CN102993037B - Preparation method for L-ornithine phenylacetate - Google Patents
Preparation method for L-ornithine phenylacetate Download PDFInfo
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- CN102993037B CN102993037B CN201210473649.6A CN201210473649A CN102993037B CN 102993037 B CN102993037 B CN 102993037B CN 201210473649 A CN201210473649 A CN 201210473649A CN 102993037 B CN102993037 B CN 102993037B
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- toluylic acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- LRSYFEZBIMVWRY-VWMHFEHESA-N (2s)-2,5-diaminopentanoic acid;2-phenylacetic acid Chemical compound NCCC[C@H](N)C(O)=O.OC(=O)CC1=CC=CC=C1 LRSYFEZBIMVWRY-VWMHFEHESA-N 0.000 title claims abstract description 21
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000003756 stirring Methods 0.000 claims abstract description 23
- 239000000243 solution Substances 0.000 claims abstract description 21
- 239000007864 aqueous solution Substances 0.000 claims abstract description 19
- 239000013078 crystal Substances 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003729 cation exchange resin Substances 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000012296 anti-solvent Substances 0.000 claims description 5
- -1 supercarbonate Natural products 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 claims description 2
- 229940009098 aspartate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229940086735 succinate Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 8
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 abstract description 6
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 abstract 4
- 229960003104 ornithine Drugs 0.000 abstract 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 229960003424 phenylacetic acid Drugs 0.000 abstract 1
- 239000003279 phenylacetic acid Substances 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 208000014644 Brain disease Diseases 0.000 description 6
- 208000032274 Encephalopathy Diseases 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 229940049953 phenylacetate Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- 241000370738 Chlorion Species 0.000 description 2
- 206010016803 Fluid overload Diseases 0.000 description 2
- 206010019663 Hepatic failure Diseases 0.000 description 2
- 206010020575 Hyperammonaemia Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 238000001784 detoxification Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 229960003244 ornithine hydrochloride Drugs 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- GGTYBZJRPHEQDG-WCCKRBBISA-N (2s)-2,5-diaminopentanoic acid hydrochloride Chemical compound Cl.NCCC[C@H](N)C(O)=O GGTYBZJRPHEQDG-WCCKRBBISA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- 208000000857 Hepatic Insufficiency Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- JFLIEFSWGNOPJJ-JTQLQIEISA-N N(2)-phenylacetyl-L-glutamine Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CC1=CC=CC=C1 JFLIEFSWGNOPJJ-JTQLQIEISA-N 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals and relates to a preparation method for L-ornithine phenylacetate. The preparation method comprises the following steps of: mixing L-ornithine aqueous solution with phenylacetic acid solution; stirring and reacting the mixture; and crystallizing the obtained L-ornithine phenylacetate solution to separate out L-ornithine phenylacetate in the form of crystal. The preparation method is a one-step reaction, has a simple and gentle process, provides effective reference for the high purity and industrialization of the L-ornithine and phenylacetic acid, has a low toxic and side effect of the product, and ensures the safety of clinical medication. Compared with the prior art, the preparation method provided by the invention has low cost, high yield, and high product purity, and is suitable for industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of preparation method of L-ornithine phenyl acetate.
Background technology
Hepatogenic encephalopathy is by the imbalance of the central nervous system function based on the metabolism disorder syndrome clinically caused by various subspecies hepatic diseases, and by liver detoxification function, complete and exhaustion causes.Its clinical manifestation sickens for consciousness, dystropy, stupor, blood ammonia rising etc.When liver failure, the decline of liver urea synthesis and removing ammonia even disappears, so that directly enter human circulation from the ammonia of enteron aisle without liver detoxification, blood ammonia is raised, and hyperammonemia is to central nervous system tool toxic action, therefore reducing blood ammonia is one of effective measure for the treatment of hepatogenic encephalopathy.
L-Orn salt and phenylacetate can respectively or combinationally use to treat hyperammonemia and hepatogenic encephalopathy, also have patent and document description to be used for the treatment of the L-Orn of hepatogenic encephalopathy and the composition of phenylacetate.But, there is shortcoming when they are used for the treatment of disease (as the hepatogenic encephalopathy) relevant with hepatopathy in some salt, particularly sodium salt or chloride salt.First, due to the absorption of some salt (such as sodium salt) high density to ascites inherently may have been had, the liver problem sufferer of body fluid overload or electrolyte imbalance is danger close; Secondly, because increasing of osmotic pressure makes intravenous injection become more difficult, and dilute again injection for intravenous by tank solution and then can cause fluid overload.Therefore, need the synthesis of L-Orn and phenylacetate to prepare and be conducive to treating hepatogenic encephalopathy.
Research shows, L-Orn and phenylacetate better water-soluble, use by oral or intravenous injection, ammonia concentration in the reduction hepatic encephalopathy body that it can be stable.Its mechanism is: L-Orn can promote the synthesis making glutamine, and during hepatic insufficiency, human body mainly reduces blood ammonia by the synthesis of glutamine.Glutamine too much in body is not only unfavorable to human body, and ammonia concentration can be gone up at enteron aisle decomposition generation ammonia.When toluylic acid exists, toluylic acid can synthesize phenylacetyl glutamine with glutamine in kidney, discharges in body with urine, reduces the toxic level of ammonia.
The preparation method of the L-ornithine phenyl acetate of external report is at present: set out with L-ornithine hydrochloride, first add the Isolating chlorinated silver precipitation of silver benzoate and obtain L-Orn phenylformic acid, add sodium phenylacetate again and obtain L-ornithine phenyl acetate, its complex process, study route is loaded down with trivial details, as (patent CN 102421432A) introduces the heavy metal ion such as silver ions, toxic side effect is large, has a great impact the clinical effectiveness of medicine.
Summary of the invention
The object of the invention is, for above-mentioned technical problem, to provide a kind of preparation method of L-ornithine phenyl acetate.
The object of the invention is to be realized by following technical proposal:
A preparation method for L-ornithine phenyl acetate, the method is that the L-Orn aqueous solution that first will dissociate mixes with toluylic acid solution, stirs and reacts, then the L-ornithine phenyl acetate solution obtained is carried out crystallization makes it separate out with the form of crystal.
Described preparation method, wherein the preparation method of the free L-Orn aqueous solution can be, by water-soluble for L-Orn salt, regulate pH to 1.5-3, upper cation exchange resin column, then washes pillar removing impurity (as impurity such as salt ions) with water, then uses ammoniacal liquor wash-out L-Orn, by elutriant concentrating under reduced pressure, obtain the L-Orn aqueous solution dissociated; Cation exchange resin column preferred JK006 type cation exchange resin column.
The preparation method of described L-ornithine phenyl acetate, wherein said L-Orn salt is one or more in the vitriol of L-Orn, nitrate, acetate, oxalate, formate, hydrochloride, Citrate trianion, carbonate, benzoate, succinate, tartrate, ascorbate salt, aspartate, supercarbonate, maleate, glutaminate, fumarate, mesylate, benzene sulfonate, tosilate or phosphoric acid salt.
Described preparation method, the solvent system of wherein said toluylic acid solution be selected from water, methyl alcohol, ethanol, acetone, ether or acetonitrile one or more.
Described preparation method, in wherein said reactant, the mol ratio of L-Orn and toluylic acid is 2 ﹕ 1 ~ 1 ﹕ 2; The temperature that the L-Orn aqueous solution and toluylic acid solution stirring are reacted controls at 10 DEG C ~ 75 DEG C, and stir speed (S.S.) controls at 80rpm ~ 200rpm.
Described preparation method, wherein crystallization method can adopt and in solution, to add anti-solvent or evaporating solvent or reduce temperature or add the methods such as crystal seed, or the combination of these methods.
Described preparation method, wherein anti-solvent can be selected from one or more in following material: hexanaphthene, ethanol, Virahol (IPA), 1-acetone, acetone, methylcarbonate, benzonitrile, N-crassitude (NMP), methylene dichloride (DCM), ether, dimethyl sulfoxide (DMSO) (DMSO), 2-butanols, ethyl acetate (EtOAc), isopropyl benzene, acetonitrile, ethyl formate, methyl acetate, isobutyl acetate, Nitromethane 99Min., 3-methyl-1-butanol, t-butyl methyl ether, methyl-phenoxide, tetrahydrofuran (THF), toluene, diisopropyl ether; The add-on of anti-solvent is 1:9 ~ 9:1 with L-Orn toluylic acid liquor capacity ratio.
Described preparation method, wherein crystallization method preferably adds anti-solvent Virahol, and is cooled to 2-6 DEG C, leaves standstill crystallization in 2-4 hour.Virahol is preferably 4 to 1 with the volume ratio of L-Orn toluylic acid solution.
Described preparation method, adopts reduction temperature to carry out temperature in the method for crystallization and controls at 1 DEG C ~ 20 DEG C.
Described preparation method, the amount of wherein adding crystal seed is 0.1 ~ 10wt% of L-Orn toluylic acid content in L-Orn toluylic acid solution, is preferably 0.5 ~ 5wt%.
Beneficial effect of the present invention:
The invention of this operational path is single step reaction, process is simply gentle, for the high purity of L-Orn and toluylic acid and preparation of industrialization provide effective reference, product toxic side effect is low, ensure that the security of clinical application, and compared with existing Technology, preparation method's cost of the present invention is low, yield is high, and product purity is high, is suitable for suitability for industrialized production.
Specific implementation method
The present invention is further elaborated by the following examples, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
16.8gL-ornithine hydrochloride (dissociating L-Orn containing 13.2g) is dissolved in 500mL water, after regulating pH to 2, flows through the pillar of filling JK006 type Zeo-karb.Rinse pillar with 300mL water, wash away the impurity such as chlorion wherein, then use the ammoniacal liquor wash-out L-Orn of 2mol/L of 400mL, by elutriant concentrating under reduced pressure to 200mL, obtain the L-Orn aqueous solution (containing L-Orn 0.1mol) dissociated.6.8g toluylic acid is dissolved in 400mL water under 75 DEG C of water bath condition, by the toluylic acid aqueous solution under 75 DEG C of conditions, control stir speed (S.S.) at 80rpm, add the aqueous solution (L-Orn and toluylic acid mol ratio are 2:1) of above-mentioned free L-Orn while stirring, stir after 20 minutes, evaporation concentration is to 24mL, limit is at room temperature stirred, limit slowly adds acetone 56mL, the volume ratio of acetone and above-mentioned mixed aqueous solution is made to be 7:3, 1 DEG C is cooled to after stirring 30min, add crystal seed 0.2g, at 1 DEG C, leave standstill 3 be as a child settled out crystalline solid (L-ornithine phenyl acetate), isolated by vacuum filtration obtains crystal, with washing with acetone, at 45 DEG C, forced air drying is spent the night, obtain L-ornithine phenyl acetate 8.8g.Purity 98.5% after measured, productive rate 44%.
Embodiment 2
20gL-ornithine hydrochloride (dissociating L-Orn containing 15.7g) is dissolved in 500mL water, after regulating pH to 2, flows through the pillar of filling JK006 type Zeo-karb.Rinse pillar with 300mL water, wash away the impurity such as chlorion wherein, then use the ammoniacal liquor wash-out L-Orn of 2mol/L of 400mL, by elutriant concentrating under reduced pressure to 200mL, obtain the L-Orn aqueous solution (containing L-Orn 0.119mol) dissociated.16.2g toluylic acid (L-Orn and toluylic acid mol ratio are 1:1) is added, stirring and dissolving in 100mL ethanol.By the ethanolic soln of toluylic acid at room temperature, control stir speed (S.S.) at 140rpm, add in the L-Orn aqueous solution while stirring, stir 20min.By the mixing solutions concentrating under reduced pressure after stirring to about 55mL, limit is at room temperature stirred, limit slowly adds 220mL Virahol, makes the volume ratio of Virahol and above-mentioned mixed aqueous solution be 4:1, stirs and is cooled to 4 DEG C after 30 minutes, add crystal seed 0.638g, at 4 DEG C, leave standstill 3 be as a child settled out crystalline solid (L-ornithine phenyl acetate), isolated by vacuum filtration obtains crystal, by washed with isopropyl alcohol, at 45 DEG C, forced air drying is spent the night, and obtains L-ornithine phenyl acetate 22.3g.Purity 98.9% after measured, productive rate 69.9%.
Embodiment 3
20gL-ornithine nitrate (dissociating L-Orn containing 13.5g) is dissolved in 500mL water, after regulating pH to 2, flow through the pillar of filling JK006 type Zeo-karb, wash away the impurity such as nitrate ion wherein, use the ammoniacal liquor wash-out L-Orn of the 2mol/L of 400mL again, by elutriant concentrating under reduced pressure to 200mL, obtain the L-Orn aqueous solution (containing L-Orn 0.102mol) dissociated.27.9g toluylic acid (L-Orn and toluylic acid mol ratio are 1:2) is added, stirring and dissolving in 100mL methyl alcohol.By the methanol solution of toluylic acid at ambient temperature, control stir speed (S.S.) 200rpm, add in the L-Orn aqueous solution while stirring, stir 20min.By the mixing solutions concentrating under reduced pressure after stirring to about 50ml, limit is at room temperature stirred, limit slowly adds 250mL dimethyl sulfoxide (DMSO), makes the volume ratio of dimethyl sulfoxide (DMSO) and above-mentioned mixed aqueous solution be 5:1, is cooled to 15 DEG C after stirring 30min, add crystal seed 0.82g, at 15 DEG C, leave standstill 3 be as a child settled out crystalline solid (L-ornithine phenyl acetate), isolated by vacuum filtration obtains crystal, washs by dimethyl sulfoxide (DMSO), dried overnight at 45 DEG C, obtains L-ornithine phenyl acetate 14.7g.Purity 98.7% after measured, productive rate 35.6%.
Claims (7)
1. a preparation method for L-ornithine phenyl acetate, the L-Orn aqueous solution that it is characterized in that first dissociating mixes with toluylic acid solution, stirs and reacts, then the L-ornithine phenyl acetate solution obtained is carried out crystallization makes it separate out with the form of crystal;
Wherein, crystallization method adds anti-solvent Virahol, and be cooled to 2-6 DEG C, leaves standstill crystallization in 2-4 hour; Virahol is 4 to 1 with the volume ratio of L-Orn toluylic acid solution; When crystallization, in solution, add crystal seed, the amount of adding crystal seed is 0.1 ~ 10wt% of L-Orn toluylic acid content in L-Orn toluylic acid solution.
2. preparation method according to claim 1, it is characterized in that the preparation method of the free L-Orn aqueous solution is, by water-soluble for L-Orn salt, regulate pH to 1.5-3, upper cation exchange resin column, then washes pillar removing impurity with water, then uses ammoniacal liquor wash-out L-Orn, by elutriant concentrating under reduced pressure, obtain the L-Orn aqueous solution dissociated.
3. preparation method according to claim 2, is characterized in that cation exchange resin column is JK006 type cation exchange resin column.
4., according to the preparation method of the L-ornithine phenyl acetate described in claim 2, it is characterized in that described L-Orn salt is one or more in the vitriol of L-Orn, nitrate, acetate, oxalate, formate, hydrochloride, Citrate trianion, carbonate, benzoate, succinate, tartrate, ascorbate salt, aspartate, supercarbonate, maleate, glutaminate, fumarate, mesylate, benzene sulfonate, tosilate or phosphoric acid salt.
5. preparation method according to claim 1, it is characterized in that the solvent system of described toluylic acid solution is selected from water, methyl alcohol, ethanol, acetone, ether or acetonitrile one or more.
6. preparation method according to claim 1, is characterized in that the mol ratio of L-Orn and toluylic acid in described reactant is 2 ﹕ 1 ~ 1 ﹕ 2; The temperature that the L-Orn aqueous solution and toluylic acid solution stirring are reacted controls at 10 DEG C ~ 75 DEG C, and stir speed (S.S.) controls at 80rpm ~ 200rpm.
7. preparation method according to claim 1, is characterized in that the amount of described interpolation crystal seed is 0.5 ~ 5wt% of L-Orn toluylic acid content in L-Orn toluylic acid solution.
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| GB965637A (en) * | 1962-04-23 | 1964-08-06 | Tanabe Seiyaku Co | L-ornithine l-aspartate |
| US5227007A (en) * | 1990-09-28 | 1993-07-13 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing crystals of salt of acidic amino acid and basic amino acid |
| CN102421432A (en) * | 2009-04-03 | 2012-04-18 | 欧塞拉治疗有限公司 | L-ornithine phenyl acetate and methods of making thereof |
| CN102625699A (en) * | 2009-06-08 | 2012-08-01 | Ucl商业有限公司 | Treatment of portal hypertension and restoration of liver function using L-ornithine phenylacetate |
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| GB965637A (en) * | 1962-04-23 | 1964-08-06 | Tanabe Seiyaku Co | L-ornithine l-aspartate |
| US5227007A (en) * | 1990-09-28 | 1993-07-13 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing crystals of salt of acidic amino acid and basic amino acid |
| CN102421432A (en) * | 2009-04-03 | 2012-04-18 | 欧塞拉治疗有限公司 | L-ornithine phenyl acetate and methods of making thereof |
| CN102625699A (en) * | 2009-06-08 | 2012-08-01 | Ucl商业有限公司 | Treatment of portal hypertension and restoration of liver function using L-ornithine phenylacetate |
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