CN108101934B - Process for the preparation of trabectedin and intermediates thereof - Google Patents

Process for the preparation of trabectedin and intermediates thereof Download PDF

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Publication number
CN108101934B
CN108101934B CN201711180265.4A CN201711180265A CN108101934B CN 108101934 B CN108101934 B CN 108101934B CN 201711180265 A CN201711180265 A CN 201711180265A CN 108101934 B CN108101934 B CN 108101934B
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compound
trabectedin
preparation
formula
acid
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CN108101934A (en
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张顺吉
陈亚
田伟伟
孙绍光
李燕兵
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Jiangsu Hengrui Medicine Co Ltd
Chengdu Suncadia Pharmaceuticals Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Chengdu Suncadia Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • 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

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  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides processes for the preparation of trabectedin and intermediates thereof. In particular, the invention provides a compound salt of a trabectedin intermediate formula I-1 and a preparation method thereof, wherein P is1、P2Is a hydroxy protecting group, P3Is an amino protecting group, R1Is an alkyl group. Also provided is a process for preparing trabectedin using the compound having the structure of formula I-1.

Description

Process for the preparation of trabectedin and intermediates thereof
Technical Field
The present invention relates to a process for the preparation of trabectedin and the corresponding salts of its intermediate S) -3- [ 4-methoxy-3, 5-bis (tert-butyldimethylsilyloxy) ] phenyl-2- (allyloxyacylamino) 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 ecteinascidins (Ecteinascidia turbinata), and the results are small, but the total synthesis is difficult because the trabectedin contains a plurality of chiral centers.
Figure BDA0001479030380000011
Therefore, it is necessary to develop a synthetic method for producing trabectedin useful as an antitumor agent.
WO2001058905 discloses that (S) -3- [ 4-methoxy-3, 5-bis (tert-butyldimethylsilyloxy) ] phenyl-2- (allyloxyacylamino) propionic acid (Corey 3) compound is a key intermediate for synthesizing trabectedin, but the Corey3 compound is an oily substance, needs complicated column chromatography to achieve the purification effect, 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- [ 4-methoxy-3, 5-di (tert-butyldimethylsilyloxy) ] phenyl-2- (allyloxyacylamino) propionic acid, which is improved in physicochemical properties to be suitable for industrial production and packaging transfer. Meanwhile, the Corey3 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.
Figure BDA0001479030380000012
Wherein TBS is tert-butyl dimethyl silicon base.
Disclosure of Invention
The present invention provides compounds useful as intermediates in the synthesis of trepetidine.
The present invention provides compounds of formula I-1:
Figure BDA0001479030380000021
wherein, P1、P2Each independently 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; p3Is an amino protecting group; r1Is an alkyl 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 as an inorganic base or an organic base, the inorganic base forms an inorganic salt with the compound of formula I-1, including but not limited to calcium salt, sodium salt, potassium salt, the corresponding inorganic base selected includes but not limited to calcium hydroxide, sodium hydroxide, potassium hydroxide; the organic base forms an organic salt with the compound of formula I-1, including but not limited to di-n-butylamine salt, tert-butylamine salt, diisopropylamine salt, and D/L-phenylglycinamide salt, with the corresponding organic base selected including but not limited to di-n-butylamine, tert-butylamine, diisopropylamine, and D/L-phenylglycinamide.
Further, the base molecule is an organic base, preferably comprising di-n-butylamine, tert-butylamine, diisopropylamine, D/L-phenylglycinamide, more preferably L-phenylglycinamide, diisopropylamine.
In a particular embodiment of the invention, the compound of formula I-1 may exist as a single stereoisomer, with high stereoisomeric purity, having the formula:
Figure BDA0001479030380000022
in some embodiments, R is1The alkyl group is selected from, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, and more preferably methyl.
In a preferred embodiment of the invention, said amino protecting group (P)3) is-CO2An allyl group having the formula:
Figure BDA0001479030380000031
in some embodiments, the compound of formula I-1 wherein the base molecule is L-phenylglycinamide has the formula:
Figure BDA0001479030380000032
further, the hydroxyl protecting group P1、P2Each independently preferably tert-butyldimethylsilyl (TBDMS or TBS),
Figure BDA0001479030380000033
in some embodiments, the compound of formula I-1 wherein the base molecule is diisopropylamine has the formula:
Figure BDA0001479030380000034
further, the hydroxyl protecting group P1、P2Each independently preferably tert-butyldimethylsilyl (TBDMS or TBS),
Figure BDA0001479030380000041
the present invention also provides a process for the preparation of trabectedin, which comprises the step of preparing trabectedin from any one of the compounds I-1 to I-7 as described hereinbefore.
In some embodiments, the preparation of trabectedin may be carried out as follows:
Figure BDA0001479030380000042
in some embodiments, the preparation of trabectedin may be carried out as follows:
Figure BDA0001479030380000043
in some embodiments, the preparation of trabectedin may be carried out as follows:
Figure BDA0001479030380000044
further, the compound of formula I-6, after being freed from the acid, is condensed with a Corey 4 compound and subsequently subjected to the step of preparing trabectedin as described in WO2001058905, the contents of which are incorporated in the present description by reference to WO2001058905,
Figure BDA0001479030380000051
the invention also provides a preparation method of the compound I-1, which comprises the step of preparing the compound of the formula I-1 by salifying the compound I and alkali,
Figure BDA0001479030380000052
wherein R is1、P1、P2、P3And M is as described in formula I-1.
Further, the compound of formula I may exist as a single stereoisomer, with high stereoisomeric purity, having the formula:
Figure BDA0001479030380000053
in the preferred embodiment of the present invention, R is1Alkyl is preferably methyl, soThe amino protecting group (P)3) preferably-CO2An allyl group having the formula:
Figure BDA0001479030380000054
further, the alkali molecules are L-phenylglycinamide and diisopropylamine.
Further, the hydroxyl protecting group P1、P2Each independently preferably tert-butyldimethylsilyl (TBDMS or TBS),
Figure BDA0001479030380000055
the solvent used for the above salt formation is preferably C1-C4Alcohols of (2), such as methanol, ethanol; ester solvents such as ethyl acetate; ether solvents such as methyl t-butyl ether, ethyl ether, propyl ether; chlorinated hydrocarbon solvent such as dichloromethane or its mixed solvent, acetonitrile, acetone, more preferably methyl tert-butyl ether, diethyl ether, propyl ether, ethanol, acetonitrile, acetone, methanol, and ethyl acetate as precipitation solvent. The equivalent of the corresponding base is preferably 1 to 2 equivalents, and may be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 equivalents.
The invention also provides a method for purifying the compound I, which comprises the steps of preparing the compound I-1 by salifying the compound I and a base, and then dissociating the compound I and an acid. The acid of the present invention 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 of the formula I-1 by salifying the compound I and a base.
The invention also provides application of any compound of the formulas I-1 to I-7 in preparing the trabectedin compound.
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, preferably said hydroxy protection is selected from benzyl, methoxyethoxymethyl ether, methoxymethyl ether, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl.
The "amino-protecting Groups" according to the invention are suitable Groups known in the art for protecting hydroxyl Groups, see the literature ("Protective Groups in Organic Synthesis", 5Th. ed. T.W.Greene)&P.g.m.wuts). The amino protecting group together with the nitrogen atom to which it is bound forms an amide, alkylamine, alkenylamine or arylamine, preferably, the amino protecting group is-CO2An allyl group.
The number of atoms in the alkyl, alkyl group or aryl group is not particularly limited and should be known to or can be determined by one of ordinary skill in the art. In particular embodiments, the alkyl group is a C1-6An alkyl group. In another embodiment, the aryl group is a C6-14And (4) an aryl group.
"alkyl" refers to a saturated aliphatic hydrocarbon group selected from alkyl groups containing 1 to 6 carbon atoms (which may be described as C)1-6Alkyl groups). Non-limiting examples includeMethyl, 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.
"aryl" refers to an aromatic group having at least one conjugated pi-electron ring and includes carbocyclic aryl, heterocyclic aryl (also referred to as heteroaryl groups), and biaryl groups, all of which may be optionally substituted. The aryl group may include 6 to 14 carbon atoms, non-limiting examples include phenyl, pyridyl, or naphthyl.
The agents for use in the present invention are commercially available.
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:
Figure BDA0001479030380000071
the compound Corey 3(1.2kg, obtained according to the method of patent WO 2001058905) was dissolved in methyl tert-butyl ether (MTBE, 20L), L-phenylglycinamide (0.35kg) was added, stirred at 50 ℃ for 0.5 h, part of the solvent (10L) was removed under reduced pressure and filtered, yielding 1.4kg of compound Ia, 91% yield and 99% HPLC purity.
1HNMR(BRUKER-400MHz,DMSO-d6)：δ7.64(s,1H),7.50-7.10(m,7H),6.43(s,2H),6.0-5.7(m,1H),5.3-5.1(m,3H),4.6-4.3(m,4H),4.1-3.9(m,1H),3.64(s,3H),3.0-2.9(m,1H),2.8-2.6(m,1H),2.11(s,1H),1.00(s,18H),0.17(s,12H).
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 Corey3 in a proper organic solvent, adding alkali molecules dissolved in the organic solvent, stirring for 0.5 hour at the temperature of 50 ℃, removing part of the solvent by decompression and filtering to obtain the product.
Figure BDA0001479030380000072
Figure BDA0001479030380000081
From the data of the above experimental examples, it was readily found that dicyclohexylamine and triethylamine were not able to form salts with the compound Corey3 and formed solids, whereas in several bases able to form salts with the compound Corey3, L-phenylglycinamide showed good salt-forming efficiency and the obtained salts were of high purity.
Example 3:
Figure BDA0001479030380000082
in a 250mL reaction flask, compound Ia (10g) was dissolved in toluene (100mL), an aqueous hydrochloric acid solution (60mL containing 0.51g of hydrogen chloride) was added dropwise, the mixture was stirred vigorously for 1 hour, a little insoluble matter was removed by filtration, and the mixture was separated, dried, and concentrated under reduced pressure to give compound Corey3(8 g).
Dissolving a compound Corey3 and a compound Corey 4(3.8g, 1eq., prepared according to the methods of the documents J.Am.chem.Soc.1996,118, 9202-9203) in dichloromethane (100mL) in 250mL, adding 1-hydroxy-7-azobenzotriazol (HOAT, 3g, 1.5eq.) and 2-chloro-1, 3-dimethylimidazolium hexafluorophosphate (CIP, 6g, 1.5eq.), stirring at room temperature for 4-5 hours, adding water for quenching reaction, separating, extracting with dichloromethane, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain the target compound Corey6(9.6g, 84% of total yield in two steps).
Example 4: preparation of diisopropylammonium (S) -2- (((allyloxy) formyl) amino) -3- (3, 5-di ((tert-butyldimethylsilyl) oxy) -4-methoxyphenyl) propionate compound
A100 mL reaction flask was charged with Corey 3(3.20g, 5.93mmol, 90.96% pure in HPLC) and acetonitrile (16.0mL), dissolved with stirring, and a solution of diisopropylamine (0.66g, 6.52mmol) in acetonitrile (16.0mL) was added dropwise, whereupon a solid precipitated. The reaction system is heated to reflux, stirred, crystallized, filtered and dried to obtain a target product of 3.25g, 98.76% pure in HPLC, and the yield is 85.6%.
MS m/z(ESI):540.2781[M+H]+
1H NMR(400Hz,CDCl3)：δ6.34(s,2H),5.95-5.83(m,1H),5.49-5.46(m,1H),5.27(d,J＝17.2Hz,1H),5.17(d,J＝10.0Hz,1H),4.52(d,J＝5.6Hz,2H),4.23(brs,1H),3.65(s,3H),3.23-3.19(m,2H),3.06-3.02(m,1H),2.92-2.87(m,1H),1.27-1.13(m,12H),0.97(s,18H),0.13(s,12H).
Example 5: preparation of diisopropylammonium (S) -2- (((allyloxy) formyl) amino) -3- (3, 5-di ((tert-butyldimethylsilyl) oxy) -4-methoxyphenyl) propionate compound
A100 mL reaction flask was charged with Corey 3(0.80g,1.48mmol, 90.96% pure in HPLC) compound and acetone (4.0mL), dissolved with stirring, and a solution of diisopropylamine (0.17g,1.63mmol) in acetone (4.0mL) was added dropwise, whereupon a solid precipitated. The reaction system is heated to reflux, stirred, crystallized, filtered and dried to obtain 0.76g of a target product, 98.31% pure in HPLC and 79.6% of yield.
Example 6: preparation of diisopropylammonium (S) -2- (((allyloxy) formyl) amino) -3- (3, 5-di ((tert-butyldimethylsilyl) oxy) -4-methoxyphenyl) propionate compound
A100 mL reaction flask was charged with Corey 3(0.80g,1.48mmol, 90.96% pure in HPLC) and ethyl acetate (4.0mL), the mixture was dissolved under stirring, a solution of diisopropylamine (0.17g,1.63mmol) in ethyl acetate (4.0mL) was added dropwise at 15-25 ℃ and a solid precipitated after completion of the addition. The reaction system is heated to reflux, stirred, crystallized, filtered and dried to obtain 0.60g of a target product, 98.44% pure in HPLC and 63.5% of yield.

Claims (6)

1. A compound of formula I-1:
Figure FDA0003316739660000011
wherein, P1、P2Are all tert-butyl dimethyl silicon base; p3is-CO2An allyl group; r1Is methyl; m is an organic base molecule selected from L-phenylglycinamide or diisopropylamine.
2. A process for the preparation of compound I-1, comprising the step of salifying compound I with a corresponding base to prepare a compound of formula I-1,
Figure FDA0003316739660000012
wherein, P1、P2、P3、R1And M is as defined in claim 1.
3. A method for purifying compound I, which comprises the step of obtaining a compound of formula I-1 by the preparation method of claim 2, and then dissociating the compound with an acid.
4. The method of claim 3, wherein the acid is selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.
5. A method of preparing trabectedin comprising the step of synthesizing trabectedin from the compound of claim 1.
6. A process for the preparation of trabectedin comprising the preparation process as claimed in claim 2 or the purification process as claimed in claim 3 or 4.
CN201711180265.4A 2016-11-24 2017-11-23 Process for the preparation of trabectedin and intermediates thereof Withdrawn - After Issue CN108101934B (en)

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CN110092802B (en) * 2019-06-21 2022-01-07 爱斯特（成都）生物制药股份有限公司 Method for preparing trepetidine intermediate
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CN1425017A (en) * 2000-02-11 2003-06-18 哈佛大学的校长及成员们 Synthetic process for intermediate for ecteinascidin and phthalascidin compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1425017A (en) * 2000-02-11 2003-06-18 哈佛大学的校长及成员们 Synthetic process for intermediate for ecteinascidin and phthalascidin compounds

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* Cited by examiner, † Cited by third party
Title
A New, More Efficient, and Effective Process for the Synthesis of a Key Pentacyclic Intermediate for Production of Ecteinascidin and Phthalascidin Antitumor Agents;Eduardo J. Martinez等;《Org. Lett.》;20000315;第2卷(第7期);第993-996页 *

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