JPS6148819B2 - - Google Patents
Info
- Publication number
- JPS6148819B2 JPS6148819B2 JP4103082A JP4103082A JPS6148819B2 JP S6148819 B2 JPS6148819 B2 JP S6148819B2 JP 4103082 A JP4103082 A JP 4103082A JP 4103082 A JP4103082 A JP 4103082A JP S6148819 B2 JPS6148819 B2 JP S6148819B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- acid
- naphthyl
- methoxy
- chloroform
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 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 claims description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- -1 alkyl (6-methoxy-2-naphthyl)propionic acid Chemical compound 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 46
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 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
- 239000012044 organic layer Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-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
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- XWJUDDGELKXYNO-QMMMGPOBSA-N desmethylnaproxen Chemical compound C1=C(O)C=CC2=CC([C@@H](C(O)=O)C)=CC=C21 XWJUDDGELKXYNO-QMMMGPOBSA-N 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 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
- 230000006340 racemization Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、式()
で示されるd―2―(6―メトキシ―2―ナフチ
ル)プロピオン酸(以下化合物()という。)
の新規な製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula () d-2-(6-methoxy-2-naphthyl)propionic acid represented by (hereinafter referred to as compound ())
The present invention relates to a new manufacturing method.
化合物()は、抗炎症,解熱および鎮痛作用
を有する化合物であり、「ナプロキセン」の名称
で医薬品として汎用されている。化合物()を
製造する方法としては化合物()のラセミ体か
らシンコニジン(特公昭48―702)、デヒドロアビ
エチルアミン(特公昭53―39421)、N―アルキル
―D―グルカミン(特開昭56―18939)等の分割
剤を用いて光学分割する方法、(2)―l―メントー
ルを用いる光学分割法(特願昭56―31860)が知
られている。しかるに、これら光学分割法には、
分割剤が高価である、化学的に不安定である、分
割の際の選択収率が低い、また、分割残液から得
られるdl体混合物のラセミ化工程が高温長時間で
ある等の問題点があつた。 Compound () is a compound that has anti-inflammatory, antipyretic, and analgesic effects, and is commonly used as a pharmaceutical under the name "naproxen." The method for producing compound () is to prepare cinchonidine (Japanese Patent Publication No. 48-702), dehydroabiethylamine (Japanese Patent Publication No. 53-39421), N-alkyl-D-glucamine (Japanese Patent Publication No. 56-18939) from the racemic form of compound (). ), and (2) an optical resolution method using -l-menthol (Japanese Patent Application No. 31860/1983) are known. However, these optical resolution methods have
Problems include that the resolving agent is expensive, it is chemically unstable, the selective yield during resolution is low, and the racemization process of the dl-isomer mixture obtained from the residual solution of resolution is high temperature and long time. It was hot.
本発明者らは、化合物()のより安価な新規
製法について鋭意検討し、
一般式()
(但し式中、Rは炭素数1ないし4のアルキル
基を示す。)
で示されるd―2―(6―メトキシ―2―ナフチ
ル)プロピオン酸アルキルエステル(以下化合物
()という)を該当のdl体混合物から効率良く
得る方法を既に確立している。(特願昭56―
56731)本発明はこの化合物()を立体保持的
に加水分解することにより化合物()を経済的
に効率良く得る製法を確立したものである。 The present inventors have intensively investigated a new, cheaper method for producing the compound (), and have found that the general formula () is (However, in the formula, R represents an alkyl group having 1 to 4 carbon atoms.) The corresponding dl We have already established a method for efficiently obtaining it from a body mixture. (Special application 1982-
56731) The present invention establishes a production method for economically and efficiently obtaining compound () by hydrolyzing this compound () in a steric-retentive manner.
一般に、光学活性なカルボン酸のアルキルエス
テルを加水分解する場合、塩基性条件下では、立
体保持はかなり困難である。また酸性条件下でも
完全な立体保持をするとは限らない。 Generally, when hydrolyzing alkyl esters of optically active carboxylic acids, steric retention is quite difficult under basic conditions. Furthermore, complete steric retention is not necessarily achieved even under acidic conditions.
(一例として「化学総説“不斉反応の化学”日
本化学会編(1974)252頁、4.1化学的方法及び
255頁、4.4熱による方法」を参照)
他方、dl―2―(6―メトキシ―2―ナフチ
ル)プロピオン酸アルキルエステルを酸性条件で
加水分解する方法として、「0.1ないし5容量%酸
を含む酸安定性溶媒で10℃ないし溶液の沸とう温
度で行う方法」(特公昭56―27503)が知られてい
る。しかし、この条件で光学的に活性な化合物
()の加水分解を本発明者らが行なつたところ
意外にもほゞ100%立体保持的であつたが反応は
遅かつた。即ち比較例1に示した通り、dl体での
収率60%(特公昭56―2705、第3頁第5列.例1
参照)に対し、化合物()(d体)の収率は12
%と著しく低かつた。また、この加水分解条件で
反応率を上げるべく反応時間を延長すると
式()
で示されるd―2―(6―ヒドロキシ―2―ナフ
チル)プロピオン酸(以下化合物()とい
う。)
の副生が増大し、光学的に不活性な場合の特公昭
56―2705の明細書例1の記述通りの結果は得られ
なかつた。また、これらの問題点の他に反応の容
積効率を上げるために化合物()の濃度を上げ
るとさらに反応が遅くなるという問題が発生し
た。 (For example, see 4.1 Chemical Methods and
On the other hand, as a method for hydrolyzing dl-2-(6-methoxy-2-naphthyl)propionic acid alkyl ester under acidic conditions, there is a method for hydrolyzing dl-2-(6-methoxy-2-naphthyl)propionic acid alkyl ester under acidic conditions. A method using a stable solvent at 10℃ or the boiling temperature of the solution'' (Japanese Patent Publication No. 56-27503) is known. However, when the present inventors hydrolyzed the optically active compound (2) under these conditions, the reaction was surprisingly slow although the steric retention was almost 100%. That is, as shown in Comparative Example 1, the yield of the dl form was 60% (Japanese Patent Publication No. 56-2705, page 3, column 5. Example 1
), the yield of compound () (d-isomer) is 12
%, which was extremely low. In addition, if the reaction time is extended to increase the reaction rate under these hydrolysis conditions, the formula () The by-product of d-2-(6-hydroxy-2-naphthyl)propionic acid (hereinafter referred to as compound ()) increases and is optically inactive.
No. 56-2705, the results described in Specification Example 1 could not be obtained. In addition to these problems, when the concentration of the compound () is increased in order to increase the volumetric efficiency of the reaction, a problem arises in that the reaction becomes even slower.
そこで本発明者らは、立体保持的に、効率良く
(換言すると短時間、高濃度下で高反応率)、かつ
化合物()の副生を極力抑える条件について鋭
意検討し、次の方法が最適であることを見出し
た。即ち、硫酸、塩化水素、臭化水素または過塩
素酸の1種または2種以上から成る鉱酸を10乃至
50重量%含有する含水低級脂肪酸溶液中、化合物
()を加水分解により処理する方法である。 Therefore, the present inventors have diligently investigated conditions that are efficient in terms of steric retention (in other words, high reaction rate in a short period of time and at high concentrations) and minimize the by-product of compound (), and have found the following method to be optimal. I found that. That is, 10 to 10% of mineral acids consisting of one or more of sulfuric acid, hydrogen chloride, hydrogen bromide, or perchloric acid are added.
This is a method in which compound () is treated by hydrolysis in a 50% by weight water-containing lower fatty acid solution.
上記、本発明の方法を詳しく説明する。使用す
る低級脂肪酸としては、ぎ酸、酢酸またはプロピ
オン酸が例示でき、必要があればこれらを混合し
て用いることも可能である。 The above method of the present invention will be explained in detail. Examples of the lower fatty acids to be used include formic acid, acetic acid, and propionic acid, and if necessary, it is also possible to use a mixture of these.
鉱酸としては、硫酸、塩化水素、臭化水素、ヨ
ウ化水素、過塩素酸、または硝酸が例示でき、必
要があればこれらを混合して用いることも可能で
ある。 Examples of mineral acids include sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, perchloric acid, and nitric acid, and it is also possible to use a mixture of these if necessary.
鉱酸濃度としては、低いと反応が遅くなり、所
要の反応時間が長びき(比較例1)、逆に鉱酸濃
度が高過ぎてもスルホン化、ニトロ化等の副反応
が増大し、また化合物()の生成量が著しく増
し(比較例2)、生成物の純度が下るため10ない
し50重量%が好ましい。 If the mineral acid concentration is too low, the reaction will be slow and the required reaction time will be prolonged (Comparative Example 1), and if the mineral acid concentration is too high, side reactions such as sulfonation and nitration will increase, and 10 to 50% by weight is preferred because the amount of compound () produced increases significantly (Comparative Example 2) and the purity of the product decreases.
反応温度は、20℃ないし溶液の沸とう温度であ
る。また、出発原料の化合物()のエステル部
のアルキル基としては、直鎖または分枝の炭素数
1ないし4の低級アルキル基、就中、メチル、エ
チル、イソプロピル、n―プロピルまたはt―ブ
チル基が望ましい。 The reaction temperature is 20°C to the boiling temperature of the solution. In addition, the alkyl group in the ester moiety of the starting material compound () is a linear or branched lower alkyl group having 1 to 4 carbon atoms, especially a methyl, ethyl, isopropyl, n-propyl or t-butyl group. is desirable.
なお、本発明の鉱酸濃度の範囲でも、化合物
()のエステル基の加水分解率が、85〜95%を
超えると、化合物()のカルボン酸に対する化
合物()の生成比率が増大する傾向がある。従
つて、化合物()のエステル基の加水分解率が
85〜95%になつたら、エステルの加水分解反応を
終了して後処理をするのが好ましい。 Furthermore, even within the mineral acid concentration range of the present invention, if the hydrolysis rate of the ester group of compound () exceeds 85 to 95%, the production ratio of compound () to the carboxylic acid of compound () tends to increase. be. Therefore, the hydrolysis rate of the ester group of compound () is
When it reaches 85 to 95%, it is preferable to terminate the ester hydrolysis reaction and perform post-treatment.
次に比較例1(溶液の鉱酸濃度を、本発明の特
許請求範囲の下限値10重量%より低くした場合の
実験例)、比較例2(溶液の鉱酸濃度を、本発明
の特許請求範囲の上限値50重量%より高くした場
合の実験例)及び本発明の方法の実施例1乃至10
を示して、本発明を更に詳しく具体的に説明す
る。 Next, Comparative Example 1 (experimental example in which the mineral acid concentration of the solution was lower than the lower limit of 10% by weight of the claims of the present invention), Comparative Example 2 (the mineral acid concentration of the solution was lowered to below the lower limit of 10% by weight of the claims of the present invention), Experimental examples when the upper limit of the range is higher than 50% by weight) and Examples 1 to 10 of the method of the present invention
The present invention will be explained in more detail with reference to the following.
比較例 1
(特公昭56―27503の例1の反応条件に従つた場
合)
メタノール5ml、水5ml、35%塩酸0.2gの混
合液(塩化水素濃度0.8重量%)にd―2―(6
―メトキシ―2―ナフチル)プロピオン酸メチル
エステル1g〔α〕20 D=+78.6゜(クロロホル
ム)を加え、24時間加熱還流した。実施例1と同
様に処理し、未反応のd―2―(6―メトキシ―
2―ナフチル)プロピオン酸メチルエステル0.87
g(回収率87%、〔α〕20 D=+80.9゜)と化合物
()0.11gを得た。収率12%、〔α〕20 D=+67.9
゜
(クロロホルム)、化合物()の含有量2.0%
(特公昭56―27503の記述ではdl体での反応で収率
60%、純度100%とされている。)
実施例1と比較すると、本発明の方法により短
時間で立体保持的に、高収率で同じ純度の目的物
を与えていることがわかる。Comparative Example 1 (When following the reaction conditions of Example 1 of Japanese Patent Publication No. 56-27503) d-2-(6
-Methoxy-2-naphthyl)propionic acid methyl ester (1 g [α] 20 D = +78.6° (chloroform) was added, and the mixture was heated under reflux for 24 hours. Treated in the same manner as in Example 1, unreacted d-2-(6-methoxy-
2-Naphthyl) propionic acid methyl ester 0.87
(recovery rate 87%, [α] 20 D =+80.9°) and 0.11 g of compound () were obtained. Yield 12%, [α] 20 D = +67.9
゜ (chloroform), content of compound () 2.0%
(According to the description in Japanese Patent Publication No. 56-27503, the yield is obtained by the reaction with the dl form.
It is said to be 60% pure and 100% pure. ) Comparison with Example 1 shows that the method of the present invention provides the target product in a short time, with steric retention, in high yield, and with the same purity.
比較例 2
酢酸0.4g、95%硫酸1.68g、水0.2gの混合液
(硫酸濃度70重量%)にd―2―(6―メトキシ
―2―ナフチル)プロピオン酸エチルエステル
1.0gを加え、60℃で3.5時間反応させた。実施例
4と同様に処理し分析すると反応率は71%、化合
物()の含有量は19.3%であつた。化合物
()の生成比が非常に高くなり、また生成物に
も黄色の着色が認められた。Comparative Example 2 d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester in a mixed solution of 0.4 g of acetic acid, 1.68 g of 95% sulfuric acid, and 0.2 g of water (sulfuric acid concentration 70% by weight)
1.0 g was added and reacted at 60°C for 3.5 hours. When treated and analyzed in the same manner as in Example 4, the reaction rate was 71% and the content of compound () was 19.3%. The production ratio of compound () was extremely high, and yellow coloration was also observed in the product.
実施例 1
酢酸1g、35%塩酸0.5gの混合液(塩化水素
濃度12重量%)にd―2―(6―メトキシ―2―
ナフチル)プロピオン酸メチルエステル(〔α〕20 D
=+78.6゜(クロロホルム)、光学純度〜100%)
1gを加え、60℃で4時間反応させた。冷却後、
水を加えトルエン―酢酸エチル(混合比1:2)
で抽出し、有機層を5%水酸化ナトリウム水溶液
で洗い、水洗後溶媒を留去すると未反応のd―2
―(6―メトキシ―2―ナフチル)プロピオン酸
メチルエステル0.2gが得られた。Example 1 d-2-(6-methoxy-2-
Naphthyl) propionic acid methyl ester ([α] 20 D
= +78.6° (chloroform), optical purity ~100%)
1 g was added and reacted at 60°C for 4 hours. After cooling,
Add water and toluene-ethyl acetate (mixing ratio 1:2)
The organic layer was extracted with 5% sodium hydroxide aqueous solution, and after washing with water, the solvent was distilled off to remove unreacted d-2.
0.2 g of -(6-methoxy-2-naphthyl)propionate methyl ester was obtained.
アルカリ層を塩酸で酸性化した後、トルエン―
酢酸エチルで抽出し、水洗後溶媒を留去すると化
合物()0.75gが得られた。収率80%、〔α〕20 D
=+68゜(クロロホルム)、光学純度98.4%e.e.。
このものをHPLC(nucleosil 50―5、4.6φ×
250mm、酢酸/クロロホルム0.2%)で分析すると
化合物()の含有率が2.0%であつた。 After acidifying the alkaline layer with hydrochloric acid, toluene-
After extraction with ethyl acetate and washing with water, the solvent was distilled off to obtain 0.75 g of compound (). Yield 80%, [α] 20 D
= +68° (chloroform), optical purity 98.4%ee.
This was analyzed by HPLC (nucleosil 50-5, 4.6φ×
250 mm, acetic acid/chloroform 0.2%), the content of compound () was 2.0%.
以下に化合物()および化合物()の物性
値を示す。 The physical property values of Compound () and Compound () are shown below.
化合物 ()
実施例1で得られた化合物()を含有する化
合物()の結晶をメタノールから再結すること
により取得した。Compound () Crystals of compound () containing compound () obtained in Example 1 were obtained by recrystallizing from methanol.
融点;157.5℃
〔α〕20 D;+69.1゜(C=1,クロロホルム)化
合物()(純度約90%)
融点;183〜185℃
〔α〕20 D;+65.5゜(C=0.05、クロロホルム)
NMR(DMSO−d6);δ1.43(3H,d,7
Hz)、3.76(1H,q,7Hz)、6.9〜7.8(6H,
m)、9.67(1H,s)、12.15(1H,broad s)
IR(KBr);3200,1690,1600,1380,1185,
1160,1140cm-1
MS(m/e);216(37.M+)、171(100)
実施例 2
酢酸1g、35%塩酸0.5gの混合液(塩化水素
濃度12重量%)にd―2―(6―メトキシ―2―
ナフチル)プロピオン酸エチルエステル(〔α〕20 D
=+48.6゜(クロロホルム)光学純度〜100%)
1gを加え、60℃で6時間反応させた。実施例1
と同様に処理し化合物()0.57gが得られた。
収率64%
〔α〕20 D=+66.7゜(クロロホルム)、光学純度
96.5%e.e.、化合物()の含有率2.2%。Melting point; 157.5°C [α] 20 D ; +69.1° (C = 1, chloroform) compound () (purity approximately 90%) Melting point; 183-185°C [α] 20 D ; +65.5° (C = 0.05 , chloroform) NMR (DMSO-d 6 ); δ1.43 (3H, d, 7
Hz), 3.76 (1H, q, 7Hz), 6.9~7.8 (6H,
m), 9.67 (1H, s), 12.15 (1H, broad s) IR (KBr); 3200, 1690, 1600, 1380, 1185,
1160, 1140cm -1 MS (m/e); 216 (37.M + ), 171 (100) Example 2 Add d-2 to a mixed solution of 1 g of acetic acid and 0.5 g of 35% hydrochloric acid (hydrogen chloride concentration 12% by weight) -(6-methoxy-2-
naphthyl) propionic acid ethyl ester ([α] 20 D
= +48.6° (chloroform) optical purity ~100%)
1 g was added and reacted at 60°C for 6 hours. Example 1
0.57 g of compound () was obtained.
Yield 64% [α] 20 D = +66.7° (chloroform), optical purity
96.5%ee, content of compound () 2.2%.
実施例 3
酢酸6g、35%塩酸3gの混合液(塩化水素濃
度12重量%)にd―2―(6―メトキシ―2―ナ
フチル)プロピオン酸エチルエステル2gを加
え、60℃で5時間反応後、溶媒を50℃で留去し
た。実施例1と同様に処理し、化合物()1.67
gを得た。Example 3 2 g of d-2-(6-methoxy-2-naphthyl)propionate ethyl ester was added to a mixed solution of 6 g of acetic acid and 3 g of 35% hydrochloric acid (hydrogen chloride concentration: 12% by weight), and the mixture was reacted at 60°C for 5 hours. , the solvent was distilled off at 50°C. Treated in the same manner as in Example 1, compound () 1.67
I got g.
収率94%。〔α〕20 D=+68.6゜(クロロホル
ム)、光学純度99.37e.e.、化合物()の含有率
4.9%。 Yield 94%. [α] 20 D = +68.6° (chloroform), optical purity 99.37ee, content of compound ()
4.9%.
実施例 4
酢酸1g、50%硫酸0.5gの混合液(硫酸濃度
17重量%)にd―2―(6―メトキシ―2―ナフ
チル)プロピオン酸エチルエステル1gを加え、
70℃で6時間反応させた。冷却後水を加えトルエ
ン―酢酸エチルで抽出し、水洗後、有機層の溶媒
を留去し、得られた混合物の一部をジアゾメタン
処理しGC(キヤピラリーカラム、OV―101、
20m)分析すると反応率58%であつた。収率55
%、〔α〕20 D66.7゜(クロロホルム)、光学純度96
.5
%e.e.またHPLC分析によると化合物()に対
し、2.1%の化合物()が含まれていた。Example 4 A mixed solution of 1 g of acetic acid and 0.5 g of 50% sulfuric acid (sulfuric acid concentration
17% by weight) was added with 1 g of d-2-(6-methoxy-2-naphthyl)propionate ethyl ester,
The reaction was carried out at 70°C for 6 hours. After cooling, water was added and extracted with toluene-ethyl acetate. After washing with water, the solvent of the organic layer was distilled off, and a part of the resulting mixture was treated with diazomethane and subjected to GC (capillary column, OV-101,
20m) Analysis revealed a reaction rate of 58%. Yield 55
%, [α] 20 D 66.7° (chloroform), optical purity 96
.Five
%ee Also, according to HPLC analysis, it contained 2.1% of compound () compared to compound ().
実施例 5
酢酸2.8g、47%臭化水素酸0.8gの混合液(臭
化水素濃度10重量%)にd―2―(6―メトキシ
―2―ナフチル)プロピオン酸エチルエステル1
gを加え50℃で7.5時間反応させた。実施例1と
同様に処理し、化合物()0.58gを得た。Example 5 d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester 1 in a mixed solution of 2.8 g of acetic acid and 0.8 g of 47% hydrobromic acid (hydrogen bromide concentration 10% by weight)
g was added and reacted at 50°C for 7.5 hours. It was treated in the same manner as in Example 1 to obtain 0.58 g of compound ().
収率65%、〔α〕20 D=+67.7゜(クロロホルム)
光学純度98.0%e.e.、化合物()の含有率1.4
%。 Yield 65%, [α] 20 D = +67.7° (chloroform)
Optical purity 98.0%ee, content of compound () 1.4
%.
実施例 6
酢酸15.5g、47%臭化水素酸7.6gの混合液
(臭化水素16重量%)にd―2―(6―メトキシ
―2―ナフチル)プロピオン酸エチルエステル5
gを加え、60℃で4時間反応させた。実施例1と
同様に処理し、未反応のd―2―(6―メトキシ
―2―ナフチル)プロピオン酸エチルエステル
0.52g(回収率10%、〔α〕20 D=+46゜)、化合物
()3.84gを得た。収率86%、〔α〕20 D=+65.2
゜
(クロロホルム)、光学純度94.4%e.e.、
実施例 7
酢酸1g、44%ヨウ化水素酸0.5gの混合液
(ヨウ化水素濃度15重量%)にd―2―(6―メ
トキシ―2―ナフチル)プロピオン酸エチルエス
テル1gを加え、60℃で6時間反応させた。実施
例1と同様に処理し化合物()0.59gを得た。Example 6 d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester 5 was added to a mixed solution of 15.5 g of acetic acid and 7.6 g of 47% hydrobromic acid (16% by weight of hydrogen bromide).
g was added thereto, and the mixture was reacted at 60°C for 4 hours. Unreacted d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester treated in the same manner as in Example 1
0.52 g (recovery rate 10%, [α] 20 D = +46°) and 3.84 g of compound () were obtained. Yield 86%, [α] 20 D = +65.2
(chloroform), optical purity 94.4%ee, Example 7 d-2-(6-methoxy-2-naphthyl) in a mixed solution of 1 g of acetic acid and 0.5 g of 44% hydroiodic acid (hydriodide concentration 15% by weight) ) 1 g of propionic acid ethyl ester was added and reacted at 60°C for 6 hours. The mixture was treated in the same manner as in Example 1 to obtain 0.59 g of compound ().
収率66%、〔α〕20 D=+67.9゜(クロロホル
ム)、光学純度98.3%e.e.、化合物()の含有率
2.1%。 Yield 66%, [α] 20 D = +67.9° (chloroform), optical purity 98.3%ee, content of compound ()
2.1%.
実施例 8
酢酸1g、42%過塩素酸0.5gの混合液(過塩
素酸濃度14重量%)に、d―2―(6―メトキシ
―2―ナフチル)プロピオン酸エチルエステル1
gを加え、60℃で6時間反応させた。実施例1と
同様に処理し、化合物()0.73gを得た。Example 8 To a mixed solution of 1 g of acetic acid and 0.5 g of 42% perchloric acid (perchloric acid concentration 14% by weight), 1 part of d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester was added.
g was added thereto, and the mixture was reacted at 60°C for 6 hours. The mixture was treated in the same manner as in Example 1 to obtain 0.73 g of compound ().
収率82%、〔α〕20 D=+67.1゜(クロロホル
ム)、光学純度97.1%e.e.、化合物()の含有率
3.6%。 Yield 82%, [α] 20 D = +67.1° (chloroform), optical purity 97.1%ee, content of compound ()
3.6%.
実施例 9
ぎ酸1g、47%臭化水素酸0.5gの混合液(臭
化水素16重量%)にd―2―(6―メトキシ―2
―ナフチル)プロピオン酸エチルエステル1gを
加え、60℃で6時間反応させた。実施例4と同様
に処理すると反応率66%、収率63%、〔α〕20 D64.3
゜(クロロホルム)、光学純度93.1%e.e.、化合物
()の含有率は5.3%であつた。Example 9 d-2-(6-methoxy-2
1 g of ethyl (naphthyl) propionate was added, and the mixture was reacted at 60°C for 6 hours. When treated in the same manner as in Example 4, reaction rate was 66%, yield was 63%, [α] 20D 64.3
(chloroform), the optical purity was 93.1%ee, and the content of compound () was 5.3%.
実施例 10
酢酸1g、47%臭化水素酸1gの混合液(臭化
水素24重量%)にd―2―(6―メトキシ―2―
ナフチル)プロピオン酸エチルエステル1gを加
え、60℃で6時間反応させた。実施例4と同様に
処理し分析すると反応率は59%であつた。収率56
%、〔α〕20 D63.9゜(クロロホルム)、光学純度92
.5
%e.e.。Example 10 d-2-(6-methoxy-2-
1 g of ethyl naphthyl propionate was added, and the mixture was reacted at 60°C for 6 hours. When treated and analyzed in the same manner as in Example 4, the reaction rate was 59%. Yield 56
%, [α] 20 D 63.9° (chloroform), optical purity 92
.Five
%ee.
Claims (1)
硝酸の1種または2種以上から成る鉱酸を10乃至
50重量%含有する含水低級脂肪酸溶液中、d―2
―(6―メトキシ―2―ナフチル)プロピオン酸
アルキルエステルを加水分解することを特徴とす
るd―2―(6―メトキシ―2―ナフチル)プロ
ピオン酸の製造方法。1. 10 or more mineral acids consisting of one or more of sulfuric acid, hydrogen chloride, hydrogen bromide, perchloric acid, or nitric acid.
In a water-containing lower fatty acid solution containing 50% by weight, d-2
- A method for producing d-2-(6-methoxy-2-naphthyl)propionic acid, which comprises hydrolyzing an alkyl (6-methoxy-2-naphthyl)propionic acid ester.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4103082A JPS58157745A (en) | 1982-03-16 | 1982-03-16 | D-2-(6-methoxy-2-naphthyl)propionic acid |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4103082A JPS58157745A (en) | 1982-03-16 | 1982-03-16 | D-2-(6-methoxy-2-naphthyl)propionic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS58157745A JPS58157745A (en) | 1983-09-19 |
JPS6148819B2 true JPS6148819B2 (en) | 1986-10-25 |
Family
ID=12596994
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP4103082A Granted JPS58157745A (en) | 1982-03-16 | 1982-03-16 | D-2-(6-methoxy-2-naphthyl)propionic acid |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS58157745A (en) |
-
1982
- 1982-03-16 JP JP4103082A patent/JPS58157745A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS58157745A (en) | 1983-09-19 |
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