WO2013002253A1 - Method for producing benzophenone derivative - Google Patents

Abstract

Provided are: a compound represented by general formula (I) (wherein R^1a and R^1b may be the same as or different from each other and independently represent a benzyl group substituted by one to three halogen atoms, wherein, when the number of the halogen atoms is two or three, the halogen atoms may be the same as or different from each other; R² represents a lower alkyl group which may have a substituent; and R³ represents a lower alkoxycarbonyl group which may have a substituent) or a salt thereof, which is useful in, for example, a method for producing an intermediate for the synthesis of a benzophenone derivative having an anti-tumor activity and the like; a method for producing a benzophenone derivative represented by general formula (III) (wherein R^1a, R^1b, R² and R³ are as defined above; R⁴ represents a lower alkyl group which may have a substituent; and R⁵ represents an aliphatic heterocyclic alkyl group which may have a substituent) or a salt thereof, the method being characterized by comprising reacting a compound represented by general formula (II) (wherein R⁴ and R⁵ are as defined above) or a salt thereof in the presence of an acid; and others.

Description

Method for producing benzophenone derivative

The present invention relates to a method for producing a synthetic intermediate of a benzophenone derivative having antitumor activity and the like.

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). According to the description in 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. In this synthesis method, a dihydroxybenzene derivative in which hydroxy is protected with allyl is used.

In the synthesis of benzophenone derivatives by Friedel-Crafts reaction of dihydroxybenzene derivatives and benzoic acid derivatives, examples using dihydroxybenzene derivatives in which hydroxy is protected with benzyl are known (Non-Patent Documents 1 to 5).

International Publication No. 2005/000778 Pamphlet International Publication No. 2006/088193 Pamphlet

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).
(1) Formula (I)

(Wherein 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)

(In the formula, 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)

^{(Wherein, 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.
(5) The method for producing a benzophenone derivative or a salt thereof according to any one of (1) to (3), wherein R ² is ethyl.
(6) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (5), wherein R ³ is lower alkoxycarbonyl.
(7) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (5), wherein R ³ is methoxycarbonyl.

(8) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (7), wherein R ⁴ is lower alkyl.
(9) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (7), wherein R ⁴ is methyl.
(10) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (9), wherein R ⁵ is an aliphatic heterocyclic alkyl.
(11) R ⁵ is 2-position benzophenone derivatives or the preparation of a salt thereof according to any one of the ethyl substituted with aliphatic heterocyclic group (1) to (9).
(12) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (9), wherein R ⁵ is 2-morpholinoethyl.
(13) The process for producing a benzophenone derivative or a salt thereof according to any one of (1) to (12), wherein the acid is trifluoroacetic acid.
(14) Formula (I)

Wherein R ^1a , R ^1b , R ² and R ³ are as defined above, or a salt thereof, and formula (II)

(Wherein R ⁴ and R ⁵ are as defined above) or a salt thereof, in the presence of an acid, to react,

Wherein 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. (IV)

Wherein R ² , R ⁴ and R ⁵ are as defined above,
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.
(17) The method for producing a benzophenone derivative or a salt thereof according to the above (14) to (16), wherein R ² is lower alkyl.
(18) The method for producing a benzophenone derivative or a salt thereof according to the above (14) to (16), wherein R ² is ethyl.
(19) The process for producing a benzophenone derivative or a salt thereof according to any one of the above (14) to (18), wherein R ³ is lower alkoxycarbonyl.
(20) The process for producing a benzophenone derivative or a salt thereof according to any one of (14) to (18), wherein R ³ is methoxycarbonyl.

(21) The process for producing a benzophenone derivative or a salt thereof according to any one of (14) to (20), wherein R ⁴ is lower alkyl.
(22) The process for producing a benzophenone derivative or a salt thereof according to any one of (14) to (20), wherein R ⁴ is methyl.
(23) benzophenone derivatives or the preparation of a salt thereof according to any one of the R ⁵ is aliphatic heterocyclic alkyl (14) to (22).
(24) The process for producing a benzophenone derivative or a salt thereof according to any one of the above (14) to (22), wherein R ⁵ is ethyl substituted at the 2-position with an aliphatic heterocyclic group.
(25) The process for producing a benzophenone derivative or a salt thereof according to any one of (14) to (22), wherein R ⁵ is 2-morpholinoethyl.
(26) The process for producing a benzophenone derivative or a salt thereof according to any one of (14) to (25), wherein R ⁶ is N, N-bis (2-methoxyethyl) aminocarbonyl.
(27) A benzophenone derivative represented by the formula (IV) is

2- {2-ethyl-3,5-dihydroxy-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenyl} -N, N-bis (2-methoxyethyl) ) A process for producing a benzophenone derivative or a salt thereof according to (14), which is acetamide.
(28) Formula (I)

(Wherein 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.
(29) The compound or a salt thereof according to the above (28), wherein R ^1a and R ^1b are 3,4-dichlorobenzyl, R ² is ethyl, and R ³ is methoxycarbonyl.
(30) Formula (III)

(Wherein R ^1a , R ^1b , R ² , R ³ , R ⁴ and R ⁵ are as defined above) or a salt thereof.
(31) The above wherein R ^1a and R ^1b are 3,4-dichlorobenzyl, R ² is ethyl, R ³ is methoxycarbonyl, R ⁴ is methyl, and R ⁵ is 2-morpholinoethyl (30) The benzophenone derivative or a salt thereof according to the above.

The present invention provides a method for producing a synthetic intermediate of a benzophenone derivative having antitumor activity and the like.

Hereinafter, the compounds represented by the formulas (I), (II), (III) and (IV) are referred to as compounds (I), (II), (III) and (IV), respectively. The same applies to the compounds of other formula numbers.
In the definition of each group of compounds (I), (II), (III) and (IV),
Lower alkyl, lower alkoxycarbonyl, N-lower alkylaminocarbonyl, and lower alkyl part of N, 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, isooctyl, nonyl, decyl and the like. The two lower alkyl moieties of N, N-dilower alkylaminocarbonyl may be the same or different.

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. Heterocyclic groups, bicyclic or tricyclic condensed 3- to 8-membered rings containing at least one atom selected from a nitrogen atom, oxygen atom and sulfur atom, etc. , More specifically aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H- Pyranyl, 5,6-dihydro-2H-pyranyl, tetrahydrothiopyranyl, oxazolidinyl, morpholino, mol Linyl, thioxazolidinyl, thiomorpholino, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxa Zolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquina Zolinyl, dihydrobenzodioxanyl, dihydroquinolyl, dihydroisoquinolyl, dihydrodibenzoazepinyl and the like can be mentioned.

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. Here, 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. Examples of ammonium salts include ammonium and tetramethylammonium salts, examples of organic amine addition salts include morpholine addition salts and piperidine addition salts, and 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.
Next, the manufacturing method of this invention is demonstrated. In the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the production method, introduction of a protective group commonly used in organic synthetic chemistry and Removal methods [e.g., Protective Groups in Organic Synthesis, 4th edition, written by TWGreene, John Wiley & Sons Inc. (2006), etc. ] Can be used to produce the target compound.
Manufacturing method

(Wherein, R ^1a , R ^1b , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above)
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). .

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.
Examples of 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, amide 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.

The 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.

In addition, 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.

Hereinafter, embodiments of the present invention will be described with reference to examples and reference examples. However, the present invention is not limited to these.

Methyl 3,5-bis (3,4-dichlorobenzyloxy) -2-ethyl-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenylacetate (compound) by Friedel-Crafts reaction 3) Production Trifluoroacetic acid (25 mL, 333 mmol) and trifluoroacetic anhydride (6.7 mL, 46 mmol) were added to compound A (4.5 g, 14 mmol), and the mixture was stirred at 25 ° C. for 1 hour. Toluene (5 mL) and compound B (5.0 g, 9.5 mmol) were added to the reaction mixture, and the mixture was reacted at 25 ° C. for 18 hours. The reaction mixture was added dropwise to a mixed solvent of ethyl acetate (225 mL) and water (200 mL), and the pH was adjusted to 6.5 with a 10 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 to 50 mL. After adding n-heptane (100 mL) to the residue, the mixture was stirred at 45 ° C. for 1 hour and allowed to stand at 25 ° C. overnight. Then, after stirring at 5 ° C. for 2 hours, the precipitated crystals were filtered to obtain Compound 3 (7.0 g, 93%).
¹ H NMR (CDCl ₃ ): 1.12 (t, J = 7.3 Hz, 3H), 2.51-2.53 (m, 4H), 2.68 (q, J = 7.3 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H), 3.49 (s, 3H), 3.67 (s, 2H), 3.67-3.80 (m, 4H), 3.90 (s, 3H), 4.20 (t, J = 5.9 Hz, 2H), 4.83 (s, 2H ), 5.03 (s, 2H), 6.41 (s, 1H), 6.76-6.87 (m, 2H), 6.91 (d, J = 1.8 Hz, 1H), 7.21-7.34 (m, 3 H), 7.49 (d , J = 8.2 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H).

2- {2-ethyl-3,5-dihydroxy-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenyl} -N, N-bis (2-methoxyethyl) using compound 3 ) Acetamide monohydrochloride (compound F) production step 1: 3,5-bis (3,4-dichlorobenzyloxy) -2-ethyl-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) ) Preparation of benzoyl] phenylacetic acid (Compound C) Methanol (50 mL), THF (50 mL) and 4 mol / L aqueous sodium hydroxide (35 mL) were added to Compound 3 (10 g, 13 mmol) at 60 ° C. For 1 hour. The reaction mixture was concentrated under reduced pressure, methanol (150 mL) was added, and the pH was adjusted to 6.5 with 6 mol / L hydrochloric acid. After stirring at 45 ° C. for 1 hour and at 25 ° C. for 1 hour, the precipitated crystals were filtered to obtain Compound C (9.5 g, 96%).
¹ H NMR (DMSO-d ₆ ): 1.06 (t, J = 7.3 Hz, 3H), 2.40-2.55 (m, 4H), 2.58 (q, J = 7.3 Hz, 2H), 2.70 (t, J = 5.6 Hz, 2H), 3.48 (s, 2H), 3.50-3.65 (m, 4H), 3.75 (s, 3H), 4.14 (t, J = 5.7 Hz, 2H), 5.03 (s, 2H), 5.24 (s , 2H), 6.83-6.95 (m, 2H), 6.95-7.05 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.47-7.52 (m, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 12.25 (br s, 1H) .

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. Bis (2-methoxyethyl) amine (2.1 mL, 14 mmol) was added to the reaction mixture and stirred for 2 hours. The reaction mixture was cooled to 25 ° C., ethyl acetate (43 mL) and brine (85 mL) were added, and the mixture was neutralized with 6 mol / L hydrochloric acid and separated. Ethyl acetate (43 mL) was added to the aqueous layer for extraction, and the organic layers were combined and concentrated under reduced pressure. Ethyl acetate (26 mL) and heptane (26 mL) were added to the residue, and the mixture was stirred at 50 ° C. for 1 hour and at 5 ° C. for 2 hours. The precipitated crystals were filtered to obtain compound D (9.3 g, 95%). It was.
¹ H NMR (CDCl ₃ ): 1.11 (t, J = 7.3 Hz, 3H), 2.56-2.70 (m, 6H), 2.85 (t, J = 6.0 Hz, 2H), 3.15 (s, 3H), 3.21 ( t, J = 5.6 Hz, 2H), 3.30 (s, 3H), 3.35 (t, J = 5.2 Hz, 2H), 3.36-3.52 (m, 4H), 3.65-3.75 (m, 4H), 3.78 (s , 2H), 3.88 (s, 3H), 4.19 (t, J = 5.9 Hz, 2H), 4.80 (s, 2H), 5.01 (s, 2H), 6.37 (s, 1H), 6.75-6.84 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 1.4 Hz, 1H), 7.21-7.33 (m, 2H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.51-7.57 (m, 2H).

Step 3: 2- {2-Ethyl-3,5-dihydroxy-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenyl} -N, N-bis (2-methoxyethyl) Preparation of Acetamide (Compound E) THF (16 mL), 2-propanol (60 mL) and water (8 mL) were added to Compound D (8.0 g, 9.0 mmol) and heated to 50 ° C., then ammonium formate (5.7 g, 90 mmol) and 5% palladium carbon (Pd / C) (400 mg) were added and stirred for 2 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. 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. To the residue were added 2-propanol (13 mL) and water (62 mL), 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%).
¹ H-NMR (DMSO-d ₆ ): 0.99 (t, J = 7.4 Hz, 3H), 2.37 (q, J = 7.4 Hz, 2H), 2.45-2.50 (m, 4H), 2.70 (t, J = 5.8 Hz, 2H), 3.04 (t, J = 6.1 Hz, 2H), 3.07 (s, 3H), 3.19 (s, 3H), 3.22 (t, J = 6.1 Hz, 2H), 3.31 (t, J = 5.3 Hz, 2H), 3.38 (t, J = 5.3 Hz, 2H), 3.51 (s, 2H), 3.57 (t, J = 4.6 Hz, 4H), 3.76 (s, 3H), 4.13 (t, J = 5.8 Hz, 2H), 6.34 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H) , 9.05 (br s, 1H), 9.34 (br s, 1H).

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.
¹ H-NMR (DMSO-d ₆ ): 0.97 (t, J = 7.3 Hz, 3H), 2.34 (q, J = 7.3 Hz, 2H), 3.06 (s, 3H), 3.04-3.07 (m, 2H) , 3.18 (s, 3H), 3.15-3.23 (m, 4H), 3.36-3.44 (m, 4H), 3.48-3.51 (m, 6H), 3.76 (s, 3H), 3.81-3.83 (m, 2H) , 3.93-3.97 (m, 2H), 4.47 (m, 2H), 6.37 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 1.8 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 9.09 (br s, 1H), 9.37 (br s, 1H), 11.3 (br s, 1H).

Friedel-Crafts reaction of compound (I) with 4-chlorobenzyloxy Compound A (0.72 g, 2.3 mmol) was treated with trifluoroacetic acid (3.5 mL, 47 mmol) and trifluoroacetic anhydride (1.1 mL, 7.5 mmol). In addition, the mixture was stirred at 25 ° C. for 30 minutes. Toluene (0.7 mL) and methyl 2- [3,5-bis (4-chlorobenzyloxy) -2-ethylphenyl] acetate (Compound G) (0.70 g, 1.5 mmol) were added to the reaction mixture. Stir for hours. 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 residue was purified by silica gel column chromatography (ethyl acetate / heptane = 70/30 to 90/10), and 3,5-bis (4-chlorobenzyloxy) -2-ethyl-6- [3-methoxy-4- Methyl (2-morpholin-4-ylethoxy) benzoyl] phenylacetate (Compound 1) (0.90 g, 83%) was obtained.
¹ H NMR (CDCl ₃ ): 1.10 (t, J = 7.3 Hz, 3H), 2.51-2.74 (m, 6H), 2.89 (t, J = 5.9 Hz, 2H), 3.48 (s, 3H), 3.65 ( s, 2H), 3.70-3.79 (m, 4H), 3.88 (s, 3H), 4.21 (t, J = 5.9 Hz, 2H), 4.84 (s, 2H), 5.03 (s, 2H), 6.44 (s , 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.80-6.89 (m, 2H), 7.11-7.19 (m, 2H), 7.25-7.40 (m, 5H), 7.52 (d, J = 1.9 Hz, 1H).

Friedel-Crafts reaction of compound (I) with 2,4-dichlorobenzyloxy Compound A (0.62 g, 2.0 mmol) to trifluoroacetic acid (3.5 mL, 47 mmol) and trifluoroacetic anhydride (0.92 mL, 6.5 mmol) ) And stirred at 25 ° C. for 30 minutes. Toluene (0.7 mL) and methyl 2- [3,5-bis (2,4-dichlorobenzyloxy) -2-ethylphenyl] acetate (Compound I) (0.70 g, 1.3 mmol) were added to the reaction mixture, After stirring at 25 ° C. for 6 hours, the mixture was allowed to stand overnight. 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 residue was purified by silica gel column chromatography (ethyl acetate / heptane = 70/30 to 90/10), and 3,5-bis (2,4-dichlorobenzyloxy) -2-ethyl-6- [3-methoxy- Methyl 4- (2-morpholin-4-ylethoxy) benzoyl] phenylacetate (Compound 2) (0.95 g, 92%) was obtained.
¹ H NMR (CDCl ₃ ): 1.13 (t, J = 7.2 Hz, 3H), 2.54-2.75 (m, 6H), 2.85-2.95 (m, 2H), 3.49 (s, 3H), 3.66 (s, 2H ), 3.71-3.79 (m, 4H), 3.90 (s, 3H), 4.21 (t, J = 5.8 Hz, 2H), 4.95 (s, 2H), 5.15 (s, 2H), 6.41 (s, 1H) , 6.78 (s, 1H), 6.81 (s, 1H), 7.00 (dd, J = 8.3, 2.1 Hz, 1H), 7.23-7.34 (m, 3H), 7.37-7.47 (m, 2H), 7.55 (d , J = 1.8 Hz, 1H).

Production process 1 of methyl 2- [3,5-bis (3,4-dichlorobenzyloxy) -2-ethylphenyl] acetate (compound B)
Dissolve methyl 3,5-dihydroxyphenylacetate (250 g, 1.37 mol) in DMF (1.25 L) and add potassium carbonate (474 g, 3.43 mol) and 3,4-dichlorobenzyl chloride (617 g, 3.16 mol). The mixture was further stirred at 50 ° C. for 5 hours. Ethyl acetate (2.50 L) was added to the reaction mixture and filtered, and 5% brine (2.50 L) and 1 mol / L hydrochloric acid (25 mL) were added to the filtrate to separate the layers. The organic layer was washed with 10% brine (2.50 L) and concentrated under reduced pressure. Toluene was added to the residue, followed by concentration under reduced pressure to obtain methyl 2- [3,5-bis (3,4-dichlorobenzyloxy) phenyl] acetate (Compound K). Compound K was directly used in the next step.
¹ H NMR (CDCl ₃ ): 3.56 (s, 2H), 3.69 (s, 3H), 4.16 (s, 4H), 6.45-6.57 (m, 3H), 7.20-7.30 (m, 2H), 7.40-7.57 (m, 4H).

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. 2-Propanol (1.00 L) was added to the residue, and the mixture was stirred at 55 ° C. for 1 hour, and then cooled to room temperature. 2-Propanol (2.00 L) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and at 5 ° C. for 2 hours. The precipitated crystals were filtered to obtain methyl 2- [2-acetyl-3,5-bis (3,4-dichlorobenzyloxy) phenyl] acetate (Compound L) (590 g, 79%).
¹ H NMR (CDCl ₃ ): 2.50 (s, 3H), 3.69 (s, 3H), 3.70 (s, 2H), 5.00 (s, 2H), 5.02 (s, 2H), 6.46 (m, 2H), 7.17-7.25 (m, 2H), 7.48-7.53 (m, 4H).

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. 2-propanol (800 mL) was added to the residue, and the mixture was stirred at 55 ° C. for 1 hour, and then cooled to room temperature. 2-Propanol (1.60 L) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and at 5 ° C. for 2 hours. The reaction mixture was filtered to obtain a crude product.

Add THF (800 mL) and ethanol (800 mL) to the resulting crude product, and dissolve by heating to 55 ° C. Ethanol (800 mL) was added to the reaction mixture, the mixture was cooled to 40 ° C., seed crystals (40.0 mg, 0.01 wt%) were added, and the mixture was stirred for 1 hr. The reaction mixture was stirred at room temperature for 1 hour and at 5 ° C. for 2 hours. The precipitated crystals were filtered to obtain Compound B (332 g, 85%).
¹ H NMR (CDCl ₃ ): 1.09 (t, J = 7.4 Hz, 3H), 2.66 (q, J = 7.4 Hz, 2H), 3.64 (s, 2H), 3.69 (s, 3H), 4.96 (s, 2H), 4.98 (s, 2H), 6.43 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 7.18-7.30 (m, 2H), 7.44 (d, J = 3.5 Hz, 1H), 7.47 (d, J = 3.5 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H).
Step 3 (conversion from compound L to compound B) can also be synthesized by the following method.

Compound L (2.0 g, 3.69 mmol) was dissolved in toluene (10 mL), trifluoroacetic acid (6 mL) was added, and the mixture was cooled to 0 ° C. Sodium borohydride (419 mg, 11.1 mmol) was slowly added and stirred at 20 ° C. for 24 hours. The reaction mixture was added dropwise to a mixed solution of water (5 mL) and toluene (10 mL), 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 under reduced pressure. Toluene (4 mL) and n-heptane (16 mL) were added to the residue, and the mixture was stirred at 50 ° C for 1 hour and at room temperature for 1 hour. The precipitated crystals were filtered to obtain Compound B (1.74 g, 89%).

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. The reaction mixture was filtered, and the filtrate was concentrated to 1000 mL under reduced pressure to obtain an acetonitrile solution containing ethyl 3-methoxy-4- (2-morpholin-4-ylethoxy) benzoate (Compound N). Used as is in the next step.
¹ H-NMR (DMSO-d ₆ ): 1.31 (t, J = 7.1 Hz, 3H), 2.48 (t, J = 4.5 Hz, 4H), 2.71 (t, J = 5.9 Hz, 2H), 3.57 (t , J = 4.5 Hz, 4H), 3.82 (s, 3H), 4.14 (t, J = 5.9 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H ), 7.45 (d, J = 1.6 Hz, 1H), 7.56 (dd, J = 8.4, 1.6 Hz, 1H).

Process 2
Ethanol (500 mL) and a 3 mol / L aqueous sodium hydroxide solution (850 mL, 2.55 mol) were added to the acetonitrile solution of compound N obtained in step 1, and the mixture was stirred at 45 ° C. for 3 hours. The reaction mixture was cooled to 5 ° C., neutralized with concentrated hydrochloric acid, and ethyl acetate (500 mL) and 2-methyl-1-propanol (1.50 L) were added to separate the layers. Ethyl acetate (250 mL) and 2-methyl-1-propanol (750 mL) were added to the aqueous layer for extraction, and then the organic layers were combined and concentrated to 1000 mL under reduced pressure. Ethyl acetate was added to the residue and stirred at 15 ° C. for 1 hour. The precipitated crystals were filtered to obtain a crude product (318 g, 83%). Methanol (50 mL) was added to the obtained crude product (5.0 g, 13 mmol), and the mixture was stirred for 2 hours under reflux. The reaction mixture was cooled to 15 ° C. and stirred for 2 hours. The precipitated crystals were filtered to obtain Compound A (3.3 g, 74%).
¹ H-NMR (DMSO-d ₆ ): 3.20-3.37 (m, 2H), 3.38-3.70 (m, 2H), 3.57 (t, J = 4.9 Hz, 2H), 3.82 (s, 3H), 3.85- 4.00 (m, 2H), 3.91 (s, 2H), 4.55 (t, J = 4.9 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.56 (dd, J = 8.4, 1.8 Hz, 1H).

Comparative Example 1: 2- {2-Ethyl-3,5-dihydroxy-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) with Friedel-Crafts reaction using benzene derivatives with allyloxy Benzoyl] phenyl} -N, N-bis (2-methoxyethyl) acetamide (compound E) production process 1: Friedel-Crafts reaction using benzene derivative with allyloxy Compound A (4.7 g, 16 mmol) and 2 To methyl-(3,5-diallyloxy-2-ethylphenyl) acetate (compound Q) (4.3 g, 15 mmol) was added trifluoroacetic acid (43 mL) and trifluoroacetic anhydride (7.5 mL, 53 mmol). Stir for 1.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added, and the pH was adjusted to 9.0 with 6 mol / L aqueous sodium hydroxide solution, followed by liquid separation. The organic layer was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 10/1), and 3,5-diallyloxy-2-ethyl-6- [3-methoxy-4- (2-morpholine-4 Methyl -ylethoxy) benzoyl] phenylacetate (Compound P) (7.0 g, 86%) was obtained.
¹ H-NMR (CDCl ₃ ): 1.09 (t, J = 7.5 Hz, 3H), 2.57-2.70 (m, 6H), 2.83 (t, J = 5.4 Hz, 2H), 3.45 (s, 3H), 3.58 (s, 2H), 3.69 (t, J = 4.7 Hz, 4H), 3.82 (s, 3H), 4.21 (t, J = 5.4 Hz, 2H), 4.42 (d, J = 4.8 Hz, 2H), 4.63 (d, J = 4.8 Hz, 2H), 4.96-5.09 (m, 2H), 5.29 (dd, J = 10.5, 1.5 Hz, 1H), 5.54 (dd, J = 17.3, 1.5 Hz, 1H), 5.63- 5.78 (m, 1H), 6.04-6.18 (m, 1H), 6.63 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 1.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H).

Process 2
Methanol (54 mL) and 2 mol / L aqueous sodium hydroxide solution (42 mL) were added to compound P (6.0 g, 11 mmol), and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, the pH was adjusted to 6.8 with 4 mol / L hydrochloric acid, and the precipitated crystals were filtered to give 3,5-diallyloxy-2-ethyl-6- [3-methoxy-4- (2 -Morpholin-4-ylethoxy) benzoyl] phenylacetic acid (Compound R) (4.4 g, 75%) was obtained.
¹ H-NMR (acetone-d ₆ ): 1.12 (t, J = 7.5 Hz, 3H), 2.53 (t, J = 4.7 Hz, 4H), 2.69 (q, J = 7.5 Hz, 2H), 2.76 (t , J = 5.9 Hz, 2H), 3.58 (s, 2H), 3.58 (t, J = 4.7 Hz, 4H), 3.81 (s, 3H), 4.18 (t, J = 5.9 Hz, 2H), 4.47 (dt , J = 4.8, 1.7 Hz, 2H), 4.68 (dt, J = 5.0, 1.7 Hz, 2H), 5.00 (dq, J = 10.5, 1.7 Hz, 1H), 5.04 (dq, J = 17.1, 1.7 Hz, 1H), 5.28 (dq, J = 10.5, 1.7 Hz, 1H), 5.48 (dq, J = 17.1, 1.7 Hz, 1H), 5.71 (ddt, J = 17.1, 10.5, 4.8 Hz, 1H), 6.14 (ddt , J = 17.1, 10.5, 5.0 Hz, 1H), 6.72 (s, 1H), 6.96 (d, J = 8.3 Hz, 1H), 7.30 (dd, J = 8.3, 2.1 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H).

Process 3
Compound R (100 mg, 0.19 mmol) to THF (1 mL), 1,1'-dicarbonyldiimidazole (0.036 mL, 0.24 mmol), 1-hydroxybenzotriazole monohydrate (31 mg, 0.20 mmol), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (39.1 mg, 0.20 mmol) was added, and the mixture was stirred at 20 ° C. for 8 hr. Ethyl acetate (15 mL) and water (15 mL) were added to the reaction mixture, and the phases were separated. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to give 2- {3,5-diallyloxy-2-ethyl-6- [3-methoxy-4- (2-morpholine). -4-ylethoxy) benzoyl] phenyl} -N, N-bis (2-methoxyethyl) acetamide (Compound S) (111 mg, 92%) was obtained.
¹ H-NMR (CDCl ₃ ): 1.09 (t, J = 7.4 Hz, 3H), 2.53-2.66 (m, 6H), 2.85 (t, J = 6.0 Hz, 2H), 3.15 (s, 3H), 3.19 (t, J = 5.6 Hz, 2H), 3.29 (s, 3H), 3.34 (t, J = 5.6 Hz, 2H), 3.35-3.48 (m, 4H), 3.72 (t, J = 4.5 Hz, 4H) , 3.77 (s, 2H), 3.88 (s, 3H), 4.18 (t, J = 6.0 Hz, 2H), 4.36 (dt, J = 4.8, 1.7 Hz, 2H), 4.55 (dt, J = 4.8, 1.7 Hz, 2H), 5.07-4.97 (m, 2H), 5.28 (dq, J = 10.2, 1.7 Hz, 1H), 5.44 (dq, J = 17.4, 1.7 Hz, 1H), 5.69 (ddt, J = 17.4, 10.2, 4.8 Hz, 1H), 6.07 (ddt, J = 17.4, 10.2, 4.8 Hz, 1H), 6.40 (s, 1H), 6.80 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.6 , 1.8 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H).

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. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100 / 0-80 / 20), crystallized with ethyl acetate and 2- {2-ethyl-3,5-dihydroxy-6- [3-methoxy -4- (2-morpholin-4-ylethoxy) benzoyl] phenyl} -N, N-bis (2-methoxyethyl) acetamide (Compound E) (2.1 g, 94%) was obtained.
¹ H-NMR (DMSO-d ₆ ): 0.99 (t, J = 7.4 Hz, 3H), 2.37 (q, J = 7.4 Hz, 2H), 2.45-2.50 (m, 4H), 2.70 (t, J = 5.8 Hz, 2H), 3.04 (t, J = 6.1 Hz, 2H), 3.07 (s, 3H), 3.19 (s, 3H), 3.22 (t, J = 6.1 Hz, 2H), 3.31 (t, J = 5.3 Hz, 2H), 3.38 (t, J = 5.3 Hz, 2H), 3.51 (s, 2H), 3.57 (t, J = 4.6 Hz, 4H), 3.76 (s, 3H), 4.13 (t, J = 5.8 Hz, 2H), 6.34 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H) , 9.05 (br s, 1H), 9.34 (br s, 1H).

The above 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). On the other hand, Example 1 is a Friedel-Crafts reaction using a benzene derivative in which hydroxy is protected with 3,4-dichlorobenzyl, and Example 2 is a method for producing Compound E from the benzophenone derivative obtained in Example 1. Is shown. Here, the production methods of Examples 1 and 2 are referred to as invention methods, and the production method of Comparative Example 1 is referred to as a conventional method.

Comparing the total yield from the Friedel-Crafts reaction to the step of obtaining compound E in the inventive method and the conventional method, it was 70% in the inventive method, and 56% in the conventional method. Therefore, it can be said that the invention method is superior to the conventional method in terms of yield.
In addition, when comparing the purification methods of each intermediate and compound E in each production method, the conventional method uses silica gel column chromatography three times, whereas the invention method does not use silica gel column chromatography. All obtained the target compound by crystallization. In the case of industrial mass synthesis, crystallization is more advantageous in terms of operability and cost than column chromatography. In addition, in the method of the invention, all intermediates are obtained as crystals, whereas in the conventional method, some intermediates are obtained as oily substances, but crystals are generally more advantageous in terms of operability and physical properties. There are many points. Therefore, the invention method can be said to be superior to the conventional method in terms of the purification method and the physical properties of the intermediate.

On the other hand, in the deprotection of the hydroxy protecting group, bis (triphenylphosphine) palladium (II) dichloride is used in the conventional method, and Pd / C is used in the invention method. In general, it is known that a homogeneous catalyst such as bis (triphenylphosphine) palladium (II) dichloride is difficult to remove, and a heterogeneous catalyst such as Pd / C is easy to remove. On the other hand, in the synthesis of a compound that is an active ingredient of a medicine, strict standards are set for contamination of impurities. Therefore, compared with the conventional method using a homogeneous catalyst that is difficult to remove, the invention method using a heterogeneous catalyst that is easy to remove is considered to be superior as a method for producing a pharmaceutical active ingredient.

Comparative Example 2: Friedel-Crafts reaction of benzyl compound Compound A (1.4 g, 4.5 mmol) and methyl 2- (3,5-dibenzyloxy-2-ethylphenyl) acetate (Compound U) (1.0 g, 2.6 mmol) ) Was added trifluoroacetic acid (10 mL) and trifluoroacetic anhydride (3.6 mL, 26 mmol), and the mixture was stirred at 0 ° C. for 30 minutes. The 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 residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 20/1), and 3,5-dibenzyloxy-2-ethyl-6- [3-methoxy-4- (2-morpholine- Methyl 4-ylethoxy) benzoyl] phenylacetate (Compound T) (1.3 g, 68%) was obtained.
¹ H-NMR (CDCl ₃ ): 1.11 (t, J = 7.5 Hz, 3H), 2.59 (t, J = 4.7 Hz, 4H), 2.67 (q, J = 7.5 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 3.48 (s, 3H), 3.66 (s, 2H), 3.73 (t, J = 4.7 Hz, 4H), 3.88 (s, 3H), 4.20 (t, J = 6.0 Hz, 2H ), 4.88 (s, 2H), 5.06 (s, 2H), 6.51 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.92-7.00 (m, 2H), 7.17-7.23 (m, 2H), 7.31 (dd, J = 8.4, 2.1 Hz, 1H), 7.45-7.33 (m, 6H), 7.53 (d, J = 2.1 Hz, 1H).

As described above, the yield of this reaction (68%) was lower than the yields of Examples 1, 3 and 4 (93%, 83% and 92%, respectively). From these results, the production method of the benzophenone derivative of the present invention using dihydroxybenzene in which hydroxy is protected with halobenzyl is superior in yield compared to the method using dihydroxybenzene in which hydroxy is protected with benzyl. It has been suggested.

The present invention provides a method for producing a synthetic intermediate of a benzophenone derivative having antitumor activity and the like.

Claims (31)

1. Formula (I)
   

   

   (Wherein 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)
   

   

   (In the formula, R ⁴ represents a lower alkyl which may have a substituent,
   Wherein R ⁵ represents an optionally substituted aliphatic heterocyclic alkyl) or a salt thereof in the presence of an acid, the compound represented by formula (III)
   

   

   (Wherein R ^1a , R ^1b , R ² , R ³ , R ^4, and R ⁵ are as defined above), or a salt thereof.
2. 2. The process for producing a benzophenone derivative or a salt thereof according to claim ^1, wherein R ^1a and R ^1b are dichlorobenzyl.
3. 2. The process for producing a benzophenone derivative or a salt thereof according to claim ^1, wherein R ^1a and R ^1b are 3,4-dichlorobenzyl.
4. 4. The process for producing a benzophenone derivative or a salt thereof according to claim 1, wherein R ² is lower alkyl.
5. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 1 to 3, wherein R ² is ethyl.
6. 6. The process for producing a benzophenone derivative or a salt thereof according to claim 1, wherein R ³ is lower alkoxycarbonyl.
7. 6. The process for producing a benzophenone derivative or a salt thereof according to claim 1, wherein R ³ is methoxycarbonyl.
8. 8. The process for producing a benzophenone derivative or a salt thereof according to claim 1, wherein R ⁴ is lower alkyl.
9. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 1 to 7, wherein R ⁴ is methyl.
10. 10. The process for producing a benzophenone derivative or a salt thereof according to claim 1, wherein R ⁵ is an aliphatic heterocyclic alkyl.
11. 10. The process for producing a benzophenone derivative or a salt thereof according to any one of claims 1 to 9, wherein R ⁵ is ethyl substituted at the 2-position with an aliphatic heterocyclic group.
12. 10. The process for producing a benzophenone derivative or a salt thereof according to any one of claims 1 to 9, wherein R ⁵ is 2-morpholinoethyl.
13. The process for producing a benzophenone derivative or a salt thereof according to any one of claims 1 to 12, wherein the acid is trifluoroacetic acid.
14. Formula (I)
    

    

    Wherein R ^1a , R ^1b , R ² and R ³ are as defined above, or a salt thereof, and formula (II)
    

    

    (Wherein R ⁴ and R ⁵ are as defined above) or a salt thereof, in the presence of an acid, to react,
    

    

    Wherein 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. (IV)
    

    

    Wherein R ² , R ⁴ and R ⁵ are as defined above,
    R ⁶ represents an optionally substituted N-lower alkylaminocarbonyl or an optionally substituted N, N-dilower alkylaminocarbonyl)) or a salt thereof. Manufacturing method.
15. 15. The process for producing a benzophenone derivative or a salt thereof according to claim 14, wherein R ^1a and R ^1b are dichlorobenzyl.
16. 15. The process for producing a benzophenone derivative or a salt thereof according to claim 14, wherein R ^1a and R ^1b are 3,4-dichlorobenzyl.
17. 17. The process for producing a benzophenone derivative or a salt thereof according to claim 14, wherein R ² is lower alkyl.
18. 17. The process for producing a benzophenone derivative or a salt thereof according to claim 14, wherein R ² is ethyl.
19. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 18, wherein R ³ is lower alkoxycarbonyl.
20. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 18, wherein R ³ is methoxycarbonyl.
21. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 20, wherein R ⁴ is lower alkyl.
22. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 20, wherein R ⁴ is methyl.
23. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 22, wherein R ⁵ is an aliphatic heterocyclic alkyl.
24. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 22, wherein R ⁵ is ethyl substituted at the 2-position with an aliphatic heterocyclic group.
25. The process for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 22, wherein R ⁵ is 2-morpholinoethyl.
26. The method for producing a benzophenone derivative or a salt thereof according to any one of claims 14 to 25, wherein R ⁶ is N, N-bis (2-methoxyethyl) aminocarbonyl.
27. The benzophenone derivative represented by the formula (IV) is
    

    

    2- {2-ethyl-3,5-dihydroxy-6- [3-methoxy-4- (2-morpholin-4-ylethoxy) benzoyl] phenyl} -N, N-bis (2-methoxyethyl) 15. The method for producing a benzophenone derivative or a salt thereof according to claim 14, which is acetamide.
28. Formula (I)
    

    

    (Wherein 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.
29. 29. The compound or a salt thereof according to claim 28, wherein R ^1a and R ^1b are 3,4-dichlorobenzyl, R ² is ethyl, and R ³ is methoxycarbonyl.
30. Formula (III)
    

    

    (Wherein R ^1a , R ^1b , R ² , R ³ , R ⁴ and R ⁵ are as defined above) or a salt thereof.
31. The R ^1a and R ^1b are 3,4-dichlorobenzyl, R ² is ethyl, R ³ is methoxycarbonyl, R ⁴ is methyl, and R ⁵ is 2-morpholinoethyl. A benzophenone derivative or a salt thereof.