JPS6019794A - Novel amidobenzoic acid derivative - Google Patents
Novel amidobenzoic acid derivativeInfo
- Publication number
- JPS6019794A JPS6019794A JP12710883A JP12710883A JPS6019794A JP S6019794 A JPS6019794 A JP S6019794A JP 12710883 A JP12710883 A JP 12710883A JP 12710883 A JP12710883 A JP 12710883A JP S6019794 A JPS6019794 A JP S6019794A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- acid derivative
- represented
- general formula
- 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.)
- Granted
Links
- 239000002253 acid Substances 0.000 title claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 abstract description 31
- -1 (substituted) phenyl Chemical group 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 abstract description 3
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 3
- 239000011574 phosphorus Substances 0.000 abstract description 3
- 230000003266 anti-allergic effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000007239 Wittig reaction Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- AVCVDUDESCZFHJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound [Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 AVCVDUDESCZFHJ-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 5
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QZWSCOXXIITFGQ-UHFFFAOYSA-N 2-[(2-bromoacetyl)amino]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC(=O)CBr QZWSCOXXIITFGQ-UHFFFAOYSA-N 0.000 description 1
- OKAPEGBSNZHDIW-UHFFFAOYSA-N 2-[(2-chloroacetyl)amino]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC(=O)CCl OKAPEGBSNZHDIW-UHFFFAOYSA-N 0.000 description 1
- LZCIQUSCMLPTQE-UHFFFAOYSA-N 2-[(2-iodoacetyl)amino]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC(=O)CI LZCIQUSCMLPTQE-UHFFFAOYSA-N 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 241000533845 Enterolobium cyclocarpum Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical class [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- UCOXJYUSJIHXPZ-UHFFFAOYSA-N [PH4]C1=CC=CC=C1 Chemical compound [PH4]C1=CC=CC=C1 UCOXJYUSJIHXPZ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001768 cations Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid group Chemical class C(C=CC1=CC=CC=C1)(=O)O WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VGGTWLRWWCYXEU-UHFFFAOYSA-N methyl 2-(2-chloropropanoylamino)benzoate Chemical compound COC(=O)C1=CC=CC=C1NC(=O)C(C)Cl VGGTWLRWWCYXEU-UHFFFAOYSA-N 0.000 description 1
- JFZUABNDWZQLIJ-UHFFFAOYSA-N methyl 2-[(2-chloroacetyl)amino]benzoate Chemical compound COC(=O)C1=CC=CC=C1NC(=O)CCl JFZUABNDWZQLIJ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- RMZAYIKUYWXQPB-UHFFFAOYSA-N trioctylphosphane Chemical compound CCCCCCCCP(CCCCCCCC)CCCCCCCC RMZAYIKUYWXQPB-UHFFFAOYSA-N 0.000 description 1
- QQBLOZGVRHAYGT-UHFFFAOYSA-N tris-decyl phosphite Chemical compound CCCCCCCCCCOP(OCCCCCCCCCC)OCCCCCCCCCC QQBLOZGVRHAYGT-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
本発明は新規なアミド安息香酸誘導体に関するものであ
る。、更に詳しくいえば、本発明は一般式％式％
（式中のＲ１及びＲ４はそれぞれ水素原子又は炭素数が
１〜３の低級アルキル基であり、Ｙは互いに同じでも異
なっていてもよく、炭素数が１〜４の直鎖状又は枝分れ
状の低級アルコキシル基、水酸基及び炭素数が２〜５の
ア／ルオキシ基の中から選ばれる基であり、ηは２又は
３である）で表わされる芳香族カルボン酸誘導体の製造
中間体として有用な、一般式
〔式中のＲ１は前記と同じ意味をもち Ｒ２は水素原子
又はＺと隣接炭素原子との間で二重結合を形成するもの
であり、Ｒ３は炭素原子数が１〜３の低級アルキル基で
あり、２は式
（ただし、各式中のＸＩは炭素原子数が１〜１ｏの直鎖
状又は枝分れ状のアルキル基、フェニル基又は置換フェ
ニル基、Ｘ２は炭素原子数が１〜１ｏの直鎖状又は枝分
れ状のアルコギシル基、Ｈａｈｎ塩素原子、臭素原子又
はヨウ素原子）で示されるリン含有残基である〕
で表わされるアミド安息香酸誘導体に関するものである
。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel amidobenzoic acid derivatives. More specifically, the present invention is based on the general formula % (wherein R1 and R4 are each a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, Y may be the same or different from each other, A group selected from a linear or branched lower alkoxyl group having 1 to 4 carbon atoms, a hydroxyl group, and an alkyloxy group having 2 to 5 carbon atoms, and η is 2 or 3) Useful as an intermediate for the production of aromatic carboxylic acid derivatives represented by the general formula [wherein R1 has the same meaning as above and R2 forms a double bond between a hydrogen atom or Z and an adjacent carbon atom] , R3 is a lower alkyl group having 1 to 3 carbon atoms, and 2 is a formula (wherein XI in each formula is a linear or branched alkyl group having 1 to 1 carbon atoms). a phenyl group or substituted phenyl group, ] This relates to an amidobenzoic acid derivative represented by:
一般式（］）で表わされる芳香族カルボン酸アミド誘導
体、特に式
で表わされるＮ−（３，４−ジメトキシシンナモイル）
アントラニル酸は、人を含む哺乳動物において顕著な抗
アレルギー作用を示し、アレルギーに起因する種々の疾
患、例えば気管支ぜん息、アトピー性成フ炎、アレルギ
ー性鼻炎等の予防及び治療用医薬品としてきわめて有用
な化合物である。Aromatic carboxylic acid amide derivatives represented by the general formula (]), especially N-(3,4-dimethoxycinnamoyl) represented by the formula
Anthranilic acid exhibits remarkable antiallergic effects in mammals including humans, and is extremely useful as a drug for the prevention and treatment of various diseases caused by allergies, such as bronchial asthma, atopic inflammation, and allergic rhinitis. It is a compound.
４−
この一般式（１）で表わされる化合物は公知の化合物で
あり、その製造方法もいくつか知られている。4- The compound represented by this general formula (1) is a known compound, and several methods for producing it are also known.
これまで、この化合物を製造する方法の中で最も一般的
な方法は、一般式
（式中のＲ１，Ｙ及びｎは前記と同じ意味をもつ）で表
わされる核置換ケイ皮酸類の反応性官能的誘導体と、一
般式
（式中のＲ４は前記と同じ意味をもつ）で表わされるア
ントラニル酸又はそのエステル類とを反応させる方法で
ある。しかしながら、この製造方法は反応操作が比較的
面倒であり、まだ加熱等による副反応生成物が不純物が
混入し、精製にも手間を要する上に、反応性官能的誘導
体として酸ハロゲン化物を用いる場合、その製造時にハ
ロゲン化水素ガスなどのイ］害なガスが発生する々どの
離点があった３、
本発明者らはこのような問題点を解消すべく研究した結
果、ウイテイヒ（ｗ］ｔｉ；ｉ、ｇ）反応を応用するこ
とにより、きわめて簡１ｉに、効率よく一般式（］）で
表わされる化合物を製造できることを見出ｌ〜だ。本発
明はその製造方法において出発原料として用いられる新
規なアミド安息香酸誘導体に関するものである。Until now, the most common method for producing this compound has been to use a reactive functional group of nuclear-substituted cinnamic acids represented by the general formula (in which R1, Y and n have the same meanings as above). This is a method of reacting a derivative with anthranilic acid or an ester thereof represented by the general formula (R4 in the formula has the same meaning as above). However, in this production method, the reaction operation is relatively troublesome, side reaction products due to heating etc. are still contaminated with impurities, purification is also time-consuming, and furthermore, when using an acid halide as a reactive functional derivative, The inventors conducted research to solve these problems, and as a result of their research, they found that they were able to produce a ; i, g) By applying the reaction, we found that the compound represented by the general formula (]) can be produced very simply and efficiently. The present invention relates to a novel amidobenzoic acid derivative used as a starting material in its production method.
すなわち、本発明の一般式（２）の化合物でＺが式（Ｘ
’）３Ｐ＝ （式中のＸｌは前記と同じ意味をもつ）で
ある化合物と、あるいは、一般式（２）の化合物でＺが
式
（式中のＸｌ 、 ｙ２及びＨａｔは前記と同じ意味を
もつ）である化合物を塩基性物質で処理して、一般式
（式中のＲ１及びＲ３は前記と同じ意味をもち ｚ＋は
式
％式％）
但し、各式中のＸｌ及びＸ２は前記と同じ意味をもち、
Ｂは塩基性物質から誘導される陽イオンである）で表わ
されるリンイリド誘導体を製造した後、これらの化合物
と、一般式
（式中のＹ及びｎは前記と同じ意味をもつ）で表わされ
る核置換ベンズアルデヒド類とを室温ないし冷却下に反
応させ、必要に応じ加水分解することにより容易に一般
式（１）の化合物を得ることができる。That is, in the compound of general formula (2) of the present invention, Z is the formula (X
') 3P= (Xl in the formula has the same meaning as above) or a compound of general formula (2) where Z is the formula (Xl, y2 and Hat in the formula have the same meaning as above) A compound with the general formula (R1 and R3 in the formula have the same meanings as above, z+ is the formula % formula %) is treated with a basic substance. have meaning,
B is a cation derived from a basic substance) After producing phosphorus ylide derivatives represented by these compounds and a nucleus represented by the general formula (Y and n in the formula have the same meanings as above), The compound of general formula (1) can be easily obtained by reacting a substituted benzaldehyde at room temperature or under cooling, followed by hydrolysis if necessary.
この製造方法は従来の方法に比べ反応操作が非常に簡ｊ
ｌｉであり、１だ、反応がきわめて緩イ１表条件で進行
するため副反応が起りにくく最終物の精製も容易である
という利点がある。更に又、全製造過程において従来法
における酸・・ロゲン化物の製造時に発生する・・ロゲ
ン化水素ガスのような有害なガスを発生ずることもない
。したがって、本発明の一般式（２）の化合物を１１）
発原料として用いることにより、従来より容易に、効率
よく一般式（１）の化合物を製造することができる。This production method has a much simpler reaction operation than conventional methods.
li, 1 has the advantage that the reaction proceeds very slowly under conditions shown in Table 1, side reactions are less likely to occur and purification of the final product is easy. Furthermore, the entire manufacturing process does not generate harmful gases such as hydrogen halogen gas, which is generated during the production of acids and halides in conventional methods. Therefore, the compound of general formula (2) of the present invention is
By using it as a starting material, the compound of general formula (1) can be produced more easily and efficiently than before.
このように、本発明の一般式（２）で表わされる化合物
は、医薬品として有用々−一般式１）で表わされる芳香
族カルボン酸アミド誘導体の製造中間体としてきわめて
有用である１、
本発明の一般式（２）で表わされるアミド安息香酸誘導
体は以下の」：うにして製造することができる。As described above, the compound represented by the general formula (2) of the present invention is extremely useful as a pharmaceutical intermediate for producing the aromatic carboxylic acid amide derivative represented by the general formula 1). The amidobenzoic acid derivative represented by the general formula (2) can be produced in the following manner.
す々わち、一般式
％式％（８）
（式中のｘｌは前記と同じ意味をもつ）又は一般式
％式％（９）
（式中のＸ２は前記と同じ意味をもつ）で表わされるリ
ン化合物と、一般式
（式中のＲ１、Ｒ２、Ｒ３及びＨａｔは前記と同じ意味
をもつ）
で表わされる２−（α−ハロアシルアミノ）安息香酸エ
ステルとを不活性有機溶媒中、例えばベンゼン、トルエ
ン、キシレンなどの中、又は無溶媒で数時間〜十数時間
加熱すれば、一般式（２）の化合物でＺが式
（式中のｙｌ 、 Ｘ２及びＨａ７は前記と同じ意味を
もつ）
に相当する化合物を製造することができる。このように
して得だ化合物の中でＺが式
％式％）
（式中のＸｌ及びＨａ ｌは前記と同じ意味をもつ）に
相当する化合物は、これを不活性溶媒、例えば水、エチ
ルアルコール、ベンゼン、ジエチルエーテル、ジオキサ
ン、テトラヒドロフラン、塩化メチレンなど及びこれら
の混合液中、塩基性物質、例えば水酸化すトリウム、水
酸化カリタス・、水素化すトリウノ１、ナトリウノ・メ
トキシド、ナトリウムエトキシド、ポタシウムーｔ−ブ
トキシド、ナトリウムアミド、リチウｌ、アミドなどで
処理することによってＺが式
％式％）
（式中のＸｌけ前記と同じ意味をもつ）で表わされる化
合物に変えることができる。That is, represented by the general formula % formula % (8) (xl in the formula has the same meaning as above) or the general formula % formula % (9) (X2 in the formula has the same meaning as above) A phosphorus compound and a 2-(α-haloacylamino)benzoic acid ester represented by the general formula (R1, R2, R3 and Hat have the same meanings as above) in an inert organic solvent, e.g. When heated in benzene, toluene, xylene, etc. or in the absence of a solvent for several hours to over ten hours, a compound of general formula (2) with Z in the formula (where yl, X2 and Ha7 have the same meanings as above) can be obtained. ) can be produced. Among the compounds obtained in this way, those corresponding to the formula , benzene, diethyl ether, dioxane, tetrahydrofuran, methylene chloride, etc., and in mixtures thereof, basic substances such as sodium hydroxide, caritas hydroxide, hydrogenated sodium methoxide, sodium ethoxide, potassium chloride, etc. - By treatment with butoxide, sodium amide, lithium, amide, etc., Z can be changed into a compound represented by the formula % (wherein Xl has the same meaning as above).
この製造方法において原イ？１として用いられる一般式
（８）及び（９）の化合物はいずれも公知の化合物であ
り、市販品として入手できるが、又は文献記載の方法に
よって容易に製造することができる。このような化合物
として、例えば、トリフェニルポスフィン、トリス（４
−メトキシフェニル）ボスフィン、トリス（４−メチル
フェニル）ボスフィン、トリーｎ−ブチルホスフィン、
トリーｎ−オクチルホスフィン、トリメチルホスファイ
ト、トリエチルホスファイト、トリイソプロピルホスフ
ァイト、トリーｎ−ブチルホスファイト、トリーｎ−デ
シルホスファイト、などをあげることができる３゜
もう一方の原料として用いられる一般式ｏ１で表わされ
る２−（α−ハロアシルアミノ）安息香酸エステル類も
公知の化合物であり、文献記載の方法により容易に製造
することができる。このようカ化合物として、例えば、
２−（クロルアセチルアミン）安息香酸、２−（ブロム
アセチルアミノ）安息香酸、２−（ヨードアセチルアミ
ノ）安息香酸、２−（２−クロルプロピオニルアミノ）
安息香酸、２−（２−ブロムプロピオニルアミノ）安息
香酸、２−（２−ヨードプロピオニルアミノ）安息香酸
々どの安息片酸類の低級アルキルエステル、例エバメチ
ルエステル、エチルエステル、フロビルエステル々どを
あげることができる。Is there any problem with this manufacturing method? The compounds of general formulas (8) and (9) used as compound 1 are both known compounds and can be obtained as commercially available products, or can be easily produced by methods described in literature. Examples of such compounds include triphenylphosphine, tris(4
-methoxyphenyl)bosphine, tris(4-methylphenyl)bosphine, tri-n-butylphosphine,
Tri-n-octyl phosphine, trimethyl phosphite, triethyl phosphite, tri-isopropyl phosphite, tri-n-butyl phosphite, tri-n-decyl phosphite, etc. 3゜ General formula used as the other raw material 2-(α-haloacylamino)benzoic acid esters represented by o1 are also known compounds and can be easily produced by methods described in literature. Such compounds include, for example,
2-(Chloracetylamino)benzoic acid, 2-(bromoacetylamino)benzoic acid, 2-(iodoacetylamino)benzoic acid, 2-(2-chloropropionylamino)
Lower alkyl esters of benzoic acids such as benzoic acid, 2-(2-bromopropionylamino)benzoic acid, 2-(2-iodopropionylamino)benzoic acid, such as evamethyl ester, ethyl ester, flobyl ester, etc. I can give it to you.
本発明の一般式（２）で表わされるアミド安息香酸誘導
体は新規な化合物であり、抗アレルギー剤として有用な
一般式（１）で表わされる芳香族カルボン酸アミド誘導
体の製造中間体としてきわめて有用々化合物である。本
発明の一般式（２）の化合物を製造原料として用いるこ
とにより、きわめて単純な操作で容易に効率よく一般式
（１）の芳香族カルボン酸アミド誘導体を得ることがで
きる。The amidobenzoic acid derivative represented by the general formula (2) of the present invention is a new compound, and is extremely useful as an intermediate for the production of the aromatic carboxylic acid amide derivative represented by the general formula (1), which is useful as an antiallergic agent. It is a compound. By using the compound of the general formula (2) of the present invention as a production raw material, the aromatic carboxylic acid amide derivative of the general formula (1) can be easily and efficiently obtained by extremely simple operations.
以下、実施例により本発明をさらに詳細に説明する。々
お各実施例中の化合物における融点はすべて未補正であ
る。Hereinafter, the present invention will be explained in more detail with reference to Examples. All melting points for compounds in each example are uncorrected.
実施例１
トリフェニルホスフィン２０．０１ｉ’ 、！： Ｎ−
クロルアセチルアントラニル酸メチル１．２．Ｏｆとを
ベンゼン１３０ｍ１！に溶解し、１７時間加熱還流した
。冷接析出しだ結晶をろ取、乾燥して、〔（２−メトキ
シカルボニルフェニル）カルバモイルメチル〕トリノエ
ニルホスホニウムクロリド９．０７を得た。Example 1 Triphenylphosphine 20.01i',! : N-
Methyl chloracetylanthranilate 1.2. Of benzene 130m1! and heated under reflux for 17 hours. The cold precipitated crystals were collected by filtration and dried to obtain 9.07 of [(2-methoxycarbonylphenyl)carbamoylmethyl]trinoenylphosphonium chloride.
融点 １６３〜１６５℃（分解）
赤外線吸収スペクトル（ＫＢｒ）
ｉｌｃ＝ｏ ： １７０５ 、１６７０ｃｒｎ’核磁気
共鳴スペクトル（９０ＭＨ２，ｃＤｃｔ３）δ： ３．
７０（３Ｈ，Ｓ）、 ５．４９ （２Ｈ，ｄ、Ｊ＝１５
Ｈｚ）７．０〜８．０（１，９Ｈ，ｍ）、１１．６２（
ＩＨ，Ｓ）元素分析値（Ｃ２８Ｈ２、ＣｔＮ０３Ｐとし
て）０％ Ｈ％ Ｎ％
計算値 ６８，６４ ５．１４ ２．８６実測値 ６８
．４２ ５．１１ ２．６８実施例２
［（２−メトキシカルボニルフェニル）カルバモイルメ
チル〕トリノエニルホスホニウムクロリド５．１６ｆに
水１５０ ｍｌとベンゼア１００ｍ１を加え、水冷下か
きまぜながら０．４８ Ｓ’の水酸化ナトリウムを水２
０ｔｎＩ！に溶かした液を滴下した。滴下後、さらに１
５分間かきまぜた後ベンゼン層を分取し、水洗後無水硫
酸マグネジウドで乾燥した。溶媒を減圧下に留去し、残
留物をベンゼン−ジエチルエーテルで再結晶１−で、［
（２−％１．キンカルボニルフェニル）カルバモイルメ
チレン］ ｌ−１）フェニルホスホラン４．７７をイ（
ｉた。Melting point: 163-165°C (decomposed) Infrared absorption spectrum (KBr) ilc=o: 1705, 1670 crn' Nuclear magnetic resonance spectrum (90 MH2, cDct3) δ: 3.
70 (3H, S), 5.49 (2H, d, J=15
Hz) 7.0-8.0 (1.9H, m), 11.62 (
IH, S) Elemental analysis value (as C28H2, CtN03P) 0% H% N% Calculated value 68,64 5.14 2.86 Actual value 68
．． 42 5.11 2.68 Example 2 Add 150 ml of water and 100 ml of benzea to 5.16 f of [(2-methoxycarbonylphenyl)carbamoylmethyl]trinoenylphosphonium chloride, and hydroxylate 0.48 S' while stirring under water cooling. sodium to 2 parts water
0tnI! The solution dissolved in the solution was added dropwise. After dropping, add 1 more
After stirring for 5 minutes, the benzene layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from benzene-diethyl ether.
(2-% 1.quincarbonylphenyl)carbamoylmethylene] l-1) phenylphosphorane 4.77
It was.
融点 １６０〜１６：３℃
赤外線吸収スペクトル（ＫＩＢｒ）
−〇＝Ｏ： １６７０Ｌ−Ｉｎ’
核磁気共鳴スペクトル（りＯＭＴ（Ｚ 、 ＣＤＣ１３
）δ： ：１．８２ （３Ｈ，Ｆｔ） 、 ６．（ｉ−
８，８（２０Ｔ−Ｔ、ｍ） 。Melting point 160-16:3℃ Infrared absorption spectrum (KIBr) -〇=O: 1670L-In' Nuclear magnetic resonance spectrum (RI OMT (Z, CDC13
) δ: :1.82 (3H, Ft), 6. (i-
8,8 (20T-T, m).
１０．４３（ＩＨ，Ｓ）
元素分析値（Ｃ２８■１□、、Ｎ０１Ｐとして）０％
Ｉ−Ｔ％ Ｎ ％
割算値 ７４． ＋６ ５．３３ ３．０９実測値 ７
１１．ＩＱ ！’ｉ、１４ ２．８６実施例３
トリエチルホスファイト１６．ＯｆｆとＮ−クロルアセ
チルアントラニル酸メチル９．Ｏ５ｉ’とを１４０〜１
５０℃で３１１Ｓ間反応さけ−だ。反応終了後過剰のト
リエチルポスファイトを減圧下に留去して、油状１５−
物の［（２−メトキシカルボニルフェニル）カルバモイ
ルメチル〕ホスホン酸ジエチル］、３．０ｆｉ′ヲ得た
。10.43 (IH, S) Elemental analysis value (C28■1□,, as N01P) 0%
IT% N% Divide value 74. +6 5.33 3.09 Actual value 7
11. IQ! 'i, 14 2.86 Example 3 Triethyl Phosphite 16. Off and methyl N-chloroacetylanthranilate9. O5i' and 140~1
Preferably react for 311S at 50°C. After the reaction was completed, excess triethyl phosphite was distilled off under reduced pressure to obtain 3.0 fi' of oily 15-product [(2-methoxycarbonylphenyl)carbamoylmethyl]diethylphosphonate].
赤外線吸収スペクトル（液膜）
一〇〇：１６８５α−１
核磁気共鳴スペクトル（９０ＭＨ２，Ｏ旧１３）δ：
１．３３（６Ｈ，ｔ、Ｊ＝７Ｈｚ）、３．０３（２Ｈ，
ｄ。Infrared absorption spectrum (liquid film) 100:1685α-1 Nuclear magnetic resonance spectrum (90MH2, O former 13) δ:
1.33 (6H, t, J=7Hz), 3.03 (2H,
d.
Ｊ＝２０Ｈｚ）、３．８９（３Ｈ，Ｓ）、４．１３（２
Ｈ。J = 20Hz), 3.89 (3H, S), 4.13 (2
H.
ｑ、Ｊ＝７Ｈｚ）、４．２２（２Ｈ，ｑ、、Ｔ＝７Ｈｚ
）。q, J=7Hz), 4.22(2H,q,, T=7Hz
).
６．９−８．８ （４Ｈ，ｍ） 、 ］、１．２２（Ｉ
Ｈ、Ｓ）実施例４
トリイソプロピルホスファイト８．３２ ｆとＮ −ク
ロルアセチルアントラニル酸メチル９．１７とを１３０
〜１４０℃で１時間、さらに１５０℃で３０分加熱して
、油状物の〔（２−メトキシカルボニルフェニル）カル
バモイルメチル〕ホスホン酸ジイソプロピル１４．２２
を得た。6.9-8.8 (4H, m), ], 1.22 (I
H, S) Example 4 Triisopropyl phosphite 8.32 f and methyl N-chloroacetylanthranilate 9.17
Heating at ~140°C for 1 hour and then at 150°C for 30 minutes gave an oily product of diisopropyl [(2-methoxycarbonylphenyl)carbamoylmethyl]phosphonate 14.22
I got it.
赤外線吸収スペクトル（液膜）
ｕＣＯ： １６８０Ｃｎ１’
核磁気共鳴スペクトル（９０ＭＨ２、ＣＤＣｌ３）＝１
６＝
δ： ＋、３ｏ（＋２ｎ、ａ、、：ｒ＝６ｎｚ）、２．
９６（２ｎ。Infrared absorption spectrum (liquid film) uCO: 1680Cn1' Nuclear magnetic resonance spectrum (90MH2, CDCl3) = 1
6=δ: +, 3o(+2n, a, , :r=6nz), 2.
96 (2n.
ｄ 、Ｊ＝２２Ｈｚ）、 ３．８６（３Ｈ，ｓ）、４．
５〜５−０ （２Ｈ＋ ｍ ） ＋ ６−９〜８．８
（４Ｈ＋ ｍ ） ＋１、１ 、１２ （Ｉ Ｔ（、ｓ
）
実施例５
トリエチルホスファイｌ−７，ＯｆとＮ−（２−クロル
プロピオニル）アントラニル酸メチル５．０７とをアル
ゴン気流下２００℃で７時間加熱した。反応終了後過剰
のトリエチルホスファイトを減圧下に留去して、油状物
の＋１−〔（２−メトキシカルボニルフェニル）カルバ
モイルメチレンロホン酸ジエチル６．５７を得だ。d, J=22Hz), 3.86 (3H, s), 4.
5~5-0 (2H+m) + 6-9~8.8
(4H+ m ) +1, 1, 12 (IT(,s
) Example 5 Triethylphosphite 1-7,Of and 5.07 g of methyl N-(2-chloropropionyl)anthranilate were heated at 200° C. for 7 hours under an argon stream. After the reaction was completed, excess triethyl phosphite was distilled off under reduced pressure to obtain 6.57 g of diethyl +1-[(2-methoxycarbonylphenyl)carbamoylmethylenelophonate.
赤外線吸収スペクトル（液膜）
４ＣＯ＝ １６８５ａｎ’
核磁気共鳴スペクトル（９０ＭＨ２，ＣＤＣｌ３ ）δ
： １．３１（６Ｈ，１；、Ｊ＝７Ｈｚ）、１．５４（
３Ｈ。Infrared absorption spectrum (liquid film) 4CO = 1685an' Nuclear magnetic resonance spectrum (90MH2, CDCl3) δ
: 1.31 (6H, 1;, J=7Hz), 1.54 (
3H.
６−ａ、 、 Ｊ＝２３）ＴＺ 、 Ｊ＝７Ｔ（Ｚ ）
、 ３．０５（ＬＨ。6-a, , J=23)TZ, J=7T(Z)
, 3.05 (LH.
（］、Ｑ 、 Ｊ＝２３Ｈｚ 、 Ｊ＝７Ｈｚ ） 、
３．９（３Ｈ。(], Q, J=23Hz, J=7Hz),
3.9 (3H.
Claims (1)
キル基であり Ｔ（２は水素原子又はＺと隣接炭素原子
との間で二重結合を形成するものであり Ｒ３は炭素原
子数が１〜３の低級アルキル基であり、Ｚは式 （ただし Ｘ＋は炭素数が１〜１０の直鎖状又は枝分れ
状のアルギル基、フェニル基又は置換フ １− エニル基、Ｘ２は炭素原子数が１〜１０の直鎖状又は枝
分れ状のアルコキシル基、ＨａＬは塩素原子、臭素原子
又はヨウ素原子）で示されるリン含有残基である〕 で表わさ・れるアミド安息香酸誘導体。 ２式 ％式％ で表わされる特許請求の範囲第１項記載のアミド安息香
酸誘導体。 ３式 ％式％ で表わされる特許請求の範囲第１項記載のアミド安息香
酸誘導体。 ４式 で表わされる特Ｍ’ｌ’ 請求の範囲第１項記載のアミ
ド安腑香酸誘導体１． ５式 で表わされる特許請求の範囲第１項記載のアミド安息香
酸誘導体。 で表わされる特許請求の範囲第１項記載のアミド安息香
酸誘導体。[Claims] 1 General formula [In the formula, R1 is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and T (2 is a hydrogen atom or a double bond between Z and an adjacent carbon atom] R3 is a lower alkyl group having 1 to 3 carbon atoms, and Z is a formula (where X+ is a linear or branched argyl group having 1 to 10 carbon atoms, a phenyl group, or Substituted 1-enyl group; An amide benzoic acid derivative represented by 2. An amide benzoic acid derivative according to claim 1, which is represented by formula %. 3 An amide benzoic acid derivative according to claim 1, which is represented by formula %. Acid derivative.Amidobenzoic acid derivative according to claim 1, represented by the formula 4. Amidobenzoic acid derivative according to claim 1, represented by the formula 5. The amidobenzoic acid derivative according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12710883A JPS6019794A (en) | 1983-07-13 | 1983-07-13 | Novel amidobenzoic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12710883A JPS6019794A (en) | 1983-07-13 | 1983-07-13 | Novel amidobenzoic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6019794A true JPS6019794A (en) | 1985-01-31 |
| JPH0373557B2 JPH0373557B2 (en) | 1991-11-22 |
Family
ID=14951798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12710883A Granted JPS6019794A (en) | 1983-07-13 | 1983-07-13 | Novel amidobenzoic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6019794A (en) |
-
1983
- 1983-07-13 JP JP12710883A patent/JPS6019794A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0373557B2 (en) | 1991-11-22 |
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