CN101445475A - Method for preparing (trans)-4-cyclohexyl-L-proline - Google Patents
Method for preparing (trans)-4-cyclohexyl-L-proline Download PDFInfo
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- CN101445475A CN101445475A CNA200810163751XA CN200810163751A CN101445475A CN 101445475 A CN101445475 A CN 101445475A CN A200810163751X A CNA200810163751X A CN A200810163751XA CN 200810163751 A CN200810163751 A CN 200810163751A CN 101445475 A CN101445475 A CN 101445475A
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- cyclohexyl
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- 238000000034 method Methods 0.000 title claims abstract description 18
- XRZWVSXEDRYQGC-ZJUUUORDSA-N (2s,4s)-4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1N[C@H](C(=O)O)C[C@H]1C1CCCCC1 XRZWVSXEDRYQGC-ZJUUUORDSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 35
- 239000003054 catalyst Substances 0.000 claims abstract description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910000510 noble metal Inorganic materials 0.000 claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000012429 reaction media Substances 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 7
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 6
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 5
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 52
- 239000000706 filtrate Substances 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- 238000002360 preparation method Methods 0.000 claims description 31
- 238000001914 filtration Methods 0.000 claims description 26
- 238000007599 discharging Methods 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 18
- 238000001291 vacuum drying Methods 0.000 claims description 16
- 229960002429 proline Drugs 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 238000009835 boiling Methods 0.000 claims description 12
- 239000010970 precious metal Substances 0.000 claims description 12
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 10
- 230000006837 decompression Effects 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- -1 therefore Substances 0.000 abstract description 4
- 208000012839 conversion disease Diseases 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- JHHOFXBPLJDHOR-ZJUUUORDSA-N (2s,4s)-4-phenylpyrrolidin-1-ium-2-carboxylate Chemical compound C1N[C@H](C(=O)O)C[C@H]1C1=CC=CC=C1 JHHOFXBPLJDHOR-ZJUUUORDSA-N 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 130
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 65
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 230000009466 transformation Effects 0.000 description 32
- 238000010268 HPLC based assay Methods 0.000 description 25
- 238000001816 cooling Methods 0.000 description 25
- 239000003643 water by type Substances 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 238000003756 stirring Methods 0.000 description 14
- 238000005303 weighing Methods 0.000 description 9
- 101150003085 Pdcl gene Proteins 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 239000008098 formaldehyde solution Substances 0.000 description 7
- 238000013019 agitation Methods 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 238000000643 oven drying Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 4
- 239000005541 ACE inhibitor Substances 0.000 description 4
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 4
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229960002490 fosinopril Drugs 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 239000010948 rhodium Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000004904 shortening Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical class [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- HOBJEFOCIRXQKH-UHFFFAOYSA-N 5-(hydroxymethyl)pyrrolidin-2-one Chemical compound OCC1CCC(=O)N1 HOBJEFOCIRXQKH-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 101001044245 Arabidopsis thaliana Insulin-degrading enzyme-like 1, peroxisomal Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- TVTJZMHAIQQZTL-WATAJHSMSA-M sodium;(2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylate Chemical compound [Na+].C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C([O-])=O)CCCC1=CC=CC=C1 TVTJZMHAIQQZTL-WATAJHSMSA-M 0.000 description 1
- 230000009441 vascular protection Effects 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a method for preparing (trans)-4-cyclohexyl-L-proline as shown in formula (II), and the method is as follows: (trans)-4-phenyl-L-proline as shown in formula (I) is taken as raw material, the direct catalytic hydrogenation reaction is carried out in a reaction medium in the presence of a noble metal catalyst loaded by a carrier, and the (trans)-4-cyclohexyl-L-proline is obtained from reaction products by post-processing. The reaction medium is water or alcohol-water solution, the alcohol is methanol, ethanol or the mixture of the two; and noble metal in the noble metal catalyst loaded by the carrier is Pd, Pt, Ru or Rh. The invention takes the water or the alcohol-water solution as the reaction medium, therefore, raw materials are easy to obtain and easy to process, the reaction process is simple, the catalyst is low in cost, the reaction medium is moderate, reaction equipment are difficult to be corroded, and the invention is characterized by high reaction conversion rate, high selectivity, very small amount of three wastes, low production cost, and the like, thereby being an environment-friendly method for preparing the (trans)-4-cyclohexyl-L-proline and having broad application prospects.
Description
(1) technical field
The present invention relates to a kind of is the method for the direct shortening preparation of raw material water in the presence of supported precious metal catalyst (instead)-4-cyclohexyl-L-proline(Pro) by (instead)-4-phenyl-L-proline(Pro).
(2) background technology
Fosinopril is unique angiotensin converting enzyme inhibitor (ACEI) that contains the phospho acid ester group; lipotropy is strong; onset is slow; easily permeate through cell membranes enters tissue, thereby reduces local AT II, makes the capillary blood vessel diastole; thereby have best heart and a vascular protection effect; fosinopril list medical instrument has the maximum reducing effect, but paddy/p-ratio 50%, so hypotensive effect is slowly and steadily.Fosinopril (sodium) is phosphorous Zinc metallopeptidase Zace1 (ACE) inhibitor of being developed by the expensive treasured of U.S. Bu Maishi (Bristol-MyersSquibb) company.Put goods on the market in Britain first in 1991, went on the market in the U.S. and Italy in succession in 1991 and 1992.In recent years, sales volume increases rapidly.
(instead)-4-cyclohexyl-L-proline(Pro) is the important intermediate of synthetic third generation angiotensin converting enzyme inhibitor (ACEI) fosinopril (Fosinopril).At present, the synthetic method of (instead)-4-cyclohexyl-L-proline(Pro) mainly contains two kinds of approach; A kind of is with synthetic (the instead)-4-cyclohexyl through reducing of (instead)-4-phenyl-L-proline(Pro) raw material-L-proline(Pro).Described a kind ofly with 4-phenyl-3 in US 4 734 508 patents, 4-dihydro-L-proline(Pro) is a raw material, uses Li-NH earlier under-78 ℃
3Handle (instead)-4-phenyl-L-proline(Pro), then under-33 ℃, in dehydrated alcohol, use Li-NH
3Chemical reduction, and then at Pd (OH)
2There is down logical H in/C catalyzer
2Reduction preparation (instead)-4-cyclohexyl-L-proline(Pro) method.This method operational condition is harsh, need in low temperature-78 ℃ and-33 ℃ of operations down, and synthesis yield also low only be 42.5%.Being not suitable for suitability for industrialized production uses.It is raw material with (instead)-4-phenyl-L-proline(Pro) that people such as Thottathil provide a kind of, and through the method for catalytic hydrogenation preparation (instead)-4-cyclohexyl-L-proline hydrochlorate, its specific operation process is: 50g (instead)-4-phenyl-L-proline(Pro) and 10g PtO
2Catalyzer is suspended in the 1200mL dehydrated alcohol, with the anhydrous HC l-C of 46.5mL
2H
5OH solution (5.62mol/L) is handled until (instead)-4-phenyl-L-proline(Pro) dissolving.Feed H
2Press 50psi, room temperature reaction spends the night.Reaction finishes after-filtration and removes catalyzer, the decompression precipitation.Residue with ether handle 60g (instead)-4-cyclohexyl-L-proline hydrochlorate product [US 4 501 901, and US4 734 508].This method needs at anhydrous HCl-C
2H
5Carry out shortening in the OH medium, equipment is had corrosive nature.
Another kind method is to be raw material through synthetic (the instead)-4-cyclohexyl of reactions such as catalytic reduction-L-proline(Pro) with (instead)-4-cyclohexenyl-L-proline derivative.People such as Chen Xiao have reported that a kind of is raw material with N-benzyl-5-oxo-L-proline(Pro), through synthetic (the instead)-N-benzyl of carbon alkylation reaction-4-cyclohexenyl-5-oxo-L-proline(Pro), then catalytic hydrogenation gets (instead)-N-benzyl-4-cyclohexyl-5-oxo-L-proline(Pro) in the presence of the 10%Pd/C catalyzer.Then, above-mentioned product and bromobenzyl react (instead)-N-benzyl-4-cyclohexyl-5-oxo-L-proline(Pro) phenylcarbinol ester, again with Lawesson ' s reagent react conversionization (instead)-N-benzyl-4-cyclohexyl-5-sulfo--L-proline(Pro) phenylcarbinol ester.Then, after the Raney-Ni reflow treatment, get (instead)-4-cyclohexyl-L-proline(Pro) [Tetrahedron:Asymmetry, 2002,13 (1): 43] with 10%Pd/C catalyst deprotection base.In this operational path, key is to have utilized in the presence of the normal LiHMDS of twice, but in C (4) position alkylation, reach a spot of esterification by product, and N-benzyl-5-oxo-L-proline(Pro) is trans: cis=18:1 in N-benzyl-5-oxo-L-proline(Pro) stereoselectivity.The greatest problem of this method is that synthesis yield is low.It is that raw material is converted into 5-methylol-2-pyrrolidone through chemical reduction with 5-oxo-L-proline(Pro) that US 4 588 819 patents provide a kind of, again through condensation reaction, alkylation reaction, deprotection base and catalytic reduction preparation (instead)-4-cyclohexyl-L-proline(Pro).Alkylation reaction needs at low temperatures that (78 ℃) carry out in this synthetic method, and its industrial applications is restricted.
(3) summary of the invention
In order to overcome the deficiency among the existing preparation method, the preparation method's who has selectivity difference, product is a mixture often; The preparation method's reactions steps that has is longer, and yield is low etc.; The catalytic hydrogenation that has needs to carry out in anhydrous HCl-ethanol medium.The present invention relates to a kind of is the method for the direct shortening preparation of raw material water in the presence of supported precious metal catalyst (instead)-4-cyclohexyl-L-proline(Pro) with (instead)-4-phenyl-L-proline(Pro).
The method that the purpose of this invention is to provide the preparation that a kind of technology is simple, transformation efficiency is high, selectivity is high, quantity of three wastes is few, production cost is low (instead)-4-cyclohexyl-L-proline(Pro).
For realizing goal of the invention, the invention provides following technical scheme:
A kind of preparation method suc as formula (the instead)-4-cyclohexyl-L-proline(Pro) shown in (II), being raw material suc as formula (the instead)-4-phenyl-L-proline(Pro) shown in (I), in reaction medium, direct catalytic hydrogenation reaction in the presence of by carrier loaded noble metal catalyst, reaction product gets (instead)-4-cyclohexyl-L-proline(Pro) through aftertreatment; Described reaction medium is water or alcohol-water solution, and described alcohol is methyl alcohol, ethanol or their mixing; Precious metal in the described carrier-supported precious metal catalyzer is Pd, Pt, Ru or Rh.
Carrier in the carrier loaded noble metal catalyst of the present invention is recommended as gac, silica gel or gama-alumina, preferred gac, and the charge capacity of precious metal is 3%-20% in the described carrier loaded noble metal catalyst.Described noble metal catalyst is one of example down: Pt/C catalyzer, Ru/C catalyzer, Rh/C catalyzer.Described carrier loaded usage of noble metal catalysts is 3.0～30%, preferred 4.0～20% of (instead)-4-phenyl-L-proline(Pro) quality.
When described reaction medium is a water, described catalytic hydrogenation reaction comprises the steps: that (instead)-4-cyclohexyl-L-proline(Pro), water makes suspension liquid, usually add 37% an amount of hydrochloric acid and regulate pH to 1.5～6.0, the preferred pH that regulates is 2.5～6.0, add carrier loaded noble metal catalyst, the control hydrogen pressure is 1.0～2.5MPa, temperature is 100～200 ℃, carried out catalytic hydrogenation reaction 3～24 hours, hydrogen is complete until inhaling, and reaction product obtains (instead)-4-cyclohexyl-L-proline(Pro) through aftertreatment.When not adding hydrochloric acid, pH usually approaches 6, so do not add hydrochloric acid, reaction also can normally be carried out.
When described reaction medium is an alcohol-water solution, described alcohol is methyl alcohol, ethanol or their mixing, the volume ratio of described alcohol and water is 0～5:1, the volume ratio of preferred alcohols and water is 0.5:1, alcohol is 0～5:1 with the volume ratio of water, wherein 0 implication is that pure amount can be infinitely close to 0, when the amount of alcohol is 0, is the catalytic hydrogenation reaction that reaction medium is a water; Described catalytic hydrogenation reaction comprises the steps: that (instead)-4-cyclohexyl-L-proline(Pro) is suspended in water-pure mixed solution, add carrier loaded noble metal catalyst, the control hydrogen pressure is 1.0～2.5MPa, temperature is 100～200 ℃, carried out catalytic hydrogenation reaction 3～24 hours, hydrogen is complete until inhaling, and reaction product obtains (instead)-4-cyclohexyl-L-proline(Pro) through aftertreatment.
It is 1.1～2.0MPa that catalytic hydrogenation reaction is more preferably controlled hydrogen pressure, and temperature is 120～160 ℃, and the reaction times is 4～12 hours.
Aftertreatment of the present invention is carried out as follows: reaction finishes, and discharging is filtered, and filtrate decompression is concentrated into 1/4 of original volume～/ 3, transfers pH to 6～7, adds the C of residue volume percent 20%～50%
2H
5OH and by the gac of residue 0.3%～5%g/ml, reflux 3min～5min, heat filtering, solids washs with boiling water, merging filtrate is cooled to-1～1 ℃, filter, filter cake after 60～70 ℃ of vacuum-drying (instead)-4-cyclohexyl-L-proline(Pro).
Described supported palladium, platinum or ruthenium catalyst preparation process are: the muriate that takes by weighing precious metal is dissolved in the hydrochloric acid, with carrier and water, is heated to boiling, under agitation, the muriatic solution that slowly adds precious metal is neutralized to NaOH solution and is weakly alkaline, continues stirring, slowly drip formaldehyde solution then, continue to be heated to 80 ℃, stir 1～3h, cool off, filter, dry, vacuum-drying makes the noble metal support amount and is 5～25% supported precious metal catalyst; Described carrier is gac, silica gel or gama-alumina, and the muriate of described precious metal is Palladous chloride, platinum chloride or ruthenium chloride.
Described load rhodium catalyst preparation process is: take by weighing three hydration rhodium chlorides and be dissolved in the water, add carrier, stirred 1-3 hour, be heated to 80 ℃ and slowly be evaporated to dried.Drying is 2 hours under 105 ℃, then in 300 ℃ of logical hydrogen reductions down, makes the load rhodium catalyst of different loads amount.Described carrier is gac, silica gel or gama-alumina,
The present invention compares with existing preparation (instead)-4-cyclohexyl-L-proline(Pro) method, the present invention is a reaction medium with water or alcohol-water, raw material is easy to get and easily handles, reaction process is simple, catalyzer is inexpensive, reaction medium is gentle, be difficult for corrosion reaction equipment, characteristics such as reaction conversion ratio height, selectivity height, quantity of three wastes is few, production cost is low are the methods of a kind of eco-friendly preparation (instead)-4-cyclohexyl-L-proline(Pro), have broad prospect of application.
(4) embodiment
Further specify of the present invention below in conjunction with specific embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1 Preparation of Catalyst
The Pt-supported catalyst preparation:
Take by weighing 6g PdCl
2(containing Pd59.5%) is dissolved in the 75mL1mol/L hydrochloric acid.47.5g gac and 500mL water place there-necked flask, are heated to boiling, under agitation, slowly add PdCl
2Solution is neutralized to 20%NaOH solution and is weakly alkaline, continues to stir 15 minutes, and Dropwise 35 % formaldehyde solution 100mL slowly continues to be heated to 80 ℃ then, stirs 2h.After the cooling, filter, dry, put into the vacuum drying oven drying, make the Pd/C catalyzer 50.6g of Pd charge capacity 7%.
By above-mentioned preparation method, the carrier that makes Pd charge capacity 7% successively is the Pt-supported catalyst 50.8g that silica gel carries the gama-alumina of Pd catalyzer 51g, Pd charge capacity 7%.
Take by weighing 2g PdCl
2(containing Pd59.5%) is dissolved in the 75mL 1mol/L hydrochloric acid.38.5g gac and 500mL water place there-necked flask, are heated to boiling, under agitation, slowly add PdCl
2Solution is neutralized to 20%NaOH solution and is weakly alkaline, continues to stir 15 minutes, and Dropwise 35 % formaldehyde solution 100mL slowly continues to be heated to 80 ℃ then, stirs 2h.After the cooling, filter, dry, put into the vacuum drying oven drying, make the Pd/C catalyzer 39.5g of Pd charge capacity 3%.
Take by weighing 4g PdCl
2(containing Pd59.5%) is dissolved in the 75mL 1mol/L hydrochloric acid.45.2g gac and 500mL water place there-necked flask, are heated to boiling, under agitation, slowly add PdCl
2Solution is neutralized to 20%NaOH solution and is weakly alkaline, continues to stir 15 minutes, and Dropwise 35 % formaldehyde solution 100mL slowly continues to be heated to 80 ℃ then, stirs 2h.After the cooling, filter, dry, put into the vacuum drying oven drying, make the Pd/C catalyzer 49.5g of Pd charge capacity 5%.
Take by weighing 5g PdCl
2(containing Pd59.5%) is dissolved in the 75mL 1mol/L hydrochloric acid.12g gac and 500mL water place there-necked flask, are heated to boiling, under agitation, slowly add PdCl
2Solution is neutralized to 20%NaOH solution and is weakly alkaline, continues to stir 15 minutes, and Dropwise 35 % formaldehyde solution 100mL slowly continues to be heated to 80 ℃ then, stirs 2h.After the cooling, filter, dry, put into the vacuum drying oven drying, make the Pd/C catalyzer 14.9g of Pd charge capacity 20%.
The loaded Pt catalyst preparation:
Take by weighing 1.0 grams, six water Platinic chlorides (containing Pt38%) and be dissolved in the 15mL 1mol/L hydrochloric acid, 7.0 gram gacs and 60 ml waters place there-necked flask.Reflux 2 hours is cooled to room temperature.With in the 20%NaOH solution and pH=12, continue to stir 15 minutes, Dropwise 35 % formaldehyde solution 20mL slowly continues to be heated to 80 ℃ then, stirs 2h.After the cooling, filter, dry, put into the vacuum drying oven drying, make the Pt/C catalyzer 7.2g of Pt charge capacity 5%.
Load Ru Preparation of Catalyst:
Take by weighing 1.0g RuCl
3(containing Ru73%) is dissolved in the 15mL 1mol/L hydrochloric acid.7.4g gac and 100mL water place there-necked flask, are heated to boiling, under agitation, slowly add RuCl
3Solution is neutralized to 20%NaOH solution and is weakly alkaline, continues to stir 15 minutes, and Dropwise 35 % formaldehyde solution 20mL slowly continues to be heated to 80 ℃ then, stirs 2h.After the cooling, filter, dry, put into the vacuum drying oven drying, make the Ru/C catalyzer 7.6g of Ru charge capacity 5%.
Load Rh Preparation of Catalyst:
Take by weighing in 1.0g three hydration rhodium chlorides (containing Rh39%) dissolving water 60 ml waters, add 7.5 gram gacs, stirred 2 hours, be heated to 80 ℃ and slowly be evaporated to dried.105 ℃ dry 2 hours down, then in 300 ℃ of logical hydrogen reductions down, make charge capacity and be 5% Rh/C catalyzer 7.7g.
Embodiment 2
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 1.0 again and restrain the 7%Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 120 ℃ of control reaction temperature are at the H of 1.6MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 11 hours, continues reaction 1 hour.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Filtrate decompression is concentrated into about 50 milliliters, and the NaOH aqueous solution pH=6.5 that neutralizes adds 15 milliliters of C
2H
5OH and 0.2g gac, reflux 5min.Heat filtering, solids washs with a small amount of boiling water.Merging filtrate is cooled to about 0 ℃, filter, solids after 60-70 ℃ of vacuum-drying (instead)-4-cyclohexyl-L-proline(Pro) (fusing point is 263 ℃-265 ℃, specific optical rotation-30.7 °), yield reaches 80%.
Embodiment 3
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 1.0 again and restrain the 7%Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 140 ℃ of control reaction temperature are at the H of 1.6MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 8 hours, continues reaction 3 hours.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 98.6% of (instead)-4-cyclohexyl-L-proline(Pro).
Filtrate decompression is concentrated into about 50-60 milliliter, and the NaOH aqueous solution pH=6.5 that neutralizes adds 15 milliliters of C
2H
5OH and 0.2g gac, reflux 5min.Heat filtering, solids washs with a small amount of boiling water.Merging filtrate about being cooled to ℃, filters, solids after 60-70 ℃ of vacuum-drying (instead)-4-cyclohexyl-L-proline(Pro), product is through efficient liquid phase chromatographic analysis content 99.1%, yield reaches 79%.
Embodiment 4
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 1.0 again and restrain the 5%Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 150 ℃ of control reaction temperature are at the H of 1.6MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 8 hours, continues reaction 3 hours.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.6% of (instead)-4-cyclohexyl-L-proline(Pro).
Filtrate decompression is concentrated into about 60 milliliters, and the NaOH aqueous solution pH=6.2 that neutralizes adds 15 milliliters of C
2H
5OH and 0.2g gac, reflux 5min.Heat filtering, solids washs with a small amount of boiling water.Merging filtrate is cooled to about 0 ℃, filters, and solids gets (instead)-4-cyclohexyl-L-proline(Pro) after 60-70 ℃ of vacuum-drying, and product is through efficient liquid phase chromatographic analysis content 99.1%, and yield reaches 79.2%.
Embodiment 5
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 0.5 again and restrain the 5%Pt/C catalyzer that embodiment 1 makes.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 155 ℃ of control reaction temperature are at the H of 1.6MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 6 hours, continues reaction 4 hours.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.7% of (instead)-4-phenyl-L-proline(Pro), the yield 98.4% of (instead)-4-cyclohexyl-L-proline(Pro).
Filtrate decompression is concentrated into about 60 milliliters, and the NaOH aqueous solution pH=6.3 that neutralizes adds 15 milliliters of C
2H
5OH and 0.2g gac, reflux 5min.Heat filtering, solids washs with a small amount of boiling water.Merging filtrate is cooled to about 0 ℃, filters, and solids gets (instead)-4-cyclohexyl-L-proline(Pro) after 60-70 ℃ of vacuum-drying, and product is through efficient liquid phase chromatographic analysis content 99.0%, and yield reaches 77.2%.
Embodiment 6
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 0.5 again and restrain the 5%Rh/C catalyzer that embodiment 1 makes.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 155 ℃ of control reaction temperature are at the H of 2.5MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 4 hours, continues reaction 2 hours.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 7
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 0.5 again and restrain the 5%Pd/SiO that embodiment 1 makes
2Catalyzer.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 155 ℃ of control reaction temperature are at the H of 2.0MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 10 hours, continues reaction 2 hours.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 8
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 0.5 again and restrain 5%Pd/ γ-Al that embodiment 1 makes
2O
3Catalyzer.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 160 ℃ of control reaction temperature are at the H of 2.0MPa
2Catalytic hydrogenation is 12 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 90% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro) (in (the instead)-4-phenyl-L-proline(Pro) that reacts).
Embodiment 9
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 0.5 again and restrain the 5%Ru/C catalyzer that embodiment 1 makes.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 200 ℃ of control reaction temperature are at the H of 2.5MPa
2Catalytic hydrogenation is 12 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 56% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro) (in (the instead)-4-phenyl-L-proline(Pro) that reacts).
Embodiment 10
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 150 ml waters, 2.0 milliliter of 37% hydrochloric acid, this moment, system pH was 1.6 to add 1.0 again and restrain the 5%Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 155 ℃ of control reaction temperature are at the H of 2.0MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 2 hours, continues reaction 2 hours.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.2% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 11-15
Adopt 37% hydrochloric acid consumption described in the different 37% hydrochloric acid consumption alternate embodiments 7, other condition is with embodiment 7 except that the reaction times, and it the results are shown in table 1.
Table 1
| The embodiment title | 37% hydrochloric acid consumption (mL) | System pH | Reaction times is (little | (instead)-4-phenyl-L-dried meat ammonia | (instead)-4-cyclohexyl-L-proline(Pro) |
| The time) | Acid transformation efficiency (%) | Yield (%) | |||
| Embodiment 11 | 1.6 | 1.8 | 5 | 100 | 99.6 |
| Embodiment 12 | 1.2 | 1.9 | 6 | 99.97 | 99.5 |
| Embodiment 13 | 0.8 | 2.1 | 8 | 99.98 | 99.5 |
| Embodiment 14 | 0.5 | 2.5 | 10 | 99.96 | 99.5 |
| Embodiment 15 | 0 | 6 | 12 | 99.4 | 99.1 |
Embodiment 16
The 5% Pd/C catalyzer that embodiment 1 described in the 7% Pd/C catalyzer alternate embodiment 14 that employing embodiment 1 makes makes, reaction times is 9 hours, other condition is with embodiment 14, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.2% of (instead)-4-cyclohexyl-L-proline(Pro).。
Embodiment 17
The 5% Pd/C catalyzer that 1 gram embodiment 1 described in the 7%Pd/C catalyzer alternate embodiment 15 that employing 2 gram embodiment 1 make makes, reaction times is 11 hours, other condition is with embodiment 15, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.6% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 18
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 1.0 again and restrain the 7%Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 100 ℃ of control reaction temperature are at the H of 2.0MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling, and about 24 hours, continues reaction 2 hours.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99% of (instead)-4-phenyl-L-proline(Pro), the yield 98% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 19
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 200 ml waters, 0.8 milliliter of 37% hydrochloric acid, this moment, system pH was 2.0 to add 1.0 again and restrain the 7% Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and about 120 ℃ of control reaction temperature are at the H of 1.6MPa
2Catalytic hydrogenation is 12 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 98% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 20-22
Adopt the temperature of reaction described in the different temperature of reaction alternate embodiments 19, other condition is with embodiment 16, and it the results are shown in table 2.
Table 2
| The embodiment title | Temperature of reaction (℃) | (instead)-4-phenyl-L-proline(Pro) transformation efficiency (%) | (instead)-4-cyclohexyl-L-proline(Pro) yield (%) |
| Embodiment 20 | 140 | 99.91 | 99.6 |
| Embodiment 21 | 160 | 99.97 | 99.5 |
| Embodiment 22 | 200 | 99.98 | 99.5 |
Embodiment 23-26
Adopt different H
2H described in the pressure alternate embodiment 20
2Pressure, other condition is with embodiment 20, and it the results are shown in table 3.
Table 3
| The embodiment title | H 2Pressure (MPa) | (instead)-4-phenyl-L-proline(Pro) transformation efficiency (%) | (instead)-4-cyclohexyl-L-proline(Pro) yield (%) |
| Embodiment 23 | 1.0 | 99.8 | 99.2 |
| Embodiment 24 | 1.4 | 99.97 | 99.6 |
| Embodiment 24 | 2.0 | 99.98 | 99.5 |
| Embodiment 26 | 2.5 | 100 | 99.4 |
Embodiment 27-30
Adopt (the instead)-4-phenyl-L-proline(Pro) charging capacity described in different (instead)-4-phenyl-L-proline(Pro) charging capacity alternate embodiment 24, other condition is with embodiment 24, and it the results are shown in table 4.
Table 4
| The embodiment title | The amount (gram) of (instead)-4-phenyl-L-proline(Pro) | (instead)-4-phenyl-L-proline(Pro) transformation efficiency (%) | (instead)-4-cyclohexyl-L-proline(Pro) yield (%) |
| Embodiment 27 | 5 | 100 | 99.6 |
| Embodiment 28 | 15 | 99.98 | 99.5 |
| Embodiment 29 | 20 | 85.5 | 99.4 |
| Embodiment 30 | 25 | 71.4 | 99.5 |
Embodiment 31
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 150 ml waters, 0.5 milliliter of 37% hydrochloric acid, this moment, system pH was 2.5 to add 1.0 again and restrain the 7% Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and 150 ℃ of control reaction temperature are at the H of 1.6MPa
2Catalytic hydrogenation is 12 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 32
Adopt the catalyzer described in catalyzer (without any processing) alternate embodiment 31 after using among the embodiment 31, other condition is with embodiment 31.Filtrate is through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 98.9% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 33
Adopt the catalyzer described in catalyzer (without any processing) alternate embodiment 31 after using among the embodiment 32, other condition is with embodiment 28.Filtrate is through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.1% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 34
At volume is 500 milliliters, is equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, the 7%Pd/C catalyzer that pack into 15 gram (instead)-4-phenyl-L-proline(Pro), 250 ml waters and 3.0 gram embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and 135 ℃ of control reaction temperature are at the H of 1.25MPa
2Catalytic hydrogenation is 12 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 35
Adopt the catalyzer described in catalyzer (without any processing) alternate embodiment 31 after using among the embodiment 34, other condition is with embodiment 31, filtrate is through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 36
Adopt the catalyzer described in catalyzer (without any processing) alternate embodiment 34 after using among the embodiment 35, other condition is with embodiment 34.Filtrate is through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.2% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 37
At volume is 500 milliliters, is equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, the 7% Pd/C catalyzer that pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 250 ml waters and 2.0 gram embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and 140 ℃ of control reaction temperature are at the H of 1.25MPa
2Catalytic hydrogenation is 11 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Filtrate decompression is concentrated into about 100 milliliters, adds 20 milliliters of C
2H
5OH.Be cooled to about 0 ℃, filter, solids gets (instead)-4-cyclohexyl-L-proline(Pro) after 60-70 ℃ of vacuum-drying, and yield reaches 71%.
Embodiment 38
At volume is 500 milliliters, is equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, the 20% Pd/C catalyzer that pack into 20 gram (instead)-4-phenyl-L-proline(Pro), 250 ml waters and 0.6 gram embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and 155 ℃ of control reaction temperature are at the H of 1.5MPa
2Catalytic hydrogenation is 18 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 39
At volume is 500 milliliters, is equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, the 3% Pd/C catalyzer that pack into 20 gram (instead)-4-phenyl-L-proline(Pro), 250 ml waters and 6 gram embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and 155 ℃ of control reaction temperature are at the H of 1.5MPa
2Catalytic hydrogenation is 16 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.1% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 40
The 3% Pd/C catalyzer that 6 gram embodiment 1 described in the 3% Pd/C catalyzer alternate embodiment 39 that employing 5 gram embodiment 1 make make, other condition is with embodiment 39.Filtrate is through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.2% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 41
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, 25 gram (the instead)-4-phenyl-L-proline(Pro) of packing into, 150 ml waters, 100 milliliters of ethanol and 2.0 restrain the 7%Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and control reaction temperature 135-140 ℃, at the H of 1.0-1.25MPa
2Catalytic hydrogenation is 11 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99% of (instead)-4-cyclohexyl-L-proline(Pro).
Add 50 milliliters of C in the filtrate
2H
5OH is cooled to about 0 ℃, keeps 3 hours.Filter, solids gets (instead)-4-cyclohexyl-L-proline(Pro) after 60-70 ℃ of vacuum-drying, and yield reaches 63%.
Embodiment 42
At volume is 500 milliliters, be equipped with in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument, 25 gram (the instead)-4-phenyl-L-proline(Pro) of packing into, 150 ml waters, 100 milliliters of ethanol and 4.0 restrain the 7% Pd/C catalyzer that embodiment 1 make.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and control reaction temperature 135-140 ℃, at the H of 1.0-1.25MPa
2Catalytic hydrogenation is 11 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.1% of (instead)-4-cyclohexyl-L-proline(Pro).
Add 50 milliliters of C in the filtrate
2H
5OH is cooled to about 0 ℃, keeps 3 hours.Filter, solids gets (instead)-4-cyclohexyl-L-proline(Pro) after 60-70 ℃ of vacuum-drying, and yield reaches 64%.
Embodiment 43
Adopt 150 ml waters, the 100 milliliters of ethanol described in 150 ml waters, the 150 milliliters of ethanol alternate embodiments 41, other condition is with embodiment 41.Filtrate is through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.2% of (instead)-4-cyclohexyl-L-proline(Pro).
Embodiment 44
At volume is 500 milliliters, the 5% Pd/C catalyzer that pack into 10 gram (instead)-4-phenyl-L-proline(Pro), 50 ml waters, 150 ml methanol and 1.0 gram embodiment 1 make is installed in the autoclave of agitator, electric heater, airway, pressure and temperature indicating instrument.Then, reactive system is respectively replaced three times with nitrogen and hydrogen successively, and control reaction temperature 125-130 ℃, at the H of 1.0-1.25MPa
2Catalytic hydrogenation is 16 hours under the pressure.The discharging of cooling back, filtration, filtrate be through the HPLC assay determination, the transformation efficiency 99.9% of (instead)-4-phenyl-L-proline(Pro), the yield 99.1% of (instead)-4-cyclohexyl-L-proline(Pro).
Claims (10)
1. preparation method suc as formula (the instead)-4-cyclohexyl-L-proline(Pro) shown in (II), it is characterized in that described method is: being raw material suc as formula the phenyl of (instead)-4-shown in (I)-L-proline(Pro), in reaction medium, direct catalytic hydrogenation reaction in the presence of by carrier loaded noble metal catalyst, reaction product gets (instead)-4-cyclohexyl-L-proline(Pro) through aftertreatment; Described reaction medium is water or alcohol-water solution, and described alcohol is methyl alcohol, ethanol or their mixing; Precious metal in the described carrier-supported precious metal catalyzer is Pd, Pt, Ru or Rh;
2. the preparation method of (instead)-4-cyclohexyl as claimed in claim 1-L-proline(Pro) is characterized in that the carrier in the described carrier loaded noble metal catalyst is gac, silica gel or gama-alumina.
3. the preparation method of (instead)-4-cyclohexyl as claimed in claim 1-L-proline(Pro) is characterized in that the carrier in the described carrier loaded noble metal catalyst is a gac, and the charge capacity of described precious metal is 3～20%.
4. the preparation method of (instead)-4-cyclohexyl as claimed in claim 3-L-proline(Pro) is characterized in that described carrier loaded noble metal catalyst is one of following example: Pt/C catalyzer, Ru/C catalyzer, Rh/C catalyzer.
5. the preparation method of (instead)-4-cyclohexyl as claimed in claim 2-L-proline(Pro) is characterized in that described carrier loaded usage of noble metal catalysts is 3.0～30% of (instead)-4-phenyl-L-proline(Pro) quality.
6. the preparation method of (instead)-4-cyclohexyl as claimed in claim 2-L-proline(Pro) is characterized in that described carrier loaded usage of noble metal catalysts is 4.0～20% of (instead)-4-phenyl-L-proline(Pro) quality.
7. the preparation method of (instead)-4-cyclohexyl as claimed in claim 5-L-proline(Pro), it is characterized in that described reaction medium is a water, described catalytic hydrogenation reaction comprises the steps: that (instead)-4-cyclohexyl-L-proline(Pro), water makes suspension liquid, control pH value is 1.5～6.0, add carrier loaded noble metal catalyst, the control hydrogen pressure is 1.0～2.5MPa, temperature is 100～200 ℃, carried out catalytic hydrogenation reaction 3～24 hours, hydrogen is complete until inhaling,, reaction product obtains (instead)-4-cyclohexyl-L-proline(Pro) through aftertreatment.
8. the preparation method of (instead)-4-cyclohexyl as claimed in claim 5-L-proline(Pro), it is characterized in that described reaction medium is an alcohol-water solution, the volume ratio of described alcohol and water is 0～5:1, described catalytic hydrogenation reaction comprises the steps: that (instead)-4-cyclohexyl-L-proline(Pro) is suspended in water-pure mixed solution, add carrier loaded noble metal catalyst, the control hydrogen pressure is 1.0～2.5MPa, temperature is 100～200 ℃, carried out catalytic hydrogenation reaction 3～24 hours, hydrogen is complete until inhaling, and reaction product obtains (instead)-4-cyclohexyl-L-proline(Pro) through aftertreatment.
9. as the preparation method of claim 1,7 or 8 described (instead)-4-cyclohexyl-L-proline(Pro), it is characterized in that described aftertreatment carries out as follows: reaction finishes, discharging, filter, filtrate decompression is concentrated into 1/4～1/3 of original volume, transfer pH to 6～7, add residue volume percent 20%～50%C
2H
5OH and by the gac of residue 0.3%～5%g/mL, reflux 3min～5min, heat filtering, solids washs with boiling water, merging filtrate is cooled to-1～1 ℃, filter, filter cake after 60-70 ℃ of vacuum-drying (instead)-4-cyclohexyl-L-proline(Pro).
10. the preparation method of (instead)-4-cyclohexyl as claimed in claim 7-L-proline(Pro) is characterized in that described pH value is to control by 37% hydrochloric acid soln.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810163751XA CN101445475B (en) | 2008-12-30 | 2008-12-30 | Method for preparing (trans)-4-cyclohexyl-L-proline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108727242A (en) * | 2018-05-31 | 2018-11-02 | 常州制药厂有限公司 | A kind of preparation method of the trans- -4- cyclohexyl-L-PROLINE of blood-pressure drug key intermediate |
| CN111303002A (en) * | 2020-02-28 | 2020-06-19 | 浙江工业大学 | Method for treating fosinopril intermediate mother liquor |
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| US4337201A (en) * | 1980-12-04 | 1982-06-29 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl substituted prolines |
| US4501901A (en) * | 1983-09-19 | 1985-02-26 | E. R. Squibb & Sons, Inc. | Method for making substituted prolines |
| US4588819A (en) * | 1984-11-19 | 1986-05-13 | E. R. Squibb & Sons, Inc. | Process and intermediates for preparing trans-4-substituted-s-prolines |
| US4734508A (en) * | 1987-05-01 | 1988-03-29 | E. R. Squibb & Sons, Inc. | Process and intermediates for preparing 4-substituted proline derivatives |
| CN100569749C (en) * | 2005-09-30 | 2009-12-16 | 上海医药工业研究院 | The preparation method of 4-carbonyl-(S)-proline derivative |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108727242A (en) * | 2018-05-31 | 2018-11-02 | 常州制药厂有限公司 | A kind of preparation method of the trans- -4- cyclohexyl-L-PROLINE of blood-pressure drug key intermediate |
| CN111303002A (en) * | 2020-02-28 | 2020-06-19 | 浙江工业大学 | Method for treating fosinopril intermediate mother liquor |
| CN111303002B (en) * | 2020-02-28 | 2021-05-07 | 浙江工业大学 | Method for treating fosinopril intermediate mother liquor |
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