JPH0319216B2 - - Google Patents
Info
- Publication number
- JPH0319216B2 JPH0319216B2 JP3948782A JP3948782A JPH0319216B2 JP H0319216 B2 JPH0319216 B2 JP H0319216B2 JP 3948782 A JP3948782 A JP 3948782A JP 3948782 A JP3948782 A JP 3948782A JP H0319216 B2 JPH0319216 B2 JP H0319216B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- reaction
- tetrahydrofuran
- ether
- solution
- 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
- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 C1 - C6 alkyl Chemical group 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- 239000011737 fluorine Chemical group 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 239000007818 Grignard reagent Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 150000004795 grignard reagents Chemical class 0.000 description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- GHJKHGDTSTWNIT-UHFFFAOYSA-N butyl 2-phenylpropanoate Chemical compound CCCCOC(=O)C(C)C1=CC=CC=C1 GHJKHGDTSTWNIT-UHFFFAOYSA-N 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SDCQIQBANDMXMI-UHFFFAOYSA-M benzene;iodomanganese(1+) Chemical compound I[Mn+].C1=CC=[C-]C=C1 SDCQIQBANDMXMI-UHFFFAOYSA-M 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- BVBHVVRVSMBCPW-UHFFFAOYSA-N 1-bromo-4-(2-methylpropyl)benzene Chemical compound CC(C)CC1=CC=C(Br)C=C1 BVBHVVRVSMBCPW-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 4
- QWYFOIJABGVEFP-UHFFFAOYSA-L manganese(ii) iodide Chemical compound [Mn+2].[I-].[I-] QWYFOIJABGVEFP-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HTRNHWBOBYFTQF-UHFFFAOYSA-N 4-bromo-2-fluoro-1-phenylbenzene Chemical group FC1=CC(Br)=CC=C1C1=CC=CC=C1 HTRNHWBOBYFTQF-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000005416 organic matter Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- NHEFSTXHZRGAIH-UHFFFAOYSA-M sodium;2-bromopropanoate Chemical compound [Na+].CC(Br)C([O-])=O NHEFSTXHZRGAIH-UHFFFAOYSA-M 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 241001465754 Metazoa Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- INMAEXGIVZJYIJ-UHFFFAOYSA-N butyl 2-bromopropanoate Chemical compound CCCCOC(=O)C(C)Br INMAEXGIVZJYIJ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002697 manganese compounds Chemical class 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 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 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、α−置換フエニル−アルカンカルボ
ン酸誘導体の新規な製造方法に関する。更に詳し
く言えば、本発明は一般式
（式中、Ｒは水素、C1〜C4アルキルまたはア
ラルキル基であり、R1は水素、C1〜C6アルキル、
アラルキル、アリール、フツ素化アリールまたは
アリールオキシ基であり、R2は水素またはフツ
素原子である）
で表わされる化合物、即ちα−置換フエニル−
アルカンカルボン酸を製造するのに有益な中間体
の製法に関する。
上記化合物は、人間や動物に対して消炎、鎮
痛、解熱等の薬効を有し、なかでもＲがメチル
基、R1がイソブチル基、R2が水素原子である化
合物に対応するカルボン酸およびＲがメチル基、
R1がフエニル基、R2がフツ素原子に対応するカ
ルボン酸またはこれらの塩はとりわけ優れた消
炎、鎮痛、解熱の薬理効果を示すことが知られて
いる。
本発明は、この様な医薬を効率良く製造する過
程において重要な、中間体ないし前駆体の製法に
関する。
これらのα−置換フエニル−アルカンカルボン
酸またはその塩の従来より知られている製造法と
しては、例えば特公昭40−7491号、特公昭43−
22297号、特公昭44−25076号、特公昭47−18105
号等の各公報に記載され公知である。これらの方
法は何れも良く知られた化学反応を巧みに組合せ
たものであるが、一般に工程が長く、操作も複雑
で必ずしも満足できるものではない。
本発明者らは、前記中間体ないし前駆体である
一般式
（式中、ＹはC1〜C4アルキル基、リチウム、
ナトリウム、カルシウム等のアルカリ、アルカリ
土類金属原子であり、Ｒ，R1，R2は前記に同じ）
で表わされる、化合物のカルボキシル基に保護
基を有する化合物、即ちα−置換フエニル−ア
ルカンカルボン酸誘導体の合成について鋭意研究
の結果、従来知られている方法に較べ、工程数が
少なく容易に純度よく目的物を得る新規な製造法
を見出し本発明に至つた。
即ち、本発明は、下記反応式により容易に得ら
れる一般式
（式中R1はC1〜C6アルキル、アラルキル、ア
リール、フツ素化アリールまたはアリールオキシ
基であり、R2は水素またはフツ素原子、Ｘはヨ
ウ素、臭素、塩素などのハロゲン原子である）
で表わされる化合物、即ちハロゲン化マンガン
化合物と、一般式
（式中Ｒは水素、C1〜C4アルキルまたはアラ
ルキル基であり、Ｘはハロゲン原子例えば塩素、
臭素、沃素、ＹはC1〜C4アルキル基、リチウム、
ナトリウム、マグネシウム、カルシウム等のアル
カリ、アルカリ土類金属原子である）
なる化合物と反応させることにより、化合物を
得ることを特徴としている。
得られた化合物は、次いでＹがアルキル基の
場合は加水分解し、金属の場合は酸性にすること
により容易に一般式
（式中の符号は前記に同じ）
で表わされるα−置換フエニル−アルカンカルボ
ン酸に変換し得る。
本発明の方法に於て出発物質として使用される
化合物は、次の様にして製造することが最適で
ある。フエニルブロマイド化合物と金属マグネシ
ウムとを、無水テトラヒドロフラン中で窒素気流
下で反応させる通常のグリニアール試薬を得る反
応に準じて行い、相当するフエニルのグリニアー
ル試薬を得ることができる。次いで、無水沃化マ
ンガンのテトラヒドロフランの懸濁液（一部溶
解）中に上記グリニアール試薬を−20〜−30℃で
滴下すると、容易にフエニルヨウ化マンガン（化
合物）のテトラヒドロフラン懸濁液を得ること
ができる。
本発明の方法、即ち化合物と化合物とより
化合物を製造する方法を次に詳述する。
化合物は概して室温まで安定であるから、上
述の如く製造したフエニル沃化マンガンのテトラ
ヒドロフラン懸濁液を窒素気流中−20〜30℃好ま
しくは−５〜０℃に冷却し、これに化合物を添
加かくはんする。添加後、反応液は灰色に変化す
る。反応温度を−５〜室温（25℃）の範囲で（対
象物質によつて反応温度が異る）10〜24時間かく
はんする。反応進行に伴い着色度が増し黒褐色と
なる。
反応後、反応液を飽和塩化アンモン中に投入し
て加水分解した後酸性としエチルエーテルで抽出
する。有機層を10％酸性亜硫酸ソーダで洗浄し更
に水洗する。
本発明の目的物である化合物はこの様にして
得られ、それが塩である場合はそのまま単離して
医薬の用途に利用することも可能である。然しな
がらこの化合物は、単離することなく次の反応
工程に利用するのが良く、以下に述べる工程を経
ることにより化合物すなわちα−置換フエニル
−アルカンカルボン酸に変換される。但し、化合
物におけるＹが金属原子の場合とアルキル基の
場合とで以後の処理条件が相違する。
ａ）Ｙが金属原子の場合
エーテル層に５％カセイソーダを加えて生成物
を抽出し、次いでこのカセイソーダ水溶液を塩酸
酸性にし析出する有機物をエーテルで再抽出し無
水硫酸ソーダで乾燥後エーテルを留去し粗生成物
を得る。
粗生成物は、適当な有機溶剤で再結晶するか或
は逆相クロマトグラフイーで分離することによつ
て化合物の精製物を得る。
ｂ）Ｙがアルキル基の場合
エーテル層を無水硫酸ソーダで乾燥後エーテル
を留去し、フエニル−アルカンカルボン酸エステ
ルの粗生成物を得る。粗生成物にカセイソーダを
含むメタノール水系溶液を加えて数時間加熱環流
して後、メタノールを留去し、適当量の水を加え
て塩酸酸性として析出する有機物をエーテル抽出
し、エーテル層を無水硫酸で乾燥後エーテルを留
去して相当するカルボン酸粗生成物を得る。粗生
成物から適当な有機溶剤で再結晶するか或は逆相
クロマトグラフイーで分離することによつて化合
物の精製物を得る。
次に実施例を示し、本発明を更に具体的に説明
する。
実施例 １
２−（２−フルオロ−４−ビフエニリル）プロ
ピオン酸の製法
金属マグネシウム片0.122ｇ（0.005モル）、ヨ
ウド小片およびテトラヒドロフラン７ml中に窒素
気流下に４−ブロモ−２−フルオロビフエニル
1.005ｇ（0.004モル）をテトラヒドロフラン３ml
に溶解した溶液を室温で滴下する。滴下開始後、
数分で反応が開始し金属マグネシウムの溶解が観
察される。次第に発熱するが温度が35℃に達した
ならその温度に保つ様４−ブロモ−２−フルオロ
ビフエニルのテトラヒドロフラン溶液の滴下を調
節し、40分を要して滴下を終了する。室温にて
1.5時間かくはんしこのグリニアール反応を完結
させた。
一方、別の反応器中でテトラヒドロフラン20ml
に無水沃化マンガン1.240ｇ（0.004モル）を加え
窒素気流中懸濁（一部溶解）かくはんし、−20℃
に冷却する。これに上述の如くして得た４−ブロ
モ−２−フルオロビフエニルのグリニアール試薬
のテトラヒドロフラン溶液を約40分を要して滴下
した。更に０℃で30分かくはんした。反応懸濁液
は最初の桃色から黄緑色に変化しグリニアール試
薬が沃化マンガン化合物に変化したことを示し
た。
上記沃化マンガン化合物のテトラヒドロフラン
の懸濁液中に０℃で２−ブロモプロピオン酸ナト
リウム0.70ｇ（0.004モル）を添加し、更に０℃
で10時間かくはんした。反応後は、灰褐色となつ
た。反応混合物を飽和塩化アンモン50ml中に添加
して反応物質を分解し更にこの液に塩酸を加えて
PH２まで酸性としてかくはんしエーテルを加えて
抽出した。
エーテル層は、10％酸性亜硫酸ソーダの35mlで
２回、水洗１回行い、次いで10％カセイソーダの
30mlで２回抽出した。カセイソーダ抽出液を塩酸
酸性とし析出した有機物をエーテル抽出しエーテ
ルを留去して油状物を得た。この油状物を放置す
れば固化しこれをｎ−ヘキサンより再結晶し融点
110〜112℃の２−（２−フルオロ−４−ビフエニ
ル）プロピオン酸の結晶0.684ｇ（収率70％、対
４−ブロモ−２−フルオロビフエニル）が得られ
た。得られた物質は、薄層クロマトグラフイー
（逆相RP−８使用）で、展開溶剤メタノール：ギ
酸：水＝75：15：10によりRf＝0.42の１スポツト
を示した。
元素分析値 C15H15FO2
Ｃ Ｈ Ｆ
分析値(%) 73.83 5.33 7.64
計算値(%) 73.75 5.36 7.78
The present invention relates to a novel method for producing α-substituted phenyl-alkane carboxylic acid derivatives. More specifically, the present invention relates to the general formula (wherein R is hydrogen, C1 - C4 alkyl or aralkyl group, R1 is hydrogen, C1 - C6 alkyl,
aralkyl, aryl, fluorinated aryl or aryloxy group, R 2 is hydrogen or fluorine atom), i.e. α-substituted phenyl-
The present invention relates to a process for producing intermediates useful for producing alkane carboxylic acids. The above compounds have medicinal effects such as anti-inflammatory , analgesic , and antipyretic effects on humans and animals, and in particular, carboxylic acids and R is a methyl group,
It is known that carboxylic acids in which R 1 is a phenyl group and R 2 is a fluorine atom, or salts thereof, exhibit particularly excellent pharmacological effects of anti-inflammatory, analgesic, and antipyretic effects. The present invention relates to a method for producing intermediates or precursors that are important in the process of efficiently producing such drugs. Conventionally known production methods for these α-substituted phenyl-alkane carboxylic acids or salts thereof include, for example, Japanese Patent Publication Nos. 40-7491 and 43-74.
No. 22297, Special Publication No. 1977-25076, Special Publication No. 18105, No. 47-1810
It is described in various publications such as No. 1 and is publicly known. All of these methods skillfully combine well-known chemical reactions, but the steps are generally long and the operations are complicated, so they are not always satisfactory. The present inventors have discovered that the intermediate or precursor has the general formula (In the formula, Y is a C 1 to C 4 alkyl group, lithium,
An alkali or alkaline earth metal atom such as sodium or calcium, and R, R 1 , R 2 are the same as above) A compound having a protecting group on the carboxyl group of the compound, that is, α-substituted phenyl-alkane carbon As a result of extensive research into the synthesis of acid derivatives, we have discovered a new manufacturing method that requires fewer steps and easily obtains the desired product with high purity compared to conventionally known methods, leading to the present invention. That is, the present invention provides a general formula that can be easily obtained from the following reaction formula. (In the formula, R 1 is a C 1 to C 6 alkyl, aralkyl, aryl, fluorinated aryl or aryloxy group, R 2 is hydrogen or a fluorine atom, and X is a halogen atom such as iodine, bromine, chlorine, etc.) ), that is, a halogenated manganese compound, and a compound represented by the general formula (In the formula, R is hydrogen, C1 - C4 alkyl or aralkyl group, and X is a halogen atom such as chlorine,
Bromine, iodine, Y is a C 1 - C 4 alkyl group, lithium,
It is characterized by obtaining a compound by reacting it with a compound (which is an alkali or alkaline earth metal atom such as sodium, magnesium, or calcium). The obtained compound can then be easily converted into the general formula by hydrolysis if Y is an alkyl group or acidification if Y is a metal. (The symbols in the formula are the same as above) It can be converted into an α-substituted phenyl-alkanecarboxylic acid represented by The compounds used as starting materials in the method of the present invention are optimally produced as follows. The corresponding phenyl Grignard reagent can be obtained by reacting a phenyl bromide compound and metallic magnesium in anhydrous tetrahydrofuran under a nitrogen stream in a manner similar to the reaction for obtaining a normal Grignard reagent. Next, by dropping the Grignard reagent mentioned above at -20 to -30°C into a suspension (partially dissolved) of anhydrous manganese iodide in tetrahydrofuran, a suspension of phenyl manganese iodide (compound) in tetrahydrofuran can be easily obtained. can. The method of the present invention, ie, the method for producing a compound from two compounds, will be described in detail below. Since the compound is generally stable up to room temperature, the suspension of phenylmanganese iodide in tetrahydrofuran prepared as described above is cooled to -20 to 30°C, preferably -5 to 0°C in a nitrogen stream, and the compound is added thereto and stirred. do. After the addition, the reaction solution turns gray. Stir at a reaction temperature in the range of -5 to room temperature (25°C) for 10 to 24 hours (reaction temperature varies depending on the target substance). As the reaction progresses, the degree of coloration increases and becomes blackish brown. After the reaction, the reaction solution was poured into saturated ammonium chloride for hydrolysis, then acidified and extracted with ethyl ether. Wash the organic layer with 10% acidic sodium sulfite and then with water. The compound that is the object of the present invention can be obtained in this way, and if it is a salt, it can be isolated as it is and used for pharmaceutical purposes. However, this compound is preferably used in the next reaction step without being isolated, and is converted into the compound, ie, the α-substituted phenyl-alkane carboxylic acid, through the steps described below. However, the subsequent processing conditions are different depending on whether Y in the compound is a metal atom or an alkyl group. a) When Y is a metal atom Add 5% caustic soda to the ether layer to extract the product, then acidify the caustic soda aqueous solution with hydrochloric acid, re-extract the precipitated organic matter with ether, dry with anhydrous sodium sulfate, and then distill off the ether. A crude product is obtained. The crude product is recrystallized from a suitable organic solvent or separated by reverse phase chromatography to obtain a purified compound. b) When Y is an alkyl group After drying the ether layer over anhydrous sodium sulfate, the ether is distilled off to obtain a crude product of phenyl-alkane carboxylic acid ester. After adding a methanol aqueous solution containing caustic soda to the crude product and heating under reflux for several hours, methanol was distilled off, an appropriate amount of water was added, and the organic matter precipitated as acidified with hydrochloric acid was extracted with ether, and the ether layer was extracted with anhydrous sulfuric acid. After drying, the ether is distilled off to obtain the corresponding crude carboxylic acid product. A purified product of the compound is obtained from the crude product by recrystallization from a suitable organic solvent or separation by reverse phase chromatography. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples. Example 1 Process for producing 2-(2-fluoro-4-biphenylyl)propionic acid 4-bromo-2-fluorobiphenyl was added to 0.122 g (0.005 mol) of magnesium metal, small iodine pieces, and 7 ml of tetrahydrofuran under a nitrogen stream.
1.005g (0.004mol) in 3ml of tetrahydrofuran
Add dropwise the solution at room temperature. After starting dripping,
The reaction starts in a few minutes and dissolution of metallic magnesium is observed. Although the mixture gradually generates heat, once the temperature reaches 35°C, the dropwise addition of the tetrahydrofuran solution of 4-bromo-2-fluorobiphenyl is adjusted so as to maintain the temperature, and the dropwise addition is completed in 40 minutes. at room temperature
The Grignard reaction was completed by stirring for 1.5 hours. Meanwhile, in another reactor 20 ml of tetrahydrofuran
Add 1.240 g (0.004 mol) of anhydrous manganese iodide to the solution, suspend (partially dissolve) in a nitrogen stream, and stir at -20°C.
Cool to A tetrahydrofuran solution of the Grignard reagent of 4-bromo-2-fluorobiphenyl obtained as described above was added dropwise thereto over a period of about 40 minutes. The mixture was further stirred at 0°C for 30 minutes. The reaction suspension changed from an initial pink color to a yellow-green color, indicating that the Grignard reagent had been converted to a manganese iodide compound. 0.70 g (0.004 mol) of sodium 2-bromopropionate was added to the above suspension of manganese iodide compound in tetrahydrofuran at 0°C, and then at 0°C.
I stirred it for 10 hours. After the reaction, the color turned grayish brown. The reaction mixture was added to 50 ml of saturated ammonium chloride to decompose the reactant, and then hydrochloric acid was added to this liquid.
The mixture was acidified to pH 2, stirred, and extracted with ether. The ether layer was washed twice with 35 ml of 10% acidic sodium sulfite and once with water, then washed with 10% caustic soda.
Extracted twice with 30 ml. The caustic soda extract was acidified with hydrochloric acid, the precipitated organic matter was extracted with ether, and the ether was distilled off to obtain an oily substance. If this oil is left to stand, it will solidify, and it will be recrystallized from n-hexane and its melting point will be
0.684 g of crystals of 2-(2-fluoro-4-biphenyl)propionic acid (yield 70%, based on 4-bromo-2-fluorobiphenyl) were obtained at 110-112°C. The obtained substance showed one spot of Rf=0.42 by thin layer chromatography (using reverse phase RP-8) using a developing solvent of methanol:formic acid:water=75:15:10. Elemental analysis value C 15 H 15 FO 2 C H F Analysis value (%) 73.83 5.33 7.64 Calculated value (%) 73.75 5.36 7.78
【表】
実施例 ２
２−（４−イソブチルフエニル）プロピオン酸
の製法
金属マグネシウム片0.146ｇ（0.006モル）、ヨ
ード小片およびテトラヒドロフラン10ml中に窒素
気流下にパラ−ブロモイソブチルベンゼン1.066
ｇ（0.005モル）をテトラヒドロフラン５mlに溶
解した溶液を室温で滴下した。滴下開始後、数分
で反応が開始し徐々に温度が上昇し40℃に達す
る。その温度を保つ様にパラ−ブロムイソブチル
ベンゼンのテトラヒドロフラン溶液の滴下を調節
し30分を要して滴下を終了した。室温で２時間か
くはんを続け、このグリニアール反応を完結させ
た。
一方、別の反応器中でテトラヒドロフラン20ml
中に無水沃化マンガン1.544ｇ（0.005モル）を加
え窒素気流中懸濁（一部溶解）かくはんし−20℃
に冷却する。これに上述で得たパラ−ブロモイソ
ブチルベンゼンのグリニアール試薬のテトラヒド
ロフラン溶液を−20℃以下に保ち約30分を要して
滴下した。滴下終了後、０℃で１時間かくはんを
続けた。反応懸濁液は、黄緑色となり沃化マンガ
ン化合物に変化したことを示した。
次いでこの沃化マンガン化合物の懸濁液中に０
℃で２−ブロモプロピオン酸ナトリウム0.875ｇ
（0.005モル）を添加し更に０℃で７時間かくはん
した。反応液は、黄緑色から次第に灰褐色に変化
した。
反応混合物の後処理方法は、実施例１と同様に
行い粗生成物（油状）を得た。これをｎ−ヘキサ
ンより再結晶し融点75〜77℃の２−（４−イソブ
チル）フエニルプロピオン酸の結晶0.774ｇ（収
率75％、対パラ−ブロモイソブチルベンゼン）を
得た。
元素分析値 C13H18O2
Ｃ Ｈ
分析値 75.58 8.85
計算値 75.73 8.74[Table] Example 2 Process for producing 2-(4-isobutylphenyl)propionic acid 0.146 g (0.006 mol) of metal magnesium pieces, small iodine pieces, and 1.066 g of para-bromoisobutylbenzene in 10 ml of tetrahydrofuran under a nitrogen stream.
A solution of 0.005 mol) dissolved in 5 ml of tetrahydrofuran was added dropwise at room temperature. After the dropwise addition begins, the reaction starts within a few minutes, and the temperature gradually rises to 40°C. The dropwise addition of the tetrahydrofuran solution of para-bromoisobutylbenzene was adjusted so as to maintain the temperature, and the dropwise addition was completed in 30 minutes. Stirring was continued for 2 hours at room temperature to complete the Grignard reaction. Meanwhile, in another reactor 20 ml of tetrahydrofuran
Add 1.544 g (0.005 mol) of anhydrous manganese iodide to the solution and suspend (partially dissolve) in a nitrogen stream. Stir at -20°C.
Cool to The tetrahydrofuran solution of the Grignard reagent of para-bromoisobutylbenzene obtained above was added dropwise to the solution over a period of about 30 minutes while keeping the temperature below -20°C. After the addition was completed, stirring was continued for 1 hour at 0°C. The reaction suspension turned yellow-green, indicating that it had changed into a manganese iodide compound. Then, in this suspension of manganese iodide compound, 0
Sodium 2-bromopropionate 0.875g at °C
(0.005 mol) was added and further stirred at 0°C for 7 hours. The reaction solution gradually changed from yellow-green to grayish-brown. The reaction mixture was post-treated in the same manner as in Example 1 to obtain a crude product (oil). This was recrystallized from n-hexane to obtain 0.774 g of crystals of 2-(4-isobutyl)phenylpropionic acid (yield 75%, based on para-bromoisobutylbenzene) having a melting point of 75-77°C. Elemental analysis value C 13 H 18 O 2 C H Analysis value 75.58 8.85 Calculated value 75.73 8.74
【表】
実施例 ３
２−フエニルプロピオン酸の製法
金属マグネシウム片0.39ｇ（0.016モル）、ヨウ
ド小片、およびテトラヒドロフラン10ml中に窒素
気流下にブロムベンゼン2.36ｇ（0.015モル）を
テトラヒドロフラン５mlに溶解した溶液を10〜13
℃で滴下した。発熱反応であるのでブロムベンゼ
ン溶液の滴下速度を調節することにより同温度を
保つ様にした。約30分を要して滴下した後、室温
に1.5時間かくはんを続けグリニアール反応を完
結させた。
一方、別の反応器でテトラヒドロフラン40ml中
に無水沃化マンガン4.6ｇ（0.015モル）を加え、
窒素気流中懸濁（一部溶解）かくはんし−20℃に
冷却する。これに上述の様にして得たブロムベン
ゼンのグリニアール試薬のテトラヒドロフラン溶
液を反応温度を−20℃以下に保ち約30分を要して
滴下した。反応液全体が黄緑色に変化しフエニル
マンガンアイオダイドの生成が観察された。温度
を室温まであげて30分間かくはんしこの反応を完
結させた。
次いでこの沃化マンガン化合物の懸濁液を−10
℃に冷却し、２−ブロモプロピオン酸ナトリウム
2.62ｇ（0.015モル）を添加し更に０℃で１時間、
室温で一夜かくはんした。反応液は、黒褐色に変
化した。
反応混合物は、実施例１と同様の方法で処理
し、褐色油状の粗生成物2.6ｇを得た。これを逆
相カラムクロマトグラフイーにより分取し２−フ
エニルプロピオン酸として微黄色芳香を有する油
状物1.78ｇ（収率79.0％対ブロムベンゼン）を得
た。
元素分析値 C9H10O2
Ｃ Ｈ
分析値 71.34 6.56
計算値 71.98 6.71[Table] Example 3 Process for producing 2-phenylpropionic acid 0.39 g (0.016 mol) of metal magnesium pieces, small iodine pieces, and 2.36 g (0.015 mol) of bromobenzene were dissolved in 5 ml of tetrahydrofuran under a nitrogen stream in 10 ml of tetrahydrofuran. solution 10-13
It was added dropwise at ℃. Since this was an exothermic reaction, the same temperature was maintained by adjusting the dropping rate of the bromobenzene solution. After the dropwise addition took about 30 minutes, stirring was continued for 1.5 hours at room temperature to complete the Grignard reaction. Meanwhile, in another reactor, 4.6 g (0.015 mol) of anhydrous manganese iodide was added to 40 ml of tetrahydrofuran.
Suspend (partly dissolve) in a stream of nitrogen, stir and cool to -20°C. A tetrahydrofuran solution of the Grignard reagent of bromobenzene obtained as described above was added dropwise to this solution over a period of about 30 minutes while maintaining the reaction temperature at -20°C or lower. The entire reaction solution turned yellow-green, and formation of phenylmanganese iodide was observed. The temperature was raised to room temperature and stirred for 30 minutes to complete the reaction. Next, this suspension of manganese iodide compound was heated to -10
Cool to °C and add sodium 2-bromopropionate.
Added 2.62g (0.015mol) and further heated at 0℃ for 1 hour.
Stir overnight at room temperature. The reaction solution turned blackish brown. The reaction mixture was treated in the same manner as in Example 1 to obtain 2.6 g of a brown oily crude product. This was fractionated by reverse phase column chromatography to obtain 1.78 g (yield 79.0% vs. bromobenzene) of an oily substance with a faint yellow aroma as 2-phenylpropionic acid. Elemental analysis value C 9 H 10 O 2 C H Analysis value 71.34 6.56 Calculated value 71.98 6.71
【表】
実施例 ４
２−フエニルプロピオン酸ブチル（ｎ）の製法
ブロムベンゼンを原料とするグリニアール試薬
を得る反応およびそれからフエニルマンガンアイ
オダイドを得る方法は、実施例３と全く同様に行
つた。
フエニルマンガンアイオダイドのテトラヒドロ
フラン懸濁液を−10℃に冷却し、２−ブロモプロ
ピオン酸ブチル（ｎ）エステル3.14ｇ（0.015モ
ル）を10mlのテトラヒドロフランに溶解した溶液
を20分間で滴下した。更に０℃で１時間、室温で
一夜かくはんを続けた。褐色の反応混合物を飽和
塩化アンモン50ml中に添加して反応物質を分解
し、更にこの液に塩酸を加えてPH２まで酸性とし
て後エーテル抽出した。
エーテル層は、10％酸性亜硫酸ソーダの35mlで
２回、水洗２回行い、無水硫酸ソーダで乾燥した
後エーテルを留去して粗生成物（油状）3.27ｇを
得た。この粗生成物を逆相カラムクロマトグラフ
イーにより分取し、２−フエニルプロピオン酸ブ
チル（ｎ）油状物2.19ｇ（収率71％対ブロムベン
ゼン）を得た。
元素分析値 C13H18O2
Ｃ Ｈ
分析値 75.51 8.68
計算値 75.69 8.80[Table] Example 4 Method for producing butyl 2-phenylpropionate (n) The reaction to obtain the Grignard reagent using bromobenzene as a raw material and the method to obtain phenylmanganese iodide from it were carried out in exactly the same manner as in Example 3. . A suspension of phenylmanganese iodide in tetrahydrofuran was cooled to -10°C, and a solution of 3.14 g (0.015 mol) of butyl 2-bromopropionate (0.015 mol) dissolved in 10 ml of tetrahydrofuran was added dropwise over 20 minutes. Stirring was continued for an additional 1 hour at 0°C and overnight at room temperature. The brown reaction mixture was added to 50 ml of saturated ammonium chloride to decompose the reactant, and the solution was acidified to pH 2 by adding hydrochloric acid, followed by extraction with ether. The ether layer was washed twice with 35 ml of 10% acidic sodium sulfite and twice with water, dried over anhydrous sodium sulfate, and the ether was distilled off to obtain 3.27 g of a crude product (oil). This crude product was separated by reverse phase column chromatography to obtain 2.19 g of butyl 2-phenylpropionate (n) oil (yield 71% vs. bromobenzene). Elemental analysis value C 13 H 18 O 2 C H Analysis value 75.51 8.68 Calculated value 75.69 8.80
【表】
２−フエニルプロピオン酸の製法
上述の様にして得た２−フエニルプロピオン酸
ブチル（ｎ）3.0ｇとメチルアルコール30ml、5N
−カセイソーダ７mlの混合物を５時間環流加水分
解した。メチルアルコールを減圧下に留去し水30
mlを添加する。エーテル50mlを加えエーテル可溶
部を抽出し去り、アルカリ性水溶液を分離した。
アルカリ性水溶液は、5N−塩酸を、加えて酸性
とし、分離してきた油状物をエーテルで抽出し、
エーテル溶液は、無水硫酸ソーダで乾燥後、エー
テルを留去して油状物質1.95ｇ（収率89.4％）を
得た。このものは次の分析結果より２−フエニル
プロピオン酸と確認した。
元素分析値 C9H10O2
Ｃ Ｈ
分析値 72.03 6.59
計算値 71.98 6.71[Table] Method for producing 2-phenylpropionic acid 3.0 g of butyl 2-phenylpropionate (n) obtained as described above and 30 ml of methyl alcohol, 5N
- A mixture of 7 ml of caustic soda was hydrolyzed at reflux for 5 hours. Distill methyl alcohol under reduced pressure and add 30% water
Add ml. 50 ml of ether was added to extract the ether-soluble portion, and the alkaline aqueous solution was separated.
The alkaline aqueous solution is made acidic by adding 5N hydrochloric acid, and the separated oil is extracted with ether.
The ether solution was dried over anhydrous sodium sulfate, and the ether was distilled off to obtain 1.95 g (yield: 89.4%) of an oily substance. This product was confirmed to be 2-phenylpropionic acid based on the following analysis results. Elemental analysis value C 9 H 10 O 2 C H Analysis value 72.03 6.59 Calculated value 71.98 6.71
Claims (1)
ラルキル基、R1は水素、C1〜C6アルキル、アラ
ルキル、アリール、フツ素化アリールまたはアリ
ールオキシ基、R2は水素またはフツ素原子であ
り、ＹはC1〜C4アルキル基、リチウム、ナトリ
ウム、カルシウム等のアルカリ、アルカリ土類金
属原子である） で表わされる化合物の製造方法であつて、 一般式： （式中、Ｘはハロゲン原子であり、R1，R2は
上記に同じ） で表わされる化合物と、 一般式 （式中、Ｘ，Ｙは上記に同じ） で表わされる化合物とを反応させることを特徴
とするα−置換フエニル−アルカンカルボン酸誘
導体の製法。 ２ 化合物におけるＸがヨウ素である特許請求
の範囲第１項記載の製法。 ３ 化合物が
【式】である特許 請求の範囲第１または２項記載の製法。 ４ 化合物が である特許請求の範囲第１または２項記載の製
法。[Claims] 1. General formula: (wherein R is hydrogen, C1 - C4 alkyl or aralkyl group, R1 is hydrogen, C1 - C6 alkyl, aralkyl, aryl, fluorinated aryl or aryloxy group, R2 is hydrogen or fluorine Y is a C1 - C4 alkyl group, alkali or alkaline earth metal atom such as lithium, sodium, calcium, etc.) A method for producing a compound represented by the general formula: (In the formula, X is a halogen atom, and R 1 and R 2 are the same as above) and a compound represented by the general formula (wherein X and Y are the same as above) A method for producing an α-substituted phenyl-alkane carboxylic acid derivative, characterized by reacting with a compound represented by the following. 2. The manufacturing method according to claim 1, wherein X in the compound is iodine. 3. The manufacturing method according to claim 1 or 2, wherein the compound is [Formula]. 4 The compound is The manufacturing method according to claim 1 or 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3948782A JPS58157744A (en) | 1982-03-15 | 1982-03-15 | Production of alpha-substituted phenylalkanecarboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3948782A JPS58157744A (en) | 1982-03-15 | 1982-03-15 | Production of alpha-substituted phenylalkanecarboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58157744A JPS58157744A (en) | 1983-09-19 |
| JPH0319216B2 true JPH0319216B2 (en) | 1991-03-14 |
Family
ID=12554405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3948782A Granted JPS58157744A (en) | 1982-03-15 | 1982-03-15 | Production of alpha-substituted phenylalkanecarboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58157744A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005255577A (en) * | 2004-03-10 | 2005-09-22 | Asahi Kasei Pharma Kk | Method of continuous production using tubular reactor |
-
1982
- 1982-03-15 JP JP3948782A patent/JPS58157744A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58157744A (en) | 1983-09-19 |
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