CN115677728A - Preparation method of ecteinascidin compound intermediate - Google Patents
Preparation method of ecteinascidin compound intermediate Download PDFInfo
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- CN115677728A CN115677728A CN202211363002.8A CN202211363002A CN115677728A CN 115677728 A CN115677728 A CN 115677728A CN 202211363002 A CN202211363002 A CN 202211363002A CN 115677728 A CN115677728 A CN 115677728A
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- -1 ecteinascidin compound Chemical class 0.000 title claims abstract description 35
- 229960000977 trabectedin Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000007800 oxidant agent Substances 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 28
- 230000007935 neutral effect Effects 0.000 claims abstract description 28
- 230000001590 oxidative effect Effects 0.000 claims abstract description 20
- 229940126062 Compound A Drugs 0.000 claims abstract description 17
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical group OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 11
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical group O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical compound O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 229940015043 glyoxal Drugs 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 4
- LXJDKGYSHYYKFJ-UHFFFAOYSA-N cyclohexadecanone Chemical group O=C1CCCCCCCCCCCCCCC1 LXJDKGYSHYYKFJ-UHFFFAOYSA-N 0.000 claims description 3
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- RBSLJAJQOVYTRQ-UHFFFAOYSA-N croconic acid Chemical compound OC1=C(O)C(=O)C(=O)C1=O RBSLJAJQOVYTRQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 claims description 2
- CHCLGECDSSWNCP-UHFFFAOYSA-N methoxymethoxyethane Chemical compound CCOCOC CHCLGECDSSWNCP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 28
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical class 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 abstract description 15
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 15
- 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 description 12
- 238000003786 synthesis reaction Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- ZXBSOTYVIHPBDT-UHFFFAOYSA-M 1-methylpyridin-1-ium-4-carbaldehyde;iodide Chemical compound [I-].C[N+]1=CC=C(C=O)C=C1 ZXBSOTYVIHPBDT-UHFFFAOYSA-M 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- SOEVVANXSDKPIY-UHFFFAOYSA-M sodium glyoxylate Chemical compound [Na+].[O-]C(=O)C=O SOEVVANXSDKPIY-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- NOUZOVBGCDDMSX-UHFFFAOYSA-N 3,5-ditert-butylcyclohexa-3,5-diene-1,2-dione Chemical compound CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1 NOUZOVBGCDDMSX-UHFFFAOYSA-N 0.000 description 1
- WJXQFVMTIGJBFX-UHFFFAOYSA-N 4-methoxytyramine Chemical compound COC1=CC=C(CCN)C=C1O WJXQFVMTIGJBFX-UHFFFAOYSA-N 0.000 description 1
- 241000798369 Ecteinascidia turbinata Species 0.000 description 1
- 241001152962 Halocynthia papillosa Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 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 invention provides a preparation method for preparing an ecteinascidin compound intermediate by taking an electrically neutral organic oxidant as a unique auxiliary agent, which comprises the steps of dissolving a compound A in an organic solvent, adding the electrically neutral organic oxidant, and reacting for 1-25 hours at 50-70 ℃. The method has the advantages of simple operation, cheap and easily obtained reagents, no need of catalyst and other auxiliary agents for auxiliary reaction, mild and mild reaction conditions, low solvent consumption, high yield and little environmental pollution, and is suitable for industrial production of key intermediates of ecteinascidin compounds.
Description
Technical Field
The invention belongs to the field of compound synthesis, and particularly relates to a preparation method of an ecteinascidin compound intermediate.
Background
Tribetidine (Trabectedin; ET-743) is an alkylating agent separated and extracted from the body of red sea squirt (Ecteinascidia turbinata) of the Caribbean tunicaceae, is a first novel marine anti-soft tissue tumor drug, and has the following structure:
however, since the source of the trabectedin is limited and the yield is low as a natural product isolated from animals, the artificial synthesis of the trabectedin has been a research hotspot in recent years.
In many existing reported synthetic routes of trabectedin, the compound B is a key intermediate, and the structure of the compound B is as follows:
for example, cuevas et al, ma et al, disclose the reaction of Compound B with 5- (2-aminoethyl) -2-methoxyphenol to prepare trabectedin as follows (Organic Letters, volume2, issue16, pages2545-2548 CN109912629B):
in addition, he et al disclose the synthesis of another ecteinascidin compound using intermediate compound B: rubictidine (angelnote Chemie, international Edition,58 (12), 3975-3975.
Therefore, the compound B plays an important role in the synthesis process of ecteinascidin compounds, however, the synthesis routes of the compound B have the defects of severe conditions, complex operation, high cost and the like.
Corey et al synthesized trabectedin for the first time in 1996, and reported that 4-formyl-1-methylpyridin-1-ium iodide, which is very expensive, was used in the process of synthesizing the intermediate, and a reaction system (20 equivalents were added) was required to be added in an extremely excessive amount, which not only resulted in high cost, but also resulted in complicated operation of the preparation process, difficulty in purification, and low yield. (J.am.chem.Soc.1996, 118, 9202-9203).
Since this method was first reported, although many researchers used various means to synthesize trabectedin the course of subsequent studies, the method disclosed in e.j.corey et al, 1996, was used as a reference for synthesizing intermediate compound B using 4-formyl-1-methylpyridin-1-ium iodide as an oxidizing agent. For example: fukuyama et al also synthesized intermediate compound B in 2002 using 4-formyl-1-methylpyridin-1-ium iodide as an oxidant, and finally completed the synthesis of trabectedin. (J.am.chem.Soc.2002, 124, 6552-6554); jieping Zhu et al also completed the work of synthesizing intermediate compound B in 2006 using 4-formyl-1-methylpyridin-1-ium iodide as an oxidizing agent. (J.am.chem.Soc.2006, 128, 87-89); the total synthesis of the trabectedin is completed by about 2019, the used intermediate compound B is obtained by oxidizing 4-formyl-1-methylpyridine-1-onium iodide, and the synthesis condition and the yield of the intermediate compound B are not improved; (Angewandte Chemie, international Edition (2019), 58 (12), 3972-3975). The method for synthesizing the compound B described in patent publication No. CN1096463C is also the same as that of e.j.
It can be seen that the method disclosed in e.j.corey et al for the synthesis of compound B has been used for a long time, and thus the difficulties of large addition of the oxidant 4-formyl-1-methylpyridin-1-ium iodide, high cost, complicated operation, difficult purification and low yield have not been solved.
In recent years, there have also been studies attempting to achieve the synthesis of compound B using other oxidizing agents instead of 4-formyl-1-methylpyridin-1-ium iodide, for example: in chinese patent No. CN107739387B, sodium glyoxylate and sulfate are added into a mixed solution of a sodium acetate-acetic acid buffer solution and an organic solvent, and the intermediate compound B is obtained by reacting under the protection of an inert gas and performing a series of post-treatment operations such as water washing, extraction, pulping and the like. Although the method improves the yield of the compound B, the used sodium glyoxylate reagent is still expensive, the reaction needs the protection of inert gas, the conditions are relatively harsh, and the post-treatment operation is complicated. In the preparation method of the trabectedin disclosed in the Chinese patent application with the publication number of CN114805398A, 3, 5-di-tert-butyl-1, 2-benzoquinone is used as an oxidant, and zinc chloride and oxalic acid serving as catalysts are added to react under the anhydrous and oxygen-free conditions to prepare an intermediate compound B. However, the reaction operation is also complicated, and the post-treatment must be performed by column chromatography to obtain B with high purity.
In general, the improved process disclosed in the above-mentioned patents/patent applications, while avoiding the use of 4-formyl-1-methylpyridin-1-ium iodide, still requires more severe reaction conditions, similar to those disclosed in the original e.j.corey et al, requiring control of the absence of water and oxygen; in addition, the whole reaction system needs to be participated in by a catalyst, so that the post-treatment operation is complicated, the whole process cost is high, and the industrial production of the trabectedin is restricted.
In summary, the process for producing the intermediate compound B from the compound a always has a technical prejudice that the reaction needs to be achieved by controlling anhydrous and oxygen-free conditions or by using a catalyst to assist an oxidant. In order to further realize the expanded and industrialized production of the intermediate compound B and further realize the mass production of the ecteinascidin compound, the preparation method of the key intermediate compound B of the ecteinascidin compound, which has the advantages of simple operation, mild reaction conditions, low cost and high yield, is further provided, and has important significance.
Disclosure of Invention
The invention aims to provide a preparation method of an ecteinascidin compound key intermediate compound B, which has the advantages of simple operation, mild reaction conditions, low cost and high yield.
The invention provides the application of an electroneutral organic oxidant as a unique auxiliary agent in the reaction for preparing an ecteinascidin compound intermediate; the reaction for preparing the ecteinascidin compound intermediate is a reaction for preparing a compound B by taking a compound A as a reactant;
the chemical conversionThe compound A is:
or a salt thereof, compound B is:
wherein R is hydrogen or a hydroxy protecting group.
The invention also provides a preparation method of the ecteinascidin compound intermediate, which comprises the following steps:
(1) Dissolving the compound A or the salt thereof in an organic solvent;
(2) Adding an electrically neutral organic oxidant to react to obtain a compound B;
the reaction formula is as follows:
wherein R is hydrogen or a hydroxyl protecting group.
Further, the hydroxyl-protecting group is methoxymethyl ether, methoxymethyl ethyl ether, or allyl.
Further, the electrically neutral organic oxidant in step (2) has at least one carbonyl group, preferably at least two carbonyl groups.
Further, the structure of the electrically neutral organic oxidizer is shown as formula I:
wherein R is 1 、R 2 Each independently selected from: hydrogen, hydroxy, C 1～5 Alkyl radical, C 1～5 Alkoxy, phenyl, or R 1 、R 2 Are linked to form a 3-to 7-membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl, carbonyl, amino, halogen, cyano or mercapto; n is an integer of 0 to 6;
g is selected from CO, NH or CR a R b Wherein R in each repeating unit a 、R b Each independently selected from hydrogen, hydroxy, amino, halogen, cyano or mercapto.
Further, the above R 1 、R 2 Each independently selected from: hydrogen, hydroxy, methyl, ethoxy, phenyl, or R 1 、R 2 Linked to form a 5-to 6-membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl or carbonyl, and n is an integer of 0 to 4.
Further, the electrically neutral organic oxidizer is represented by formula I-A:
wherein n1 is 1 or 2, and R 1 、R 2 Each independently selected from: hydrogen, hydroxy, C 1～5 Alkyl radical, C 1～5 Alkoxy, phenyl;
preferably, R 1 、R 2 Each independently selected from: hydrogen, hydroxy, methyl, ethoxy, phenyl.
Further, the electrically neutral organic oxidizer is represented by formula I-B:
wherein n is 1 or 2;
G 1 is nothing, CO, NH or CR c R d ，G 2 Is none, CO, NH or CR e R f ，G 3 Is nothing, CO, NH or CR g R h (ii) a Wherein R is c 、R d 、R e 、R f 、R g 、R h Each independently selected from hydrogen, hydroxy, amino, mercapto or cyano, or R c 、R e Are linked to form a chemical bond, or R e 、R g The linkage forms a chemical bond.
Further, the above R c 、R d 、R e 、R f 、R g 、R h Each independently selected from hydrogen, hydroxy, or R c 、R e Are linked to form a chemical bond, or R e 、R g The linkage forms a chemical bond.
Further, the electrically neutral organic oxidizer is selected from any one of the following compounds or hydrates thereof:
still further, the electrically neutral organic oxidizer is alloxan.
Further, the organic solvent in step (1) is selected from N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, 1, 4-dioxane, tetrahydrofuran or N-methylpyrrolidone; n, N-dimethylformamide is preferred.
Further, the molar ratio of the compound A to the electrically neutral organic oxidant is as follows: 1, (1-5); preferably: 1:2.
Further, the reaction conditions are 50-70 ℃ for 1-24 hours; preferably at 60 ℃ for 2 to 24 hours.
Furthermore, the electrically neutral organic oxidant is glyoxylic acid, glyoxylic acid ester, glyoxal, methylglyoxal, diethyl ketomalonate or phenylglyoxal, and the reaction time is 10 to 14 hours, preferably 12 hours;
or, the electrically neutral organic oxidant is cyclohexadecanone or croconic acid, and the reaction time is 20 to 24 hours, preferably 24 hours;
or, the electrically neutral organic oxidant is alloxan, and the reaction time is 1 to 3 hours, preferably 2 hours.
Further, the preparation method also comprises the following post-treatment steps:
(a) Pouring the reaction liquid obtained after the reaction in the step (2) into inorganic base or organic base aqueous solution at the temperature of 0-4 ℃;
(b) Standing to separate out a solid, and filtering to obtain a solid, namely the compound B.
Further, the step (a) is: pouring the reaction liquid obtained after the reaction in the step (2) into a saturated sodium bicarbonate aqueous solution, a sodium carbonate aqueous solution or a triethylamine aqueous solution at the temperature of 0 ℃.
The invention has the beneficial effects that: the invention uses the electroneutral organic oxidant as the only auxiliary agent for preparing the key intermediate of the ecteinascidin compound, does not need the participation of other auxiliary agents such as a catalyst and the like, can obtain the intermediate of the ecteinascidin compound with high yield by simple and rapid post-treatment under mild and non-harsh conditions, and overcomes the technical prejudice that the anhydrous and anaerobic conditions must be controlled or the catalyst needs to participate in the process of preparing the key intermediate compound B of the ecteinascidin compound.
The method has the advantages of simple operation, cheap and easily obtained reagents, reaction in a water-containing system, mild and non-harsh reaction conditions, low solvent consumption, high yield and little environmental pollution, and is suitable for industrially producing the key intermediate of the ecteinascidin compounds.
Description of terms:
in the present invention, "R c 、R e The case where the linkage forms a chemical bond "means that a carbon-carbon double bond is formed between G1 and G2 and another substituent (R) on the carbon atom d 、R f ) Are each independently selected from hydrogen, hydroxy, amino, mercapto or cyano. "or R e 、R g The case of linkage forming a chemical bond "means that a carbon-carbon double bond is formed between G2 and G3, and another substituent (R) on the carbon atom f 、R h ) Are each independently selected from hydrogen, hydroxy, amino, mercapto or cyano.
"hydroxy protecting group": suitable Groups for hydroxyl protection are known in the art, see the literature ("Protective Groups in Organic Synthesis",5Th Ed. T.W.Greene &P.G.M.Wuts) for hydroxyl protecting Groups.
"electrically neutral organic oxidizer": refers to a substance without electric charge, which takes carbon atoms as a structural framework of a compound and has the ability of acquiring electrons.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products, and are obtained by purchasing products sold in the market.
Example 1 preparation of key intermediates of ecteinascidins
Compound A hydrochloride (1g, 1.5 mmol) was dissolved in DMF (20 mL), and aqueous methylglyoxal solution (547mg, 3.0mmol,40wt% in H was added 2 O), stirred at 60 ℃ for 12 hours, after completion of the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was filtered to obtain product B (0.9 g, yield 95%).
Example 2
Compound A hydrochloride (1g, 1.5mmol) was dissolved in DMF (20 mL), an aqueous glyoxylic acid solution (449mg, 3.0mmol,50wt% in H was added 2 O), stirred at 60 ℃ for 12 hours, after completion of the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was filtered to obtain product B (0.86 g, yield 92%).
Example 3
Compound A hydrochloride (1g, 1.5 mmol) was dissolved in DMF (20 mL), glyoxylic ester (306mg, 3.0 mmol) was added and stirred at 60 ℃ for 12 hours, and after completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was filtered to give product B (0.88 g, yield 94%).
Example 4
Compound A hydrochloride (1g, 1.5mmol) was dissolved in DMF (20 mL), and an aqueous glyoxal solution (435mg, 3.0mmol,40wt% was added 2 O), stirring at 60 ℃ for 12 hours, and allowing the mixture to reactUpon completion, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was then filtered to obtain product B (0.86 g, yield 92%).
Example 5
Compound A hydrochloride (1g, 1.5 mmol) was dissolved in DMF (20 mL), diethyl ketomalonate (522mg, 3.0 mmol) was added, the mixture was stirred at 60 ℃ for 12 hours, and after completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was then filtered to obtain product B (0.82 g, yield 88%).
Example 6
Compound A hydrochloride (1g, 1.5 mmol) was dissolved in DMF (20 mL), phenylglyoxal (402mg, 3.0 mmol) was added, stirring was carried out at 60 ℃ for 12 hours, and when the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was then filtered to obtain product B (0.85 g, yield 90%).
Example 7
Compound A hydrochloride (1g, 1.5 mmol) was dissolved in DMF (20 mL), cyclohexadecanone (504mg, 3.0mmol) was added, and the reaction mixture was stirred at 60 ℃ for 24 hours, after completion of the reaction, poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, and filtered to obtain product B (0.86 g, yield 91%).
Example 8
Compound A hydrochloride (1g, 1.5 mmol) was dissolved in DMF (20 mL), ketonic acid (426mg, 3.0 mmol) was added and stirred at 60 ℃ for 24 hours, and after completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was filtered to obtain product B (0.84 g, 89% yield).
Example 9
Compound A hydrochloride (1g, 1.5 mmol) was dissolved in DMF (20 mL), alloxan (480mg, 3.0mmol) was added, and the mixture was stirred at 60 ℃ for 2 hours, and when the reaction was completed, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution at 0 ℃ to precipitate a solid, which was then filtered to obtain product B (0.92 g, yield 96%).
The electrically neutral organic oxidant and the reaction conditions and corresponding yields are shown in table 1:
wherein, the glyoxylic acid, the glyoxylate and the glyoxal are all added in the form of aqueous solution.
Each electrically neutral organic oxidizer has the following structure:
in conclusion, the invention provides a synthesis method of an ecteinascidin compound key intermediate, which is simple to operate, has the advantages of cheap and easily-obtained reagents, mild and mild reaction conditions, low solvent consumption, high yield and small environmental pollution, can be used for reaction in a water-containing system, and is suitable for industrial production of the ecteinascidin compound key intermediate.
Claims (17)
1. Use of a neutral organic oxidant as the sole auxiliary agent in a reaction for the preparation of an ecteinascidin compound intermediate; the reaction for preparing the ecteinascidin compound intermediate is a reaction for preparing a compound B by taking a compound A as a reactant;
the compound A is:
or a salt thereof, compound B is:
wherein R is hydrogen or a hydroxy protecting group.
2. A preparation method of an ecteinascidin compound intermediate is characterized by comprising the following steps:
(1) Dissolving the compound A or the salt thereof in an organic solvent;
(2) Adding an electrically neutral organic oxidant to react to obtain a compound B;
the reaction formula is as follows:
wherein R is hydrogen or a hydroxy protecting group.
3. The method of claim 2, wherein the hydroxyl protecting group is methoxymethyl ether, methoxymethyl ethyl ether, or allyl.
4. The method of claim 2, wherein the electrically neutral organic oxidizer of step (2) has a structure comprising at least one carbonyl group, preferably at least two carbonyl groups.
5. The method of claim 4, wherein the electrically neutral organic oxidizer has the structure of formula I:
wherein R is 1 、R 2 Each independently selected from: hydrogen, hydroxy, C 1～5 Alkyl radical, C 1～5 Alkoxy, phenyl, or R 1 、R 2 Linked to form a 3-to 7-membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl, carbonyl, amino, halogen, cyano or mercapto; n is an integer of 0 to 6;
g is selected from CO, NH or CR a R b Wherein R in each repeating unit a 、R b Are respectively independentSelected from hydrogen, hydroxy, amino, halogen, cyano or mercapto.
6. The method of claim 5, wherein R is 1 、R 2 Each independently selected from: hydrogen, hydroxy, methyl, ethoxy, phenyl, or R 1 、R 2 Linked to form a 5-to 6-membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl or carbonyl, and n is an integer of 0 to 4.
7. The method of claim 6, wherein the electrically neutral organic oxidizer is of formula I-a:
wherein n1 is 1 or 2, and R 1 、R 2 Each independently selected from: hydrogen, hydroxy, C 1～5 Alkyl radical, C 1～5 Alkoxy, phenyl;
preferably, R 1 、R 2 Each independently selected from: hydrogen, hydroxy, methyl, ethoxy, phenyl.
8. The method of claim 6, wherein the electrically neutral organic oxidizer is of formula I-B:
wherein n is 1 or 2;
G 1 is nothing, CO, NH or CR c R d ，G 2 Is nothing, CO, NH or CR e R f ，G 3 Is nothing, CO, NH or CR g R h (ii) a Wherein R is c 、R d 、R e 、R f 、R g 、R h Each independently selected from hydrogen, hydroxy, amino, mercapto or cyano, or R c 、R e Are linked to form a chemical bond, or R e 、R g The linkage forms a chemical bond.
9. The method of claim 8, wherein R is c 、R d 、R e 、R f 、R g 、R h Each independently selected from hydrogen, hydroxy, or R c 、R e Are linked to form a chemical bond, or R e 、R g The linkage forms a chemical bond.
10. The method according to any one of claims 4 to 10, wherein the electrically neutral organic oxidizer is selected from any one of the following compounds or hydrates thereof:
11. the method of claim 10, wherein the electrically neutral organic oxidizer is alloxan.
12. The method according to claim 2, wherein the organic solvent in the step (1) is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, 1, 4-dioxane, tetrahydrofuran and N-methylpyrrolidone; n, N-dimethylformamide is preferred.
13. The method of claim 2, wherein the molar ratio of compound a to electrically neutral organic oxidizer is: 1, (1-5); preferably: 1:2.
14. The method according to claim 2, wherein the reaction is carried out under conditions of 50 to 70 ℃ for 1 to 24 hours; preferably 60 ℃ for 2 to 24 hours.
15. The method according to claim 14, wherein the electrically neutral organic oxidizer is glyoxylic acid, glyoxylic acid ester, glyoxal, methylglyoxal, diethyl ketomalonate or phenylglyoxal, and the reaction time is 10 to 14 hours, preferably 12 hours;
or, the electric neutral organic oxidant is cyclohexadecanone or croconic acid, and the reaction time is 20-24 hours, preferably 24 hours;
or, the electric neutral organic oxidant is alloxan, and the reaction time is 1-3 hours, preferably 2 hours.
16. The method of claim 2, further comprising the post-treatment step of:
(a) Pouring the reaction liquid obtained after the reaction in the step (2) into an inorganic base or organic base aqueous solution at the temperature of 0-4 ℃;
(b) Standing to separate out a solid, and filtering to obtain a solid, namely the compound B.
17. The method of claim 16, wherein step (a) is: and (3) pouring the reaction liquid obtained after the reaction in the step (2) into a saturated sodium bicarbonate aqueous solution, a sodium carbonate aqueous solution or a triethylamine aqueous solution at 0 ℃.
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| CN202211363002.8A CN115677728A (en) | 2022-11-02 | 2022-11-02 | Preparation method of ecteinascidin compound intermediate |
| PCT/CN2023/082268 WO2024093091A1 (en) | 2022-11-02 | 2023-03-17 | Preparation method for intermediate of ecteinascidin compound |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001077115A1 (en) * | 2000-04-12 | 2001-10-18 | Pharma Mar, S.A. | Antitumoral ecteinascidin derivatives |
| CN103038240A (en) * | 2010-05-25 | 2013-04-10 | 法马马有限公司 | Synthetic process for the manufacture of ecteinascidin compounds |
| CN107522698A (en) * | 2016-06-20 | 2017-12-29 | 浙江海正药业股份有限公司 | A kind of Preparation Method And Their Intermediate of ET-743 |
| CN107739387A (en) * | 2017-10-16 | 2018-02-27 | 上海皓元生物医药科技有限公司 | A kind of method for the key intermediate compound for preparing ET-743 |
| CN114805398A (en) * | 2021-01-22 | 2022-07-29 | 江苏恒瑞医药股份有限公司 | Preparation method of ecteinascidin compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1999050217A1 (en) * | 1998-03-31 | 1999-10-07 | Bayer Aktiengesellschaft | Valiolone, a method of preparing it, and its use to prepare acarbose and voglibose |
| GB0202544D0 (en) * | 2002-02-04 | 2002-03-20 | Pharma Mar Sa | The synthesis of naturally occuring ecteinascidins and related compounds |
| US7687508B2 (en) * | 2006-07-28 | 2010-03-30 | Bristol-Myers Squibb Company | Cyclic derivatives as modulators of chemokine receptor activity |
| US7629351B2 (en) * | 2006-07-28 | 2009-12-08 | Bristol-Myers Squibb Company | N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino) pyrrolidin-1-yl)cyclohexyl)acetamide and other modulators of chemokine receptor activity, crystalline forms and process |
| WO2013043826A1 (en) * | 2011-09-21 | 2013-03-28 | Abbvie Inc. | Tricyclic compounds useful as protein kinase inhibitors |
| WO2013146970A1 (en) * | 2012-03-29 | 2013-10-03 | 第一三共株式会社 | Novel quinoline derivative |
| CN109912629B (en) * | 2017-12-13 | 2021-12-24 | 浙江中科创越药业有限公司 | Preparation of Natural product Trabectedin |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001077115A1 (en) * | 2000-04-12 | 2001-10-18 | Pharma Mar, S.A. | Antitumoral ecteinascidin derivatives |
| CN103038240A (en) * | 2010-05-25 | 2013-04-10 | 法马马有限公司 | Synthetic process for the manufacture of ecteinascidin compounds |
| CN107522698A (en) * | 2016-06-20 | 2017-12-29 | 浙江海正药业股份有限公司 | A kind of Preparation Method And Their Intermediate of ET-743 |
| CN107739387A (en) * | 2017-10-16 | 2018-02-27 | 上海皓元生物医药科技有限公司 | A kind of method for the key intermediate compound for preparing ET-743 |
| CN114805398A (en) * | 2021-01-22 | 2022-07-29 | 江苏恒瑞医药股份有限公司 | Preparation method of ecteinascidin compound |
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