JPS6216940B2 - - Google Patents
Info
- Publication number
- JPS6216940B2 JPS6216940B2 JP52123594A JP12359477A JPS6216940B2 JP S6216940 B2 JPS6216940 B2 JP S6216940B2 JP 52123594 A JP52123594 A JP 52123594A JP 12359477 A JP12359477 A JP 12359477A JP S6216940 B2 JPS6216940 B2 JP S6216940B2
- Authority
- JP
- Japan
- Prior art keywords
- reference example
- formula
- amidine
- yield
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- -1 methoxyphenyl Chemical group 0.000 claims description 27
- 150000002576 ketones Chemical class 0.000 claims description 12
- 239000012024 dehydrating agents Substances 0.000 claims description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 150000001409 amidines Chemical class 0.000 description 49
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 39
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 30
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 150000002081 enamines Chemical class 0.000 description 27
- 238000000034 method Methods 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 10
- 238000009835 boiling Methods 0.000 description 9
- 238000004364 calculation method Methods 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002808 molecular sieve Substances 0.000 description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 229960003424 phenylacetic acid Drugs 0.000 description 2
- 239000003279 phenylacetic acid Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- KYGSYTRHCDNSGS-UHFFFAOYSA-N 1-phenylpent-4-en-1-one Chemical compound C=CCCC(=O)C1=CC=CC=C1 KYGSYTRHCDNSGS-UHFFFAOYSA-N 0.000 description 1
- UZGKAASZIMOAMU-UHFFFAOYSA-N 124177-85-1 Chemical compound NP(=O)=O UZGKAASZIMOAMU-UHFFFAOYSA-N 0.000 description 1
- SJZYLHAGVNSSLO-UHFFFAOYSA-N 2-dibenzofuran-2-ylpropanoic acid Chemical compound C1=CC=C2C3=CC(C(C(O)=O)C)=CC=C3OC2=C1 SJZYLHAGVNSSLO-UHFFFAOYSA-N 0.000 description 1
- YRNDGUSDBCARGC-UHFFFAOYSA-N 2-methoxyacetophenone Chemical compound COCC(=O)C1=CC=CC=C1 YRNDGUSDBCARGC-UHFFFAOYSA-N 0.000 description 1
- YYEROYLAYAVZNW-UHFFFAOYSA-N 2-methyl-2-phenylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=CC=C1 YYEROYLAYAVZNW-UHFFFAOYSA-N 0.000 description 1
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical compound CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 1
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- VXDSLUMUNWTSDB-UHFFFAOYSA-N acetic acid;chloroform;methanol Chemical compound OC.CC(O)=O.ClC(Cl)Cl VXDSLUMUNWTSDB-UHFFFAOYSA-N 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- DRVIYZBYLAGXMP-UHFFFAOYSA-N hexane;pentan-2-one Chemical compound CCCCCC.CCCC(C)=O DRVIYZBYLAGXMP-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- WXDDGOHMUKLOKV-UHFFFAOYSA-N phenyl-[3-(1-pyrrolidin-1-ylprop-1-enyl)phenyl]methanone Chemical compound C=1C=CC(C(=O)C=2C=CC=CC=2)=CC=1C(=CC)N1CCCC1 WXDDGOHMUKLOKV-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Description
本発明は式
（式中R1はフエニル、メトキシフエニル、イソブ
チルフエニル、置換シクロヘキシルフエニル、シ
クロヘキセニルフエニル、ハロゲンビフエニル、
ベンゾイルフエニル、メトキシナフチル、ジベン
ゾフラニル、メトキシフエノチアジニル又はハロ
ゲンカルボリニル基を意味し、R4は水素、メチ
ル、エチル、イソプロピル又はアリル基を意味
し、R5は水素又はメチル基を意味する）
にて示されるカルボン酸誘導体の製法に係る。
本発明により製造される上記カルボン酸誘導体
を含めて、芳香族置換カルボン酸類が消炎鎮痛作
用、解熱作用乃至血液凝固（血栓）阻止作用を有
しており医薬として有用であることは特公昭40−
7491、同43−22297、同47−18105公報等に開示さ
れているように既に周知である。
然るに、医薬として有効であるにも拘らず斯か
る芳香族置換カルボン酸類は、従来一般には５乃
至７工程を経て製造されており工業的に不利であ
つた。
斯くて、本発明の主たる目的は、工程数を減じ
た工業的に有利なカルボン酸誘導体の新規製法を
提供することである。
本発明によれば、上記の式にて示されるカルボ
ン酸誘導体は、式
R1−CO−R2
（式中R1はフエニル、メトキシフエニル、イソブ
チルフエニル、置換シクロヘキシルフエニル、シ
クロヘキセニルフエニル、ハロゲンビフエニル、
ベンゾイルフエニル、メトキシナフチル、ジベン
ゾフラニル、メトキシフエノチアジニル又はハロ
ゲンカルボリニル基を意味し、R2はメチル、エ
チル、プロピル、イソプロピル又はビニルエチル
基を意味する）
にて示されるケトンと、式
R3−Ｈ
（式中R3はジメチルアミノ、ピロリジル、ピペリ
ジル又はモルホリル基を意味する）
にて示される第２級アミン化合物とを不活性溶媒
中脱水剤の存在において反応せしめ、生成する式
（式中R1及びR3は前記の意味を有し、R4は水素、
メチル、エチル、イソプロピル又はアリル基を意
味し、R5は水素又はメチル基を意味する）
にて示されるエナミンを式
N3−Ａ
（式中Ａはジメチルリン酸、ジエチルリン酸、ジ
フエニルリン酸、シアノ又はトシル基を意味す
る）
にて示されるアジド化合物と反応せしめ、次いで
生成する式
（式中R1、R3、R4、R5及びＡは前記の意味を有す
る）
にて示されるアミジンを加水分解することにより
製造される。
本発明方法の実施に際して使用される溶媒とし
ては、エナミン合成に際してはベンゼン又はトル
エンを、又アミジン合成に際しては酢酸エチル又
はテトラヒドロフランを、又アミジンの加水分解
に際してエチレングリコールを用いるのが好まし
い。
尚、本発明方法を実施する場合の中間生成物で
あるエナミン及びアミジンは共に好収率を以て得
られるが、アミジンへの変換即ちアジド化合物こ
とにジフエニル燐酸アジドによる１・３−双極性
付加−脱窒素転位反応に際しては不活性ガス、例
えばアルゴン気流下でこれを行なうことにより収
率が更に向上し、又エナミンの単離を行なわずに
連続的に処理を行なつた方が収率に於て若干有利
である。
次に、参考例及び実施例に関連して本発明方法
を更に詳細に説明する。
参考例 １
（エナミンの合成）
プロピオフエノン9.38ｇと、ピロリジン14.93
ｇと、三弗化硼素エーテラート0.99ｇとをベンゼ
ン50ml中に溶解し、脱水剤としてモレキユラーシ
ーブ4Aを用いコープの装置にて67時間に亘り還
流処理する。減圧下に溶媒を留去後、残渣を減圧
蒸留すれば79％の収率にてエナミン10.33ｇが得
られる。沸点101℃／３mmHg。
参考例 ２
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例１記載の方法により得たるエナミン1.01
ｇを酢酸エチル15ml中に溶解し、これにジフエニ
ル燐酸アジド（DPPA）1.65ｇを滴下する。混合
物を室温に於て１時間撹拌し、40℃に加熱して１
時間反応せしめた後に、２時間還流処理した。反
応溶液に酢酸エチル−ベンゼン（１：１混合物）
100mlを添加し、各30mlの５％クエン酸、水、飽
和食塩水、飽和重炭酸ナトリウム水溶液、水、飽
和食塩水にて順次洗浄し、無水硫酸マグネシウム
にて乾燥し、次いで減圧下に溶媒を留去する。残
渣をベンゼン−酢酸エチル（５：１混合物）の系
でシリカゲルカラムクロマトグラフイーすれば、
燐酸アミジン1.91ｇ（収率81％）が得られる。酢
酸エチル−ヘキサンから再結晶すれば融点74〜76
℃の無色針状晶となる。
元素分析（C25H27N2O3P）
計算 C69.11 H6.26 N6.45
実測 C68.72 H6.53 N6.47
参考例 ３
参考例２と同様にして、但し反応溶媒として酢
酸エチルの代りにテトラヒドロフランを用いた
処、所望生成物の収率は80％であつた。
参考例 ４
（アミジンの合成）
（式中Phはフエニル基を意味する）
プロピオフエノン670mgと、ピロリジン1.07ｇ
と、三弗化硼素エーテラート0.07ｇとをトルエン
30ml中に溶解し、モレキユラーシーブ4Aを脱水
剤としてコープの装置にて40時間に亘り還流処理
する。減圧下に溶媒を留去し、DPPA1.65ｇとテ
トラヒドロフラン15mlとを添加しアルゴン気流下
室温に於て24時間撹拌する。然る後に、参考例２
に於けると同様の後処理を行なえば、燐酸アミジ
ン1.83ｇが得られる（ケトンよりの収率84％）。
参考例 ５
（エナミンの合成）
プロピオフエノン5.36ｇと、モルホリン10.45
ｇと、三弗化硼素エーテラート0.28ｇとをトルエ
ン30ml中に溶解し、参考例１と同様にして67時間
に亘り還流処理した後に、減圧下に溶媒を留去
し、残渣を減圧蒸留すれば、エナミン4.46ｇ（収
率50.9％）が得られる。沸点103℃／３mmHg。
参考例 ６
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例５記載の方法により得たるエナミン1.10
ｇとDPPA1.65ｇとを酢酸エチル15ml中に溶解
し、室温に於て１時間並びに55℃に於て15分間撹
拌した後に３時間に亘り還流処理する。参考例２
に於けると同様の後処理を行なえば、燐酸アミジ
ン1.54ｇ（収率63％）が得られる。酢酸エチル−
ヘキサンから再結晶すれば、融点71〜73.5℃の無
色プリズム晶となる。
元素分析（C25H27N2O4P）
計算 C66.65 H6.04 N6.22
実測 C66.79 H6.12 N6.30
参考例 ７
プロピオフエノン2.68ｇと、ピペリジン5.30ｇ
と、三弗化硼素エーテラート0.14ｇとをトルエン
30ml中に溶解し、次いで参考例１と同様にして処
理すればエナミン2.50ｇ（収率50％）が得られ
る。沸点99.5〜100℃／３mmHg。
参考例 ８
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例７記載の方法により得たるエナミン1.09
ｇと、DPPA1.65ｇとを酢酸エチル15ml中に溶解
し、室温に於て１時間15分、50℃に於て30分間、
80℃に於て30分間撹拌した後に３時間に亘り還流
処理する。次いで参考例２と同様にして後処理す
れば、燐酸アミジン1.61ｇ（収率67％）が得られ
る。これを酢酸エチル−ヘキサンより再結晶すれ
ば、融点67〜69℃の無色柱状晶となる。
元素分析（C26H29N2O3P）
計算 C69.63 H6.52 N6.25
実測 C69.66 H6.60 N6.61
実施例 １
参考例４記載の方法により得たるアミジン１・
303ｇ及び水酸化カリウム2.94ｇをエチレングリ
コール40ml中に溶解し、12時間に亘り還流処理す
る。反応混合物を水300mlにて稀釈し、炭酸ガス
を通じてPH約９となし、次いでエチルエーテルに
て洗浄する。水層を塩酸にて酸性となした後に酢
酸エチルにて抽出し、有機層を水及び飽和食塩水
にて洗浄し、硫酸マグネシウムにて乾燥後、減圧
下に溶媒を留去すれば、ヒドラトロパ酸408mg
（収率91％）が得られる。
沸点103〜105℃／３mmHg。
参考例 ９
（ケトンの合成）
４−イソブチルプロピオフエノンの製造
メチレンクロリド36mlに塩化アルミニウム
10.56ｇを添加し、氷冷撹拌しつつプロピオニル
クロリド7.77ｇを20分間中に滴下する。得たる混
合物に、イソブチルベンゼン8.04ｇを１時間中に
滴下し、室温に於て２時間撹拌した後に一夜放置
する。氷120ｇと濃塩酸17mlとの混合物中に反応
溶液を注加し、メチレンクロリド層を分取し、水
層をクロロホルムにて抽出し、両抽出層を合併
し、水、２％水酸化ナトリウム水溶液及び水にて
順次洗浄し、硫酸ナトリウムにて乾燥し、減圧下
に溶媒を留去する。残渣を減圧蒸溜すれば、目的
ケトン9.86ｇ（収率87％）が得られる。沸点86〜
87℃／0.3mmHg。
この化合物の２・４−ジニトロフエニルヒドラ
ゾンの融点は170〜171.5℃である。
元素分析（C19H22N4O4）
計算 C61.61 H5.99 N15.13
実測 C61.72 H6.03 N14.85
参考例 10
（エナミンの合成）
参考例９記載の方法により得たる４−イソブチ
ルプロピオフエノン3.80ｇと、ピロリジン4.27ｇ
と、三弗化硼素エーテラート0.28ｇとを乾燥ベン
ゼン40ml中に溶解し、モレキユラーシーブ−4A
を脱水剤として用いてコープの装置にて50時間に
亘り還流処理する。減圧下に溶媒を留去した後
に、残渣を減圧蒸留すればエナミン3.84ｇ（収率
79％）が得られる。沸点112〜114℃／0.4mmHg。
参考例 11
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例10記載の方法により得たるエナミン1.22
ｇとDPPA1.65ｇとをテトラヒドロフラン15ml中
に溶解し、室温に於て１時間及び40℃に於て１時
間撹拌した後に２時間に亘つて還流処理する。然
る後に、参考例２と同様の後処理を行なえば、粘
稠オイルとして燐酸アミジン1.87ｇ（収率76％）
が得られる。
元素分析（C29H35N2O3P）
計算 C71.00 H7.19 N5.71
実測 C71.01 H7.20 N5.76
参考例 12
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例９記載の方法により得たる４−イソブチ
ルプロピオフエノン0.95ｇと、ピロリジン1.07ｇ
と三弗化硼素エーテラートとをベンゼン60ml中に
溶解し、次いで参考例10に記載のようにして反応
せしめる。反応混合物より溶媒を減圧下に留去
し、残渣にテトラヒドロフラン15mlを添加し、
DPPA1.65ｇを撹拌添加し、室温に於て１時間且
つ40℃に於て１時間撹拌し、得たる混合物を更に
２時間還流処理する。然る後、参考例２に於ける
と同様にして後処理を行なえば、所望のアミジン
1.83ｇ（収率75％）が得られる。
参考例 13
（アミジンの合成）
参考例12記載の方法に於て、反応をアルゴン気
流下で行なえば、アミジン1.91ｇ（収率78％）が
得られる。
実施例 ２
（式中Phはフエニル基を意味する）
参考例12又は13記載の方法により得たるアミジ
ン1.473ｇと水酸化カリウム2.95ｇとをエチレン
グリコール35ml中に溶解し12時間に亘り還流処理
する。然る後に実施例１に於けると同様な後処理
を行なえば所望のイブプロフエン489mg（収率79
％）が得られる。これを石油ベンジンより再結晶
すれば、融点74〜75℃の無色針状晶となる（文献
値によれば−小暮等Agr.Biol.Chem第39巻、第
1427頁、1975年−この化合物の融点は75〜76.5℃
である）。
参考例 14
（エナミンの合成）
原料ケトン6.43ｇと、ピロリジン6.40ｇと、三
弗化硼素エーテラート0.43ｇとをベンゼン50ml中
に溶解し、脱水剤としてモレキユラーシーブ4A
を用いコープの装置にて68時間に亘り還流処理す
る。減圧下に溶媒を留去した後残渣を減圧蒸溜す
れば所望エナミン5.25ｇ（収率65％）が得られ
る。沸点148〜152℃／0.2mmHg。
参考例 15
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例14記載の方法により得たるエナミン1.07
ｇとDPPA1.32ｇとをテトラヒドロフラン12ml中
に溶解し、アルゴン気流下に室温に於て１時間、
40℃に於て２時間且つ50℃に於て１時間に亘り撹
拌処理する。然る後に反応混合物を参考例２に於
けると同様に後処理を行なえば所望のアミジン
1.33ｇ（収率65％）が得られる。これを酢酸エチ
ル−ヘキサンより再結晶すれば、融点102.5〜105
℃の無色針状晶となる。
元素分析（C30H31N2O3P）
計算 C70.02 H6.07 N5.45
実測 C70.18 H6.28 N5.52
参考例 16
（アミジンの合成）
（式中Phはフエニル基を意味する）
原料ケトン1.07ｇと、ピロリジン1.07ｇと三弗
化硼素エーテラート0.07ｇとを参考例14に於ける
と同様に処理して反応せしめた後に、減圧下に反
応混合物より溶媒を留去し、アルゴン気流下に残
渣にテトラヒドロフラン15mlとDPPA1.65ｇとを
添加し、室温に於て11時間且つ40℃に於て１時間
撹拌し次いで２時間に亘り還流処理する。然る
後、参考例２に於けると同様に後処理を行なえ
ば、所望のアミジン2.10ｇ（原料ケトンよりの収
率82％）が得られる。
実施例 ３
（式中Phはフエニル基を意味する）
参考例15又は16記載の方法により得たるアミジ
ン515mgと水酸化カリウム0.35ｇとをエチレング
リコール10ml中に溶解し８時間に亘り還流処理す
る。反応混合物を実施例１に於けると同様に処理
すれば83％収率にて粗生成物が得られ、これを更
にクロロホルム−メタノール−酢酸（200：10：
１）の系でシリカゲルカラムクロマトグラフイー
すれば無色針状晶として所望のナプロキセンが
157mg（収率71％）得られる。融点151.5〜152.5
℃。
参考例 17
（アミジンの合成）
（式中Phはフエニル基を意味する）
原料ケトン601mgと、ピロリジン640mgと、三弗
化硼素エーテラート40mgとをトルエン30ml中に溶
解し、脱水剤としてモレキユラーシーブ4Aを用
い、アルゴン気流下にコープの装置にて42時間に
亘り還流処理する。減圧下に溶媒を留去し、テト
ラヒドロフラン９ml及びDPPA990mgを添加し、
アルゴン気流下に室温に於て１時間且つ40℃に於
て１時間撹拌し次いで２時間に亘り還流処理す
る。反応混合物を次いで参考例２に於けると同様
にして後処理すれば、無色粘稠油状物としての所
望のアミジン1.11ｇ（原料ケトンよりの収率71
％）が得られる。
実施例 ４
（式中Phはフエニル基を意味する）
参考例17記載の方法により得たるアミジン825
mgと水酸化カリウム1.57ｇとをエチレングリコー
ル30ml中に溶解し７時間に亘り還流処理する。然
る後、反応混合物を実施例１に於けると同様にし
て後処理すれば、所望の２−（２−ジベンゾフリ
ル）−プロピオン酸345mg（収率92％）が得られ
る。これを酢酸エチル−ヘキサンより再結晶すれ
ば、融点141〜142.5℃の無色針状晶となる。
参考例 18
（アミジンの合成）
（式中Phはフエニル基を意味する）
原料エナミン（１−〔１−（３−ベンゾイルフエ
ニル）１−プロペニル〕ピロリジン）0.71ｇと、
DPPA0.81ｇとをテトラヒドロフラン7.5ml中に溶
解し、アルゴン気流下に室温に於て１時間及び40
℃に於て１時間撹拌し次いで２時間に亘り還流処
理する。反応混合物をヘキサン−酢酸エチル
（１：３混合物）の系でシリカゲルカラムクロマ
トグラフイーする以外は参考例２に於けると同様
に後処理すれば所望の燐酸アミジン0.93ｇ（収率
72％）が得られる。
IRスペクトル：νＫＢｒ ｎａｘcm-11656（Ｃ＝Ｏ）1559
、
1484、1241、1196、918
NMRスペクトル：δppm、（CDCl3）
The present invention is based on the formula (In the formula, R 1 is phenyl, methoxyphenyl, isobutylphenyl, substituted cyclohexylphenyl, cyclohexenyl phenyl, halogen biphenyl,
means benzoylphenyl, methoxynaphthyl, dibenzofuranyl, methoxyphenothiazinyl or halogencarbolinyl group, R4 means hydrogen, methyl, ethyl, isopropyl or allyl group, R5 means hydrogen or methyl group This refers to the method for producing carboxylic acid derivatives shown in Japanese Patent Publication No. 1973-1999 (1973) revealed that aromatic substituted carboxylic acids, including the above-mentioned carboxylic acid derivatives produced by the present invention, have anti-inflammatory and analgesic effects, antipyretic effects, and blood coagulation (thrombus) inhibiting effects, and are useful as medicines.
It is already well known as disclosed in Publications No. 7491, No. 43-22297, No. 47-18105, etc. However, although these aromatic substituted carboxylic acids are effective as medicines, they have conventionally been produced through five to seven steps, which is disadvantageous from an industrial standpoint. Therefore, the main object of the present invention is to provide a new industrially advantageous method for producing carboxylic acid derivatives with a reduced number of steps. According to the present invention, the carboxylic acid derivative represented by the above formula has the formula R 1 -CO-R 2 (wherein R 1 is phenyl, methoxyphenyl, isobutylphenyl, substituted cyclohexylphenyl, cyclohexenylphenyl). enyl, halogen biphenyl,
a ketone represented by the formula A formula produced by reacting a secondary amine compound represented by R 3 -H (in the formula R 3 means dimethylamino, pyrrolidyl, piperidyl or morpholyl group) in the presence of a dehydrating agent in an inert solvent. (In the formula, R 1 and R 3 have the above meanings, R 4 is hydrogen,
methyl, ethyl, isopropyl or allyl group, and R 5 means hydrogen or methyl group). (meaning a cyano or tosyl group) is reacted with an azide compound represented by (In the formula, R 1 , R 3 , R 4 , R 5 and A have the above-mentioned meanings.) It is produced by hydrolyzing an amidine represented by the following formula. As the solvent used in carrying out the method of the present invention, it is preferable to use benzene or toluene for enamine synthesis, ethyl acetate or tetrahydrofuran for amidine synthesis, and ethylene glycol for amidine hydrolysis. Incidentally, enamine and amidine, which are intermediate products when carrying out the method of the present invention, are both obtained in good yields, but conversion to amidine, that is, 1,3-dipolar addition-elimination with diphenylphosphoric acid azide, is necessary. During the nitrogen rearrangement reaction, the yield can be further improved by carrying out the reaction under an inert gas flow, such as argon, and the yield can be further improved by performing the treatment continuously without isolating the enamine. It is slightly advantageous. Next, the method of the present invention will be explained in more detail with reference to Reference Examples and Examples. Reference example 1 (synthesis of enamine) Propiophenone 9.38g and pyrrolidine 14.93g
g and 0.99 g of boron trifluoride etherate were dissolved in 50 ml of benzene and refluxed for 67 hours in a Cope apparatus using molecular sieve 4A as a dehydrating agent. After distilling off the solvent under reduced pressure, the residue is distilled under reduced pressure to obtain 10.33 g of enamine with a yield of 79%. Boiling point 101℃/3mmHg. Reference example 2 (synthesis of amidine) (In the formula, Ph means a phenyl group) Enamine 1.01 obtained by the method described in Reference Example 1
g is dissolved in 15 ml of ethyl acetate, and 1.65 g of diphenylphosphoric azide (DPPA) is added dropwise thereto. The mixture was stirred at room temperature for 1 hour and then heated to 40°C for 1 hour.
After reacting for an hour, the mixture was refluxed for 2 hours. Add ethyl acetate-benzene (1:1 mixture) to the reaction solution.
The solution was washed with 30 ml each of 5% citric acid, water, saturated saline, saturated sodium bicarbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, and then removed the solvent under reduced pressure. To leave. If the residue is subjected to silica gel column chromatography using a benzene-ethyl acetate (5:1 mixture) system,
1.91 g (yield 81%) of amidine phosphate is obtained. Melting point 74-76 if recrystallized from ethyl acetate-hexane
It forms colorless needle crystals at ℃. Elemental analysis (C 25 H 27 N 2 O 3 P) Calculation C69.11 H6.26 N6.45 Actual measurement C68.72 H6.53 N6.47 Reference example 3 Same as Reference example 2, but using ethyl acetate as the reaction solvent. Using tetrahydrofuran instead, the yield of the desired product was 80%. Reference example 4 (synthesis of amidine) (In the formula, Ph means phenyl group) 670 mg of propiophenone and 1.07 g of pyrrolidine
and 0.07 g of boron trifluoride etherate in toluene.
Dissolve in 30 ml of water and reflux for 40 hours using Molecular Sieve 4A as a dehydrating agent in a Cope apparatus. The solvent was distilled off under reduced pressure, 1.65 g of DPPA and 15 ml of tetrahydrofuran were added, and the mixture was stirred at room temperature under an argon atmosphere for 24 hours. After that, reference example 2
By carrying out the same post-treatment as in , 1.83 g of amidine phosphoric acid is obtained (yield 84% from ketone). Reference example 5 (synthesis of enamine) 5.36g of propiophenone and 10.45g of morpholine
g and 0.28 g of boron trifluoride etherate are dissolved in 30 ml of toluene and treated under reflux for 67 hours in the same manner as in Reference Example 1. The solvent is distilled off under reduced pressure and the residue is distilled under reduced pressure. , 4.46 g of enamine (yield 50.9%) is obtained. Boiling point 103℃/3mmHg. Reference example 6 (synthesis of amidine) (In the formula, Ph means a phenyl group) Enamine 1.10 obtained by the method described in Reference Example 5
g and 1.65 g of DPPA were dissolved in 15 ml of ethyl acetate, stirred at room temperature for 1 hour and at 55° C. for 15 minutes, and then refluxed for 3 hours. Reference example 2
By carrying out the same post-treatment as in , 1.54 g (yield 63%) of amidine phosphoric acid is obtained. Ethyl acetate
If recrystallized from hexane, it becomes colorless prismatic crystals with a melting point of 71-73.5°C. Elemental analysis (C 25 H 27 N 2 O 4 P) Calculation C66.65 H6.04 N6.22 Actual measurement C66.79 H6.12 N6.30 Reference example 7 2.68g of propiophenone and 5.30g of piperidine
and 0.14 g of boron trifluoride etherate in toluene.
30 ml and then treated in the same manner as in Reference Example 1 to obtain 2.50 g of enamine (yield: 50%). Boiling point 99.5-100℃/3mmHg. Reference example 8 (synthesis of amidine) (In the formula, Ph means a phenyl group) Enamine 1.09 obtained by the method described in Reference Example 7
g and 1.65 g of DPPA were dissolved in 15 ml of ethyl acetate, and heated at room temperature for 1 hour and 15 minutes and at 50°C for 30 minutes.
After stirring at 80°C for 30 minutes, the mixture was refluxed for 3 hours. Then, by post-treatment in the same manner as in Reference Example 2, 1.61 g (yield: 67%) of phosphoric acid amidine is obtained. If this is recrystallized from ethyl acetate-hexane, it becomes colorless columnar crystals with a melting point of 67-69°C. Elemental analysis (C 26 H 29 N 2 O 3 P) Calculation C69.63 H6.52 N6.25 Actual measurement C69.66 H6.60 N6.61 Example 1 Amidine 1 obtained by the method described in Reference Example 4
303 g and 2.94 g of potassium hydroxide are dissolved in 40 ml of ethylene glycol and refluxed for 12 hours. The reaction mixture was diluted with 300 ml of water, brought to a pH of about 9 by passing carbon dioxide gas, and then washed with ethyl ether. The aqueous layer is acidified with hydrochloric acid, extracted with ethyl acetate, the organic layer is washed with water and saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. 408mg
(Yield 91%) is obtained. Boiling point 103-105℃/3mmHg. Reference Example 9 (Synthesis of ketone) Production of 4-isobutylpropiophenone Aluminum chloride in methylene chloride 36ml
10.56 g was added, and 7.77 g of propionyl chloride was added dropwise over 20 minutes while stirring on ice. 8.04 g of isobutylbenzene was added dropwise to the resulting mixture within 1 hour, and after stirring at room temperature for 2 hours, it was left overnight. The reaction solution was poured into a mixture of 120 g of ice and 17 ml of concentrated hydrochloric acid, the methylene chloride layer was separated, the aqueous layer was extracted with chloroform, the two extracted layers were combined, and water and a 2% aqueous sodium hydroxide solution were added. and water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Distilling the residue under reduced pressure yields 9.86 g (yield: 87%) of the desired ketone. Boiling point 86~
87℃/0.3mmHg. The melting point of this compound, 2,4-dinitrophenylhydrazone, is 170-171.5°C. Elemental analysis (C 19 H 22 N 4 O 4 ) Calculation C61.61 H5.99 N15.13 Actual measurement C61.72 H6.03 N14.85 Reference example 10 (Synthesis of enamine) 3.80 g of 4-isobutylpropiophenone obtained by the method described in Reference Example 9 and 4.27 g of pyrrolidine
and 0.28 g of boron trifluoride etherate were dissolved in 40 ml of dry benzene and mixed with molecular sieve-4A.
was used as a dehydrating agent and refluxed for 50 hours in a Cope apparatus. After distilling off the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain 3.84 g of enamine (yield:
79%). Boiling point 112-114℃/0.4mmHg. Reference example 11 (synthesis of amidine) (In the formula, Ph means a phenyl group) Enamine 1.22 obtained by the method described in Reference Example 10
g and 1.65 g of DPPA were dissolved in 15 ml of tetrahydrofuran, stirred for 1 hour at room temperature and 1 hour at 40°C, and then refluxed for 2 hours. After that, if the same post-treatment as in Reference Example 2 is performed, 1.87 g of amidine phosphate (yield 76%) is obtained as a viscous oil.
is obtained. Elemental analysis (C 29 H 35 N 2 O 3 P) Calculation C71.00 H7.19 N5.71 Actual measurement C71.01 H7.20 N5.76 Reference example 12 (Synthesis of amidine) (In the formula, Ph means a phenyl group) 0.95 g of 4-isobutylpropiophenone obtained by the method described in Reference Example 9 and 1.07 g of pyrrolidine
and boron trifluoride etherate are dissolved in 60 ml of benzene and then reacted as described in Reference Example 10. The solvent was distilled off from the reaction mixture under reduced pressure, and 15 ml of tetrahydrofuran was added to the residue.
1.65 g of DPPA is added with stirring, stirred for 1 hour at room temperature and 1 hour at 40°C, and the resulting mixture is refluxed for a further 2 hours. After that, if the post-treatment is carried out in the same manner as in Reference Example 2, the desired amidine can be obtained.
1.83 g (75% yield) is obtained. Reference Example 13 (Synthesis of Amidine) In the method described in Reference Example 12, if the reaction is carried out under an argon stream, 1.91 g of amidine (yield 78%) is obtained. Example 2 (In the formula, Ph means a phenyl group) 1.473 g of amidine obtained by the method described in Reference Example 12 or 13 and 2.95 g of potassium hydroxide are dissolved in 35 ml of ethylene glycol and treated under reflux for 12 hours. After that, if the same post-treatment as in Example 1 is carried out, the desired ibuprofen 489 mg (yield 79
%) is obtained. If this is recrystallized from petroleum benzene, it becomes colorless needle crystals with a melting point of 74-75°C (according to literature values - Kogure et al. Agr. Biol. Chem Vol. 39,
Page 1427, 1975 - The melting point of this compound is 75-76.5°C
). Reference example 14 (synthesis of enamine) 6.43g of raw material ketone, 6.40g of pyrrolidine, and 0.43g of boron trifluoride etherate were dissolved in 50ml of benzene, and Molecular Sieve 4A was added as a dehydrating agent.
The mixture was refluxed for 68 hours using a Cope apparatus. After the solvent is distilled off under reduced pressure, the residue is distilled under reduced pressure to obtain 5.25 g (yield: 65%) of the desired enamine. Boiling point 148-152℃/0.2mmHg. Reference example 15 (synthesis of amidine) (In the formula, Ph means a phenyl group) Enamine 1.07 obtained by the method described in Reference Example 14
g and 1.32 g of DPPA were dissolved in 12 ml of tetrahydrofuran and heated at room temperature for 1 hour under an argon stream.
Stirring was carried out at 40°C for 2 hours and at 50°C for 1 hour. Afterwards, the reaction mixture is post-treated in the same manner as in Reference Example 2 to obtain the desired amidine.
1.33 g (yield 65%) is obtained. If this is recrystallized from ethyl acetate-hexane, the melting point is 102.5-105.
It forms colorless needle crystals at ℃. Elemental analysis (C 30 H 31 N 2 O 3 P) Calculation C70.02 H6.07 N5.45 Actual measurement C70.18 H6.28 N5.52 Reference example 16 (Synthesis of amidine) (In the formula, Ph means a phenyl group) 1.07 g of raw material ketone, 1.07 g of pyrrolidine, and 0.07 g of boron trifluoride etherate were treated and reacted in the same manner as in Reference Example 14, and then reacted under reduced pressure. The solvent was distilled off from the reaction mixture, and 15 ml of tetrahydrofuran and 1.65 g of DPPA were added to the residue under an argon atmosphere, stirred at room temperature for 11 hours and at 40°C for 1 hour, and then refluxed for 2 hours. . Thereafter, by carrying out post-treatment in the same manner as in Reference Example 2, 2.10 g of the desired amidine (82% yield from the starting ketone) was obtained. Example 3 (In the formula, Ph means a phenyl group.) 515 mg of amidine obtained by the method described in Reference Example 15 or 16 and 0.35 g of potassium hydroxide are dissolved in 10 ml of ethylene glycol and refluxed for 8 hours. The reaction mixture was treated in the same manner as in Example 1 to obtain a crude product with a yield of 83%, which was further diluted with chloroform-methanol-acetic acid (200:10:
If silica gel column chromatography is performed using the system 1), the desired naproxen will be obtained as colorless needle crystals.
157 mg (yield 71%) is obtained. Melting point 151.5-152.5
℃. Reference example 17 (synthesis of amidine) (In the formula, Ph means a phenyl group) 601 mg of raw material ketone, 640 mg of pyrrolidine, and 40 mg of boron trifluoride etherate were dissolved in 30 ml of toluene, and using molecular sieve 4A as a dehydrating agent, under an argon stream. Reflux treatment for 42 hours in a Cope apparatus. The solvent was distilled off under reduced pressure, and 9 ml of tetrahydrofuran and 990 mg of DPPA were added.
The mixture was stirred for 1 hour at room temperature and 1 hour at 40° C. under an argon atmosphere, and then refluxed for 2 hours. The reaction mixture was then worked up as in Reference Example 2 to obtain 1.11 g of the desired amidine as a colorless viscous oil (yield 71 g from the starting ketone).
%) is obtained. Example 4 (In the formula, Ph means a phenyl group) Amidine 825 obtained by the method described in Reference Example 17
mg and 1.57 g of potassium hydroxide were dissolved in 30 ml of ethylene glycol and refluxed for 7 hours. The reaction mixture is then worked up as in Example 1 to obtain 345 mg (92% yield) of the desired 2-(2-dibenzofuryl)-propionic acid. When this is recrystallized from ethyl acetate-hexane, it becomes colorless needle-like crystals with a melting point of 141-142.5°C. Reference example 18 (synthesis of amidine) (In the formula, Ph means a phenyl group) 0.71 g of raw material enamine (1-[1-(3-benzoylphenyl)1-propenyl]pyrrolidine),
0.81 g of DPPA was dissolved in 7.5 ml of tetrahydrofuran and heated for 1 hour and 40 minutes at room temperature under an argon atmosphere.
Stir for 1 hour at 0.degree. C. and reflux for 2 hours. The desired phosphoamide 0.93 g (yield
72%). IR spectrum: ν KBr nax cm -1 1656 (C=O) 1559
,
1484, 1241, 1196, 918 NMR spectrum: δppm, ( CDCl3 )
【表】
実施例 ５
（式中Phはフエニル基を意味する）
参考例18記載の方法により得たるアミジン423
mgと水酸化カリウム0.77ｇをエチレングリコール
15ml中に溶解し、６時間還流処理する。反応混合
物を水200mlにあけ、炭酸ガスを吹き込みPH約９
としエチルエーテル50mlで５回洗浄後、水層を濃
塩酸で酸性にし、酢酸エチル50mlで４回抽出す
る。酢酸エチル抽出液を水、飽和食塩水で洗浄
後、硫酸マグネシウムで乾燥する。減圧蒸留して
得られた残渣をクロマトグラフイにより精製する
ことによつて粗酸139mgが得られた。アセトン5.5
ml中に粗酸を溶解しジヨーンズ試薬（E.R.H.
Jones J.Chem.Soc.1953.2548）を溶液が青黄色
から赤黄色に変わるまで滴下する。そして少量の
イソプロパノールを液の色が無色になるまで加え
る。更にクロロホルム190mlに溶解し、水で洗浄
し、無水硫酸マグネシウムで乾燥後、減圧下で溶
媒を留去すると無色粘稠な油状物として目的の酸
123mgが得られる（収率：62％）。
IRスペクトル：νｃａｐ ｎａｘcm-11730、1705（−
COOH）、1655[Table] Example 5 (In the formula, Ph means a phenyl group) Amidine 423 obtained by the method described in Reference Example 18
mg and potassium hydroxide 0.77g with ethylene glycol
Dissolve in 15 ml and reflux for 6 hours. Pour the reaction mixture into 200ml of water and blow in carbon dioxide until the pH is about 9.
After washing five times with 50 ml of ethyl ether, the aqueous layer is acidified with concentrated hydrochloric acid and extracted four times with 50 ml of ethyl acetate. The ethyl acetate extract is washed with water and saturated brine, and then dried over magnesium sulfate. The residue obtained by distillation under reduced pressure was purified by chromatography to obtain 139 mg of crude acid. acetone 5.5
Dissolve the crude acid in mL of Johns reagent (ERH).
Jones J.Chem.Soc.1953.2548) until the solution changes from blue-yellow to red-yellow. Then add a small amount of isopropanol until the liquid becomes colorless. Further, the target acid was dissolved in 190 ml of chloroform, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired acid as a colorless viscous oil.
123 mg are obtained (yield: 62%). IR spectrum: ν cap nax cm -1 1730, 1705 (-
COOH), 1655
【式】
NMRスペクトル：δppm、（CDCl3）
1.50（3H、ｄ、Ｊ＝6.6Hz）
3.76（1H、ｑ、Ｊ＝6.6Hz）
7.2〜7.75（9H、ｍ）
11.29（1H、broad）
参考例 19
（アミジンの合成）
（式中Phはフエニル基を意味する）
原料エナミン（１−〔１−（２−フルオロ−４−
ビフエニル）−１−プロペニル〕ピロリジン531mg
と、DPPA0.62ｇとをテトラヒドロフラン６ml中
に溶解し、アルゴン気流下に室温に於て１時間及
び40℃に於て１時間撹拌し次いで２時間に亘り還
流処理する。反応混合物をヘキサン−酢酸エチル
（１：３混合物）の系でシリカゲルカラムクロマ
トグラフイーする以外は参考例２に於けると同様
に後処理すれば所望の燐酸アミジン674ｇ（収率
68％）が得られる。酢酸エチル−ヘキサンより再
結晶すれば融点70〜73℃の無色パウダーとなる。
NMRスペクトル：δppm、CDCl3
[Formula] NMR spectrum: δppm, (CDCl 3 ) 1.50 (3H, d, J = 6.6Hz) 3.76 (1H, q, J = 6.6Hz) 7.2-7.75 (9H, m) 11.29 (1H, broad) Reference example 19 (Synthesis of amidine) (In the formula, Ph means a phenyl group) Raw material enamine (1-[1-(2-fluoro-4-
(biphenyl)-1-propenyl]pyrrolidine 531mg
and 0.62 g of DPPA were dissolved in 6 ml of tetrahydrofuran, stirred for 1 hour at room temperature and 1 hour at 40° C. under a stream of argon, and then refluxed for 2 hours. By post-treating the reaction mixture in the same manner as in Reference Example 2 except that the reaction mixture was subjected to silica gel column chromatography using a hexane-ethyl acetate (1:3 mixture) system, 674 g of the desired amidine phosphate (yield:
68%). Recrystallization from ethyl acetate-hexane gives a colorless powder with a melting point of 70-73°C. NMR spectrum: δppm, CDCl3
【表】
元素分析（C31H30N2O3FP）
計算 C70.44 H5.72 N5.30
実測 C70.34 H5.95 N5.08
実施例 ６
（式中Phはフエニル基を意味する）
参考例19記載の方法により得たるアミジン528
mgと水酸化カリウム0.3ｇをエチレングリコール
10mlに溶解し、８時間還流する。反応混合物を実
施例１記載の如く処理することにより目的の酸73
mgが得られた（収量：30％）。この粗酸をエチル
アセトン−ヘキサンから再結晶すると融点113〜
114℃の無色の結晶が得られた。
参考例 20
（エナミンの合成）
ｎ−ブチロフエノン4.44ｇと、ピロリジン6.40
ｇと、三弗化硼素エーテラート0.43ｇとをトルエ
ン50ml中に溶解し、脱水剤としてモレキユラーシ
ーブ4Aを用いコープの装置にて47時間に亘り還
流処理する。減圧下に溶媒を留去した後に、残渣
を減圧蒸溜すれば、淡黄色油状物として所望のエ
ナミン4.66ｇ（収率77％）が得られる。沸点106
〜108℃／４mmHg。
参考例 21
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例20記載の方法により得たるエナミン1.01
ｇとDPPA1.65ｇとをテトラヒドロフラン15ml中
に溶解し、室温に於て１時間且つ40℃に於て１時
間撹拌した後に２時間に亘り還流処理する。然る
後に、参考例２に於けると同様に後処理を行なえ
ば、所望のアミジン1.67ｇ（収率74％）が得られ
る。これを酢酸エチル−ヘキサンより再結晶せし
めれば、融点83〜85℃の無色柱状晶となる。
元素分析（C26H29N2O3P）
計算 C69.63 H6.52 N6.25
実測 C69.80 H6.49 N6.25
参考例 22
（アミジンの合成）
参考例21記載の方法に於て、反応をアルゴン気
流下に於て行なうことにより所望のアミジン1.84
ｇ（収率82％）が得られる。
参考例 23
（アミジンの合成）
（式中Phはフエニル基を意味する）
ｎ−ブチロフエノン0.74ｇと、ピロリジン1.07
ｇと、三弗化硼素エーテラート0.07ｇとをベンゼ
ン50ml中に溶解し、参考例20に於けると同様に反
応せしめ、次いで溶媒を減圧下に留去して得た残
渣にアルゴン気流下テトラヒドロフラン15ml及び
DPPA1.65ｇを添加して参考例21に於けると同様
に反応せしめ且つ後処理を行なえば、所望のアミ
ジン1.81ｇ（原料ケトンよりの収率81％）が得ら
れる。
実施例 ７
（式中Phはフエニル基を意味する）
参考例21、22、又は23記載の方法により得たる
アミジン0.45ｇと水酸化カリウム1.00ｇとをエチ
レングリコール20mlに溶解し、６時間還流する。
反応混合物を水200mlにあけ炭酸ガスを吹き込み
PH約９とし、エチルエーテル50mlで５回洗浄後水
層を濃塩酸で酸性にし酢酸エチル50mlで４回抽出
する。酢酸エチル抽出液を水、飽和食塩水で洗浄
後、硫酸マグネシウムで乾燥する。減圧留去して
得られた残渣をクロマトグラフイにより精製する
ことによつて融点が42〜43℃の目的の２−フエニ
ル酪酸0.15ｇ（収率91％）を得る。
参考例 24
（アミジンの合成）
（式中Phはフエニル基を意味する）
原料エナミン〔J.Org.Chem第32巻第213頁
（1967）記載の方法により調製〕805mgと、
DPPA1.32ｇとをテトラヒドロフラン12ml中に溶
解し、アルゴン気流下に室温に於て１時間且つ40
℃において１時間撹拌し次いで２時間に亘り還流
処理する。反応混合物を参考例２に於けると同様
にして後処理すれば、所望のアミジン1.25ｇ（収
率70％）が得られる。これを酢酸エチル−ヘキサ
ンより再結晶すれば、融点87〜88.5℃の無色針状
晶となる。
元素分析（C26H29N2O3P）
計算 C69.63 H6.52 N6.25
実測 C69.56 H6.57 N6.31
実施例 ８
（式中Phはフエニル基を意味する）
参考例24記載の方法により得たるアミジン0.45
ｇと水酸化カリウム1.00ｇとをエチレングリコー
ル20mlに溶解し、６時間還流する。以上実施例７
の如く後処理することにより融点75〜77.5℃の目
的の２−メチル−２−フエニルプロピオン酸
0.165ｇ（収率定量的）を得る。
参考例 25
（エナミンの合成）
４−ペンテノフエノン1.60ｇと、ピロリジン
2.13ｇと、三弗化硼素エーテラート0.14ｇとをト
ルエン50ml中に溶解し、脱水剤としてモレキユラ
ーシーブ4Aを用いコープの装置にて46時間に亘
り還流処理した後に、減圧下に溶媒を留去し残渣
を減圧蒸留すれば、所望のエナミン1.68ｇ（収率
79％）が得られる。沸点80〜84℃／0.15mmHg。
参考例 26
（アミジンの合成）
（式中Phはフエニル基を意味する）
参考例25記載の方法により得たるエナミン1.07
ｇとDPPA1.65ｇとをテトラヒドロフラン15ml中
に溶解し、アルゴン気流下に室温に於て１時間且
つ40℃に於て１時間撹拌し次いで２時間に亘り還
流処理する。然る後、参考例２に於けると同様に
後処理すれば、所望のアミジン1.84ｇ（収率80
％）が得られる。
実施例 ９
（式中Phはフエニル基を意味する）
参考例26記載の方法により得たるアミジン0.46
ｇと水酸化カリウム1.00ｇとをエチレングリコー
ル20mlに溶解し、６時間還流する。以上実施例７
の如く後処理することにより融点34℃の目的の２
−アリルフエニル酢酸0.16ｇ（収率91％）を得
る。
参考例 27
（アミジンの合成）
（式中Phはフエニル基を意味する）
アセトフエノン0.60ｇと、ピロリジン1.07ｇ
と、三弗化硼素エーテラート0.07ｇとをトルエン
30ml中に溶解し、脱水剤としてモレキユラーシー
ブ4Aを用いコープの装置にてアルゴン気流下に
18時間還流処理する。減圧下に溶媒を留去し、残
渣に無水テトラヒドロフラン15ml及びDPPA1.65
ｇを添加し、アルゴン気流下に室温に於て24時間
撹拌して反応せしめ、次いで参考例２に於けると
同様に後処理すれば、所望のアミジン101mg（原
料アセトフエノンよりの収率５％）が得られる。
参考例 28
（アミジンの合成）
（式中Phはフエニル基を意味する）
４−メトキシアセトフエノン0.751ｇと、ピロ
リジン1.07ｇと、三弗化硼素エーテラート0.03ｇ
とをトルエン30ml中に溶解し、実施例28に於ける
と同様に反応せしめ、次いで減圧下に溶媒を留去
した後にDPPA1.65ｇ及びテトラヒドロフラン15
mlを添加し参考例27に於けると同様に反応せしめ
且つ後処理を行なえば、所望のアミジン245mg
（原料メトキシアセトフエノンよりの収率11％）
が得られる。
参考例27及び28で得られたアミジンを加水分解
することにより、また出発物質としてのケトン体
を変えることにより、エナミン、アミジンを経由
して次のカルボン酸誘導体を得ることができる。
Γフエニル酢酸（融点75.5〜76.5℃）
Γパラ−メトキシフエニル酢酸（融点85〜86℃）
Γ２−〔（２−メチルシクロヘキシル）−４−フエ
ニル〕プロピオン酸（融点72.5〜73.5℃）
Γ２−〔４−（１−シクロヘキセニル）−フエニ
ル〕プロピオン酸（融点105〜106℃）
Γ２−（10−メチル−７−メトキシ−２−フエノ
チアジニル）プロピオン酸（融点124〜125℃）
Γ６−クロロ−２−メチル−9H−カルバゾール
−２−酢酸（融点197〜198℃）[Table] Elemental analysis (C 31 H 30 N 2 O 3 FP) Calculation C70.44 H5.72 N5.30 Actual measurement C70.34 H5.95 N5.08 Example 6 (In the formula, Ph means a phenyl group) Amidine 528 obtained by the method described in Reference Example 19
mg and potassium hydroxide 0.3g with ethylene glycol
Dissolve in 10 ml and reflux for 8 hours. The desired acid 73 was obtained by treating the reaction mixture as described in Example 1.
mg (yield: 30%). When this crude acid is recrystallized from ethylacetone-hexane, it has a melting point of 113~
Colorless crystals were obtained at 114°C. Reference example 20 (synthesis of enamine) 4.44g of n-butyrophenone and 6.40g of pyrrolidine
g and 0.43 g of boron trifluoride etherate were dissolved in 50 ml of toluene and refluxed for 47 hours in a Cope apparatus using Molecular Sieve 4A as a dehydrating agent. After distilling off the solvent under reduced pressure, the residue is distilled under reduced pressure to obtain 4.66 g (77% yield) of the desired enamine as a pale yellow oil. boiling point 106
~108℃/4mmHg. Reference example 21 (Synthesis of amidine) (In the formula, Ph means a phenyl group) Enamine 1.01 obtained by the method described in Reference Example 20
g and 1.65 g of DPPA were dissolved in 15 ml of tetrahydrofuran, stirred for 1 hour at room temperature and 1 hour at 40°C, and then refluxed for 2 hours. Thereafter, by carrying out post-treatment in the same manner as in Reference Example 2, 1.67 g (yield: 74%) of the desired amidine was obtained. When this is recrystallized from ethyl acetate-hexane, it becomes colorless columnar crystals with a melting point of 83-85°C. Elemental analysis (C 26 H 29 N 2 O 3 P) Calculation C69.63 H6.52 N6.25 Actual measurement C69.80 H6.49 N6.25 Reference example 22 (Amidine synthesis) In the method described in Reference example 21 , the desired amidine 1.84 was obtained by carrying out the reaction under an argon atmosphere.
g (yield 82%) is obtained. Reference example 23 (synthesis of amidine) (In the formula, Ph means a phenyl group) 0.74 g of n-butylophenone and 1.07 g of pyrrolidine
g and 0.07 g of boron trifluoride etherate were dissolved in 50 ml of benzene and reacted in the same manner as in Reference Example 20. Then, the solvent was distilled off under reduced pressure. as well as
By adding 1.65 g of DPPA and carrying out the reaction and post-treatment in the same manner as in Reference Example 21, 1.81 g of the desired amidine (yield 81% from the starting ketone) is obtained. Example 7 (In the formula, Ph means a phenyl group) 0.45 g of amidine obtained by the method described in Reference Example 21, 22, or 23 and 1.00 g of potassium hydroxide are dissolved in 20 ml of ethylene glycol and refluxed for 6 hours.
Pour the reaction mixture into 200ml of water and blow in carbon dioxide gas.
After adjusting the pH to about 9 and washing 5 times with 50 ml of ethyl ether, the aqueous layer is acidified with concentrated hydrochloric acid and extracted 4 times with 50 ml of ethyl acetate. The ethyl acetate extract is washed with water and saturated brine, and then dried over magnesium sulfate. The residue obtained by distillation under reduced pressure is purified by chromatography to obtain 0.15 g (yield: 91%) of the desired 2-phenylbutyric acid having a melting point of 42-43°C. Reference example 24 (synthesis of amidine) (In the formula, Ph means a phenyl group) 805 mg of raw material enamine [prepared by the method described in J.Org.Chem, Vol. 32, p. 213 (1967)],
1.32 g of DPPA was dissolved in 12 ml of tetrahydrofuran and heated for 1 hour at room temperature under an argon atmosphere for 40 minutes.
C. for 1 hour and then refluxed for 2 hours. The reaction mixture is worked up in the same manner as in Reference Example 2 to obtain 1.25 g (70% yield) of the desired amidine. When this is recrystallized from ethyl acetate-hexane, it becomes colorless needle crystals with a melting point of 87-88.5°C. Elemental analysis (C 26 H 29 N 2 O 3 P) Calculation C69.63 H6.52 N6.25 Actual measurement C69.56 H6.57 N6.31 Example 8 (In the formula, Ph means a phenyl group) Amidine 0.45 obtained by the method described in Reference Example 24
g and 1.00 g of potassium hydroxide are dissolved in 20 ml of ethylene glycol and refluxed for 6 hours. Example 7
The desired 2-methyl-2-phenylpropionic acid with a melting point of 75-77.5℃ can be obtained by post-treatment as follows.
0.165 g (yield quantitative) is obtained. Reference example 25 (synthesis of enamine) 1.60g of 4-pentenophenone and pyrrolidine
2.13 g of boron trifluoride etherate and 0.14 g of boron trifluoride etherate were dissolved in 50 ml of toluene, and refluxed for 46 hours in a Cope apparatus using molecular sieve 4A as a dehydrating agent, and then the solvent was distilled off under reduced pressure. By distilling the residue under reduced pressure, 1.68 g of the desired enamine (yield
79%). Boiling point 80-84℃/0.15mmHg. Reference example 26 (synthesis of amidine) (In the formula, Ph means a phenyl group) Enamine 1.07 obtained by the method described in Reference Example 25
g and 1.65 g of DPPA were dissolved in 15 ml of tetrahydrofuran, stirred for 1 hour at room temperature and 1 hour at 40° C. under an argon atmosphere, and then refluxed for 2 hours. Thereafter, by post-treatment in the same manner as in Reference Example 2, 1.84 g of the desired amidine (yield 80
%) is obtained. Example 9 (In the formula, Ph means a phenyl group) Amidine 0.46 obtained by the method described in Reference Example 26
g and 1.00 g of potassium hydroxide are dissolved in 20 ml of ethylene glycol and refluxed for 6 hours. Example 7
By post-processing as in
- Obtain 0.16 g of allyl phenyl acetic acid (yield 91%). Reference example 27 (synthesis of amidine) (In the formula, Ph means phenyl group) 0.60 g of acetophenone and 1.07 g of pyrrolidine
and 0.07 g of boron trifluoride etherate in toluene.
Dissolve in 30 ml and use Molecular Sieve 4A as a dehydrating agent under an argon stream in a Cope apparatus.
Reflux for 18 hours. The solvent was distilled off under reduced pressure, and 15 ml of anhydrous tetrahydrofuran and 1.65 DPPA were added to the residue.
g, stirred for 24 hours at room temperature under an argon stream to react, and then post-treated in the same manner as in Reference Example 2 to obtain 101 mg of the desired amidine (yield 5% from the raw material acetophenone). is obtained. Reference example 28 (synthesis of amidine) (In the formula, Ph means a phenyl group) 0.751 g of 4-methoxyacetophenone, 1.07 g of pyrrolidine, and 0.03 g of boron trifluoride etherate
were dissolved in 30 ml of toluene and reacted in the same manner as in Example 28, and then after distilling off the solvent under reduced pressure, 1.65 g of DPPA and 15 g of tetrahydrofuran were added.
ml and reacted and post-treated in the same manner as in Reference Example 27, the desired amidine 245mg
(Yield 11% from raw material methoxyacetophenone)
is obtained. By hydrolyzing the amidines obtained in Reference Examples 27 and 28 or by changing the ketone body as a starting material, the following carboxylic acid derivative can be obtained via enamine and amidine. Γ Phenyl acetic acid (melting point 75.5-76.5°C) Γ para-methoxyphenylacetic acid (melting point 85-86°C) Γ2-[(2-methylcyclohexyl)-4-phenyl]propionic acid (melting point 72.5-73.5°C) Γ2-[ 4-(1-cyclohexenyl)-phenyl]propionic acid (melting point 105-106°C) Γ2-(10-methyl-7-methoxy-2-phenothiazinyl)propionic acid (melting point 124-125°C) Γ6-chloro- 2-Methyl-9H-carbazole-2-acetic acid (melting point 197-198℃)
Claims (1)
チルフエニル、置換シクロヘキシルフエニル、シ
クロヘキセニルフエニル、ハロゲンビフエニル、
ベンゾイルフエニル、メトキシナフチル、ジベン
ゾフラニル、メトキシフエノチアジニル又はハロ
ゲンカルボリニル基を意味し、R2はメチル、エ
チル、プロピル、イソプロピル又はビニルエチル
基を意味する） にて示されるケトンと、式 R3−Ｈ （式中R3はジメチルアミノ、ピロリジル、ピペリ
ジル又はモルホリル基を意味する） にて示される第２級アミン化合物とを不活性溶媒
中脱水剤の存在において反応せしめ、生成する式 （式中R1及びR3は前記の意味を有し、R4は水素、
メチル、エチル、イソプロピル又はアリル基を意
味し、R5は水素又はメチル基を意味する） にて示されるエナミンを式 N3−Ａ （式中Ａはジメチルリン酸、ジエチルリン酸、ジ
フエニルリン酸、シアノ又はトシル基を意味す
る） にて示されるアジド化合物と反応せしめ、次いで
生成する式 （式中R1、R3、R4、R5及びＡは前記の意味を有す
る） にて示されるアミジンを加水分解することを特徴
とする、式 （式中R1、R4及びR5は前記の意味を有する） にて示されるカルボン酸誘導体の製法。[Claims] 1 Formula R 1 -CO-R 2 (wherein R 1 is phenyl, methoxyphenyl, isobutylphenyl, substituted cyclohexylphenyl, cyclohexenyl phenyl, halogen biphenyl,
a ketone represented by the formula A formula produced by reacting a secondary amine compound represented by R 3 -H (in the formula R 3 means dimethylamino, pyrrolidyl, piperidyl or morpholyl group) in the presence of a dehydrating agent in an inert solvent. (In the formula, R 1 and R 3 have the above meanings, R 4 is hydrogen,
methyl, ethyl, isopropyl or allyl group, and R 5 means hydrogen or methyl group). (meaning a cyano or tosyl group) is reacted with an azide compound represented by (wherein R 1 , R 3 , R 4 , R 5 and A have the above-mentioned meanings) (In the formula, R 1 , R 4 and R 5 have the above-mentioned meanings.) A method for producing a carboxylic acid derivative represented by the following.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12359477A JPS5459238A (en) | 1977-10-17 | 1977-10-17 | Novel method for producing carboxylic acid derivatives and intermediate thereof |
| US05/922,524 US4198510A (en) | 1977-10-17 | 1978-07-07 | Piperidenylmethylidene phosphonylamidines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12359477A JPS5459238A (en) | 1977-10-17 | 1977-10-17 | Novel method for producing carboxylic acid derivatives and intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5459238A JPS5459238A (en) | 1979-05-12 |
| JPS6216940B2 true JPS6216940B2 (en) | 1987-04-15 |
Family
ID=14864463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12359477A Granted JPS5459238A (en) | 1977-10-17 | 1977-10-17 | Novel method for producing carboxylic acid derivatives and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5459238A (en) |
-
1977
- 1977-10-17 JP JP12359477A patent/JPS5459238A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5459238A (en) | 1979-05-12 |
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