CN108101881B - Process for the preparation of trabectedin and intermediates thereof - Google Patents
Process for the preparation of trabectedin and intermediates thereof Download PDFInfo
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- CN108101881B CN108101881B CN201711180537.0A CN201711180537A CN108101881B CN 108101881 B CN108101881 B CN 108101881B CN 201711180537 A CN201711180537 A CN 201711180537A CN 108101881 B CN108101881 B CN 108101881B
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- compound
- trabectedin
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- salt
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- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 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 title claims abstract description 18
- 229960000977 trabectedin Drugs 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000000543 intermediate Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical group C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 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 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 abstract description 10
- 150000003839 salts Chemical class 0.000 abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- -1 salt compound Chemical class 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 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 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
- 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
- 239000002253 acid Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 235000019260 propionic acid Nutrition 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
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 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
- IKKUKDZKIIIKJK-UHFFFAOYSA-N 2,2-diethoxyethanol Chemical compound CCOC(CO)OCC IKKUKDZKIIIKJK-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 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
- 206010039491 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
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides 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
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 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
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-O dicyclohexylazanium Chemical compound C1CCCCC1[NH2+]C1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-O 0.000 description 1
- 238000004090 dissolution 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
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001033 ether group Chemical group 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
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 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
- 238000000926 separation method Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000006257 total synthesis reaction Methods 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
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
Abstract
The present invention provides processes for the preparation of trabectedin and intermediates thereof. In particular, the invention provides tempehA salt of the tinidine intermediate compound of formula II-1, wherein P1Is a hydroxy protecting group, P2Is an amino protecting group. Also provided is a process for preparing trabectedin using the compound having the structure of formula II-1.
Description
Technical Field
The present invention relates to a process for the preparation of trabectedin and the corresponding salts of its intermediate (S) -3- (3-methyl-2-benzyloxy-4, 5-methylenedioxy) phenyl-2- (benzyloxyacylamino) propionic acid.
Background
Trabectedin (ecteinascidin 743, ET-743) is a very potent marine antineoplastic agent, ema (european Medicines agency) has been approved for marketing in europe in 2007 for the treatment of advanced soft tissue sarcomas. Trabectedin is isolated from marine ecteinasciditurantane (ecteinascidituranta), and the result is small, but the total synthesis difficulty is large because the trabectedin contains a plurality of chiral centers.
Therefore, it is necessary to develop a synthetic method for producing trabectedin useful as an antitumor agent.
CN104557850A discloses that (S) -3- (3-methyl-2-benzyloxy-4, 5-methylenedioxy) phenyl-2- (phenylmethoxyacylamino) propionic acid (II-5a) compound is a key intermediate for synthesizing trabectedin, but the compound II-5a is an oily substance, can achieve the purification effect by complex column chromatography, is complex to operate and is difficult to adapt to the requirement of industrial production. To this end, the present invention provides a salt form of (S) -3- (3-methyl-2-benzyloxy-4, 5-methylenedioxy) phenyl-2- (benzyloxyacylamino) propionic acid, which is improved in physicochemical properties to be suitable for industrial production and packaging transfer. Meanwhile, the II-5a salt compound can be crystallized and purified by using a conventional solvent to obtain a high-purity intermediate sample, and the process is simple and convenient.
Wherein Bn is benzyl, and Cbz is benzyloxycarbonyl.
Disclosure of Invention
The present invention provides compounds useful as intermediates in the synthesis of trepetidine.
The present invention provides compounds of formula II-1:
wherein, P1Is a hydroxyl protecting group which, together with the oxygen atom to which it is bound, is an ester, silyl ether, alkyl ether, arylalkyl ether, and alkoxyalkyl ether; p2Is an amino protecting group; m is a base molecule.
The base molecule of the present invention is not particularly limited and known or can be determined by one skilled in the art, and is an inorganic base or an organic base, wherein the inorganic base forms an inorganic salt with the compound of formula II-1, including but not limited to calcium salt, sodium salt, potassium salt, and the corresponding inorganic base is selected and includes but not limited to calcium hydroxide, sodium hydroxide, potassium hydroxide; the organic base forms an organic salt with the compound of formula II-1, including but not limited to triethylamine salt, diisopropylethylamine salt, aniline salt, diisopropylamine salt, and the corresponding organic base selected includes but not limited to triethylamine, diisopropylethylamine, aniline, diisopropylamine.
Further, the base molecule is an organic base, preferably comprising diisopropylethylamine, aniline, diisopropylamine, more preferably dicyclohexylamine.
In particular embodiments, the compound of formula II-1 may exist as a single stereoisomer, with high stereoisomeric purity, having the formula:
in specific embodiments, the amino protecting group (P)2) Is benzyloxycarbonyl (Cbz) having the formula:
preferably, said hydroxy protecting group (P)1) Is benzyl (Bn), an amino protecting group (P)2) Is benzyloxycarbonyl (Cbz) having the formula:
more preferably, the base molecule in the compound of formula II-1 according to the present invention is dicyclohexylammonium having the formula:
the present invention also provides a process for the preparation of trabectedin comprising the step of synthesising trabectedin from any one of the compounds II-1 to II-5 as hereinbefore described.
In a specific example, the following reaction scheme was carried out:
the invention also provides a preparation method of the compound II-1, which comprises the step of salifying the compound II and corresponding alkali to prepare the compound of the formula II-1,
wherein, P1、P2As previously described.
Further, the compound of formula II may exist as a single stereoisomer, with high stereoisomeric purity, having the formula:
in a preferred embodiment, said amino protecting group (P)2) Preferably benzyloxycarbonyl, having the formula:
wherein Cbz is benzyloxycarbonyl.
Further, the base molecule of the present invention is dicyclohexylamine.
Further, the hydroxyl protecting group P of the present invention1Preferably benzyl, having the formula:
the solvent used for the above salt formation is preferably one or a mixture of alcohols of C1-C4, such as methanol and ethanol, ester solvents, such as ethyl acetate, ether solvents, chlorohydrocarbon solvents, such as dichloromethane, and acetonitrile, more preferably ethanol, acetonitrile and methanol as the precipitation solvent. The equivalent of the corresponding base is preferably 1 to 2 equivalents.
The invention also provides a method for purifying the compound II, which comprises the steps of preparing the compound II by salifying the compound II and a corresponding base, separating to obtain a compound II-1, and then dissociating the compound II-1 with a corresponding acid, and optionally, recrystallizing the compound II-1 for one or more times and dissociating the compound II-1 with the acid. The acid is known or identifiable to those skilled in the art and is selected from, but not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid.
The invention also provides a method for preparing the trabectedin, which comprises the step of preparing the compound shown as the formula II-1 by salifying the compound II and a corresponding base.
Detailed description of the invention
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
The "hydroxy-protecting group" according to the present invention is a group known in the art as being suitable for hydroxy-protection, see hydroxy-protecting Groups in the literature ("Protective Groups in Organic Synthesis", 5th.ed.t.w.greene & p.g.m.wuts). Illustratively, the hydroxyl protecting group is taken together with the oxygen atom to which it is bound to form an ester, silyl ether, alkyl ether, arylalkyl ether, or alkoxyalkyl ether. The esters formed are acetyl (Ac), benzoyl (Bz) or pivaloyl (Piv); the silyl group formed is tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyloxymethyl (TOM) or Triisopropylsilyl (TIPS); forming an alkyl, arylalkyl, or alkoxyalkyl ether protecting group is benzyl (Bn), Methoxyethoxymethyl Ether (MEM), trityl (Tr), Dimethoxytrityl (DMT), methoxymethyl ether (MOM), or the like.
The "amino-protecting group" according to the present invention is a group known in the art as being suitable for hydroxyl protection, see amino-protecting Groups in the literature ("Protective Groups in Organic Synthesis", 5th.ed.t.w.greene & p.g.m.wuts). The amino protecting group, preferably benzyloxycarbonyl, together with the nitrogen atom to which it is bound, forms an amide, alkylamine, alkenylamine or arylamine.
The reagents for use according to the invention are commercially available and are prepared by the process described in the intermediates referred to in WO 2001058905.
The HPLC conditions used in the present invention are: the chromatography column Agilent Eclipse XDB-C184.6 x 150mm 5 μm, the mobile phase acetonitrile/water 50:50(V/V), the detection wavelength 254 nm.
Detailed Description
The present invention will be explained in detail with reference to specific examples below, so that those skilled in the art can more fully understand the specific examples of the present invention to illustrate the technical solutions of the present invention, and not to limit the present invention in any way.
Example 1:
compound II-5a (700 g, prepared according to the method of patent WO 2001058905) was dissolved in acetonitrile (7 l), dicyclohexylamine (280 g) was added, stirred at 50 ℃ for 0.5 h, part of the solvent was removed under reduced pressure and filtered to give 870 g of compound II-5, 89% yield with HPLC purity > 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).
Example 2: screening of salt-forming conditions
The salt formation conditions were screened in the above salt formation mode with reference to example 1: dissolving the compound II-5a in a proper organic solvent, adding alkali molecules dissolved by the organic solvent, stirring for 0.5 hour at 50 ℃, removing part of the solvent by decompression and filtering to obtain the product.
From the data of the above-mentioned experimental examples, it was found that the anilinoamides and triethylamine could not form salts with the compound II-5a and formed solids, while dicyclohexylamine showed good salt-forming efficiency among several bases capable of forming salts with the compound II-5a and the obtained salts had high purity.
Example 3:
in a 250mL reaction flask, compound II-5(15g) was dissolved by adding it to toluene (200mL) under stirring, then aqueous hydrochloric acid (100mL, containing 0.82g of hydrogen chloride) was added dropwise and stirred vigorously for 1 hour, a little insoluble matter was removed by filtration, and the mixture was separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound II-5a (12 g).
In a 250mL reaction bottle, a crude compound II-5acid is mixed with glycolaldehyde diethylacetal (6.2g, 2eq.), dichloromethane (100mL) is added for dissolution, 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI, 5.8g, 1.3eq.) and 4-dimethylaminopyridine (0.28g, 0.1eq.) are added for stirring at room temperature for 5-7 hours, water is added for quenching reaction, liquid separation is carried out, dichloromethane is extracted, water is washed, anhydrous sodium sulfate is dried and then is concentrated under reduced pressure to obtain a crude product, and then column chromatography purification is carried out to obtain a target compound II-6a (12.1g, the total yield of two steps is 90%).
Claims (6)
1. A compound of formula II-1:
wherein, P1Is benzyl; p2Is benzyloxycarbonyl; m is dicyclohexylamine.
2. The compound of claim 1, having the formula:
wherein Bn is benzyl, and Cbz is benzyloxycarbonyl.
3. A preparation method of a compound II-1 comprises the step of preparing the compound II-1 by salifying the compound II and an organic base M, wherein the organic base is dicyclohexylamine,
wherein, P1、P2And M is as defined in claim 1.
4. The process according to claim 3, wherein the compound of formula II is
5. A method of preparing trabectedin comprising the step of synthesizing trabectedin from a compound of claim 1 or 2.
6. A method for preparing trabectedin, comprising the preparation method of claim 3 or 4.
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