WO2013002253A1 - Procédé de préparation d'un dérivé de benzophénone - Google Patents

Procédé de préparation d'un dérivé de benzophénone Download PDF

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Publication number
WO2013002253A1
WO2013002253A1 PCT/JP2012/066368 JP2012066368W WO2013002253A1 WO 2013002253 A1 WO2013002253 A1 WO 2013002253A1 JP 2012066368 W JP2012066368 W JP 2012066368W WO 2013002253 A1 WO2013002253 A1 WO 2013002253A1
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Prior art keywords
salt
producing
benzophenone derivative
compound
ethyl
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PCT/JP2012/066368
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English (en)
Japanese (ja)
Inventor
務 松村
敏一 齋藤
和修 竹村
小林　健太郎
真里子 新田
浩二 ▲萩▼原
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協和発酵キリン株式会社
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Publication of WO2013002253A1 publication Critical patent/WO2013002253A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms

Definitions

  • the present invention relates to a method for producing a synthetic intermediate of a benzophenone derivative having antitumor activity and the like.
  • Patent Documents 1 and 2 2- ⁇ 2-ethyl-3,5-dihydroxy-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenyl ⁇ -N, N-bis (2-methoxyethyl) acetamide is It is known to be useful as an Hsp90 antagonist, an antitumor agent, etc. (Patent Documents 1 and 2).
  • Patent Document 1 the Friedel-Crafts reaction of a benzoic acid derivative and a dihydroxybenzene derivative is used to construct a benzophenone skeleton of the compound.
  • a dihydroxybenzene derivative in which hydroxy is protected with allyl is used.
  • Non-Patent Documents 1 to 5 examples using dihydroxybenzene derivatives in which hydroxy is protected with benzyl are known.
  • An object of the present invention is to provide a method for producing a synthetic intermediate of a benzophenone derivative having antitumor activity and the like.
  • the present invention relates to the following (1) to (31).
  • R 1a and R 1b represent the same or different benzyl substituted with 1 to 3 halogens, and when the halogen is 2 or 3, each halogen may be the same or different, R 2 represents optionally substituted lower alkyl, R 3 represents a lower alkoxycarbonyl which may have a substituent) or a salt thereof, and formula (II)
  • R 4 represents a lower alkyl which may have a substituent
  • R 5 is characterized in that a compound or a salt thereof represented) the aliphatic heterocyclic alkyl optionally having a substituent, the presence of an acid, reacting the formula (III)
  • R 1a, R 1b, R 2, R 3, R 4 and R 5 are respectively the same as the aforementioned
  • benzophenone derivatives or the preparation of a salt thereof (2) The method for producing a benzophenone derivative or a salt thereof according to the above (1), wherein R 1a and R 1b are dichlorobenzyl. (3) The method for producing a benzophenone derivative or a salt thereof according to the above (1), wherein R 1a and R 1b are 3,4-dichlorobenzyl. (4) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (3), wherein R 2 is lower alkyl.
  • R 1a , R 1b , R 2 and R 3 are as defined above, or a salt thereof, and formula (II)
  • R 1a , R 1b , R 2 , R 3 , R 4 and R 5 are as defined above, respectively, and a step of obtaining a salt thereof.
  • R 6 represents an optionally substituted N-lower alkylaminocarbonyl or an optionally substituted N, N-dilower alkylaminocarbonyl)) or a salt thereof.
  • Manufacturing method (15) The process for producing a benzophenone derivative or a salt thereof according to the above (14), wherein R 1a and R 1b are dichlorobenzyl. (16) The process for producing a benzophenone derivative or a salt thereof according to the above (14), wherein R 1a and R 1b are 3,4-dichlorobenzyl.
  • R 1a and R 1b represent the same or different benzyl substituted with 1 to 3 halogens, and when the halogen is 2 or 3, each halogen may be the same or different, R 2 represents optionally substituted lower alkyl, R 3 represents a lower alkoxycarbonyl which may have a substituent, or a salt thereof.
  • R 1a and R 1b are 3,4-dichlorobenzyl, R 2 is ethyl, and R 3 is methoxycarbonyl.
  • R 1a , R 1b , R 2 , R 3 , R 4 and R 5 are as defined above
  • R 1a and R 1b are 3,4-dichlorobenzyl
  • R 2 is ethyl
  • R 3 is methoxycarbonyl
  • R 4 is methyl
  • R 5 is 2-morpholinoethyl
  • the present invention provides a method for producing a synthetic intermediate of a benzophenone derivative having antitumor activity and the like.
  • N-dilower alkylaminocarbonyl include, for example, linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, Includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, iso
  • the alkylene part of the aliphatic heterocyclic alkyl has the same meaning as that obtained by removing one hydrogen atom from the lower alkyl.
  • Examples of the aliphatic heterocyclic group and the aliphatic heterocyclic group part of the aliphatic heterocyclic alkyl include, for example, a 3- to 8-membered monocyclic aliphatic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • Halogen represents each atom of fluorine, chlorine, bromine and iodine.
  • Substituents in substituted lower alkyl, substituted lower alkoxycarbonyl, N-substituted lower alkylaminocarbonyl, N-lower alkyl-N-substituted lower alkylaminocarbonyl and N, N-disubstituted lower alkylaminocarbonyl are the same or different. Examples thereof include hydroxy having 1 to 3 substituents, oxo, halogen, lower alkoxy and the like.
  • the substitution position of the substituent is not particularly limited.
  • halogen is as defined above.
  • the lower alkyl part of lower alkoxy has the same meaning as the lower alkyl.
  • Examples of the substituent in the substituted aliphatic heterocyclic alkyl are the same or different and include, for example, hydroxy, halogen, oxo, lower alkyl, lower alkoxy, aliphatic heterocyclic group having 1 to 3 substituents.
  • the substitution position of the substituent is not particularly limited. Halogen, lower alkyl and aliphatic heterocyclic groups are as defined above.
  • the lower alkyl part of lower alkoxy has the same meaning as the lower alkyl.
  • Examples of the salts of the compounds (I), (II), (III) and (IV) include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Examples of acid addition salts of compounds (I), (II), (III) and (IV) include inorganic acid salts such as hydrochloride, nitrate, sulfate and phosphate, acetate, maleate and fumaric acid.
  • Organic salts such as salts and citrates are listed.
  • Examples of metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like.
  • ammonium salts include ammonium and tetramethylammonium salts
  • examples of organic amine addition salts include morpholine addition salts and piperidine addition salts
  • examples of amino acid addition salts include glycine addition salts. Phenylalanine addition salt, lysine addition salt, aspartic acid addition salt, glutamic acid addition salt, and the like.
  • R 1a and R 1b are preferably 4-chlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, and more preferably 3,4-dichlorobenzyl.
  • Compound (III) can be obtained by reacting compound (I) and compound (II) in the presence of an acid in a solvent or without a solvent.
  • Examples of the acid include formic acid, acetic acid, propionic acid, trifluoroacetic acid, phosphoric acid, hydrochloric acid, trifluoromethanesulfonic acid, methanesulfonic acid, paratoluenesulfonic acid, and other organic acids, aluminum (III) chloride, titanium tetrachloride, three Examples thereof include Lewis acids such as boron fluoride / diethyl ether complex, boron trichloride, zinc chloride, iron chloride, aluminum triflate, copper triflate, etc., and preferably 1 to 50 equivalents are used relative to compound (I). .
  • Lewis acids such as boron fluoride / diethyl ether complex, boron trichloride, zinc chloride, iron chloride, aluminum triflate, copper triflate, etc., and preferably 1 to 50 equivalents are used relative to compound (I). .
  • the reaction can be promoted by adding 1 to 10 equivalents of acetic anhydride, trifluoroacetic anhydride, thionyl chloride, isobutyl chloroformate, 1,1′-dicarbonylimidazole and the like as additives.
  • the solvent include inert solvents such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, ethers such as tetrahydrofuran (THF), diethyl ether, diisopropyl ether and tert-butyl methyl ether.
  • Solvent such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, nitrile solvent such as acetonitrile, propylonitrile, methanol, ethanol, 1-propanol, 2-propanol, Examples thereof include alcohol solvents such as 1-butanol and 2-butanol, dimethyl sulfoxide, and the like, and these are used alone or in combination. Trifluoroacetic acid can also be used as a solvent. When an ether solvent, an amide solvent, or a nitrile solvent is used, the reaction may be performed using an excess amount of acid as necessary.
  • amide solvent such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone
  • nitrile solvent such as acetonitrile, propylonitrile
  • methanol ethanol
  • ethanol 1-propanol
  • 2-propanol Examples thereof include alcohol
  • reaction is usually carried out at a temperature between -50 ° C. and the boiling point of the solvent used for 5 minutes to 24 hours.
  • Compound (I) can be obtained by known methods [for example, Comprehensive Organic Transformations, second edition, by RC Larock, John Wiley and Sons Incorporated. (John Wiley & Sons Inc.) (1999) etc.] or a method according to them.
  • Compound (II) is a commercially available product or a known method [for example, Comprehensive Organic Transformations, 2nd Edition, by R. C. Larock, John Wiley & Sons Inc. (1999); Bioorganic & Medicinal Chemistry Letters (Bioorganic & Chemistry & Letters) (2009) etc.] or similar methods Obtainable.
  • Compound (IV) can be synthesized from compound (III) obtained by the production method of the present invention through steps such as ester hydrolysis, amidation, and deprotection. These transformations can be performed using known methods [for example, Comprehensive Organic Transformations 2nd edition (Comprehensive Organic Transformations 2nd edition), R. C. Larock, Vch Verlagsgesellscaft Mbh (1999), protective ⁇ Groups in Organic Synthesis 4th Edition (Protective Groups Organic Synthesis, 4th edition), by Green (T. W. Greene), John Wiley & Sons Inc. (2006), etc.] It is possible to do.
  • the target compound in the above production method can be isolated and purified by subjecting it to a separation and purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Some of the compounds (I), (II) and (III) may have stereoisomers such as geometric isomers and optical isomers, but the present invention includes all possible Including isomers and mixtures thereof.
  • compounds (I), (II) and (III) may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
  • Examples of the compound (III) obtained by the present invention include the following benzophenone derivatives.
  • Step 2 2- ⁇ 3,5-bis (3,4-dichlorobenzyloxy) -2-ethyl-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenyl ⁇ -N, Preparation of N-bis (2-methoxyethyl) acetamide (Compound D) Compound C (8.5 g, 11 mmol) was mixed with ethyl acetate (85 mL) and 1,1'-dicarbonyldiimidazole (4.4 g, 27 mmol). In addition, the mixture was stirred at 40 ° C. for 1.5 hours.
  • Step 3 2- ⁇ 2-Ethyl-3,5-dihydroxy-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenyl ⁇ -N, N-bis (2-methoxyethyl)
  • Acetamide Compound E
  • THF 16 mL
  • 2-propanol 60 mL
  • water 8 mL
  • ammonium formate 5.7 g, 90 mmol
  • Pd / C 5% palladium carbon
  • Ethyl acetate, THF and brine were added to the residue, and the pH was adjusted to 7.0 with a saturated aqueous sodium carbonate solution, followed by liquid separation.
  • Ethyl acetate (40 mL) and THF (40 mL) were added to the aqueous layer for extraction, and the organic layers were combined and concentrated under reduced pressure.
  • 2-propanol (13 mL) and water (62 mL) were added to the residue, and the mixture was stirred at 50 ° C for 1 hour, at 25 ° C for 1 hour, and at 5 ° C for 1 hour. , 83%).
  • Step 4 Production of Compound F Ethanol (0.4 mL) and water (0.08 mL) were added to Compound E (100 mg, 0.17 mmol) and stirred at 60 ° C for 10 minutes, and then activated carbon (10 mg) was added for 15 minutes. Stir. The reaction mixture was filtered through Celite, ethanol (0.2 mL) and concentrated hydrochloric acid (0.03 mL) were added to the filtrate, and the mixture was stirred at 55 ° C. for 30 min., Then stirred at 5 ° C. for 2 hr. (95 mg, 91%) was obtained.
  • the reaction mixture was dropped into a mixed solvent of ethyl acetate (225 mL) and water (200 mL), and the pH was adjusted to 6.5 with 6 mol / L aqueous sodium hydroxide solution, followed by liquid separation.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the reaction mixture was dropped into a mixed solvent of ethyl acetate (225 mL) and water (200 mL), and the pH was adjusted to 6.5 with 6 mol / L aqueous sodium hydroxide solution, followed by liquid separation.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Process 2 Compound K is dissolved in toluene (1.75 L), trifluoroacetic acid (550 mL), acetic acid (111 g, 1.85 mol), and trifluoroacetic anhydride (519 g, 2.47 mol) are added, and then at 20 ° C. for 18 hours. Stir. The reaction mixture was added dropwise to a mixed solution of water (3.88 L), THF (2.75 L), and toluene (1.00 L), and the pH was adjusted to 7 with a 10 mol / L aqueous sodium hydroxide solution, followed by liquid separation. The organic layer was washed with water and then concentrated to 750 mL under reduced pressure.
  • Process 3 Compound L (400 g, 0.737 mol) was dissolved in toluene (400 mL), trifluoroacetic acid (1.20 L) and triethylsilane (257 g, 2.21 mol) were added, and the mixture was stirred at 20 ° C. for 18 hours.
  • the reaction mixture was added dropwise to a mixed solution of water (2.00 L), THF (2.00 L), and toluene (1.60 L), adjusted to pH 7 with a 10 mol / L aqueous sodium hydroxide solution, and separated.
  • the organic layer was washed with water and then concentrated to about 1200 mL under reduced pressure.
  • Reference Example 1 Production process 1 of 3-methoxy-4- (2-morpholin-4-ylethoxy) benzoic acid monohydrochloride (Compound A) Dissolve ethyl vanillate (200 g, 1.02 mol) in acetonitrile (2.0 L), add potassium carbonate (317 g, 2.29 mol) and 4- (2-chloroethyl) morpholine hydrochloride (199 g, 1.07 mol), The mixture was stirred at 60 ° C. for 6 hours.
  • Compound A Dissolve ethyl vanillate (200 g, 1.02 mol) in acetonitrile (2.0 L), add potassium carbonate (317 g, 2.29 mol) and 4- (2-chloroethyl) morpholine hydrochloride (199 g, 1.07 mol), The mixture was stirred at 60 ° C. for 6 hours.
  • Process 4 Add 1,4-dioxane (44 mL), ammonium formate (1.0 g, 16 mmol), bis (triphenylphosphine) palladium (II) dichloride (0.15 g, 0.21 mmol) to compound S (2.6 g, 4.0 mmol) And refluxed for 2 hours.
  • the reaction mixture was cooled to 25 ° C., ethyl acetate (25 mL), methanol (25 mL), activated carbon (0.15 g) were added, and the mixture was stirred at 25 ° C. for 2 hr.
  • the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Comparative Example 1 is a 2- ⁇ 2-ethyl-3,5-dihydroxy-6- [3-methoxy-4- () having a Friedel-Crafts reaction using a benzene derivative in which hydroxy is protected with allyl as a key step.
  • 2 shows a method for producing 2-morpholin-4-ylethoxy) benzoyl] phenyl ⁇ -N, N-bis (2-methoxyethyl) acetamide (Compound E).
  • Example 1 is a Friedel-Crafts reaction using a benzene derivative in which hydroxy is protected with 3,4-dichlorobenzyl
  • Example 2 is a method for producing Compound E from the benzophenone derivative obtained in Example 1. Is shown.
  • the production methods of Examples 1 and 2 are referred to as invention methods
  • the production method of Comparative Example 1 is referred to as a conventional method.
  • reaction mixture was added dropwise to a mixed solvent of ethyl acetate (100 mL) and water (100 mL), and the pH was adjusted to 7.0 with a 6 mol / L aqueous sodium hydroxide solution, followed by liquid separation. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • the present invention provides a method for producing a synthetic intermediate of a benzophenone derivative having antitumor activity and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne : un composé représenté par la formule générale (I) (R1a et R1b pouvant être identiques ou différents l'un de l'autre et représentant indépendamment un groupe benzyle substitué par un à trois atomes d'halogène, les atomes d'halogène pouvant être identiques ou différents les uns des autres lorsque le nombre d'atomes d'halogène vaut deux ou trois ; R2 représentant un groupe alkyle inférieur pouvant être substitué ; et R3 représentant un groupe alcoxycarbonyle inférieur pouvant être substitué) ou un sel de celui-ci, qui est utile, par exemple, dans un procédé de préparation d'un intermédiaire pour la synthèse d'un dérivé de benzophénone présentant une activité antitumorale et analogue ; un procédé de préparation d'un dérivé de benzophénone représenté par la formule générale (III) (R1a, R1b, R2 et R3 étant tels que définis ci-dessus ; R4 représentant un groupe alkyle inférieur qui peut être substitué ; et R5 représentant un groupe alkyle hétérocyclique aliphatique qui peut être substitué) ou un sel de celui-ci, le procédé étant caractérisé en ce qu'il comprend la réaction d'un composé représenté par la formule générale (II) (R4 et R5 sont tels que définis ci-dessus) ou d'un sel de celui-ci en présence d'un acide ; et d'autres.
PCT/JP2012/066368 2011-06-27 2012-06-27 Procédé de préparation d'un dérivé de benzophénone WO2013002253A1 (fr)

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JP2011-141367 2011-06-27
JP2011141367 2011-06-27

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005000778A1 (fr) * 2003-06-27 2005-01-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de proteines de la famille hsp90

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005000778A1 (fr) * 2003-06-27 2005-01-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de proteines de la famille hsp90

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HENDRA P ET AL., BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY, vol. 73, no. 10, 2009, pages 2172 - 2182 *
NAKASHIMA T ET AL., CLINICAL CANCER RESEARCH, vol. 16, no. 10, 2010, pages 2792 - 2802 *
PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 1999, pages 249 - 272 *

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