CN108101881A - It is used to prepare the method and its intermediate of tributidine - Google Patents
It is used to prepare the method and its intermediate of tributidine Download PDFInfo
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- CN108101881A CN108101881A CN201711180537.0A CN201711180537A CN108101881A CN 108101881 A CN108101881 A CN 108101881A CN 201711180537 A CN201711180537 A CN 201711180537A CN 108101881 A CN108101881 A CN 108101881A
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- compound
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- tributidine
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000006239 protecting group Chemical group 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- -1 compound salt Chemical class 0.000 claims abstract description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 14
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 6
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical group 0.000 claims description 6
- 150000005215 alkyl ethers Chemical class 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 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 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 3
- 229960000977 trabectedin Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- OQCFWECOQNPQCG-UHFFFAOYSA-N 1,3,4,8-tetrahydropyrimido[4,5-c]oxazin-7-one Chemical compound C1CONC2=C1C=NC(=O)N2 OQCFWECOQNPQCG-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 0 Cc1c(*)c(C[C@](*)C(O)=O)cc2c1OCO2 Chemical compound Cc1c(*)c(C[C@](*)C(O)=O)cc2c1OCO2 0.000 description 1
- 241000798369 Ecteinascidia turbinata Species 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N Glycolaldehyde Chemical compound OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical class CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- OFXSXYCSPVKZPF-UHFFFAOYSA-N methoxyperoxymethane Chemical compound COOOC OFXSXYCSPVKZPF-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides the methods and its intermediate for being used to prepare tributidine.Specifically, the present invention provides 1 compound salt of tributidine intermediate Formula II and preparation method thereof, wherein P1For hydroxyl protection base, P2For amino protecting group.The method for being used to prepare tributidine with 1 structural compounds of Formula II is also provided.
Description
Technical field
The present invention relates to the method and its intermediate (S) -3- for preparing tributidine, (3- methyl -2- benzyloxies -4,5- is sub-
Methylenedioxy group) phenyl -2- (benzyloxy acyl amino) propionic acid corresponding salt.
Background technology
Tributidine (ET 743, ET-743) is that antitumor agent, EMA in 2007 are given birth in a kind of very effective sea
It is listed (European Medicines Agency) approved in Europe, for treating late period soft tissue sarcoma.Tributidine
It is isolated from marine organisms ecteinascidin (Ecteinascidiaturbinata), result is smaller, but comprising multiple
Chiral centre, fully synthetic difficulty are also larger.
Therefore, it is necessary to the synthetic method for preparing the tributidine for antitumor agent is developed.
CN104557850A discloses (S) -3- (3- methyl -2- benzyloxy -4,5- methylene-dioxies) phenyl -2- (benzene
Methoxyl group acyl amino) propionic acid (II-5a) compound is to synthesize the key intermediate of tributidine, but compound II-5a is
A kind of grease is cumbersome, it is difficult to adapt to industrial need, it is necessary to can be only achieved the effect of purifying through complicated column chromatography
It will.For this purpose, the present invention provides (S) -3- (3- methyl -2- benzyloxies -4,5- methylene-dioxy) phenyl -2- (benzyloxies
Acyl amino) propionic acid salt form, improve its physical and chemical character, be suitable for industrial production and packaging shift.It meanwhile can profit
Crystallization purifying is carried out to II-5a salt compounds with Conventional solvents, to obtain high-purity intermediate sample, simple process.
Wherein, Bn is benzyl, and Cbz is benzyloxycarbonyl group.
The content of the invention
The present invention is provided in tributidine is synthesized, the compound as intermediate.
The present invention provides the compound of Formula II -1：
Wherein, P1For hydroxyl protection base, the hydroxyl protection base is ester, first silicon together with oxygen atom in combination
Alkyl ether, alkyl ether, aryl alkyl ethers and alkoxyalkyl ether；P2For amino protecting group；M is base molecule.
Base molecule of the present invention be not limited specifically and it is known to those skilled in the art dawn or can be determined,
For inorganic base or organic base, the inorganic base forms a kind of inorganic salts with -1 compound of Formula II, includes but not limited to calcium salt, sodium
Salt, sylvite, selected corresponding inorganic base include but not limited to calcium hydroxide, sodium hydroxide, potassium hydroxide；The organic base
A kind of organic salt is formed with -1 compound of Formula II, includes but not limited to triethylamine salt, diisopropyl ethyl amine salt, aniline salt, two
Isopropyl amine salt, selected corresponding organic base include but not limited to triethylamine, diisopropyl ethyl amine, aniline, diisopropyl
Amine.
Further, the base molecule is organic base, it preferably includes diisopropyl ethyl amine, aniline, diisopropyl
Amine, more preferably dicyclohexylamine.
In a particular embodiment, -1 compound of Formula II can exist as a kind of single stereoisomer, have Gao Li
Body enantiomeric purity has following formula：
In a particular embodiment, the amino protecting group (P2) it is benzyloxycarbonyl group (Cbz), there is following formula：
Preferably, the hydroxyl protection base (P1) for benzyl (Bn), amino protecting group (P2) it is benzyloxycarbonyl group (Cbz), have
There is following formula：
The more preferable two hexamethylenes ammonium of base molecule in -1 compound of Formula II of the present invention has following formula：
The present invention also provides the method for being used to prepare tributidine, this method is included by the foregoing II-1 to II-5
In any compound synthesis tributidine the step of.
In a particular embodiment, following reaction process carries out：
The present invention also provides the preparation method of compound II-1, including compound II and corresponding alkali into salt formula
The step of II-1 compounds,
Wherein, P1、P2As previously described.
Further, Formula II compound can exist as a kind of single stereoisomer, have high stereoisomer
Purity has following formula：
In a preferred embodiment, the amino protecting group (P2) it is preferably benzyloxycarbonyl group, there is following formula：
Wherein, Cbz is benzyloxycarbonyl group.
Further, base molecule of the present invention is dicyclohexylamine.
Further, hydroxyl protection base P of the present invention1Preferably benzyl has following formula：
The above-mentioned solvent into used in salt is preferably the alcohols of C1-C4, such as methanol, ethyl alcohol, esters solvent, such as ethyl acetate,
Ether solvent, one kind of chlorinated hydrocarbon solvent such as dichloromethane or its mixed solvent, acetonitrile, more preferable ethyl alcohol, acetonitrile, methanol are made
For solvent is precipitated.The equivalent of corresponding alkali is preferably 1~2 equivalent.
The present invention also provides a kind of purification process of compound II, this method is included by compound II and corresponding alkali into salt
It prepares and after isolated II-1 compounds, then free step is carried out with corresponding acid, II-1 compounds are optionally carried out one
Dissociate after secondary or repeated recrystallize with acid.Described acid is known to those skilled in the art or identifiable, be selected from but
It is not limited to hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid.
The present invention also provides a kind of method for preparing tributidine, including the foregoing compound II and corresponding alkali
The step of into salt formula II-1 compounds.
Detailed description of the invention
Unless stated to the contrary, it is otherwise following that there are following meanings with term in the specification and in the claims.
" hydroxyl protection base " of the present invention is the group for hydroxyl protection that can be suitably known in the art, referring to text
It offers in (" Protective Groups in Organic Synthesis ", 5Th.Ed.T.W.Greene＆P.G.M.Wuts)
Hydroxy-protective group.As an example, the hydroxyl protection base is together with oxygen atom in combination, to form a kind of ester, first silicon
Alkyl ether, alkyl ether, aryl alkyl ethers or alkoxyalkyl ether.The ester of formation is acetyl group (Ac), benzoyl (Bz) or new
Valeryl (Piv)；The first silicon silylation of formation is t-Butyldimethylsilyl (TBDMS), tert-butyl diphenyl silicon substrate
(TBDPS), triisopropylsilyl oxygroup methyl (TOM) or triisopropylsilyl (TIPS)；Form alkyl ether, aryl
Alkyl ether or alkoxyalkyl ether protecting group are benzyl (Bn), methoxyethoxymethyl ether (MEM), trityl (Tr), two
Methoxytrityl (DMT), methoxy ether (MOM) or the like.
" amino protecting group " of the present invention is the group for hydroxyl protection that can be suitably known in the art, referring to text
It offers in (" Protective Groups in Organic Synthesis ", 5Th.Ed.T.W.Greene＆P.G.M.Wuts)
Amido protecting group.The amino protecting group is together with nitrogen-atoms in combination, to form a kind of amide, alkylamine, alkene
Base amine or arylamine, the amino protecting group are preferably benzyloxycarbonyl group.
It is of the present invention to be obtained with reagent by commercial sources, it is described to be referred to intermediate described in WO2001058905
Method prepares.
HPLC conditions used in the present invention：5 μm of chromatographic column Agilent Eclipse XDB-C18 4.6*150mm, mobile phase
For acetonitrile/water 50:50 (V/V), Detection wavelength 254nm.
Specific embodiment
The present invention is explained in detail below with reference to specific example so that this hair is more fully understood in those skilled in the art
Bright specific example is merely to illustrate technical scheme, does not limit the present invention in any way.
Embodiment 1：
Compound II-5a (700 grams, the method in patent WO 2001058905 is made) is dissolved in acetonitrile (7 liters)
In, dicyclohexylamine (280 grams) is added in, when stirring 0.5 is small under the conditions of 50 DEG C, partial solvent is removed in decompression rotation, filters, obtains
870 g of compound II-5, yield 89%, HPLC purity are>99%.
1HNMR(BRUKER-400MHz,DMSO-d6)δ7.55(d,2H),7.40-7.25(m,8H),6.84-6.82(d,
1H),6.72(s,1H),5.94(s,2H),4.94(s,2H),4.73(s,2H),4.1-4.0(m,2H),3.17(m,1H),2.86
(s,2H),2.67(m,1H),2.10(s,3H),2.0-1.0(m,20H).
Embodiment 2：The screening of salt-forming condition
Referring to embodiment 1 is above-mentioned salt-forming condition is screened into salt mode：Compound II-5a is dissolved in appropriate organic solvent
In, base molecule that addition is dissolved with organic solvent, when stirring 0.5 is small under the conditions of 50 DEG C, partial solvent is removed in decompression rotation, filters,
Obtain product.
From the data of above-mentioned multiple experimental examples, it is seen that benzene glycosides glutamine, triethylamine cannot be with compound II-5a into salt
And form solid, and it is several can in alkali of the compound II-5a into salt, dicyclohexylamine is shown well into salt efficiency,
And the purity of gained salt is high.
Embodiment 3：
In 250ml reaction bulbs, compound II-5 (15g) is added in toluene (200mL) after stirring and dissolving, hydrochloric acid is added dropwise
Aqueous solution (100mL, hydrogen chloride containing 0.82g), be vigorously stirred 1 it is small when, be filtered to remove a little insoluble matter, liquid separation, water washing is anhydrous
Compound II-5a (12g) is concentrated under reduced pressure to give after sodium sulphate drying.
It is in 250ml reaction bulbs, compound II-5acid crude products and glycollic aldehyde diethyl acetal (6.2g, 2eq.) is mixed
It closes, after (100mL) dissolving that adds methylene chloride, then adds 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate
(EDCI, 5.8g, 1.3eq.) and 4-dimethylaminopyridine (0.28g, 0.1eq.), be stirred at room temperature 5~7 it is small when, water quenching is added to go out instead
Should, liquid separation, dichloromethane extraction, washing, be concentrated under reduced pressure to obtain crude product after anhydrous sodium sulfate drying, then column chromatography purifies to obtain target
Compound II-6a (12.1g, two step gross production rates 90%).
Claims (15)
1. the compound of Formula II -1：
Wherein, P1For hydroxyl protection base, the hydroxyl protection base, together with oxygen atom in combination, selected from ester, monosilane
Base ether, alkyl ether, aryl alkyl ethers and alkoxyalkyl ether；P2For amino protecting group；M is organic base molecule, is preferably two different
Ethylamine, aniline, diisopropylamine, more preferably dicyclohexylamine.
2. compound according to claim 1 has following formula：
3. compound according to claim 1 or 2 has following formula：
Wherein, Cbz is benzyloxycarbonyl group.
4. compound according to claim 1 or 2 has following formula：
Wherein, Bn is benzyl, and Cbz is benzyloxycarbonyl group.
5. compound according to claim 1 or 2 has following formula：
Wherein, Bn is benzyl, and Cbz is benzyloxycarbonyl group.
6. the preparation method of compound II-1, the step of including compound II and organic base M into salt formula II-1 compounds,
Wherein, P1、P2With M as defined in claim 1.
7. preparation method according to claim 6, compound of formula H are
8. preparation method according to claim 6, compound of formula H are
Wherein, Cbz is benzyloxycarbonyl group.
9. preparation method according to claim 6, compound of formula H are
Wherein, Bn is benzyl, and Cbz is benzyloxycarbonyl group.
10. preparation method according to claim 6, it is characterised in that the base molecule is dicyclohexylamine.
11. a kind of purification process of compound II, this method include by as the preparation any one of claim 6~10 simultaneously
After isolated II-1 compounds, then with acid free step is carried out, II-1 compounds are optionally subjected to one or many heavy knots
Dissociate after crystalline substance with acid.
12. purification process according to claim 11, it is characterised in that the acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, second
Acid, trifluoroacetic acid.
13. the compound of Formula II, wherein the Formula II compound described in being characterized in that is as the purifying side described in claim 11~12
Method obtains,
Wherein, P1、P2As defined in claim 1.
14. a kind of method for preparing tributidine, this method is included by Claims 1 to 5 or 13 any one of them compounds
The step of synthesizing tributidine.
15. a kind of method for preparing tributidine, including the preparation method as any one of claim 6~10 or as weighed
Profit requires the purification process any one of 11~12.
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