates to obtain 7.2g (1S, 3aR; 6aS)-2-ethanoyl-1,2,3; 3a, 6,6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylic acid.
(1S; 3aR, 6aS) preparation of-2-ethanoyl-octahydro cyclopenta [c] pyrroles-1-carboxylic acid: by described obtained 6g (1S, 3aR; 6aS)-2-ethanoyl-1; 2,3,3a; 6; 6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylic acid, 60ml propyl alcohol and 0.6g Raney's nickel add autoclave forming reactions liquid successively, fed in raw material rear first with nitrogen by the air displacement in autoclave three times, then pass into 1.0MPa hydrogen.Stirring 5 is little is at ambient temperature completely reduced up to (1S, 3aR, 6aS)-2-ethanoyl-1,2,3,3a, 6,6a-six hydrogen cyclopenta [c] pyrroles-1-carboxylic acid.Then reacting liquid filtering is obtained filtrate and filter cake, reclaim the catalyzer in filter cake, concentrated filtrate obtains 6g (1S, 3aR, 6aS)-2-ethanoyl-octahydro cyclopenta [c] pyrroles-1-carboxylic acid.
The sample randomly drawing octahydro cyclopenta [c] pyrrole carboxylic acid derivative prepared in embodiment of the present invention 1-3 carries out liquid chromatographic detection.
The liquid chromatographic detection of (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-octahydro cyclopenta [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester as follows.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatograph;
Chromatographic column: Luna C18,4.6mm × 250mm, 5 μm;
Column temperature: 25 DEG C;
Flow velocity: 1.0ml/min;
Determined wavelength: 210nm;
Sampling volume: 5ul;
Mobile phase A: 0.1% phosphate aqueous solution;
Mobile phase B: acetonitrile;
Gradient elution program:
| Time | 0 | 0→15 | 15→25 | 25→25.1 | 25.1→30 |
| A% | 90 | 90→20 | 20 | 20→90 | 90 |
| B% | 10 | 10→80 | 80 | 80→10 | 10 |
Working time: 30min.
After detecting, as shown in Figure 1, analytical results is as shown in table 1 for the liquid chromatogram of sample.
Table 1: (1S, 3aR, 6aS)-2-tertbutyloxycarbonyl-octahydro cyclopenta [c] pyrroles-1,2 (1H)-1-carboxylic acid, ethyl ester sample chromatogram analytical results obtained in the embodiment of the present invention 1
As can be seen from Fig. 1 and table 1: octahydro cyclopenta [c] the pyrrole carboxylic acid derivative purity adopting synthetic method of the present invention obtained is higher, reaches 98.74%.
Specific embodiment described herein is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.
Claims (6)
1. a synthetic method for octahydro cyclopenta [c] pyrrole carboxylic acid derivative, is characterized in that, this synthetic method comprises the following steps:
S1, ketone group reduction react: formula (I) compound is dissolved in solvent, and reductive agent is added in this solvent, make the ketone group reduction in formula (I) compound become hydroxyl to obtain formula (II) compound, the structural formula of its Chinese style (I) and formula (II) compound is as follows:
S2, eliminative reaction: formula (II) compound obtained in step S1 is dissolved in solvent, under the effect of organic bases and dewatering agent, formula (II) compound dehydration closed-loop forms carbon-carbon double bond, obtain formula (III) compound, described organic bases is one or both in triethylamine, diisopropylethylamine, and the mol ratio of described organic bases and formula (II) compound is (2 ~ 4): 1; Described dewatering agent is one or both in diacetyl oxide, trifluoroacetic anhydride, and the mol ratio of described dewatering agent and formula (II) compound is (1 ~ 3): 1; The structural formula of its Chinese style (III) compound is as follows:
S3, hydrogenation reduction: formula (III) compound obtained in step S2 is dissolved in organic solvent, carbon-carbon double bond under the effect of catalyzer in hydrogenating reduction formula (III) compound closed loop, obtain formula (IV) compound, described catalyzer is Raney's nickel, the mass ratio of described catalyzer and formula (III) compound is (0.08 ~ 0.12): 1, and the structural formula of its Chinese style (IV) compound is as follows:
Described step S2 specifically comprises the steps: formula (II) compound obtained in step S1 and organic bases to add solvent successively, be stirred to forming reactions liquid after all dissolving, first reaction solution is cooled to-5 ~ 5 DEG C, again dewatering agent is added reaction solution, stirring 1 ~ 3 is little forms carbon-carbon double bond up to formula (II) compound dehydration closed-loop, then wash described reaction solution with weak alkaline aqueous solution, organic phase drying is concentrated to obtain formula (III) compound afterwards;
In step s 2, described solvent is one or more in methylene dichloride, trichloromethane, 1,2-ethylene dichloride;
PG is the protecting group on N, and this protecting group is benzyl, to methoxy-benzyl, carbobenzoxy-(Cbz), trityl, tertbutyloxycarbonyl, ethanoyl, fluorenylmethyloxycarbonyl; R is hydrogen, carbonatoms be less than or equal to 6 alkyl or the carbonatoms cycloalkyl, the carbonatoms that are less than or equal to 6 haloalkyl, the carbonatoms that are less than or equal to 6 be less than or equal to 6 aryl or carbonatoms be less than or equal to 6 heteroaryl.
2. the synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative according to claim 1, it is characterized in that, in step sl, described solvent is one or both mixtures in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, ethylene glycol, the trimethyl carbinol.
3. the synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative according to claim 1 and 2, it is characterized in that, in step sl, described reductive agent is one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, zinc borohydride, tetrahydrochysene lithium aluminium, and the mol ratio of described reductive agent and formula (I) compound is (1 ~ 2): 1.
4. the synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative according to claim 3, it is characterized in that, described step S1 specifically comprises the steps: formula (I) compound to be dissolved in solvent forming reactions liquid, first reaction solution is cooled to-5 ~ 5 DEG C, add reductive agent more in batches, after having fed in raw material, reaction solution is risen to room temperature and continue stirring 1 ~ 3 hour, after formula (I) compound is completely reduced, concentrated except desolventizing, resistates is poured into water, concentrates to obtain formula (II) compound with after organic solvent extraction product.
5. the synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative according to claim 1, is characterized in that, in step s3, described organic solvent is one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, ethylene glycol.
6. the synthetic method of octahydro cyclopenta [c] pyrrole carboxylic acid derivative according to claim 5, it is characterized in that, described step S3 specifically comprises the steps: formula (III) compound obtained in step S2, organic solvent and catalyzer add autoclave forming reactions liquid successively, after having fed in raw material, the air in autoclave is first used nitrogen replacement three times, pass into the hydrogen of 0.5 ~ 2.0MPa again, stir 5 ~ 7 little carbon-carbon double bonds in formula (III) compound to be at ambient temperature completely reduced, then reacting liquid filtering is obtained filtrate and filter cake, reclaim the catalyzer in filter cake, concentrated filtrate obtains formula (IV) compound, be octahydro cyclopenta [c] pyrrole carboxylic acid derivative.
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