CN1752076A - Preparation method of 2-azabicyclo[3,3,0] octane-1-carboxylic acid hydrochloride - Google Patents
Preparation method of 2-azabicyclo[3,3,0] octane-1-carboxylic acid hydrochloride Download PDFInfo
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- CN1752076A CN1752076A CN 200510061130 CN200510061130A CN1752076A CN 1752076 A CN1752076 A CN 1752076A CN 200510061130 CN200510061130 CN 200510061130 CN 200510061130 A CN200510061130 A CN 200510061130A CN 1752076 A CN1752076 A CN 1752076A
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- KXAGTYJRDCNJJJ-UHFFFAOYSA-N 2,3,3a,4,5,6-hexahydro-1h-cyclopenta[b]pyrrole-6a-carboxylic acid;hydrochloride Chemical compound Cl.C1CCC2CCNC21C(=O)O KXAGTYJRDCNJJJ-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 26
- 239000000706 filtrate Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 13
- 230000006837 decompression Effects 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 10
- 238000004904 shortening Methods 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910004298 SiO 2 Inorganic materials 0.000 claims description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 229960004217 benzyl alcohol Drugs 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- 239000012429 reaction media Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 239000012264 purified product Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- QZTJTOJRJBGRRJ-UHFFFAOYSA-N 1h-pyrrole-2-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CN1 QZTJTOJRJBGRRJ-UHFFFAOYSA-N 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007787 solid Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 6
- 229960003401 ramipril Drugs 0.000 description 6
- -1 compound 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000018044 dehydration Effects 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- 238000007599 discharging Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000011010 flushing procedure Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 206010051467 Nephrectasia Diseases 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- POTQIHURRUDRCG-UHFFFAOYSA-N nonanoic acid;hydrochloride Chemical compound Cl.CCCCCCCCC(O)=O POTQIHURRUDRCG-UHFFFAOYSA-N 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- KEDYTOTWMPBSLG-HILJTLORSA-N ramiprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 KEDYTOTWMPBSLG-HILJTLORSA-N 0.000 description 1
- 229960002231 ramiprilat Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Catalysts (AREA)
- Pyrrole Compounds (AREA)
Abstract
A process for preparing the 2-azabicyclo [3,3,0] octane-1-carboxylate hydrochloride features that the 2, 3, 3a, 4, 5, 6-hexahydro-cyclohexane pyrrole-2-carboxylate hydrochloride is catalytically hydrogenated in water to obtain the product. Its advantages are high safety and cyclic use of catalyst.
Description
(1) technical field
The present invention relates to the preparation method of a kind of 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride.
(2) background technology
Ramipril (ramipril) is a kind of hypotensor of German Hirst company development, it is a kind of long-acting, prodrug of non-sulfydryl angiotensin-converting enzyme (ACE) inhibitor efficiently, absorb in vivo and be hydrolyzed into Ramiprilat and play a role, be applicable to the choice drug of mild or moderate and essential hypertension and renal hypertension and moderate and pernicious congestive heart failure.The maximum characteristics of Ramipril are: efficient, long-acting, and few side effects, pharmaceutical dosage is little, and this product suppresses the ACE in blood plasma and each tissue, reduces Angiotensin and generates and the bradykinin inactivation, can increase renin activity, reduce blood plasma aldehyde because of ketone concentration, aldehyde is because of ketone in the minimizing urine, this product and ACE mortise can be improved myocardial metabolism and heart function, produce favourable hemodynamic effect, this product has also obviously reduced the renal vascular resistance of SHR, renal blood flow has the nephrectasia blood vessel, improves the kidney Circulation.This medicine was put on market in Germany in 1989, now sell, use in more than 20 countries, 2002 Ramipril (ramipril) sales volume be 8.7 hundred million dollars, 2003 about 9.6 hundred million dollars, estimation in 2008 reaches 8.9 hundred million dollars.
2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride is the important intermediate of synthetic cardio-cerebralvascular ACE inhibitor Ramipril medicine.Hirst company has reported and used 10%Pt/C catalyst hydrogenation 2,3 in the Glacial acetic acid medium, 3a, and 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride prepares 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride.Described in the WO2005049567 patent and in media such as organic acid such as acetate, propionic acid, used 10%Pd/C catalyst hydrogenation 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride prepares 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride.Described in the WO2005049568 patent in media such as organic acid such as acetate, propionic acid, butyric acid and prepared 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride, changed into tosilate then with the 5%Pd/C catalyst.The technology shortcoming of above-mentioned preparation 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride is that catalytic hydrogenation is all carried out the easy inactivation of catalyzer in having volatility, the big Glacial acetic acid medium of pungency.
(3) summary of the invention
Existing preparation method's moderate stimulation is big in order to overcome, the shortcoming of the easy inactivation of catalyzer, the invention provides the preparation method of a kind of 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride.
2-azabicyclo [3 of the present invention, 3,0] octane-1-carboxylic acid hydrochloride is suc as formula shown in (II), described preparation method, comprise by suc as formula (I) 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride shortening in reaction medium prepares and gets product, and described reaction medium is a water.
The catalyzer that described shortening adopts is generally noble metal catalyst, as: platinum black, palladium black, Pd/C, Pt/C, Ru/C, Pd/Al
2O
3, Pt/Al
2O
3, Ru/Al
2O
3, Pd/SiO
2, Pt/SiO
2, Ru/SiO
2
Preferably, described 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride aqueous solution adds alkali earlier and regulates pH 1.0～9.0, carries out shortening again, filters, and filtrate obtains 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride through hcl acidifying.
Above-mentioned 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride aqueous solution is preferably regulated pH 2.5～7.0.
In the described catalytic hydrogenation reaction, catalyst levels is generally 1.0～15% of reaction substrate quality, is preferably 3.0～10%; Reaction substrate of the present invention is 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride is not itself when adding alkali, then may be 2,3,3a when adding alkali according to the consumption of alkali, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid or 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylate salt.
The consumption of described catalytic hydrogenation reaction medium water is pressed 1mol 2,3,3a, and 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride calculates and is generally 500～2000ml, is preferably 750ml～1250ml.
The shortening temperature is generally 30～150 ℃, is preferably 50～100 ℃; Hydrogen pressure is generally 0.3～2.5Mpa, is preferably 0.5～1.5MPa.
Further, described product carries out the purifying of following step again: product is dissolved in alcohol, removes by filter insolubles, the filtrate decompression concentrate drying gets purified product.The Fatty Alcohol(C12-C14 and C12-C18) of described alcohol such as C1～C6 or phenylcarbinol, alcohol is generally 4～20 with the weight ratio of product: 1.Described alcohol is preferably methyl alcohol or phenylcarbinol, and alcohol is preferably 6～10 with the weight ratio of product: 1.
The present invention compared with prior art, catalytic hydrogenation is carried out at aqueous phase, and operating environment is obviously improved, production security improves; Catalyzer can inactivation, can recycle; Shorten reaction time, and the yield height has higher utility and significantly social, economic benefit.
(4) embodiment
The invention will be further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1
Contain 2,3,3a, 4,5, the 110ml solution of 6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride 73.1g (0.386mol) adds water 100ml and 4g gac, is heated to 50 ℃, stirs 30min, filters.Filtrate is neutralized to pH=3.5 with 30% NaOH solution.Place in the autoclave, add 7%Pd/C catalyzer 3g, and with 50ml water flushing pipe.Use N respectively
2And H
2Replace 3 times, about 60 ℃ of controlled temperature are at the H of 1.0MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling.Cooling back discharging, filtration.Filtrate with hcl acidifying to pH=1.0.Then, decompression dehydration gets white solid to doing.
Above-mentioned white solid 150ml phenylcarbinol heating for dissolving, filtered while hot, filtrate decompression is concentrated into dried, gets target compound 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride 67g, yield 91%.
Embodiment 2
Contain 2,3,3a, 4,5, the 110ml solution of 6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride 73.1g (0.386mol) adds water 100ml and 4g gac, is heated to 60 ℃, stirs 20min, filters.Filtrate is neutralized to pH=2.0 with 30% NaOH solution.Place in the autoclave, add 7%Pd/C catalyzer 3g, and with 50ml water flushing pipe.Use N respectively
2And H
2Replace 3 times, about 70 ℃ of controlled temperature are at the H of 1.5MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling.Cooling back discharging, filtration.Filtrate with hcl acidifying to pH=1.0.Then, decompression dehydration gets white solid to doing.
Above-mentioned white solid 200ml methyl alcohol heating for dissolving, filtered while hot, filtrate decompression is concentrated into dried, gets target compound 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride 67-5g, yield 91.2%.
Embodiment 3
Contain 2,3,3a, 4,5, the 110ml solution of 6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride 73.1g (0.386mol) adds water 100ml and 4g gac, is heated to 70 ℃, stirs 25min, filters.Filtrate is neutralized to pH=3.5 with 30% NaOH solution.Place in the autoclave, add 5%Pd/C catalyzer 5g, and with 50ml water flushing pipe.Use N respectively
2And H
2Replace 3 times, about 70 ℃ of controlled temperature are at the H of 1.5MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling.Cooling back discharging, filtration.Filtrate with hcl acidifying to pH=1.5.Then, decompression dehydration gets white solid to doing.
Above-mentioned white solid 150ml methyl alcohol heating for dissolving, filtered while hot, filtrate decompression is concentrated into dried, gets target compound 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride 68.8g, yield 93%.
Embodiment 4
Contain 2,3,3a, 4,5, the 110ml solution of 6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride 73.1g (0.386mol) adds water 100ml and 4g gac, is heated to 60 ℃, stirs 30min, filters.Filtrate is neutralized to pH=2.5 with 30% NaOH solution.Place in the autoclave, add 5%Ru/C catalyzer 3g, and with 50ml water flushing pipe.Use N respectively
2And H
2Replace 3 times, about 80 ℃ of controlled temperature are at the H of 1.0MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling.Cooling back discharging, filtration.Filtrate with hcl acidifying to pH=1.5.Then, decompression dehydration gets white solid to doing.
Above-mentioned white solid 200ml methyl alcohol heating for dissolving, filtered while hot, filtrate decompression is concentrated into dried, gets target compound 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride 71.5g, yield 96.6%.
Embodiment 5
Contain 2,3,3a, 4,5, the 110ml solution of 6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride 73.1g (0.386mol) adds water 100ml and 4g gac, is heated to 70 ℃, stirs 30min, filters.Filtrate is neutralized to pH=2.5 with 30% NaOH solution.Place in the autoclave, add 5%Pt/C catalyzer 5g, and with 50ml water flushing pipe.Use N respectively
2And H
2Replace 3 times, about 90 ℃ of controlled temperature are at the H of 1.0MPa
2Catalytic hydrogenation under the pressure, hydrogen is complete until inhaling.Cooling back discharging, filtration.Filtrate with hcl acidifying to pH=1.5.Then, decompression dehydration gets white solid to doing.
Above-mentioned white solid 200ml methyl alcohol heating for dissolving, filtered while hot, filtrate decompression is concentrated into dried, gets target compound 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride 68g, yield 91.9%.
Embodiment 6
Utilize the 10%Pd/C catalyzer to replace the 7%Pd/C catalyzer, other condition gets 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride 68.8g, yield 93% with embodiment 2.
Claims (10)
1, the preparation method of a kind of 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride comprises by 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride shortening in reaction medium prepares and gets product, it is characterized in that described reaction medium is a water.
2, preparation method as claimed in claim 1 is characterized in that catalyzer that described shortening adopts is one of following: platinum black, palladium black, Pd/C, Pt/C, Ru/C, Pd/Al
2O
3, Pt/Al
2O
3, Ru/Al
2O
3, Pd/SiO
2, Pt/SiO
2, Ru/SiO
2
3, preparation method as claimed in claim 2 is characterized in that described catalyzer is Pd/C.
4, preparation method as claimed in claim 1, it is characterized in that described 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride aqueous solution adds alkali earlier and regulates pH 1.0～9.0, carries out shortening again, filter, filtrate obtains 2-azabicyclo [3,3,0] octane-1-carboxylic acid hydrochloride through hcl acidifying.
5, preparation method as claimed in claim 4, it is characterized in that described 2,3,3a, 4,5,6-six hydrogen-pentamethylene a pair of horses going side by side pyrroles-2-carboxylic acid hydrochloride aqueous solution is regulated pH 2.5～7.0.
6, as the described preparation method of one of claim 1～5, it is characterized in that in the described catalytic hydrogenation reaction that catalyst levels is 1.0～15% of a reaction substrate quality, the shortening temperature is 30～150 ℃, hydrogen pressure is 0.3～2.5MPa.
7, preparation method as claimed in claim 6 is characterized in that described catalyst levels is 3.0～10% of a reaction substrate quality, and the shortening temperature is 50～100 ℃, and hydrogen pressure is 0.5～1.5MPa.
8, preparation method as claimed in claim 1 is characterized in that described product carries out the purifying of following step again: product is dissolved in alcohol, removes by filter insolubles, the filtrate decompression concentrate drying gets purified product.
9, preparation method as claimed in claim 8 is characterized in that described alcohol is Fatty Alcohol(C12-C14 and C12-C18) or the phenylcarbinol of C1～C6, and alcohol is 4～20: 1 with the weight ratio of product.
10, preparation method as claimed in claim 9 is characterized in that described alcohol is methyl alcohol or phenylcarbinol, and alcohol is 6～10: 1 with the weight ratio of product.
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|---|---|---|---|
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|---|---|---|---|
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3226768A1 (en) * | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (3.3.0) -OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF |
| JPS59116951U (en) * | 1983-01-25 | 1984-08-07 | 京セラミタ株式会社 | Copy machine power transmission device |
| CN1047384C (en) * | 1994-07-28 | 1999-12-15 | 北京大学 | Synthetic process of Ramipril |
| AU2003290400A1 (en) * | 2003-11-24 | 2005-06-08 | Potluri Ramesh Babu | A novel synthesis of 2-azabicyclic-3-carboxylic acids, useful as important drug intermediates |
| AU2003290401A1 (en) * | 2003-11-24 | 2005-06-08 | Potluri Ramesh Babu | A process for industrially viable preparation of (s,s,s) phenylmethyl-2-azabicyclo-(3.3.0)-octane-3-carboxylate tosylate |
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2005
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