CN109180532A - D-三七素的高效制备方法 - Google Patents
D-三七素的高效制备方法 Download PDFInfo
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- CN109180532A CN109180532A CN201810993009.5A CN201810993009A CN109180532A CN 109180532 A CN109180532 A CN 109180532A CN 201810993009 A CN201810993009 A CN 201810993009A CN 109180532 A CN109180532 A CN 109180532A
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- 238000002360 preparation method Methods 0.000 title claims description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 10
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 9
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 9
- 239000001103 potassium chloride Substances 0.000 claims abstract description 9
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 9
- PECYZEOJVXMISF-UHFFFAOYSA-N L-DAPA Natural products [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 claims abstract description 8
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims abstract description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 6
- FHOAKXBXYSJBGX-RXMQYKEDSA-N (2r)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](CO)C(O)=O FHOAKXBXYSJBGX-RXMQYKEDSA-N 0.000 claims abstract description 4
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 239000012043 crude product Substances 0.000 claims abstract description 4
- 230000020477 pH reduction Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000005915 ammonolysis reaction Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- HNQZURNWHYCIQZ-ZCFIWIBFSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-methylsulfonyloxypropanoic acid Chemical class CC(C)(C)OC(=O)N[C@@H](C(O)=O)COS(C)(=O)=O HNQZURNWHYCIQZ-ZCFIWIBFSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 claims description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 229940021746 d- serine Drugs 0.000 abstract description 9
- NEEQFPMRODQIKX-REOHCLBHSA-N N(3)-oxalyl-L-2,3-diaminopropionic acid Chemical compound OC(=O)[C@@H](N)CNC(=O)C(O)=O NEEQFPMRODQIKX-REOHCLBHSA-N 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 4
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
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- 206010029350 Neurotoxicity Diseases 0.000 description 3
- 206010044221 Toxic encephalopathy Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
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- 231100000228 neurotoxicity Toxicity 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 238000000605 extraction Methods 0.000 description 2
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- 230000023597 hemostasis Effects 0.000 description 2
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- 238000003199 nucleic acid amplification method Methods 0.000 description 2
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- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- 230000008569 process Effects 0.000 description 2
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- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- -1 succimide Chemical compound 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 208000003014 Bites and Stings Diseases 0.000 description 1
- 206010007247 Carbuncle Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UWTATZPHSA-N D-Asparagine Chemical compound OC(=O)[C@H](N)CC(N)=O DCXYFEDJOCDNAF-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
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- 208000034507 Haematemesis Diseases 0.000 description 1
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- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- 241000208343 Panax Species 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000003181 Panax pseudoginseng Nutrition 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
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- 208000004078 Snake Bites Diseases 0.000 description 1
- 206010053476 Traumatic haemorrhage Diseases 0.000 description 1
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- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
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- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015111 chews Nutrition 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 235000008434 ginseng Nutrition 0.000 description 1
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- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
本发明涉及一种止血化合物D‑三七素的高效合成方法，包括以下步骤：D‑丝氨酸首先与二碳酸二叔丁酯反应生成Boc‑D‑丝氨酸，以甲磺酰氯活化Boc‑D‑丝氨酸的羟基后发生Gabriel反应，得到N‑α‑Boc‑D‑α,β‑二氨基丙酸，最后与草酸单甲酯钾盐缩合后水解酸化得到三七素粗品，经过纯化得到三七素精品，产品含量达99.8%以上，与现有的D‑三七素合成方法相比，反应条件更加温和，操作简便，原料成本较低，环境友好，适合工业化生产，为D‑三七素后期开展临床实验解决原料来源问题。
Description
技术领域
本发明为一种止血化合物D-三七素（即β-N-二乙酰基-D-α, β-二氨基丙酸）的高效制备方法。
背景技术
三七又名田七，属于五加科人参属三七的干燥根，用于咯血，吐血，衄血，便血，崩漏，外伤出血，胸腹刺痛，跌扑肿痛。《本草纲目》记载：止血散血定痛，金刃箭伤、跌扑杖疮、血出不止者，嚼烂涂，或为末掺之，其血即止，为主吐血衄血，下血血痢，崩中经水不止，产后恶血不下，血运血痛，赤目痈肿，虎咬蛇伤诸病。《本草纲目拾遗》记载：人参补气第一，三七补血第一，味同而功亦等，故人参三七，为中药之最珍贵者。《药典》记载：三七的主要特点为“止血散淤，活血生肌”。三七素（Dencichine），又称为田七氨酸，目前已有众多研究表明其是三七的主要止血活性成分，最早由日本科学家由三七根中分离，其结构为β-草酰基-L-α,β-二氨基丙酸，分子式为C5H8N2O5，相对分子质量为176.13，为水溶性的非蛋白氨基酸。目前从天然植物三七中提取的均为L-三七素，根据现代科学（印度）第32卷153页（1963年），生物化学第3卷第三期432页（1964年），生物化学第11卷第22期4053页（1972年），《山东中医杂志》第1期43-45页（2010年）都报道了天然提取的L-三七素具有神经毒性，限制了L-三七素步入临床的道路。1975年Rao等人成功采用化学方法合成了D-三七素，为L-三七素的异构体，止血功效与L-三七素相同，但不具有神经毒性，成为非常有临床开发潜力的止血化合物。
由于三七中成分复杂，L-三七素含量较低，因此天然L-三七素单体获取较为困难，提取分离研究较少。另外由于L-三七素的神经毒性，限制了L-三七素的使用，因此D-三七素的高效、绿色合成可以解决L-三七素来源及临床受限的问题，为今后D-三七素的临床应用奠定基础。
目前L-三七素及D-三七素的合成有多种方法，D-三七素的合成可以参照L-三七素的合成。其中Rao等人是以D-天冬氨酸为起始原料，合成D-α,β-二氨基丙酸时使用30%发烟硫酸，叠氮化钠，环境污染较大，叠氮化钠目前来源受限，且产率较低，不适合工业生产。CN0010992.2报道了Hoffman降解利用L-天冬酰胺合成L-三七素的方法，使用对甲苯磺酰氯保护L-天冬酰胺，再使用溴素进行霍夫曼降解，然后使用苯酚和氢溴酸进行脱保护，最后与草酸单甲酯钾盐缩合，得到L-三七素。其中对甲苯磺酰氯为原料进行氨基保护，味道较大，溴素及溴化氢，污染非常大，废水，废气较多，环境污染问题较大，工业生产较困难。CN105439883报道了一种D-三七素的合成方法，使用D-天冬酰胺为原料，Fmoc保护，利用PIFA进行霍夫曼降解，脱Fmoc保护后与草酸单甲酯钾盐进行缩合，得到D-三七素，其中Fmoc保护剂及PIFA价格较高，且Fmoc去保护时需要使用哌啶，有毒，属于易制毒原料，购买困难，因此限制了工业生产。CN105061247报道了一种L-三七素的合成方法，使用碘苯二乙酸为原料进行霍夫曼降解得到N-α-Boc-L-α,β-二氨基丙酸，在1,4-二氧六环中与草酰氯缩合后淬灭后得到L-三七素，碘苯二乙酸价格较贵并且由于N-α-Boc-L-α,β-二氨基丙酸在有机溶剂中溶解度较差，反应时会出现反应不完全，搅拌困难等缺点，且草酰氯有极大刺激性气味，易挥发变质，且反应活性很高，易产生副产物，反应后淬灭时会大量放热和放出氯化氢，污染较大，不利于放大生产。
发明内容
本发明专利通过对既往的文献进行深入研究，在前期的工作基础上，对三七素合成进行了改进，以期采用高效，绿色，低成本的方法进行D-三七素的合成，极大程度上避免了使用高污染，高成本，高风险的试剂和操作。
D-三七素的结构如下：
本发明制备D-三七素包括以下步骤。
在0-25度下，碱性条件下，水和有机溶剂作为溶剂，D-丝氨酸与二碳酸二叔丁酯缩合生成Boc-D-丝氨酸盐，酸化游离后得到D-Boc-丝氨酸。
所述的有机溶剂为二氯甲烷，丙酮，四氢呋喃，乙腈中的一种，所述的碱为氢氧化钾，氢氧化钠，碳酸钾，碳酸氢钠中的一种，所述的酸为盐酸，硫酸，柠檬酸，硫酸氢钾中的一种。
在0-25度下，Boc-D-丝氨酸在有机溶剂中，在缚酸剂存在下，与甲磺酰氯成酯。
所述的缚酸剂为：碳酸氢钠，碳酸钠，碳酸钾，碳酸铯，三乙胺，N，N-二异丙基乙胺中的一种。
25-50度，在碱性条件下Boc-D-丝氨酸甲磺酸酯发生氨解生成N-α-Boc-D-α,β-二氨基丙酸。
所述氨源为氨水，液氨，丁二酰亚胺，邻苯二甲酰亚胺，所述的碱包括有机碱及无机碱，其中无机碱为氢氧化钠，氢氧化钾，钠氢中的一种，有机碱为水合肼，哌啶，乙二胺中的一种，所述的溶剂为二甲基亚砜，N,N-二甲基甲酰胺，N,N-二乙基乙酰胺，四氢呋喃中的一种。
在0-25度下，将N-α-Boc-D-α,β-二氨基丙酸溶于20-50%浓度的甲醇，在碱性条件下，与草酸单甲酯钾盐反应10-24h后，加酸水解并游离后，得到D-三七素粗品，经过处理纯化后，得到D-三七素精品。
所述的N-α-Boc-D-α,β-二氨基丙酸，碱及草酸单甲酯钾盐的摩尔比为1:1-2:1.2-1.8,所述的纯化方法为溶剂打浆，所述的纯化溶剂为水，丙酮，甲醇。
附图说明：
图1是D-三七素的化学结构图。
具体实施方式：
下面根据具体实施例对本发明作进一步说明。
实施例1：Boc-D-丝氨酸的合成
50L反应釜中加入14L水，1.37kg氢氧化钠，搅拌下，分批加入D-丝氨酸3kg，加完后，降温至0-5度，将7kg二碳酸二叔丁酯溶于14L四氢呋喃，滴加如反应液，加完室温反应18小时，降温至0度，滴加浓盐酸，调ph至2-3.5，加入1.5kg乙酸乙酯萃取三次，干燥后旋干，得到5kg无色油状物。
实施例2：Boc-D-丝氨酸的合成
50L反应釜中加入14L水，5kg碳酸钾，搅拌下，分批加入D-丝氨酸3kg，加完后，降温至0-5度，将7kg二碳酸二叔丁酯溶于14L四氢呋喃，滴加如反应液，加完室温反应18小时，降温至0度，滴加饱和硫酸氢钠溶液，调ph至2-3.5，加入1.5kg乙酸乙酯萃取三次，干燥后旋干，得到4kg黄色油状物。
实施例3：Boc-D-丝氨酸甲磺酸酯的合成
10L三颈瓶中，加入1kgBoc-D-丝氨酸和5L二氯甲烷搅拌溶解，加入0.6kg三乙胺，降温至0度，滴加1.12kg甲磺酰氯，滴加完成后，室温反应8小时，反应完成后，加入500ml水洗，500ml饱和硫酸氢钠溶液洗，500ml饱和氯化钠溶液洗，收集有机层，干燥，旋干，得到黄色油状物1.13kg。
实施例3：Boc-D-丝氨酸甲磺酸酯的合成
10L三颈瓶中，加入1kgBoc-D-丝氨酸和5L四氢呋喃搅拌溶解，加入0.6kg碳酸氢钠，度，滴加1.12kg甲磺酰氯，滴加完成后，室温反应8小时，反应完成后，旋干，残留物加入1.5L二氯甲烷，冷却至0-5度，0度下滴加500ml饱和硫酸氢钠，搅拌1小时后，分液，有机相用500ml饱和氯化钠溶液洗，收集有机层，干燥，旋干，得到黄色油状物1.13kg。
实施例4：N-α-Boc-D-α,β-二氨基丙酸的合成
500gBoc-D-丝氨酸甲磺酸酯溶于1LDMSO中，加入390g邻苯二甲酰亚胺钾盐，加入198g氢氧化钾，30度搅拌12小时，反应完全后，抽滤，滤液加入200g 80%水合肼，加热至80度搅拌6小时，冷却至0度，滴加4N盐酸调ph至6-7，析出大量类白色固体，抽滤，滤饼收集后用95%乙醇0度打浆2小时后抽滤，干燥，得到白色固体400g。
实施例5：N-α-Boc-D-α,β-二氨基丙酸的合成
500gBoc-D-丝氨酸甲磺酸酯溶于1LDMSO中，加入390g邻苯二甲酰亚胺钾盐，加入198g氢氧化钾，30度搅拌12小时，反应完全后，抽滤，滤液加入300g哌啶，加热至80度搅拌6小时，冷却至0度，滴加4N盐酸调ph至6-7，析出大量类白色固体，抽滤，滤饼收集后用95%乙醇0度打浆2小时后抽滤，干燥，得到白色固体210g。
实施例6：D-三七素的合成
50L 反应釜中加入 6.5L 50%甲醇水溶液，1.346kg N-α-Boc-D-α,β-二氨基丙酸的合成，冷却至 0-5℃，分批加入 332g 一水合氢氧化锂，测pH值为8左右，搅拌40min。将1.03kg草酸单甲酯钾盐溶7715mL 50%甲醇水溶液中，滴加到上述反应液中，过程中保持 0-5℃。滴加完毕后升温至室温反应 20h。抽滤，滤饼用2.5L50%甲醇水溶液和 2.5L 丙酮各洗涤一次，干燥，得白色固体 1.8kg。固体加入到 5850mL 水中，降温至 10℃以下，滴加 2N 盐酸，调节pH 值至 2.1-2.2，过程中温度控制在 0-10℃。滴加完成后，室温搅拌2-3小时，0-10温度继续搅拌 4-6 小时。抽滤，滤饼加入冰水中，搅拌2小时，抽滤滤饼分别用 2.5L 冰水，2.5L甲醇，2.5L丙酮充分分散打浆洗两次，干燥，得白色固体 930g，纯度 99.5%，外标法含量 99%。
Claims (10)
1.一种D-三七素的高效制备方法，其特征包括以下步骤：水和混合有机溶剂，在碱性条件下，对D-丝氨酸进行Boc保护，得到D-Boc-丝氨酸。
2.D-Boc-丝氨酸与甲磺酰氯成酯后在碱性条件下氨解得到N-α-Boc-D-α,β-二氨基丙酸，与草酸单甲酯钾盐缩合并酸化脱保护后，得到粗品D-三七素，后经过纯化得到D-三七素精品，反应式如下：
根据权利要求1所述的一种D-三七素的制备方法，其特征在于：0-25度下，在碱性条件下，水和有机溶剂作为溶剂，D-丝氨酸与二碳酸二叔丁酯缩合生成Boc-D-丝氨酸盐，酸化游离后得到D-Boc-丝氨酸。
3.根据权利要求1所述的一种D-三七素的制备方法，其特征在于：0-25度下，Boc-D-丝氨酸在有机溶剂中，在缚酸剂存在下，与甲磺酰氯成酯。
4.根据权利要求1所述的一种D-三七素的制备方法，其特征在于：25-50度，在碱性条件下Boc-D-丝氨酸甲磺酸酯发生Gabriel氨解反应生成N-α-Boc-D-α,β-二氨基丙酸。
5.根据权利要求1所述的一种D-三七素的制备方法，其特征在于：在0-25度下，将N-α-Boc-D-α,β-二氨基丙酸溶于20-50%浓度的甲醇，在碱性条件下，与草酸单甲酯钾盐反应10-24h后，加酸水解并游离后，得到D-三七素粗品，经过处理纯化后，得到D-三七素精品。
6.根据权利要求2所述一种D-三七素的制备方法，其特征在于：所述的有机溶剂为二氯甲烷，丙酮，四氢呋喃，乙腈中的一种，所述的碱为氢氧化钾，氢氧化钠，碳酸钾，碳酸氢钠中的一种，所述的酸为盐酸，硫酸，柠檬酸，硫酸氢钾中的一种。
7.根据权利要求3所述的一种D-三七素的制备方法，其特征在于：所述的缚酸剂为：碳酸氢钠，碳酸钠，碳酸钾，碳酸铯，三乙胺，N，N-二异丙基乙胺中的一种。
8.根据权利要求4所述的一种D-三七素的制备方法，其特征在于：所述氨源为氨水，液氨，丁二酰亚胺，邻苯二甲酰亚胺，所述的碱包括有机碱及无机碱，其中无机碱为氢氧化钠，氢氧化钾，钠氢中的一种，有机碱为水合肼，哌啶，乙二胺中的一种，所述的溶剂为二甲基亚砜，N,N-二甲基甲酰胺，N,N-二乙基乙酰胺，四氢呋喃中的一种。
9.根据权利要求5所述的一种D-三七素的制备方法，其特征在于：所述的N-α-Boc-D-α,β-二氨基丙酸，碱及草酸单甲酯钾盐的摩尔比为1:1-2:1.2-1.8,所述的纯化方法为溶剂打浆。
10.根据权利要求9所述的一种D-三七素的制备方法，其特征在于：所述的纯化溶剂为水，丙酮，甲醇。
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| CN113754551A (zh) * | 2021-09-13 | 2021-12-07 | 云南西草资源开发有限公司 | 一种止血原料三七素的制备方法 |
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