CN114805398A - Preparation method of ecteinascidin compound - Google Patents

Preparation method of ecteinascidin compound Download PDF

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CN114805398A
CN114805398A CN202210038224.6A CN202210038224A CN114805398A CN 114805398 A CN114805398 A CN 114805398A CN 202210038224 A CN202210038224 A CN 202210038224A CN 114805398 A CN114805398 A CN 114805398A
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benzoquinone
acid
compound
membered
formula
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陈亚
张磊
郭昌山
刘路
刘向玉
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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    • 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

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Abstract

The present disclosure relates to a method for preparing ecteinascidin compounds. The method has high yield and mild reaction conditions, and is suitable for industrial production.

Description

Preparation method of ecteinascidin compound
Technical Field
The disclosure belongs to the field of medicines, and relates to a preparation method of ecteinascidin compounds.
Background
Tribetidine (trade name Yondelis), developed by Qiangsheng pharmaceutical Co., Ltd., is a natural product isolated from the marine organism Ecteinascidia turbinata, but its content is extremely low, only 10 -6 ～10 -7 % w/w. Tributine was listed as a rare drug for soft tissue sarcoma in the European Union in 2001, and became the first modern marine drug. In 2004, the drug was classified by the U.S. Food and Drug Administration (FDA) as a rare drug for soft tissue sarcoma, and in europe and america, it was designated as an orphan drug for the treatment of acute lymphoblastic leukemia, soft tissue sarcoma, and ovarian cancer. Tribetidine can block tumorIn addition to the differentiation of cells in the G1/G2 cycle, the cells can also inhibit the secretion of Vascular Endothelial Growth Factor (VEGF) and the expression of its receptors. EP0309477B discloses a class of ecteinascidin compounds including ecteinascidins 729, 743 (trabectedin), 745, 759A, 759B and 770.
Figure BDA0003468963370000011
CN1096463C et al discloses a preparation method of trabectedin which compound 1 is a key intermediate, and among the methods disclosed in the current literature and patents, compound 1 is prepared by using the method of CN1096463C basically. In the reaction, very expensive N-methylpyridine carboxyformaldehyde needs to be added, and the addition amount is extremely excessive (20 equivalents are added in the patent), so that the whole process cost is extremely high, and the industrial production of the trabectedin is severely restricted.
Figure BDA0003468963370000012
Disclosure of Invention
The purpose of the present disclosure is to provide a novel method for preparing ecteinascidin compounds.
The disclosure provides a preparation method of a compound shown as a formula (I), which comprises the step of preparing a compound shown as a formula (IIA) by reacting a compound shown as a formula (II) in the presence of a benzoquinone compound and a catalyst,
Figure BDA0003468963370000021
wherein,
the benzoquinone compound is selected from
Figure BDA0003468963370000022
R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen and C 1 -C 6 Alkyl, 6-to 10-membered aryl、C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto, or, R 2 、R 3 Together with adjacent carbon atoms forming a ring system or R 3 、R 4 Together with adjacent carbon atoms forming a ring system or R 4 、R 5 Together with adjacent carbon atoms forming a ring system or R 2 、R 3 And R 4 、R 5 Taken together with the adjacent carbon atoms to form a ring system, each independently selected from the group consisting of carbocyclic, heterocyclic, aromatic and heteroaromatic rings, wherein the ring system is optionally substituted with C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxyl, amino and mercapto;
R 2 ’、R 3 ’、R 4 ’、R 5 ' each is independently selected from hydrogen, C 1 -C 6 Alkyl, 6-to 10-membered aryl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto, or, R 2 ’、R 3 ' together with the adjacent carbon atoms form a ring system or R 4 ’、R 5 ' together with the adjacent carbon atoms form a ring system or R 2 ’、R 3 ' and R 4 ’、R 5 ' taken together with adjacent carbon atoms form a ring system, each independently selected from the group consisting of carbocyclic, heterocyclic, aromatic and heteroaromatic rings, wherein said ring system is optionally substituted with C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxyl, amino and mercapto;
the catalyst is selected from protonic acid or Lewis acid;
R 1 、R 1 ’、R 1 "are each independently selected from hydrogen or a hydroxy protecting group;
ring B is selected from
Figure BDA0003468963370000031
Wherein R is 2 、R 3 、R 4 、R 5 And R 2 ’、R 3 ’、R 4 ’、R 5 ' is consistent with the group selection in benzoquinone compounds. Said corresponding, e.g. benzoquinone, compound is selected from
Figure BDA0003468963370000032
Then ring B is selected from
Figure BDA0003468963370000033
In certain embodiments, R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen and C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto.
In certain embodiments, R 2 ’、R 3 ’、R 4 ’、R 5 ' each is independently selected from hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto.
Specific examples of benzoquinone-like compounds include, but are not limited to: DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone); NQ (1, 4-naphthoquinone); TCQ (2, 3,4, 5-tetrachlorobenzoquinone); TBQ (2, 3,4, 5-tetrabromobenzoquinone); TFQ (2, 3,4, 5-tetrafluorobenzoquinone); BQ (1, 4-benzoquinone); 3, 6-di-tert-butyl-4, 5-dimethoxy-1, 2-benzoquinone; 3, 6-di-tert-butyl-4, 5-dichloro-1, 2-benzoquinone; 3, 6-di-tert-butyl-4, 5-difluoro-1, 2-benzoquinone; 3,4,5, 6-tetramethyl-1, 2-benzoquinone; 3,4,5, 6-tetraethyl-1, 2-benzoquinone; 3,4, 6-trichloro-5-methyl-1, 2-benzoquinone; 3, 6-diphenyl-4, 5-dimethoxy-1, 2-benzoquinone; 3, 6-dichloro-4, 5-dimethoxy-1, 2-benzoquinone; 3, 6-dimethyl-4, 5-dimorpholinyl-1, 2-benzoquinone; 3, 5-di-tert-butyl-1, 2-benzoquinone; 4, 5-dimethoxy-1, 2-benzoquinone; 4, 5-diethoxy-1, 2-benzoquinone; 3, 6-di-tert-butyl-1, 2-benzoquinone; 4-tert-butyl-1, 2-benzoquinone; 3, 5-dimethyl-1, 2-benzoquinone; 3, 5-di-tert-butyl-6-chloro-1, 2-benzoquinone; 4-phenylnaphthalene-1, 2-dione; 3-phenylnaphthalene-1, 2-dione; 2, 3-dimethoxy-1, 4 benzoquinone; 2, 6-diisopropyl-1, 4 benzoquinone; 2,3,5, 6-tetraiodo-1, 4 benzoquinone; 2, 5-dimethoxy-1, 4 benzoquinone; 2, 3-dimethoxy-1, 4 benzoquinone; 2, 3-dichloro-1, 4-benzoquinone; 2, 5-diethoxy-1, 4-benzoquinone; 2-phenyl-1, 4-naphthoquinone; 2-phenyl-anthraquinone; 2, 5-dibromo-3, 6-dimethoxy-1, 4-benzoquinone; 2, 3-dibromo-5, 6-dicyano-1, 4-benzoquinone; 2, 5-dichloro-3, 6-dicyano-1, 4-benzoquinone; 2, 6-dichloro-3, 5-dicyano-1, 4-benzoquinone; and 2, 3-diiodo-5, 6-dicyano-1, 4-benzoquinone, and the like.
Hydroxy protecting Groups are suitable Groups for hydroxy protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5) Th Ed.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C) 1-10 Alkyl or aryl) 3 Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 Alkoxy-substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy-substituted C 1-4 Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; may be (C) 1-10 Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl and the like; may be (C) 1-6 Alkyl or C 6-10 Aryl) sulfonyl; or (C) 1-6 Alkoxy or C 6-10 Aryloxy) carbonyl. In certain embodiments, the hydroxy protecting group is preferably methoxymethyl.
In certain embodiments, R 1 、R 1 ’、R 1 "are each independently selected from hydrogen, methoxymethyl, methoxyethoxymethyl, allyl or p-methoxybenzyl, preferably R 1 、R 1 ’、R 1 "is hydrogen, methoxymethyl, methoxyethoxymethyl or p-methoxybenzyl. .
The protic acid includes the commonly used inorganic and organic acids such as hydrochloric acid, acetic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, citric acid, benzenesulfonic acid, substituted benzenesulfonic acid, benzoic acid, substituted benzoic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like.
Lewis acids include aluminum chloride, ferric chloride, boron trifluoride, antimony pentafluoride, niobium pentachloride, zinc chloride, copper chloride, zinc sulfate, zinc triflate, ytterbium triflate, yttrium triflate, copper triflate, TMSOTf, boron trifluoride etherate, and the like. In certain embodiments, the Lewis acid is selected from zinc chloride.
In certain embodiments, the molar ratio of the compound of formula (II) to the benzoquinone-like compound may be from 2:1 to 1:20, preferably from 1:1 to 1: 10.
In certain embodiments, the molar ratio of the compound of formula (II) to the catalyst may be from 1:0.1 to 1:1.5, preferably from 1:0.5 to 1:1.
The solvent used for the reaction may be a conventional solvent such as water, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, C 1 -C 6 One or more of alkyl alcohol, acetone, ethyl acetate, preferably methanol and/or tetrahydrofuran.
The reaction temperature of the reaction may be-20 ℃ to 200 ℃, preferably 0 ℃ to 150 ℃, more preferably 0 ℃ to 70 ℃.
In certain embodiments, the method further comprises the step of reacting the compound of formula (IIA) with an acid, including common inorganic and organic acids, including but not limited to hydrochloric acid, acetic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, citric acid, benzenesulfonic acid, substituted benzenesulfonic acids, benzoic acid, substituted benzoic acids, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like. Substituted benzenesulfonic acid or benzoic acid means that benzenesulfonic acid or benzoic acid is selected from C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxyl and amino.
In certain embodiments, the molar ratio of the compound of formula (IIA) to the acid may be from 1:1 to 1: 100.
The solvent used for the reaction may be a conventional solvent. The reaction temperature of the reaction may be-20 ℃ to 200 ℃.
The disclosure also provides a preparation method of the compound shown as the formula (I), which comprises the step of reacting the compound shown as the formula (II) in the presence of a benzoquinone compound and a catalyst to prepare an intermediate compound, and the step of reacting the intermediate compound with an acid,
Figure BDA0003468963370000051
wherein,
the benzoquinone compound is selected from
Figure BDA0003468963370000052
R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen and C 1 -C 6 Alkyl, 6-to 10-membered aryl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto;
R 2 ’、R 3 ’、R 4 ’、R 5 ' Each is independently selected from hydrogen, C 1 -C 6 Alkyl, 6-to 10-membered aryl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto;
the catalyst is selected from protonic acid or Lewis acid;
R 1 、R 1 ' are each independently selected from hydrogen or a hydroxy protecting group.
The disclosure also provides a preparation method of the ecteinascidin compound, which comprises the preparation method of the compound shown in the formula (I).
The disclosure also provides a preparation method of the ecteinascidin compounds, which comprises a method for preparing the compounds shown in the formula (I) from the compounds shown in the formula (IIA) disclosed by the disclosure.
In certain embodiments, the ecteinascidin based compound is selected from one or more of ecteinascidin 729, trabectedin, ecteinascidin 745, ecteinascidin 759A, ecteinascidin 759B, and ecteinascidin 770.
In certain embodiments, the ecteinascidin compound is selected from the group consisting of trabectedin, and the method further comprises
Figure BDA0003468963370000053
In certain embodiments, R 1 Is methoxymethyl, the process further comprising
Figure BDA0003468963370000061
In certain embodiments, the ecteinascidin compound is selected from the group consisting of trabectedin, R 1 Is methoxymethyl, the process further comprising
Figure BDA0003468963370000062
In certain embodiments, the method further comprises
Figure BDA0003468963370000063
In certain embodiments, the ecteinascidin compound is selected from the group consisting of trabectedin, R 1 Is hydrogen, the process further comprising
Figure BDA0003468963370000064
The disclosure also provides a compound of formula (IIA),
Figure BDA0003468963370000071
in certain embodiments, R 1 "is hydrogen, methoxymethyl, methoxyethoxymethyl, allyl or p-methoxybenzyl.
In certain embodiments, the compound of formula (IIA) is
Figure BDA0003468963370000072
The disclosure also provides a preparation method of the compound shown in the formula (IIA), which comprises a method for preparing the compound shown in the formula (IIA) by reacting the compound shown in the formula (II) in the presence of a benzoquinone compound and a catalyst.
The preparation method of the ecteinascidin compound disclosed by the invention has the advantages of high reaction yield, mild reaction conditions, avoidance of use of expensive reagents, lower cost and suitability for industrial production.
The "alkyl" groups described in this disclosure are preferably C 1 -C 6 An alkyl group.
The "alkenyl" groups described in this disclosure are preferably C 2 -C 6 An alkenyl group.
The "alkynyl" groups described in this disclosure are preferably C 2 -C 6 Alkynyl.
The "alkylene" groups described in this disclosure are preferably C 1 -C 6 An alkylene group.
The "alkenylene" as described in the present disclosure is preferably C 2 -C 6 An alkenylene group.
"Alkenylene" as described in the present disclosure is preferably C 2 -C 6 Alkynylene radical.
The "alkoxy" groups described in this disclosure are preferably C 1 -C 6 An alkoxy group.
The "alkyl sulfide group" described in the present disclosure is preferably C 1 -C 6 An alkyl thioether group.
The "cycloalkyl" group described in the present disclosure is preferably a 3 to 12-membered, more preferably a 3 to 6-membered cycloalkyl group.
The "fused cycloalkyl" described in the present disclosure is preferably a 6 to 14-membered fused cycloalkyl, more preferably a 7 to 10-membered fused cycloalkyl.
The "heterocyclic group" described in the present disclosure is preferably a 3-to 12-membered, more preferably a 3-to 6-membered heterocyclic group.
The "fused heterocyclic group" described in the present disclosure is preferably a 6-to 14-membered fused heterocyclic group, more preferably a 7-to 10-membered fused heterocyclic group.
The "aryl" group described in the present disclosure is preferably a 6 to 14-membered, more preferably a 6 to 10-membered aryl group.
The "heteroaryl" group described in the present disclosure is preferably a 5-to 12-membered heteroaryl group, more preferably a 5-to 10-membered heteroaryl group.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "carbocyclic" refers to a ring system in a cycloalkyl group.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. "spirocarbocycle" refers to a ring system in a spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0003468963370000091
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. "fused carbocycle" refers to a ring system within a fused ring alkyl group. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0003468963370000092
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0003468963370000093
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "heterocycle" refers to a ring system within a heterocyclyl.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O) m (wherein m is an integer of 0 to 2),the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. "Spiroheterocycle" refers to a ring system within a spiroheterocycle group. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0003468963370000101
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. "fused heterocycle" refers to a ring system within a fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0003468963370000102
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. Depending on the number of component ringsTo be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0003468963370000111
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0003468963370000112
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. "aromatic ring" refers to a ring system in an aryl group. Non-limiting examples of aryl groups include:
Figure BDA0003468963370000113
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate, preferably phenyl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. "heteroaryl ring" refers to a ring system in a heteroaryl group. Non-limiting examples of heteroaryl groups include:
Figure BDA0003468963370000121
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
In the chemical structure of the compounds described in the present disclosure, a bond
Figure BDA0003468963370000123
Not specifying a configuration, i.e.If configurational isomerism is present in the chemical structure, the bond
Figure BDA0003468963370000124
Can be that
Figure BDA0003468963370000125
Or
Figure BDA0003468963370000126
Or at the same time contain
Figure BDA0003468963370000127
And
Figure BDA0003468963370000128
two configurations. In the chemical structure of the compounds described in the present disclosure, a bond
Figure BDA0003468963370000129
The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are contemplated.
Detailed Description
The present disclosure will be explained in detail with reference to specific examples below so that those skilled in the art can more fully understand that the specific examples of the present disclosure are merely illustrative of the technical solutions of the present disclosure and do not limit the present disclosure in any way.
Example 1
Figure BDA0003468963370000122
20ml of tetrahydrofuran, 20ml of absolute methanol and 2g of the compound (2) were added to a reaction flask, and stirred to dissolve the mixture, 2.6g of 3, 5-di-tert-butyl-1, 2-benzoquinone and 0.4g of zinc chloride were added, and stirred under nitrogen to react and prepare an intermediate 2A. Then, the temperature was reduced to 10 ℃ and 20ml of a saturated oxalic acid solution was added. The temperature is raised to the room temperature, and the reaction is stirred until the reaction is finished. To a reaction flask were added 40ml of dichloromethane and 60ml of water, sodium bicarbonate was added to adjust the pH to 7-8, the phases were separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with 25% sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (pure DCM to n-hexane: ethyl acetate ═ 2:1) to give compound 1(1.85g, 92%).
Example 2
200ml of tetrahydrofuran, 200ml of absolute methanol and 20g of the compound 2 were put into a reaction flask, stirred and dissolved, 26g of 3, 5-di-tert-butyl-1, 2-benzoquinone and 4g of zinc chloride were added, and stirred and reacted under nitrogen protection to prepare an intermediate 2A. Then, the temperature was reduced to 10 ℃ and 200ml of a saturated oxalic acid solution was added. Heating to 20-30 ℃, heating to room temperature, and stirring for reaction until the reaction is finished. To a reaction flask were added 400ml of dichloromethane and 600ml of water, sodium bicarbonate was added to adjust the pH to 7-8, the phases were separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with 25% sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (pure DCM to n-hexane: ethyl acetate ═ 2:1) to give compound 1(19.12g, 95%).
Example 3
Figure BDA0003468963370000131
A total of 19g of Compound 1 was charged according to the method disclosed in CN1096463C to obtain 8g of trabectedin.
Example 4 reaction without addition of catalyst
According to the method of example 1, however, no zinc chloride was added during the reaction, and the same reaction conditions were used, and it was found by TLC that substantially no compound 2A was produced, indicating that the reaction was difficult to proceed without the addition of the catalyst.
Since the present disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the present disclosure.

Claims (14)

1. A preparation method of a compound shown as a formula (I) comprises the step of reacting a compound shown as a formula (II) in the presence of a benzoquinone compound and a catalyst to prepare a compound shown as a formula (IIA),
Figure FDA0003468963360000011
wherein,
the benzoquinone compound is selected from
Figure FDA0003468963360000012
R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen and C 1 -C 6 Alkyl, 6-to 10-membered aryl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto, or, R 2 、R 3 Together with adjacent carbon atoms forming a ring system or R 3 、R 4 Together with adjacent carbon atoms forming a ring system or R 4 、R 5 Together with adjacent carbon atoms forming a ring system or R 2 、R 3 And R 4 、R 5 Taken together with adjacent carbon atoms to form a ring system, each independently selected from a 3-to 6-membered carbocyclic ring, a 3-to 6-membered heterocyclic ring, a 6-to 10-membered aromatic ring, and a 5-to 10-membered heteroaromatic ring, wherein the ring system is optionally substituted with C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxyl, amino and mercapto;
R 2 ’、R 3 ’、R 4 ’、R 5 ' each is independently selected from hydrogen, C 1 -C 6 Alkyl, 6-to 10-membered aryl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto, or, R 2 ’、R 3 ' together with the adjacent carbon atoms form a ring system or R 4 ’、R 5 ' together with the adjacent carbon atoms form a ring system or R 2 ’、R 3 ' and R 4 ’、R 5 ' taken together with the adjacent carbon atoms to form a ring system, each independently selected from a 3-to 6-membered carbocyclic ring, a 3-to 6-membered heterocyclic ring, a 6-to 10-membered aromatic ring, and a 5-to 10-membered heteroaromatic ring, wherein the ring system is optionally substituted with a pharmaceutically acceptable carrierQuilt selection C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxyl, amino and mercapto;
the catalyst is selected from protonic acid or Lewis acid;
R 1 、R 1 ’、R 1 "are each independently selected from hydrogen or a hydroxy protecting group;
ring B is selected from
Figure FDA0003468963360000021
Wherein R is 2 、R 3 、R 4 、R 5 And R 2 ’、R 3 ’、R 4 ’、R 5 ' is consistent with the group selection in benzoquinone compounds.
2. The method of claim 1, wherein R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen and C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto.
3. The method of claim 1, wherein R 2 ’、R 3 ’、R 4 ’、R 5 ' each is independently selected from hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto.
4. The process according to any one of claims 1 to 3, wherein the benzoquinone-like compound is selected from the group consisting of DDQ; NQ; TCQ; TBQ; TFQ; BQ; 3, 6-di-tert-butyl-4, 5-dimethoxy-1, 2-benzoquinone; 3, 6-di-tert-butyl-4, 5-dichloro-1, 2-benzoquinone; 3, 6-di-tert-butyl-4, 5-difluoro-1, 2-benzoquinone; 3,4,5, 6-tetramethyl-1, 2-benzoquinone; 3,4,5, 6-tetraethyl-1, 2-benzoquinone; 3,4, 6-trichloro-5-methyl-1, 2-benzoquinone; 3, 6-diphenyl-4, 5-dimethoxy-1, 2-benzoquinone; 3, 6-dichloro-4, 5-dimethoxy-1, 2-benzoquinone; 3, 6-dimethyl-4, 5-dimorpholinyl-1, 2-benzoquinone; 3, 5-di-tert-butyl-1, 2-benzoquinone; 4, 5-dimethoxy-1, 2-benzoquinone; 4, 5-diethoxy-1, 2-benzoquinone; 3, 6-di-tert-butyl-1, 2-benzoquinone; 4-tert-butyl-1, 2-benzoquinone; 3, 5-dimethyl-1, 2-benzoquinone; 3, 5-di-tert-butyl-6-chloro-1, 2-benzoquinone; 4-phenylnaphthalene-1, 2-dione; 3-phenylnaphthalene-1, 2-dione; 2, 3-dimethoxy-1, 4 benzoquinone; 2, 6-diisopropyl-1, 4 benzoquinone; 2,3,5, 6-tetraiodo-1, 4 benzoquinone; 2, 5-dimethoxy-1, 4 benzoquinone; 2, 3-dimethoxy-1, 4 benzoquinone; 2, 3-dichloro-1, 4-benzoquinone; 2, 5-diethoxy-1, 4-benzoquinone; 2-phenyl-1, 4-naphthoquinone; 2-phenyl-anthraquinone; 2, 5-dibromo-3, 6-dimethoxy-1, 4-benzoquinone; 2, 3-dibromo-5, 6-dicyano-1, 4-benzoquinone; 2, 5-dichloro-3, 6-dicyano-1, 4-benzoquinone; 2, 6-dichloro-3, 5-dicyano-1, 4-benzoquinone; and 2, 3-diiodo-5, 6-dicyano-1, 4-benzoquinone, preferably 3, 5-di-tert-butyl-1, 2-benzoquinone.
5. The method according to any one of claims 1 to 4, wherein R is 1 、R 1 ’、R 1 "are each independently selected from hydrogen, methoxymethyl, methoxyethoxymethyl, allyl or p-methoxybenzyl, preferably R 1 、R 1 ’、R 1 "is hydrogen, methoxymethyl, methoxyethoxymethyl or p-methoxybenzyl.
6. The preparation method according to any one of claims 1 to 5, wherein the catalyst is selected from hydrochloric acid, acetic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, citric acid, benzenesulfonic acid, substituted benzenesulfonic acid, benzoic acid, substituted benzoic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, aluminum chloride, iron chloride, boron trifluoride, antimony pentafluoride, niobium pentachloride, zinc chloride, copper chloride, zinc sulfate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, copper trifluoromethanesulfonate or TMSOTf, preferably aluminum chloride, iron chloride, boron trifluoride, antimony pentafluoride, niobium pentachloride, zinc chloride, copper chloride, zinc sulfate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, copper trifluoromethanesulfonate or TMSOTf, more preferably zinc chloride.
7. The process according to any one of claims 1 to 6, wherein the molar ratio of the compound of formula (II) to the benzoquinone compound is from 2:1 to 1:20, preferably from 1:1 to 1: 10.
8. The production process according to any one of claims 1 to 7, wherein the molar ratio of the compound represented by the formula (II) to the catalyst is from 1:0.1 to 1:1.5, preferably from 1:0.5 to 1:1.
9. The process according to any one of claims 1 to 8, wherein the process further comprises the step of reacting the compound of formula (IIA) with an acid, preferably hydrochloric acid, acetic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, citric acid, benzenesulfonic acid, substituted benzenesulfonic acid, benzoic acid, substituted benzoic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, preferably in a molar ratio of the compound of formula (IIA) to the acid of from 1:1 to 1: 100.
10. A preparation method of a compound shown as a formula (I) comprises the step of reacting a compound shown as a formula (II) in the presence of a benzoquinone compound and a catalyst to prepare an intermediate compound, and also comprises the step of reacting the intermediate compound with an acid,
Figure FDA0003468963360000031
wherein,
the benzoquinone compound is selected from
Figure FDA0003468963360000032
R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen and C 1 -C 6 Alkyl, 6-to 10-membered aryl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto;
R 2 ’、R 3 ’、R 4 ’、R 5 ' each is independently selected from hydrogen, C 1 -C 6 Alkyl, 6-to 10-membered aryl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylthio, halogen, cyano, hydroxy, amino and mercapto;
the catalyst is selected from protonic acid or Lewis acid;
R 1 、R 1 ' are each independently selected from hydrogen or a hydroxy protecting group.
11. A process for the preparation of ecteinascidin compounds comprising the process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 10.
12. The method according to claim 11, wherein the ecteinascidin-based compound is selected from one or more of ecteinascidin 729, trabectedin, ecteinascidin 745, ecteinascidin 759A, ecteinascidin 759B and ecteinascidin 770.
13. A compound represented by the formula (IIA),
Figure FDA0003468963360000041
wherein R is 1 ", B are as defined in claim 1, preferably R 1 "is hydrogen, methoxymethyl, methoxyethoxymethyl, allyl or p-methoxybenzyl.
14. The compound of claim 13, wherein the compound of formula (IIA) is
Figure FDA0003468963360000042
CN202210038224.6A 2021-01-22 2022-01-13 Preparation method of ecteinascidin compound Pending CN114805398A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115677728A (en) * 2022-11-02 2023-02-03 成都科岭源医药技术有限公司 Preparation method of ecteinascidin compound intermediate
WO2024093091A1 (en) * 2022-11-02 2024-05-10 成都科岭源医药技术有限公司 Preparation method for intermediate of ecteinascidin compound

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