JP6872443B2 - Improved method for producing synthetic intermediates of tolvaptan - Google Patents
Improved method for producing synthetic intermediates of tolvaptan Download PDFInfo
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- JP6872443B2 JP6872443B2 JP2017131576A JP2017131576A JP6872443B2 JP 6872443 B2 JP6872443 B2 JP 6872443B2 JP 2017131576 A JP2017131576 A JP 2017131576A JP 2017131576 A JP2017131576 A JP 2017131576A JP 6872443 B2 JP6872443 B2 JP 6872443B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 42
- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 title claims description 16
- 229960001256 tolvaptan Drugs 0.000 title claims description 14
- 239000000543 intermediate Substances 0.000 title description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 27
- 239000000347 magnesium hydroxide Substances 0.000 claims description 27
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 27
- -1 2- (4-Amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine Chemical compound 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- FLJCJPKXJWRZJB-UHFFFAOYSA-N 1-(4-amino-2-methylbenzoyl)-7-chloro-3,4-dihydro-2h-1-benzazepin-5-one Chemical compound CC1=CC(N)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(=O)CCC1 FLJCJPKXJWRZJB-UHFFFAOYSA-N 0.000 claims description 11
- AHESNFIUAHTYGS-UHFFFAOYSA-N 7-chloro-1,2,3,4-tetrahydro-1-benzazepin-5-one Chemical compound N1CCCC(=O)C2=CC(Cl)=CC=C21 AHESNFIUAHTYGS-UHFFFAOYSA-N 0.000 claims description 11
- NNCRQBJNAGEBDM-UHFFFAOYSA-N 7-chloro-1-(2-methyl-4-nitrobenzoyl)-3,4-dihydro-2h-1-benzazepin-5-one Chemical compound CC1=CC([N+]([O-])=O)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(=O)CCC1 NNCRQBJNAGEBDM-UHFFFAOYSA-N 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- LMDIDOFTXQERLH-UHFFFAOYSA-N 2-methyl-4-nitrobenzoyl chloride Chemical compound CC1=CC([N+]([O-])=O)=CC=C1C(Cl)=O LMDIDOFTXQERLH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 6
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 4
- HEDJTKIXARNIQA-UHFFFAOYSA-N 2-chloro-1-(2-methyl-4-nitrobenzoyl)-3,4-dihydro-2H-1-benzazepin-5-one Chemical compound ClC1N(C2=C(C(CC1)=O)C=CC=C2)C(C1=C(C=C(C=C1)[N+](=O)[O-])C)=O HEDJTKIXARNIQA-UHFFFAOYSA-N 0.000 claims 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 claims 1
- 239000000126 substance Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000006482 condensation reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VENGMROMZOKURN-UHFFFAOYSA-N n-[4-(7-chloro-5-oxo-3,4-dihydro-2h-1-benzazepine-1-carbonyl)-3-methylphenyl]-2-methylbenzamide Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(=O)CCC1 VENGMROMZOKURN-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- MZBVNYACSSGXID-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-1-benzazepine Chemical compound N1CCCCC2=CC=CC=C21 MZBVNYACSSGXID-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HRVRAYIYXRVAPR-UHFFFAOYSA-N 1,3,4,5-tetrahydro-1-benzazepin-2-one Chemical compound N1C(=O)CCCC2=CC=CC=C21 HRVRAYIYXRVAPR-UHFFFAOYSA-N 0.000 description 2
- WVHFBZASTMKKDB-UHFFFAOYSA-N 1-chloro-3,4-dihydro-2H-1-benzazepin-5-one Chemical compound ClN1CCCC(C2=C1C=CC=C2)=O WVHFBZASTMKKDB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010021036 Hyponatraemia Diseases 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 201000008284 inappropriate ADH syndrome Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、トルバプタンの合成中間体の改善された製造方法に関する。さらに詳しくは、本発明は、水酸化マグネシウムの存在下で、アミノ基とカルボキシル基とを縮合させることを含む、トルバプタンの合成中間体である７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンおよび７−クロロ−１−（２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを高い収率で製造する、改善された製造方法に関する。 The present invention relates to an improved method for producing synthetic intermediates of tolvaptan. More specifically, the present invention is 7-chloro-1- (2-methyl-4-nitro), a synthetic intermediate for torbaptane, which comprises condensing an amino group with a carboxyl group in the presence of magnesium hydroxide. Benzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-(2-methyl-4-[(2-methylbenzoyl) amino] benzoyl) -5- It relates to an improved production method for producing oxo-2,3,4,5-tetrahydro-1H-1-benzazepine in high yield.
トルバプタン（Ｔｏｌｖａｐｔａｎ）は、バソプレシンの拮抗活性を有する化合物であり、心不全、肝硬化、抗利尿ホルモン分泌異常症候群（ＳＩＡＤＨ）患者等で低ナトリウム血症の治療剤として用いられる。トルバプタンの化学名は、７−クロロ−５−ヒドロキシ−１−［２−メチル−４−（２−メチルベンゾイルアミノ）ベンゾイル］−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンであり、下記化学式１の構造を有する（ＵＳ５，２５８，５１０）。
＜化学式１＞
<Chemical formula 1>
トルバプタンの製造方法は、ＵＳ５，２５８，５１０、ＪＰＨ０４−１５４７６５；Ｋａｚｕｍｉ Ｋｏｎｄｏ ｅｔ ａｌ， Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ， ７（１９９９）， ｐｐ． １７４３−１７５４等に開示されている。前記製造方法は、下記反応式１のように、７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（化学式２）を２−メチル−４−ニトロベンゾイルクロライドと反応させて７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（化学式３）を製造する工程；前記化学式３の中間体を塩化スズと反応させて１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（化学式４）を製造する工程；前記化学式４の中間体を２−メチルベンゾイルクロライドと反応させて７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（化学式５）を製造する工程；および前記化学式５の中間体を水素化ホウ素ナトリウムなどの水素化剤を用いて還元させてトルバプタン（化学式１）を製造する工程を含む。
＜反応式１＞
<Reaction formula 1>
前記反応式１にしたがう製造方法において、化学式２の化合物から化学式３の中間体を製造する工程および化学式４の中間体から化学式５の中間体を製造する工程は、両方アミノ基とカルボキシル基との縮合反応であり、各工程での収率はそれぞれ３２％および５３％に過ぎない欠点がある。 In the production method according to the reaction formula 1, the step of producing the intermediate of the chemical formula 3 from the compound of the chemical formula 2 and the step of producing the intermediate of the chemical formula 5 from the intermediate of the chemical formula 4 are both amino groups and carboxyl groups. It is a condensation reaction and has the drawback that the yields in each step are only 32% and 53%, respectively.
そのような製造方法の問題点を改善するために、ＵＳ２０１３／０１９０４９０は、前記アミノ基とカルボキシル基との縮合反応を重炭酸ナトリウムなどの無機塩基の存在下で反応させる、改善された製造方法を開示している。ＵＳ２０１３／０１９０４９０にしたがって、重炭酸ナトリウムの存在下で、化学式２の化合物から化学式３の中間体を製造する工程および化学式４の化合物から化学式５の中間体を製造する工程の収率は、それぞれ８５．２％および７３．６％である。ＵＳ２０１３／０１９０４９０の製造方法によって、アミノ基とカルボキシル基との縮合反応の収率を、ある程度改善することができるが、その収率がまだ低いという問題点がある。したがって、トルバプタンの製造中間体のアミノ基とカルボキシル基との縮合反応を改善して、高い収率で中間体を製造することができる方法を開発する必要が存在する。 In order to improve the problem of such a production method, US2013 / 0190490 is an improved production method in which the condensation reaction of the amino group and the carboxyl group is reacted in the presence of an inorganic base such as sodium bicarbonate. It is disclosed. According to US2013 / 0190490, the yields of the step of producing the intermediate of Chemical Formula 3 from the compound of Chemical Formula 2 and the step of producing the intermediate of Chemical Formula 5 from the compound of Chemical Formula 4 in the presence of sodium bicarbonate are 85, respectively. It is .2% and 73.6%. The yield of the condensation reaction between the amino group and the carboxyl group can be improved to some extent by the method for producing US2013 / 0190490, but there is a problem that the yield is still low. Therefore, there is a need to develop a method capable of producing an intermediate in a high yield by improving the condensation reaction between the amino group and the carboxyl group of the intermediate for producing tolvaptan.
本発明者らは、トルバプタンの製造中間体のアミノ基とカルボキシル基との縮合反応を改善して、高い収率で中間体（すなわち、化学式３の中間体および化学式５の中間体）を製造することができる方法を開発するために多様な研究を行った。驚くべきことに、本発明者らは、特定のアルカリ土金属水酸化物である水酸化マグネシウム［Ｍｇ（ＯＨ）２］の存在下で縮合反応を行うと、化学式３の化合物および化学式５の化合物を両方９５％以上の高い収率で製造することができることを見出した。 The present inventors improve the condensation reaction between the amino group and the carboxyl group of the tolvaptan production intermediate to produce an intermediate (that is, an intermediate of chemical formula 3 and an intermediate of chemical formula 5) in a high yield. Diverse research has been done to develop ways that can be done. Surprisingly, when the condensation reaction was carried out in the presence of magnesium hydroxide [Mg (OH) 2 ], which is a specific alkaline earth metal hydroxide, the present inventors, the compound of the chemical formula 3 and the compound of the chemical formula 5 Both have been found to be able to be produced in high yields of 95% or more.
したがって、本発明は、水酸化マグネシウムの存在下で縮合反応を行うことを含む、７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（化学式３の中間体）の改善された製造方法を提供することを目的とする。 Therefore, the present invention comprises performing a condensation reaction in the presence of magnesium hydroxide, 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-. It is an object of the present invention to provide an improved method for producing tetrahydro-1H-1-benzazepine (an intermediate of Chemical Formula 3).
また、本発明は、水酸化マグネシウムの存在下で縮合反応を行うことを含む、７−クロロ−１−（２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（化学式５の中間体）の改善された製造方法を提供することを目的とする。 The present invention also comprises performing a condensation reaction in the presence of magnesium hydroxide, 7-chloro-1- (2-methyl-4-[(2-methylbenzoyl) amino] benzoyl) -5-oxo-. It is an object of the present invention to provide an improved method for producing 2,3,4,5-tetrahydro-1H-1-benzazepine (intermediate of Chemical Formula 5).
また、本発明は、前記水酸化マグネシウムの存在下で縮合反応を行うことを含む、トルバプタンの改善された製造方法を提供することを目的とする。 Another object of the present invention is to provide an improved method for producing tolvaptan, which comprises carrying out a condensation reaction in the presence of the magnesium hydroxide.
本発明の一態様によって、水酸化マグネシウムの存在下で、７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチル−４−ニトロベンゾイルクロライドと反応させることを含む、７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造方法が提供される。 According to one aspect of the present invention, 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is reacted with 2-methyl-4-nitrobenzoyl chloride in the presence of magnesium hydroxide. Provided is a method for producing 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which comprises allowing.
本発明の別の一態様によって、水酸化マグネシウムの存在下で、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチルベンゾイルクロライドと反応させることを含む、７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造方法が提供される。 According to another aspect of the present invention, in the presence of magnesium hydroxide, 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H- Reacting 1-benzazepine with 2-methylbenzoyl chloride, including 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4 , 5-Tetrahydro-1H-1-benzazepine is provided.
本発明のさらに別の一態様によって、（ａ）水酸化マグネシウムの存在下で、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチルベンゾイルクロライドと反応させて７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを製造する工程；および（ｂ）前記７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを水素化剤の存在下で還元させてトルバプタンを製造する工程を含む、トルバプタンの製造方法が提供される。 According to yet another aspect of the invention, (a) in the presence of magnesium hydroxide, 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5- Tetrahydro-1H-1-benzazepine reacted with 2-methylbenzoyl chloride to 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3, Steps for Producing 4,5-Tetrahydro-1H-1-benzazepine; and (b) 7-Chloro-1- [2-Methyl-4-[(2-Methylbenzoyl) Amino] Benzoyl] -5-oxo- A method for producing tolbaptane is provided, which comprises the step of reducing 2,3,4,5-tetrahydro-1H-1-benzazepine in the presence of a hydrogenating agent to produce tolbaptane.
トルバプタンの製造中間体のアミノ基とカルボキシル基との縮合反応を水酸化マグネシウム［Ｍｇ（ＯＨ）２］の存在下で行うと、トルバプタンの合成中間体である７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンおよび７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを９５％以上の高い収率で製造することができることが本発明により見出された。したがって、本発明の製造方法は、トルバプタンの合成中間体を高い収率で製造することができ、さらにトルバプタンの産業的大規模生産に有用に用いられる。 When the condensation reaction between the amino group and the carboxyl group of the tolvaptan production intermediate is carried out in the presence of magnesium hydroxide [Mg (OH) 2 ], 7-chloro-1- (2-methyl), which is a synthetic intermediate of tolbaptan, is carried out. -4-Nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl) ] It has been found by the present invention that -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be produced in high yields of 95% or more. Therefore, the production method of the present invention can produce a synthetic intermediate of tolvaptan in a high yield, and is useful for industrial large-scale production of tolvaptan.
本発明は、水酸化マグネシウムの存在下で、７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチル−４−ニトロベンゾイルクロライドと反応させることを含む、７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造方法を提供する。 The present invention involves reacting 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitrobenzoyl chloride in the presence of magnesium hydroxide. Provided are a method for producing 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which comprises.
前記７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造方法において、前記水酸化マグネシウムは、７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの１当量に対して、１〜１０当量比で用いられてもよく、好ましくは１〜５当量比で用いられてもよい。また、前記反応は、アセトニトリル、テトラヒドロフラン、ジクロロメタンまたはその混合物からなる群から選択された有機溶媒中で行われてもよく、好ましくはアセトニトリル中で行われてもよい。前記反応は、０ないし３０℃で行われてもよく、好ましくは０ないし２５℃で行われてもよく、より好ましくは約１０℃の温度で行われてもよい。反応時間は、反応温度などにより適切に設定することができるが、約０．５ないし約５時間程度が好ましい。得られた生成物すなわち、７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンは、層分離、アルカリｐＨへの調節、有機溶媒を用いた抽出、濃縮などの通常の方法にしたがって単離することができる。 In the method for producing 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, the magnesium hydroxide is 7-. It may be used in a ratio of 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. You may. Further, the reaction may be carried out in an organic solvent selected from the group consisting of acetonitrile, tetrahydrofuran, dichloromethane or a mixture thereof, and may be carried out preferably in acetonitrile. The reaction may be carried out at 0 to 30 ° C., preferably 0 to 25 ° C., more preferably at a temperature of about 10 ° C. The reaction time can be appropriately set depending on the reaction temperature and the like, but is preferably about 0.5 to about 5 hours. The resulting product, namely 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, was layer-separated, alkaline pH. It can be isolated according to conventional methods such as adjustment to, extraction with an organic solvent, and concentration.
本発明は、また水酸化マグネシウムの存在下で、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチルベンゾイルクロライドと反応させることを含む、７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造方法を提供する。 The present invention also presents 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine in the presence of magnesium hydroxide. 7-Chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro, which involves reacting with 2-methylbenzoyl chloride. A method for producing -1H-1-benzazepine is provided.
前記１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンは、従来の製造方法にしたがって得られたものを制限なく使用することができる。例えば、ＵＳ５，２５８，５１０；Ｋａｚｕｍｉ Ｋｏｎｄｏ ｅｔ ａｌ， Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ， ７（１９９９）， ｐｐ． １７４３−１７５４； ＵＳ２０１３／０１９０４９０； ＣＮ１０２０６０７６９等に開示された製造方法にしたがって得られた１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを制限なく使用することができる。具体的には、７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン、好ましくは上記した本発明の製造方法にしたがって得られた７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンと塩化スズを反応させて得られた生成物を、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンとして用いられてもよい。前記反応は、溶媒としてメタノール、エタノール、好ましくはメタノール中で行われてもよい。また、前記反応は０〜２５℃で行われてもよく、好ましくは１０℃以下で行われてもよい。 The 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine was obtained according to a conventional production method. It can be used without restrictions. For example, US 5,258,510; Kazumi Kondo et al, Bioorganic & Medical Chemistry, 7 (1999), pp. 1743-1754; US2013 / 0190490; 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5- obtained according to the production method disclosed in CN102060669 etc. Tetrahydro-1H-1-benzazepine can be used without limitation. Specifically, 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, preferably the above-mentioned production of the present invention. Obtained by reacting 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine obtained according to the method with tin chloride. The resulting product may be used as 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The reaction may be carried out in methanol, ethanol, preferably methanol as a solvent. Further, the reaction may be carried out at 0 to 25 ° C., preferably 10 ° C. or lower.
前記７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造方法において、前記水酸化マグネシウムは、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの１当量に対して、１〜１０当量比で用いられてもよく、好ましくは１〜５当量比で用いられてもよい。また、前記反応はアセトニトリル、テトラヒドロフラン、ジクロロメタンまたはその混合物からなる群から選択された有機溶媒と水との混合溶媒中で行われてもよく、好ましくはジクロロメタンと水との混合溶媒中で行われてもよい。前記反応は、０ないし３０℃で行われてもよく、好ましくは０ないし２５℃で行われてもよく、より好ましくは約１０℃の温度で行われてもよい。反応時間は、反応温度などにより適切に設定することができるが、約０．５ないし約５時間程度が好ましい。得られた生成物すなわち、７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンは、アルカリｐＨへの調節、抽出、濃縮などの通常の方法にしたがって単離することができる。 In the method for producing 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, The magnesium hydroxide is 1 to 1 equivalent of 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. It may be used in a ratio of 10 to 10 equivalents, preferably in a ratio of 1 to 5 equivalents. Further, the reaction may be carried out in a mixed solvent of water and an organic solvent selected from the group consisting of acetonitrile, tetrahydrofuran, dichloromethane or a mixture thereof, and is preferably carried out in a mixed solvent of dichloromethane and water. May be good. The reaction may be carried out at 0 to 30 ° C., preferably 0 to 25 ° C., more preferably at a temperature of about 10 ° C. The reaction time can be appropriately set depending on the reaction temperature and the like, but is preferably about 0.5 to about 5 hours. The resulting product, ie, 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1- Benzazepine can be isolated according to conventional methods such as adjusting to alkaline pH, extraction and concentration.
本発明は、また（ａ）水酸化マグネシウムの存在下で、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチルベンゾイルクロライドと反応させて７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを製造する工程；および（ｂ）前記７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを水素化剤（ｈｙｄｒｏｇｅｎａｔｉｎｇ ａｇｅｎｔ）の存在下で還元させてトルバプタン（７−クロロ−５−ヒドロキシ−１−［２−メチル−４−（２−メチルベンゾイルアミノ）ベンゾイル］−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン）を製造する工程を含む、トルバプタンの製造方法を提供する。 The present invention also (a) in the presence of magnesium hydroxide, 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1. -Reacting benzazepine with 2-methylbenzoyl chloride to 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro The step of producing -1H-1-benzazepine; and (b) the 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4 , 5-Tetrahydro-1H-1-benzazepine is reduced in the presence of a hydrogenating agent to torbaptane (7-chloro-5-hydroxy-1- [2-methyl-4- (2-methylbenzoylamino)). ) Benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepine) is provided.
本発明にしたがうトルバプタン製造方法において、工程（ａ）は上記したように７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造方法にしたがって行われてもよい。すなわち、前記工程（ａ）において、前記水酸化マグネシウムは、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの１当量に対して、１〜１０当量比で用いられてもよく、好ましくは１〜５当量比で用いられてもよい。また、前記反応は、アセトニトリル、テトラヒドロフラン、ジクロロメタンまたはその混合物からなる群から選択された有機溶媒と水との混合溶媒中で行われてもよく、好ましくはジクロロメタンと水との混合溶媒中で行われてもよい。 In the method for producing tolvaptan according to the present invention, the step (a) is 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3 as described above. , 4,5-Tetrahydro-1H-1-benzazepine may be produced according to the method for producing. That is, in the step (a), the magnesium hydroxide was 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-. It may be used in a ratio of 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of benzazepine. Further, the reaction may be carried out in a mixed solvent of water and an organic solvent selected from the group consisting of acetonitrile, tetrahydrofuran, dichloromethane or a mixture thereof, and is preferably carried out in a mixed solvent of dichloromethane and water. You may.
一実施形態において、工程（ａ）で用いられる１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンは、７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを塩化スズと反応させて製造され、前記７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンは、上記したように、水酸化マグネシウムの存在下で、７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチル−４−ニトロベンゾイルクロライドと反応させて製造してもよい。前記実施形態で、前記水酸化マグネシウムは、７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの１当量に対して、１〜１０当量比で用いられてもよく、好ましくは１〜５当量比で用いられてもよい。また、前記７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンと２−メチル−４−ニトロベンゾイルクロライドとの反応は、アセトニトリル、テトラヒドロフラン、ジクロロメタンまたはその混合物からなる群から選択された有機溶媒で行われてもよく、好ましくはアセトニトリル中で行われてもよい。 In one embodiment, the 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine used in step (a) is It is produced by reacting 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with tin chloride, and is produced as described above. -1- (2-Methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine was 7- in the presence of magnesium hydroxide, as described above. It may be prepared by reacting chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitrobenzoyl chloride. In the embodiment, the magnesium hydroxide is used in a ratio of 1-10 equivalents to 1 equivalent of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. May be used, preferably in a ratio of 1 to 5 equivalents. The reaction of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitrobenzoyl chloride is carried out from acetonitrile, tetrahydrofuran, dichloromethane or a mixture thereof. It may be carried out in an organic solvent selected from the group, preferably in acetonitrile.
前記７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの還元［すなわち、工程（ｂ）の還元］は、水素化剤の存在下で行われてもよい。前記還元は公知の方法、例えばＫａｚｕｍｉ Ｋｏｎｄｏ ｅｔ ａｌ， Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ, ７（１９９９）， ｐｐ. １７４３−１７５４、ＵＳ２０１３／０１９０４９０、ＷＯ２００７／０２６９７１等に開示された方法にしたがって行われてもよい。前記水素化剤は、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、ヒドリドホウ酸亜鉛などを用いてもよく、好ましくは水素化ホウ素ナトリウムを用いてもよい。前記水素化剤は、７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの１モル当たりに０．１ないし１モルの比率で用いてもよく、好ましくは０．２５ないし０．５モルの比率で用いてもよい。 Reduction of 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine [ie, Step (b) reduction] may be carried out in the presence of a hydrogenating agent. The reduction may be carried out according to a known method, for example, the method disclosed in Kazumi Kondo et al, Bioorganic & Medical Chemistry, 7 (1999), pp. 1743-1754, US2013 / 0190490, WO2007 / 026971 and the like. As the hydrogenating agent, sodium borohydride, lithium aluminum hydride, zinc hydride borate and the like may be used, and sodium borohydride may be preferably used. The hydrogenating agent is 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. It may be used at a ratio of 0.1 to 1 mol, preferably at a ratio of 0.25 to 0.5 mol per 1 mol of.
以下、本発明を下記実施例によりさらに具体的に説明する。しかし、これらの実施例は、本発明を例示的に説明するためのものであり、本発明の範囲はそれらによって制限されるものではない。 Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are for exemplifying the present invention, and the scope of the present invention is not limited thereto.
実施例１：７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造 Example 1: Preparation of 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine
１Ｌ反応器に７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（９０．０ ｇ、４６０．０ ｍｍｏｌ）およびアセトニトリル（６３０ ｍｌ）を加えて溶解させた後、反応混合物を１０℃以下で水酸化マグネシウム（１３４．１６ ｇ、２３００ ｍｍｏｌ）を加え、３０分間撹拌した。温度を維持しながら、反応混合物に２−メチル−４−ニトロベンゾイルクロライド（１１０．１７ ｇ、５５２．０ ｍｍｏｌ）を徐々に加えた後、５時間撹拌した。反応混合物を濾過して水酸化マグネシウムを除去し、蒸留水（１．３５ Ｌ）およびジクロロメタン（０．９ Ｌ）を入れ、層分離して有機層を得た。得られた有機層に蒸留水（１．５ Ｌ）を入れ、水酸化ナトリウム水溶液を使用して反応混合物のｐＨをｐＨ ９．５〜１０に調節した後、ジクロロメタン（２００ ｍｌ）を入れ、撹拌した後、有機層を分離した。得られた有機層を硫酸ナトリウム（Ｎａ２ＳＯ４）で乾燥した後、濾過し、減圧濃縮して、７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン １５６．７９ ｇを得た（収率：９５％）。 7-Chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (90.0 g, 460.0 mmol) and acetonitrile (630 ml) were added and dissolved in a 1 L reactor. After that, magnesium hydroxide (134.16 g, 2300 mmol) was added to the reaction mixture at 10 ° C. or lower, and the mixture was stirred for 30 minutes. While maintaining the temperature, 2-methyl-4-nitrobenzoyl chloride (110.17 g, 552.0 mmol) was gradually added to the reaction mixture, and then the mixture was stirred for 5 hours. The reaction mixture was filtered to remove magnesium hydroxide, distilled water (1.35 L) and dichloromethane (0.9 L) were added, and the layers were separated to obtain an organic layer. Distilled water (1.5 L) is added to the obtained organic layer, the pH of the reaction mixture is adjusted to pH 9.5 to 10 using an aqueous sodium hydroxide solution, dichloromethane (200 ml) is added, and the mixture is stirred. After that, the organic layer was separated. The obtained organic layer was dried over sodium sulfate (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2, 156.79 g of 3,4,5-tetrahydro-1H-1-benzazepine was obtained (yield: 95%).
実施例２：７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの製造 Example 2: Preparation of 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine
（１）１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの合成 (1) Synthesis of 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine
２Ｌ反応器に実施例１で製造した７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（１４０ ｇ、３９０．２１ ｍｍｏｌ）およびメタノール（３００ ｍｌ）を加え、室温で１時間撹拌した。反応混合物を１０℃以下で撹拌しながら、塩化スズ二水和物（３３８．９９ ｇ、１５０２．３１ ｍｍｏｌ）をメタノール（６００ ｍｌ）に溶かして、徐々に加えた。２３時間後、水酸化ナトリウム水溶液を使用して反応混合物のｐＨをｐＨ ８〜９に調節した後、ジクロロメタン（２００ ｍｌ）を入れて撹拌した後、濾過して反応副産物を除去した。得られた濾液にジクロロメタン（３ Ｌ）および蒸留水（２ Ｌ）を入れ、層分離して有機層を得た。得られた有機層を硫酸ナトリウム（Ｎａ２ＳＯ４）で乾燥した後、濾過し、減圧濃縮して、１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン １１５.０９ ｇを得た（収率：８９．７０％）。 7-Chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (140 g,) prepared in Example 1 in a 2 L reactor. 390.21 mmol) and methanol (300 ml) were added, and the mixture was stirred at room temperature for 1 hour. While stirring the reaction mixture at 10 ° C. or lower, tin chloride dihydrate (338.99 g, 1502.31 mmol) was dissolved in methanol (600 ml) and gradually added. After 23 hours, the pH of the reaction mixture was adjusted to pH 8-9 using an aqueous sodium hydroxide solution, followed by adding dichloromethane (200 ml), stirring, and filtering to remove reaction by-products. Dichloromethane (3 L) and distilled water (2 L) were added to the obtained filtrate, and the layers were separated to obtain an organic layer. The obtained organic layer was dried over sodium sulfate (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2, Obtained 115.09 g of 3,4,5-tetrahydro-1H-1-benzazepine (yield: 89.70%).
（２）７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンの合成 (2) Synthesis of 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine
３Ｌ 反応器に工程（１）で製造した１−（４−アミノ−２−メチルベンゾイル）−７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（７０．０ ｇ、２１２．９０ ｍｍｏｌ）およびジクロロメタン（５６０ ｍｌ）と蒸留水（１４０ ｍｌ）とを入れ、１時間撹拌した。反応混合物を１０℃以下で水酸化マグネシウム（１４．９０ ｇ、１４．９０ ｍｍｏｌ）を加え、３０分間撹拌した。反応混合物に２−メチルベンゾイルクロライド（３０．４２ ｍｌ）を徐々に加えた後、３時間撹拌した。反応混合物を濾過して水酸化マグネシウムを除去し、水酸化ナトリウム水溶液を使用して反応混合物のｐＨをｐＨ ８〜９に調節した後、有機層を分離した。得られた有機層を硫酸ナトリウム（Ｎａ２ＳＯ４）で乾燥した後、濾過し、減圧濃縮して、７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン ９１．３５ ｇを得た（収率：９６％）。 1- (4-Amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (70. 0 g, 212.90 mmol), dichloromethane (560 ml) and distilled water (140 ml) were added, and the mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was added to the reaction mixture at 10 ° C. or lower, and the mixture was stirred for 30 minutes. 2-Methylbenzoyl chloride (30.42 ml) was gradually added to the reaction mixture, and the mixture was stirred for 3 hours. The reaction mixture was filtered to remove magnesium hydroxide, the pH of the reaction mixture was adjusted to pH 8-9 using aqueous sodium hydroxide solution, and then the organic layer was separated. The obtained organic layer is dried over sodium sulfate (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl. ] -5-oxo-2,3,4,5-Tetrahydro-1H-1-benzazepine 91.35 g was obtained (yield: 96%).
実施例３：７−クロロ−５−ヒドロキシ−１−［２−メチル−４−（２−メチルベンゾイルアミノ）ベンゾイル］−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（トルバプタン）の製造 Example 3: 7-Chloro-5-Hydroxy-1- [2-Methyl-4- (2-methylbenzoylamino) Benzoyl] -2,3,4,5-Tetrahydro-1H-1-benzazepine (tolvaptan) Manufacturing
１Ｌ 反応器に７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（８０．０ ｇ、１７９．００ ｍｍｏｌ）およびメタノール（６７５ ｍｌ）を入れ、３０分間撹拌した。反応混合物に水素化ホウ素ナトリウム（２．３７ ｇ、６２．６５ ｍｍｏｌ）を入れ、１時間撹拌した。その後、反応混合物に０．５％ 希鹽酸（２３２ ｍｌ）を徐々に加え、常温で徐々に冷却した。結晶が析出されると、反応混合物を濾過した後、得られた濾過物を減圧乾燥して、７−クロロ−５−ヒドロキシ−１−［２−メチル−４−（２−メチルベンゾイルアミノ）ベンゾイル］−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピン（７３．９ ｇ、９２％）を得た。 7-Chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (80) in a 1L reactor .0 g, 179.00 mmol) and methanol (675 ml) were added and stirred for 30 minutes. Sodium borohydride (2.37 g, 62.65 mmol) was added to the reaction mixture and the mixture was stirred for 1 hour. Then, 0.5% dilute hydrochloric acid (232 ml) was gradually added to the reaction mixture, and the mixture was gradually cooled at room temperature. When the crystals were precipitated, the reaction mixture was filtered, and the obtained filtrate was dried under reduced pressure to 7-chloro-5-hydroxy-1- [2-methyl-4- (2-methylbenzoylamino) benzoyl. ] -2,3,4,5-Tetrahydro-1H-1-benzazepine (73.9 g, 92%) was obtained.
Claims (15)
（ｂ）前記７−クロロ−１−［２−メチル−４−［（２−メチルベンゾイル）アミノ］ベンゾイル］−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを水素化剤の存在下で還元させてトルバプタンを製造する工程
を含む、トルバプタンの製造方法。 (A) 2- (4-Amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine in the presence of magnesium hydroxide Reacting with methylbenzoyl chloride to 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-1- The step of producing benzazepine; and (b) the 7-chloro-1- [2-methyl-4-[(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro- A method for producing tolvaptan, which comprises a step of reducing 1H-1-benzazepine in the presence of a hydrogenating agent to produce tolbaptan.
前記７−クロロ−１−（２−メチル−４−ニトロベンゾイル）−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンが、水酸化マグネシウムの存在下で、７−クロロ−５−オキソ−２,３,４,５−テトラヒドロ−１Ｈ−１−ベンザゼピンを２−メチル−４−ニトロベンゾイルクロライドと反応させて製造されることを特徴とする請求項８〜１１のいずれかに記載の製造方法。 The 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is replaced with 7-chloro-1- (2-methyl-). 4-Nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is reacted with tin chloride to produce
The 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is 7-chloro in the presence of magnesium hydroxide. Any of claims 8 to 11, characterized in that it is produced by reacting -5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitrobenzoyl chloride. The manufacturing method described in.
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