JP3907787B2 - Method for producing benzoic acid derivative - Google Patents
Method for producing benzoic acid derivative Download PDFInfo
- Publication number
- JP3907787B2 JP3907787B2 JP16042697A JP16042697A JP3907787B2 JP 3907787 B2 JP3907787 B2 JP 3907787B2 JP 16042697 A JP16042697 A JP 16042697A JP 16042697 A JP16042697 A JP 16042697A JP 3907787 B2 JP3907787 B2 JP 3907787B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- alkali
- general formula
- benzoic acid
- derivative
- 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 - Fee Related
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 title claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 33
- 239000003513 alkali Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 13
- -1 phenylbenzoic acid ester Chemical class 0.000 claims description 13
- 239000012044 organic layer Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 6
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 5
- 238000003916 acid precipitation Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000005187 foaming Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- XWCWFMQMZZPALR-UHFFFAOYSA-N 4-(4-phenylbutoxy)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OCCCCC1=CC=CC=C1 XWCWFMQMZZPALR-UHFFFAOYSA-N 0.000 description 4
- XPBQQAHIVODAIC-UHFFFAOYSA-N 4-bromobutylbenzene Chemical compound BrCCCCC1=CC=CC=C1 XPBQQAHIVODAIC-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- QZEKRNXKYOIRAJ-UHFFFAOYSA-N 3-amino-2-(2h-tetrazol-5-yl)chromen-4-one Chemical compound O1C2=CC=CC=C2C(=O)C(N)=C1C=1N=NNN=1 QZEKRNXKYOIRAJ-UHFFFAOYSA-N 0.000 description 1
- QPHBWKNXAHIYPZ-UHFFFAOYSA-N 5-bromopentan-2-ylbenzene Chemical compound BrCCCC(C)C1=CC=CC=C1 QPHBWKNXAHIYPZ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- XWYPMOYTTQTLRE-UHFFFAOYSA-N pentyl benzenecarboperoxoate Chemical compound CCCCCOOC(=O)C1=CC=CC=C1 XWYPMOYTTQTLRE-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 239000012070 reactive reagent Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は医薬、農薬等の中間体として有用なフェニルアルコキシ安息香酸誘導体の改良された製造方法に関する。
【０００２】
【従来の技術】
本発明の上記フェニルアルコキシ安息香酸誘導体は、例えば特開平３−９５１４４号公報、特開平７−２５８１９号公報に記載された公知の化合物である。
【０００３】
【発明が解決しようとする課題】
前者の方法では高価な溶媒やナトリウムメトキシドのような反応性の高い試薬を用い、しかも精製方法も複雑であるという問題点があった。
後者の方法はフェニルアルキルハライド誘導体とヒドロキシ安息香酸エステル誘導体を、塩基性物質の存在下、反応させ、反応混合物にアルカリ水溶液を加えて加水分解する方法であり、反応の際の溶媒としては非プロトン性極性溶媒等の反応に不活性な溶媒を用い、またアルカリ水溶液との反応終了後は水を加えて抽出し、得られた水層を有機溶媒で洗浄した後に酸を加えて中和するが、この酸析の際に発泡が激しく起こるので、反応器の容積を十分に利用することができないという欠点があった。
本発明の課題は抽出操作が不要で、酸析の際に発泡が起こらず、有機溶媒で洗浄しなくても目的物を高純度かつ高収率で得ることのできる工業的に有利な且つ経済的にも有利なフェニルアルコキシ安息香酸誘導体の製造方法を提供することにある。
【０００４】
【課題を解決するための手段】
本発明は一般式（１）で表されるフェニルアルキルハライド誘導体に一般式（２）で表されるヒドロキシ安息香酸エステル誘導体を、炭酸アルカリ又は炭酸水素アルカリの存在下、イソプロピルアルコール溶媒中、反応させ、反応終了後イソプロピルアルコールを除去して得られた水相と有機層を分液して水相を除き、有機層に水及びアルカリを加えて加水分解を行って一般式（３）で表される安息香酸誘導体を得ることを特徴とする安息香酸誘導体の製造方法に係る。
【０００５】
【化４】
【０００６】
【化５】
【０００７】
【化６】
【０００８】
【発明の実施の形態】
本発明の出発原料の一般式（１）のフェニルアルキルハライド誘導体において、Ａで示される炭素数２〜５のアルキレン基としては、例えばエチレン、プロピレン、ブチレン、ペンチレン基を挙げることができる。Ｘで示されるハロゲンとしては、例えば塩素、臭素、ヨウ素等を挙げることができる。
一般式（１）の化合物の例として、例えば１−ブロモ−４−フェニルエタン、１−ブロモ−４−フェニルプロパン、１−ブロモ−４−フェニルブタン、１−ブロモ−４−フェニルペンタン、これらのブロモ基が塩素基、ヨウ素基に置換したもの等を挙げることができる。
一般式（１）のフェニルアルキルハライド誘導体は特開平３−９５１４４号、特開平７−２５８１９号に記載された公知の化合物であり、入手容易な化合物である。
【０００９】
本発明のもう一方の出発原料の一般式（２）のヒドロキシ安息香酸エステル誘導体において、Ｒで示される炭素数１〜６のアルキルとしてはメチル、エチル、プロピル、ブチル、ペンチル、ヘキシル基を挙げることができる。
一般式（２）の化合物の例として、例えばｏ，ｍまたはｐ−ヒドロキシ安息香酸メチル、ｏ，ｍまたはｐ−ヒドロキシ安息香酸エチル、ｏ，ｍまたはｐ−ヒドロキシ安息香酸プロピル、ｏ，ｍまたはｐ−ヒドロキシ安息香酸ブチル、ｏ，ｍまたはｐ−ヒドロキシ安息香酸ペンチル、ｏ，ｍまたはｐ−ヒドロキシ安息香酸ヘキシルを挙げることができる。一般式（２）のヒドロキシ安息香酸エステル誘導体も特開平３−９５１４４号、特開平７−２５８１９号に記載された公知の化合物であり、入手容易な化合物である。
【００１０】
次に式（１）のフェニルアルキルハライド誘導体と式（２）のヒドロキシ安息香酸エステル誘導体を、炭酸アルカリ又は炭酸水素アルカリの存在下、イソプロピルアルコール溶媒中、反応させ、反応終了後イソプロピルアルコールを除去して得られた水相と有機層を分液して水相を除き、有機層に水及びアルカリを加えて加水分解を行うことにより一般式（３）で表されるフェニルアルコキシ安息香酸誘導体を得ることができる。
炭酸アルカリとしては、例えば炭酸ナトリウム、炭酸カリウム等、炭酸水素アルカリとしては、例えば炭酸水素ナトリウム、炭酸水素カリウム等を挙げることができる。これらの中、特に炭酸カリウムが好ましい。炭酸アルカリ又は炭酸水素アルカリの使用量は通常化合物（１）の１モルに対して１〜５モル程度、好ましくは２〜３モル程度とするのが良い。
【００１１】
溶媒としてはイソプロパノールを使用する。イソプロパノール以外の、例えばメタノールを使用すると得られるフェニルアルコキシ安息香酸誘導体の純度が低く、このような低い純度のものを用いると、次工程の化合物の合格品が得られず、ひいては最終製品の合格品が得られず、実用上使用できない。
反応は常圧、加圧又は減圧下に、通常１０℃〜還流温度、好ましくは６０℃〜還流温度の範囲で、約１〜３０時間、好ましくは６〜２３時間行うのが好ましい。反応終了後イソプロピルアルコールを除去して得られた水相と有機層を分液して水相を除き、有機層に水及びアルカリを加えて加水分解を行う。このようにアルキル化反応の終了後に、溶媒のイソプロパノールを除去することにより、次の工程のアルカリ化合物の使用量を少なくすることができる。またこの本発明の方法では抽出操作が不要で、酸析の際に発泡が起こらず、有機溶媒で洗浄しなくても目的物を高純度かつ高収率で得ることができる。
【００１２】
アルカリ化合物としては例えば水酸化ナトリウム、水酸化カリウム等の無機塩基、ナトリウムメトキシド、ナトリウムエトキシド等の有機塩基を挙げることができる。アルカリ化合物の使用量は通常化合物（１）の１モルに対して１〜５モル程度、好ましくは２〜３モル程度とするのが良い。加水分解反応は通常１０〜８０℃、好ましくは２０〜６０℃の温度で、約１〜３０時間、好ましくは６〜２３時間行うのが好ましい。
加水分解終了後は、酸を加えて液性を弱酸性にして目的の一般式（３）で表されるフェニルアルコキシ安息香酸誘導体の結晶を得る。酸としては、塩酸、硫酸等を挙げることができる。
【００１３】
本発明では上記で得られた一般式（３）のフェニルアルコキシ安息香酸誘導体は通常の単離、精製方法により分離することができ、例えば濾過、抽出、濃縮、冷却晶析、貧溶解度溶媒添加による結晶化、クロマトグラフィー等を挙げることができる。
【００１４】
【実施例】
以下に参考例、実施例及び比較例を挙げて説明する。
実施例１
１Ｌのフラスコに、イソプロパノール４５０ml、ｐ−ヒドロキシ安息香酸メチル７９.５g、１−ブロモ−４−フェニルブタン１０５.０g及び無水炭酸カリウム１００.０gを加えて、還流下、２０時間反応させる。高速液体クロマトグラフィーにて、反応終点を確認後、水３００mlを加え、反応混合液を加熱し、イソプロパノールを回収する。回収後、反応混合物は水層と有機層の２層に分液するので、下層の水層を除く。この有機層に、水５００ml、水酸化ナトリウム４０.８gを加え、１００℃で１時間反応させる。反応終了後、室温まで冷却し、濃塩酸１１６mlを加え、液性を弱酸性pＨ４にし、析出した結晶を濾取して、４−（４−フェニルブトキシ）安息香酸１２８.２g、融点１２９.２〜１３０.６℃（収率９６.４％）を得た。
【００１５】
比較例１
１Ｌのフラスコに、メタノール４５０ml、ｐ−ヒドロキシ安息香酸メチル７９.５g、１−ブロモ−４−フェニルブタン１０５.０g及び無水炭酸カリウム１００.０gを加えて、還流下、２０時間反応させる。高速液体クロマトグラフィーにて、反応終点を確認後、水３００mlを加え、反応混合液を加熱し、メタノールを回収する。回収後、反応混合物は水層と有機層の２層に分液するので、下層の水層を除く。この有機層に、水４５０ml、水酸化ナトリウム４０.８gを加え、１００℃で１時間反応させる。反応終了後、室温まで冷却し、濃塩酸１２０mlを加え、液性を弱酸性pＨ４にし、析出した結晶を濾取して、４−（４−フェニルブトキシ）安息香酸１２１.２g、融点１２３.４〜１２７.７℃（収率９１.０％）を得た。融点が実施例１のものより低いことから純度が低いことが判る。
【００１６】
比較例２
１Ｌのフラスコに、イソプロパノール４５０ml、ｐ−ヒドロキシ安息香酸メチル７９.５g、１−ブロモ−４−フェニルブタン１０５.０g及び無水炭酸カリウム１００.０gを加えて、還流下、２０時間反応させる。高速液体クロマトグラフィーにて、反応終点を確認後、水２４０ml、水酸化ナトリウム５８.５gを加え、還流下、１時間反応させる。反応終了後、室温まで冷却し、濃塩酸１８０mlを加え、液性を弱酸性pＨ４にした。この酸析時、発泡が激しいため、３Ｌのフラスコに反応液を移動した。析出した結晶を濾取して、４−（４−フェニルブトキシ）安息香酸１２５.１g、融点１２８.５〜１３０.０℃（収率９５.２％）を得た。
【００１７】
参考例１
実施例１で得られた４−（４−フェニルブトキシ）安息香酸を出発原料として、以下、例えば特開平３−９５１４４号公報の参考例１１〜１６に準じて８−［４−（４−フェニルブトキシ）ベンゾイル］アミノ−２−（５−テトラゾリル）−４−オキソ−４Ｈ−１−ベンゾピラン（プランルカスト、抗喘息薬）を合成することができる。
【００１８】
【発明の効果】
本発明の方法によれば、抽出操作が不要で、酸析の際に発泡が起こらず、有機溶媒で洗浄しなくても目的物を高純度かつ高収率で得ることのできる工業的に有利な且つ経済的にも有利なフェニルアルコキシ安息香酸誘導体の製造方法を提供することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for producing phenylalkoxybenzoic acid derivatives useful as intermediates for pharmaceuticals, agricultural chemicals and the like.
[0002]
[Prior art]
The phenylalkoxybenzoic acid derivatives of the present invention are known compounds described in, for example, JP-A-3-95144 and JP-A-7-25819.
[0003]
[Problems to be solved by the invention]
The former method has a problem in that an expensive solvent and a highly reactive reagent such as sodium methoxide are used, and the purification method is complicated.
The latter method is a method in which a phenylalkyl halide derivative and a hydroxybenzoic acid ester derivative are reacted in the presence of a basic substance and hydrolyzed by adding an alkaline aqueous solution to the reaction mixture. An inert solvent such as a polar solvent is used, and after completion of the reaction with the alkaline aqueous solution, water is added for extraction, and the resulting aqueous layer is washed with an organic solvent and then neutralized with an acid. However, since foaming occurs vigorously during this acid precipitation, there is a drawback that the volume of the reactor cannot be fully utilized.
An object of the present invention is an industrially advantageous and economical method that does not require extraction operation, does not cause foaming during acid precipitation, and can obtain the target product in high purity and high yield without washing with an organic solvent. It is another object of the present invention to provide a method for producing a phenylalkoxybenzoic acid derivative that is advantageous.
[0004]
[Means for Solving the Problems]
In the present invention, the phenylbenzoic acid ester derivative represented by the general formula (2) is reacted with the phenylalkyl halide derivative represented by the general formula (1) in an isopropyl alcohol solvent in the presence of an alkali carbonate or an alkali hydrogen carbonate. After completion of the reaction, the aqueous phase obtained by removing isopropyl alcohol and the organic layer are separated, the aqueous phase is removed, water and alkali are added to the organic layer, and hydrolysis is performed. The present invention relates to a method for producing a benzoic acid derivative characterized in that a benzoic acid derivative is obtained.
[0005]
[Formula 4]
[0006]
[Chemical formula 5]
[0007]
[Chemical 6]
[0008]
DETAILED DESCRIPTION OF THE INVENTION
In the phenylalkyl halide derivative of the general formula (1) as a starting material of the present invention, examples of the alkylene group having 2 to 5 carbon atoms represented by A include ethylene, propylene, butylene, and pentylene groups. Examples of the halogen represented by X include chlorine, bromine and iodine.
Examples of the compound of the general formula (1) include 1-bromo-4-phenylethane, 1-bromo-4-phenylpropane, 1-bromo-4-phenylbutane, 1-bromo-4-phenylpentane, Examples include those in which a bromo group is substituted with a chlorine group or an iodine group.
The phenylalkyl halide derivatives of the general formula (1) are known compounds described in JP-A-3-95144 and JP-A-7-25819, and are readily available.
[0009]
In the hydroxybenzoic acid ester derivative of the general formula (2) as another starting material of the present invention, examples of the alkyl having 1 to 6 carbon atoms represented by R include methyl, ethyl, propyl, butyl, pentyl and hexyl groups. Can do.
Examples of compounds of general formula (2) include, for example, methyl o, m or p-hydroxybenzoate, o, m or ethyl p-hydroxybenzoate, o, m or propyl p-hydroxybenzoate, o, m or p Mention may be made of butyl hydroxybenzoate, pentyl o, m or p-hydroxybenzoate, hexyl o, m or p-hydroxybenzoate. The hydroxybenzoic acid ester derivatives of the general formula (2) are also known compounds described in JP-A-3-95144 and JP-A-7-25819, and are readily available compounds.
[0010]
Next, the phenylalkyl halide derivative of the formula (1) and the hydroxybenzoic acid ester derivative of the formula (2) are reacted in an isopropyl alcohol solvent in the presence of an alkali carbonate or an alkali hydrogen carbonate, and after completion of the reaction, the isopropyl alcohol is removed. The aqueous phase and organic layer thus obtained are separated, the aqueous phase is removed, and water and alkali are added to the organic layer for hydrolysis to obtain a phenylalkoxybenzoic acid derivative represented by the general formula (3). be able to.
Examples of the alkali carbonate include sodium carbonate and potassium carbonate. Examples of the alkali hydrogen carbonate include sodium hydrogen carbonate and potassium hydrogen carbonate. Of these, potassium carbonate is particularly preferred. The amount of alkali carbonate or alkali hydrogen carbonate used is usually about 1 to 5 mol, preferably about 2 to 3 mol, relative to 1 mol of compound (1).
[0011]
Isopropanol is used as the solvent. The purity of a phenylalkoxybenzoic acid derivative other than isopropanol, for example, obtained by using methanol is low, and if such a low purity is used, a pass product of the compound in the next step cannot be obtained, and thus a pass product of the final product. Cannot be obtained and cannot be used practically.
The reaction is preferably carried out under normal pressure, increased pressure or reduced pressure, usually in the range of 10 ° C. to reflux temperature, preferably 60 ° C. to reflux temperature for about 1 to 30 hours, preferably 6 to 23 hours. After completion of the reaction, the aqueous phase obtained by removing isopropyl alcohol and the organic layer are separated to remove the aqueous phase, and water and alkali are added to the organic layer for hydrolysis. Thus, after the completion of the alkylation reaction, the amount of the alkali compound used in the next step can be reduced by removing the solvent isopropanol. Further, in the method of the present invention, no extraction operation is required, foaming does not occur during acid precipitation, and the target product can be obtained with high purity and high yield without washing with an organic solvent.
[0012]
Examples of the alkali compound include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as sodium methoxide and sodium ethoxide. The amount of the alkali compound used is usually about 1 to 5 mol, preferably about 2 to 3 mol, per 1 mol of the compound (1). The hydrolysis reaction is usually carried out at a temperature of 10 to 80 ° C., preferably 20 to 60 ° C., for about 1 to 30 hours, preferably 6 to 23 hours.
After completion of the hydrolysis, an acid is added to make the liquid weakly acidic to obtain a target phenylalkoxybenzoic acid derivative crystal represented by the general formula (3). Examples of the acid include hydrochloric acid and sulfuric acid.
[0013]
In the present invention, the phenylalkoxybenzoic acid derivative of the general formula (3) obtained above can be separated by ordinary isolation and purification methods, such as filtration, extraction, concentration, cooling crystallization, and addition of poor solubility solvent. Examples thereof include crystallization and chromatography.
[0014]
【Example】
A description will be given below with reference examples, examples and comparative examples.
Example 1
To a 1 L flask, 450 ml of isopropanol, 79.5 g of methyl p-hydroxybenzoate, 105.0 g of 1-bromo-4-phenylbutane and 100.0 g of anhydrous potassium carbonate are added and reacted for 20 hours under reflux. After confirming the end point of the reaction by high performance liquid chromatography, 300 ml of water is added, the reaction mixture is heated, and isopropanol is recovered. After the recovery, the reaction mixture is separated into two layers, an aqueous layer and an organic layer, and the lower aqueous layer is removed. To this organic layer, 500 ml of water and 40.8 g of sodium hydroxide are added and reacted at 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 116 ml of concentrated hydrochloric acid was added to make the liquid weakly acidic pH 4 and the precipitated crystals were collected by filtration to give 128.2 g of 4- (4-phenylbutoxy) benzoic acid, melting point 129.2. ˜130.6 ° C. (96.4% yield) was obtained.
[0015]
Comparative Example 1
To a 1 L flask, 450 ml of methanol, 79.5 g of methyl p-hydroxybenzoate, 105.0 g of 1-bromo-4-phenylbutane and 100.0 g of anhydrous potassium carbonate are added and reacted for 20 hours under reflux. After confirming the end point of the reaction by high performance liquid chromatography, 300 ml of water is added, the reaction mixture is heated, and methanol is recovered. After the recovery, the reaction mixture is separated into two layers, an aqueous layer and an organic layer, and the lower aqueous layer is removed. To this organic layer, 450 ml of water and 40.8 g of sodium hydroxide are added and reacted at 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 120 ml of concentrated hydrochloric acid was added to make the liquid weakly acidic pH 4 and the precipitated crystals were collected by filtration to give 121.2 g of 4- (4-phenylbutoxy) benzoic acid, melting point 123.4. ˜127.7 ° C. (yield 91.0%) was obtained. Since the melting point is lower than that of Example 1, it can be seen that the purity is low.
[0016]
Comparative Example 2
To a 1 L flask, 450 ml of isopropanol, 79.5 g of methyl p-hydroxybenzoate, 105.0 g of 1-bromo-4-phenylbutane and 100.0 g of anhydrous potassium carbonate are added and reacted for 20 hours under reflux. After confirming the end point of the reaction by high performance liquid chromatography, 240 ml of water and 58.5 g of sodium hydroxide are added and reacted under reflux for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and 180 ml of concentrated hydrochloric acid was added to make the solution weakly acidic pH4. At the time of acid precipitation, since the foaming was intense, the reaction solution was transferred to a 3 L flask. The precipitated crystals were collected by filtration to obtain 125.1 g of 4- (4-phenylbutoxy) benzoic acid, melting point 128.5-130.0 ° C. (yield 95.2%).
[0017]
Reference example 1
Using 4- (4-phenylbutoxy) benzoic acid obtained in Example 1 as a starting material, 8- [4- (4-phenyl) will be described below in accordance with, for example, Reference Examples 11 to 16 of JP-A-3-95144. (Butoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran (pranlukast, anti-asthma drug) can be synthesized.
[0018]
【The invention's effect】
According to the method of the present invention, an extraction operation is unnecessary, foaming does not occur during acid precipitation, and the object can be obtained in high purity and high yield without washing with an organic solvent. It is possible to provide a method for producing a phenylalkoxybenzoic acid derivative which is also economically advantageous.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16042697A JP3907787B2 (en) | 1997-06-02 | 1997-06-02 | Method for producing benzoic acid derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16042697A JP3907787B2 (en) | 1997-06-02 | 1997-06-02 | Method for producing benzoic acid derivative |
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| Publication Number | Publication Date |
|---|---|
| JPH10330313A JPH10330313A (en) | 1998-12-15 |
| JP3907787B2 true JP3907787B2 (en) | 2007-04-18 |
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| JP16042697A Expired - Fee Related JP3907787B2 (en) | 1997-06-02 | 1997-06-02 | Method for producing benzoic acid derivative |
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| JP4511093B2 (en) * | 2001-12-20 | 2010-07-28 | 本州化学工業株式会社 | Method for producing alicyclic monoolefin carboxylic acid |
| WO2005095319A1 (en) | 2004-04-01 | 2005-10-13 | Sumitomo Chemical Company, Limited | Method for producing carboxylic acid compound |
| JP6503228B2 (en) * | 2015-05-27 | 2019-04-17 | 上野製薬株式会社 | Purification method of 4-hydroxybenzoic acid long chain ester |
| CN112851506B (en) * | 2020-12-31 | 2023-06-23 | 湖北英纳氏生物科技有限公司 | Industrial preparation method of 3, 5-dimethoxy-4-alkyl benzyl alcohol |
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| JPH10330313A (en) | 1998-12-15 |
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