JPH0553779B2 - - Google Patents
Info
- Publication number
- JPH0553779B2 JPH0553779B2 JP60061358A JP6135885A JPH0553779B2 JP H0553779 B2 JPH0553779 B2 JP H0553779B2 JP 60061358 A JP60061358 A JP 60061358A JP 6135885 A JP6135885 A JP 6135885A JP H0553779 B2 JPH0553779 B2 JP H0553779B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- methyl
- acid
- methoxy
- pyridine
- 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
- -1 glycidic acid ester Chemical class 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 238000004519 manufacturing process Methods 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 4
- KZVLNAGYSAKYMG-UHFFFAOYSA-N pyridine-2-sulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=N1 KZVLNAGYSAKYMG-UHFFFAOYSA-N 0.000 claims description 3
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 150000003222 pyridines Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- OTGHWLKHGCENJV-UHFFFAOYSA-N glycidic acid Chemical compound OC(=O)C1CO1 OTGHWLKHGCENJV-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 3
- 229960002009 naproxen Drugs 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- GGWCZBGAIGGTDA-UHFFFAOYSA-N 1-(6-methoxynaphthalen-2-yl)ethanone Chemical compound C1=C(C(C)=O)C=CC2=CC(OC)=CC=C21 GGWCZBGAIGGTDA-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- WBIQQQGBSDOWNP-UHFFFAOYSA-N 2-dodecylbenzenesulfonic acid Chemical compound CCCCCCCCCCCCC1=CC=CC=C1S(O)(=O)=O WBIQQQGBSDOWNP-UHFFFAOYSA-N 0.000 description 2
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- 239000002221 antipyretic Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229940060296 dodecylbenzenesulfonic acid Drugs 0.000 description 2
- MCVVUJPXSBQTRZ-UHFFFAOYSA-N methyl but-2-enoate Chemical compound COC(=O)C=CC MCVVUJPXSBQTRZ-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- RENADKAYIYTQNG-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;quinoline Chemical compound N1=CC=CC2=CC=CC=C21.CC1=CC=C(S(O)(=O)=O)C=C1 RENADKAYIYTQNG-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- AZFMSHWYDZIRNV-UHFFFAOYSA-N benzenesulfonic acid;pyridine Chemical compound C1=CC=NC=C1.OS(=O)(=O)C1=CC=CC=C1 AZFMSHWYDZIRNV-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- UIYIJLMQTSSYSI-UHFFFAOYSA-N dodecyl benzenesulfonate pyridine Chemical compound C(CCCCCCCCCCC)OS(=O)(=O)C1=CC=CC=C1.N1=CC=CC=C1 UIYIJLMQTSSYSI-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- JCZBLFLJXOALCG-UHFFFAOYSA-N methyl 2-hydroxy-3-(6-methoxynaphthalen-2-yl)but-3-enoate Chemical compound C1=C(OC)C=CC2=CC(C(=C)C(O)C(=O)OC)=CC=C21 JCZBLFLJXOALCG-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- NGASWKRTXGWPNN-UHFFFAOYSA-N tert-butyl but-3-enoate Chemical compound CC(C)(C)OC(=O)CC=C NGASWKRTXGWPNN-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 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)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
〔産業上の利用分野〕
本発明は、解熱鎮痛剤として有用なナプロキセ
ンを製造するための重要な中間体である一般式
（式中R1は低級アルキル基を表す）のブテン酸
エステル誘導体の製造方法に関する。
〔従来の技術及び発明が解決しようとする問題
点〕
解熱消炎鎮痛剤として広く用いられているナプ
ロキセンの製法には種々知られているが、有力な
方法として一般式
（式中R1は低級アルキル基を表す）
のグリシド酸エステル誘導体を臭化マグネシウム
（特開昭55−22613号）あるいは塩化マグネシウム
（特開昭57−93933号）などのルイス酸の存在下で
一般式（）のブテン酸エステル誘導体とし、さ
らにこれを、ケト酸エステル誘導体となしさらに
加水分解して最後に脱炭酸反応に施しナプロキセ
ンとする方法が知られている。しかしこれらの方
法は80〜120℃という高温で反応しなければなら
ないという操作上の問題、及び触媒を大量に必要
とし、その上収率に問題があつた。
また、ルイス酸の代りに塩化水素、硫酸、ｐ−
トルエンスルホン酸などの強酸の存在下行う方法
が知られているが、この場合副生物が多く従つて
収率に問題があつた。
上記の状況から、本発明は一般式（）のブテ
ン酸エステル誘導体を収率よく製造することにあ
る。
〔問題点を解決するための手段〕
本発明者らは、これら従来法の欠点を解決する
ために種々検討した結果、本発明を見い出した。
即ち、本発明は
一般式
（式中R1は低級アルキル基を表わす）
のグリシド酸エステル誘導体を一般式
（式中R2はフエニル基又は炭素原子数１〜12の
アルキル基１個により置換したアルキルフエニル
基を表わし、R3、R4、R5、R6、R7のそれぞれは
水素原子であるか又は任意の１又は２個はメチル
基であつて他は水素原子であるか又は互に隣り合
つた２個が炭素原子４個で結合してベンゼン環を
形成し他は水素原子である）のピリジン・スルホ
ン酸塩誘導体の存在下異性化することを特徴とす
る
一般式
（式中R1は前記同様である）
のブテン酸エステル誘導体の製造方法に関する。
本発明では、一般式（）のピリジン・スルホ
ン酸塩誘導体（以下ピリジン塩とする）の存在下
反応を行わせると、80℃より低い温度でその上グ
リシド酸に対し0.1〜20モル％という少量で収率
良くブテン酸を得ることが出来る。
本発明に用いられるピリジン塩は、種々の方法
で得ることが出来るが、例えばｐ−トルエンスル
ホン酸をピリジンに溶解して塩とし、過剰のピリ
ジンを留去した後アセトンで再結晶して得ること
が出来る〔例えばJ.Og.Chem.42、3772（1977）参
照〕。ピリジン塩として好ましくはピリジニウム
ｐ−トルエンスルホネート、ピリジニウムベンゼ
ンスルホネート、ピリジニウムドデシルベンゼン
スルホネート、３，５−ルチジニウムｐ−トルエ
ンスルホネート、キノリニウムｐ−トルエンスル
ホネートをあげることが出来る。本発明では、こ
のピリジン塩そのものを用いるばかりでなくピリ
ジン類とスルホン酸塩とを反応系に加えて系内に
ピリジン塩を形成させてもよい。この場合、ピリ
ジン類としては例えばピリジン、３，５−ルチジ
ニウム、キノリンをあげることが出来、又スルホ
ン酸類としては、例えばｐ−トルエンスルホン
酸、ベンゼンスルホン酸、ドデシルベンゼンスル
ホン酸をあげることが出来る。そして使用量とし
ては、両者を略等モル用いる。
又、本発明の原料として用いられる一般式
（）のグリシド酸は例えば式
[Industrial Application Field] The present invention relates to the general formula The present invention relates to a method for producing a butenoic acid ester derivative (wherein R 1 represents a lower alkyl group). [Prior art and problems to be solved by the invention] Various methods are known for producing naproxen, which is widely used as an antipyretic and antiinflammatory analgesic. (in the formula, R 1 represents a lower alkyl group) in the presence of a Lewis acid such as magnesium bromide (JP-A-55-22613) or magnesium chloride (JP-A-57-93933). A known method is to obtain a butenoic acid ester derivative of the general formula (), which is then converted into a ketoic acid ester derivative, which is further hydrolyzed and finally subjected to a decarboxylation reaction to obtain naproxen. However, these methods have operational problems in that the reaction must be carried out at a high temperature of 80 to 120°C, require a large amount of catalyst, and have problems in yield. Also, hydrogen chloride, sulfuric acid, p-
A method in which the reaction is carried out in the presence of a strong acid such as toluenesulfonic acid is known, but in this case many by-products are produced, resulting in a problem in yield. In view of the above circumstances, the present invention is directed to producing a butenoic acid ester derivative of the general formula () in good yield. [Means for Solving the Problems] The present inventors conducted various studies to solve the drawbacks of these conventional methods, and as a result, discovered the present invention. That is, the present invention has the general formula (in the formula, R 1 represents a lower alkyl group) is a glycidic acid ester derivative with the general formula (In the formula, R 2 represents a phenyl group or an alkyl phenyl group substituted with one alkyl group having 1 to 12 carbon atoms, and each of R 3 , R 4 , R 5 , R 6 , and R 7 is a hydrogen atom. One or two of the groups are methyl groups and the others are hydrogen atoms, or two adjacent groups are bonded with 4 carbon atoms to form a benzene ring and the others are hydrogen atoms. ) isomerized in the presence of a pyridine sulfonate derivative. (In the formula, R 1 is the same as above.) The present invention relates to a method for producing a butenoic acid ester derivative. In the present invention, when the reaction is carried out in the presence of a pyridine sulfonate derivative (hereinafter referred to as pyridine salt) of the general formula (), it is possible to perform the reaction at a temperature lower than 80°C and in a small amount of 0.1 to 20 mol% based on glycidic acid. Butenoic acid can be obtained in good yield. The pyridine salt used in the present invention can be obtained by various methods, but for example, it can be obtained by dissolving p-toluenesulfonic acid in pyridine to form a salt, distilling off excess pyridine, and then recrystallizing it with acetone. [See, for example, J.Og.Chem.42, 3772 (1977)]. Preferred examples of the pyridine salt include pyridinium p-toluenesulfonate, pyridinium benzenesulfonate, pyridinium dodecylbenzenesulfonate, 3,5-lutidinium p-toluenesulfonate, and quinolinium p-toluenesulfonate. In the present invention, not only this pyridine salt itself is used, but also a pyridine and a sulfonate may be added to the reaction system to form a pyridine salt in the system. In this case, examples of pyridines include pyridine, 3,5-lutidinium, and quinoline, and examples of sulfonic acids include p-toluenesulfonic acid, benzenesulfonic acid, and dodecylbenzenesulfonic acid. As for the amounts used, both are used in approximately equal moles. In addition, the glycidic acid of general formula () used as a raw material of the present invention is, for example,
【式】の化合物とク
ロロ酢酸エステルとを不活性ガスの下でナトリウ
ムメトキシド、あるいはナトリウムエトキシド等
の縮合剤を用い反応させて得ることができる。一
般式（）のR1基は好ましくは、メチル、エチ
ル、ｎ−プロピル、ｔ−ブチルである。
本発明では一般式（）のグリシド酸を一般式
（）のピリジン塩の存在下反応させる。反応に
当つては、ピリジン塩の使用量はグリシド酸に対
して約0.1〜20モル％好ましくは約0.5〜10モル％
である。又反応温度は約20〜80℃好ましくは約40
〜70℃である。又反応は溶媒の存在下で行われる
が、用いられる溶媒としてトルエン、キシレン等
の芳香族炭化水素、ジクロロエタン、トリクロロ
エタン等の塩素系炭化水素、ジオキサン、ジブチ
ルエーテル等のエーテル類があげられる。反応は
有機溶媒中で好ましくは撹拌しつつ行われ反応時
間は好ましくは約１〜５時間である。反応終了後
反応生成物に水を加え、有機層を分取し、水洗
し、乾燥する。有機溶媒を除去し残渣を再結晶し
て目的のブテン酸を得る。
本発明により得られたブテン酸は例えばメタノ
ール中ナトリウムメトキシドで処理した後加水分
解して式
It can be obtained by reacting a compound of the formula with a chloroacetic ester under an inert gas using a condensing agent such as sodium methoxide or sodium ethoxide. The R 1 group in general formula () is preferably methyl, ethyl, n-propyl, t-butyl. In the present invention, glycidic acid of general formula () is reacted in the presence of a pyridine salt of general formula (). In the reaction, the amount of pyridine salt used is about 0.1 to 20 mol%, preferably about 0.5 to 10 mol%, based on glycidic acid.
It is. The reaction temperature is about 20 to 80℃, preferably about 40℃.
~70℃. The reaction is carried out in the presence of a solvent, and the solvents used include aromatic hydrocarbons such as toluene and xylene, chlorinated hydrocarbons such as dichloroethane and trichloroethane, and ethers such as dioxane and dibutyl ether. The reaction is carried out in an organic solvent, preferably with stirring, and the reaction time is preferably about 1 to 5 hours. After the reaction is completed, water is added to the reaction product, and the organic layer is separated, washed with water, and dried. The organic solvent is removed and the residue is recrystallized to obtain the desired butenoic acid. The butenoic acid obtained according to the invention can be treated with, for example, sodium methoxide in methanol and then hydrolyzed to give the formula
【式】のケト
酸とし、ついでアルカリ中、過酸化水素で処理し
て式[Formula] is prepared as a keto acid, and then treated with hydrogen peroxide in an alkali to give the formula
本発明では、解熱消炎鎮痛剤として有用なナプ
ロキセンを得るための中間体として重要なブテン
酸を従来法に比べて安価な化合物少量を用い、低
い温度でしかも例えば約90％以上という高い収率
で得ることが出来るのであつて、その工業的価値
は極めて高い。
次に製法の具体的な例を示す。
〔実施例〕
実施例 １
３−メチル−３−（６−メトキシ−２−ナフチ
ル）−グリシド酸メチル83ｇをトルエン500mlに溶
解させピリジニウムｐ−トルエンスルホネート
1.53ｇ（２モル％）を加え55〜60℃で２時間撹拌
した後水200mlを加えた。有機層を分取し、水200
mlで２回水洗し、無水硫酸ナトリウムで乾燥し
た。トルエンを減圧留去し、残渣をベンゼン−ヘ
キサンから再結晶して２−ヒドロキシ−３−（６
−メトキシ−２−ナフチル）−３−ブテン酸メチ
ル77ｇを得た。収率92.8％、融点90.2〜92.3℃。
分析結果は次の通りであつた。
元素分析
実測値 計算値
Ｃ％： 70.35 70.57
Ｈ％： 6.18 5.92
IR（cm-1） 3438、1734、1625、1604、1215、
1172、1099、1035、1001、910、865
NMR（δ、ppm、TMS、CDCl3）3.76（3H、
Ｓ、−COOH3）、3.98（3H、Ｓ、−OCH3）、5.26
（1H、Ｓ、
In the present invention, butenoic acid, which is an important intermediate for obtaining naproxen, which is useful as an antipyretic and antiinflammatory analgesic, is produced using a small amount of a cheaper compound than in conventional methods, at a low temperature, and in a high yield of about 90% or more. can be obtained, and its industrial value is extremely high. Next, a specific example of the manufacturing method will be shown. [Example] Example 1 83 g of methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate was dissolved in 500 ml of toluene to prepare pyridinium p-toluenesulfonate.
After adding 1.53 g (2 mol %) and stirring at 55 to 60°C for 2 hours, 200 ml of water was added. Separate the organic layer and add 200 ml of water.
ml of water twice and dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure, and the residue was recrystallized from benzene-hexane to give 2-hydroxy-3-(6
77 g of methyl -methoxy-2-naphthyl)-3-butenoate was obtained. Yield 92.8%, melting point 90.2-92.3℃. The analysis results were as follows. Elemental analysis Actual value Calculated value C%: 70.35 70.57 H%: 6.18 5.92 IR (cm -1 ) 3438, 1734, 1625, 1604, 1215,
1172, 1099, 1035, 1001, 910, 865 NMR (δ, ppm, TMS, CDCl3 ) 3.76 (3H,
S, -COOH3 ), 3.98 (3H, S, -OCH3 ), 5.26
(1H, S,
【式】）、5.53および5.67
（2H、2S、H2C＝Ｃ）
実施例 ２
３−メチル−３−（６−メトキシ−２−ナフチ
ル）−グリシド酸ｔ−ブチル3.6ｇをｎ−ブチルエ
ーテル20mlに溶解させピリジニウムｐ−トルエン
スルホネート0.12ｇ（４モル％）を加え55〜60℃
で２時間反応した後実施例１と同様に処理し２−
ヒドロキシ−３−（６−メトキシ−２−ナフチル）
−３−ブテン酸ｔ−ブチル3.5ｇを得た。収率
97.5％、融点85.7〜86.5℃。
分析結果は次の通りであつた。
元素分析
実測値 計算値
Ｃ％： 72.63 72.59
Ｈ％： 7.09 7.05
IR（cm-1） 3510、1720、1620、1594、1250、
1155、1125、1115、1100、1030、860
NMR（δ、ppm、TMS、CDCl3）1.32（9H、
Ｓ、tBu）、3.47（1H、ｄ、OH）、3.86（3H、Ｓ、
CH3O−）、5.00（1H、ｄ、[Formula]), 5.53 and 5.67 (2H, 2S, H 2 C=C) Example 2 3.6 g of t-butyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate and 20 ml of n-butyl ether Add 0.12g (4 mol%) of pyridinium p-toluenesulfonate to 55-60°C.
After reacting for 2 hours, the mixture was treated in the same manner as in Example 1.
Hydroxy-3-(6-methoxy-2-naphthyl)
3.5 g of t-butyl-3-butenoate was obtained. yield
97.5%, melting point 85.7-86.5℃. The analysis results were as follows. Elemental analysis Actual value Calculated value C%: 72.63 72.59 H%: 7.09 7.05 IR (cm -1 ) 3510, 1720, 1620, 1594, 1250,
1155, 1125, 1115, 1100, 1030, 860 NMR (δ, ppm, TMS, CDCl3 ) 1.32 (9H,
S, tBu), 3.47 (1H, d, OH), 3.86 (3H, S,
CH 3 O−), 5.00 (1H, d,
【式】）、5.45および
5.52（2H、2S、H2C＝Ｃ）
実施例 ３
３−メチル−３−（６−メトキシ−２−ナフチ
ル）−グリシド酸メチル40ｇをトルエン250mlに溶
解させピリジン0.23ｇ、ベンゼンスルホン酸0.46
ｇ（２モル％）を加え55〜65℃で２時間撹拌した
後実施例１と同様に処理し２−ヒドロキシ−３−
（６−メトキシ−２−ナフチル）−３−ブテン酸メ
チル37.3ｇを得た。収率93.3％。
実施例 ４
３−メチル−３−（６−メトキシ−２−ナフチ
ル）−グリシド酸メチル20ｇをトルエン150mlに溶
解させピリジン0.23ｇ、ドデシルベンゼンスルホ
ン酸0.96ｇ（４モル％）を加え55〜65℃で３時間
撹拌した後、実施例１と同様に処理し２−ヒドロ
キシ−３−（６−メトキシ−２−ナフチル）−３−
ブテン酸メチル18.3ｇを得た。収率91.5％。
実施例 ５
３−メチル−３−（６−メトキシ−２−ナフチ
ル）−グリシド酸メチル20ｇをトルエン150mlに溶
解させ、３，５−ルチジン0.31ｇ、ｐ−トルエン
スルホン酸１水和物0.56ｇを加え55〜65℃で３時
間撹拌した後実施例１と同様に処理し２−ヒドロ
キシ−３−（６−メトキシ−２−ナフチル）−３−
ブテン酸メチル18.1ｇを得た。収率90.5％。
実施例 ６
３−メチル−３−（６−メトキシ−２−ナフチ
ル）−グリシド酸メチル20ｇをトルエン150mlに溶
解させ、キノリン0.38ｇ、ｐ−トルエンスルホン
酸１水和物0.56ｇを加え55〜65℃で３時間撹拌し
た後、実施例１と同様に処理し、２−ヒドロキシ
−３−（６−メトキシ−２−ナフチル）−３−ブテ
ン酸メチル18.3ｇを得た。収率91.5％。
参考例 １
６−メトキシ−２−アセチルナフタレン120ｇ、
クロロ酢酸メチル120ｇをトルエン1200mlに溶解
し、窒素気流下撹拌しながらカリウムｔ−ブトキ
シド120ｇを３〜５℃で２時間を要して徐々に加
えた。５〜７℃で１時間撹拌した後、水400mlを
加え充分撹拌した。有機層を分取し、水洗した後
無水硫酸ナトリウムで乾燥した。トルエンを減圧
留去して得られる粗結晶をベンゼンから再結晶し
て３−メチル−３−（６−メトキシ−２−ナフチ
ル）−グリシド酸メチル123ｇを得た。収率75.3
％、融点120.5〜124.1℃。
分析結果は次の通りであつた。
元素分析
実測値 計算値
Ｃ％： 70.31 70.57
Ｈ％： 6.05 5.92
IR（cm-1） 1745、1600、1260、1220、1210、
1070、1035、860、820
NMR（δ、ppm、TMS、CDCl3）1.88および
1.93（3H、2S、[Formula]), 5.45 and 5.52 (2H, 2S, H 2 C=C) Example 3 40 g of methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate was dissolved in 250 ml of toluene and pyridine 0.23 g, benzenesulfonic acid 0.46
g (2 mol%) and stirred at 55-65°C for 2 hours, treated in the same manner as in Example 1 to give 2-hydroxy-3-
37.3 g of methyl (6-methoxy-2-naphthyl)-3-butenoate was obtained. Yield 93.3%. Example 4 20 g of methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate was dissolved in 150 ml of toluene, and 0.23 g of pyridine and 0.96 g (4 mol%) of dodecylbenzenesulfonic acid were added to the mixture at 55-65°C. After stirring for 3 hours at
18.3 g of methyl butenoate was obtained. Yield 91.5%. Example 5 20 g of methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate was dissolved in 150 ml of toluene, and 0.31 g of 3,5-lutidine and 0.56 g of p-toluenesulfonic acid monohydrate were dissolved. After stirring at 55-65°C for 3 hours, the same treatment as in Example 1 was carried out to give 2-hydroxy-3-(6-methoxy-2-naphthyl)-3-
18.1 g of methyl butenoate was obtained. Yield 90.5%. Example 6 20 g of methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate was dissolved in 150 ml of toluene, and 0.38 g of quinoline and 0.56 g of p-toluenesulfonic acid monohydrate were added to the mixture. After stirring at <RTIgt;C</RTI> for 3 hours, the mixture was treated in the same manner as in Example 1 to obtain 18.3 g of methyl 2-hydroxy-3-(6-methoxy-2-naphthyl)-3-butenoate. Yield 91.5%. Reference example 1 120g of 6-methoxy-2-acetylnaphthalene,
120 g of methyl chloroacetate was dissolved in 1200 ml of toluene, and 120 g of potassium t-butoxide was gradually added over 2 hours at 3 to 5°C while stirring under a nitrogen stream. After stirring for 1 hour at 5-7°C, 400 ml of water was added and thoroughly stirred. The organic layer was separated, washed with water, and then dried over anhydrous sodium sulfate. The crude crystals obtained by distilling off toluene under reduced pressure were recrystallized from benzene to obtain 123 g of methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate. Yield 75.3
%, melting point 120.5-124.1℃. The analysis results were as follows. Elemental analysis Actual value Calculated value C%: 70.31 70.57 H%: 6.05 5.92 IR (cm -1 ) 1745, 1600, 1260, 1220, 1210,
1070, 1035, 860, 820 NMR (δ, ppm, TMS, CDCl3 ) 1.88 and
1.93 (3H, 2S,
【式】）、3.63および3.81（1H、 2S、[Formula]), 3.63 and 3.81 (1H, 2S,
【式】）、3.48および3.94（3H、2S、−
COOCH3）、4.00（3H、Ｓ、−OCH3）
参考例 ２
参考例１と同様に６−メトキシ−２−アセチル
ナフタレン5.5ｇ、クロロ酢酸ｔ−ブチル8.3ｇを
トルエン60mlに溶解し、カリウムｔ−ブトキシド
6.2ｇを用いて反応させ３−メチル−３−（６−メ
トキシ−２−ナフチル）−グリシド酸ｔ−ブチル
9.1ｇを得た。
分析結果は次の通りであつた。
元素分析
実測値 計算値
Ｃ％： 72.41 72.59
Ｈ％： 6.95 7.05
IR（cm-1） 1730、1705、1620、1595、1195、
1150、1030、850
NMR（δ、ppm、TMS、CDCl3）1.00および
1.51（9H、2S、ｔ−Bu）、1.77および1.83（3H、
2S、[Formula]), 3.48 and 3.94 (3H, 2S, -COOCH 3 ), 4.00 (3H, S, -OCH 3 ) Reference Example 2 Same as Reference Example 1, 5.5 g of 6-methoxy-2-acetylnaphthalene, chloroacetic acid Dissolve 8.3g of t-butyl in 60ml of toluene and add potassium t-butoxide.
t-butyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate
9.1g was obtained. The analysis results were as follows. Elemental analysis Actual value Calculated value C%: 72.41 72.59 H%: 6.95 7.05 IR (cm -1 ) 1730, 1705, 1620, 1595, 1195,
1150, 1030, 850 NMR (δ, ppm, TMS, CDCl3 ) 1.00 and
1.51 (9H, 2S, t-Bu), 1.77 and 1.83 (3H,
2S,
【式】）、3.44および3.60（1H、2S、[Formula]), 3.44 and 3.60 (1H, 2S,
【式】）、3.88（3H、Ｓ、−OCH3）
参考例 ３
文献の方法（T.Org.Chem.、42、3772（1977））
に従い、ｐ−トルエンスルホン酸１水和物5.7ｇ
をピリジン12mlに撹拌しながら加えた。30分撹拌
後、過剰のピリジンを減圧留去し、アセトンにて
再結晶を行ない6.5ｇをピリジニウムｐ−トルエ
ンスルホネートを得た。[Formula]), 3.88 (3H, S, -OCH 3 ) Reference example 3 Method in literature (T.Org.Chem., 42 , 3772 (1977))
According to the following, 5.7 g of p-toluenesulfonic acid monohydrate
was added to 12 ml of pyridine with stirring. After stirring for 30 minutes, excess pyridine was distilled off under reduced pressure, and recrystallization was performed with acetone to obtain 6.5 g of pyridinium p-toluenesulfonate.
Claims (1)
アルキル基１個により置換したアルキルフエニル
基を表わし、R3、R4、R5、R6、R7のそれぞれは
水素原子であるか又は任意の１又は２個はメチル
基であつて他は水素原子であるか又は互に隣り合
つた２個が炭素原子４個で結合してベンゼン環を
形成し他は水素原子である） のピリジン・スルホン酸塩誘導体の存在下異性化
することを特徴とする （式中R1は前記同様である） ２−ヒドロキシ−３−ブテン酸エステル誘導体の
製造方法。[Claims] 1. General formula (in the formula, R 1 represents a lower alkyl group) is a glycidic acid ester derivative with the general formula (In the formula, R 2 represents a phenyl group or an alkyl phenyl group substituted with one alkyl group having 1 to 12 carbon atoms, and each of R 3 , R 4 , R 5 , R 6 , and R 7 is a hydrogen atom. One or two of the groups are methyl groups and the others are hydrogen atoms, or two adjacent groups are bonded with 4 carbon atoms to form a benzene ring and the others are hydrogen atoms. ) isomerized in the presence of a pyridine sulfonate derivative. (In the formula, R 1 is the same as above.) A method for producing a 2-hydroxy-3-butenoic acid ester derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60061358A JPS61221153A (en) | 1985-03-26 | 1985-03-26 | Production of 2-hydroxy-3-butenoic ester derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60061358A JPS61221153A (en) | 1985-03-26 | 1985-03-26 | Production of 2-hydroxy-3-butenoic ester derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61221153A JPS61221153A (en) | 1986-10-01 |
| JPH0553779B2 true JPH0553779B2 (en) | 1993-08-10 |
Family
ID=13168854
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60061358A Granted JPS61221153A (en) | 1985-03-26 | 1985-03-26 | Production of 2-hydroxy-3-butenoic ester derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61221153A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5262565A (en) * | 1990-11-16 | 1993-11-16 | Eisai Co., Ltd. | Naphthalene derivatives |
-
1985
- 1985-03-26 JP JP60061358A patent/JPS61221153A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61221153A (en) | 1986-10-01 |
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