JPH0259817B2 - - Google Patents
Info
- Publication number
- JPH0259817B2 JPH0259817B2 JP17456882A JP17456882A JPH0259817B2 JP H0259817 B2 JPH0259817 B2 JP H0259817B2 JP 17456882 A JP17456882 A JP 17456882A JP 17456882 A JP17456882 A JP 17456882A JP H0259817 B2 JPH0259817 B2 JP H0259817B2
- Authority
- JP
- Japan
- Prior art keywords
- methoxy
- naphthyl
- salt
- methylpiperidine
- propionic acid
- 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
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000013078 crystal Substances 0.000 claims description 19
- 230000003287 optical effect Effects 0.000 claims description 18
- SEVXEIGENOCFRM-UHFFFAOYSA-N 2-(6-methoxynaphthalen-2-yl)propanoic acid;4-methylpiperidine Chemical compound CC1CCNCC1.C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 SEVXEIGENOCFRM-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- -1 4-methylpiperidine propionate Chemical compound 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- VKCNNDPZFOVURD-UHFFFAOYSA-N 2-naphthalen-1-ylpropanoic acid Chemical compound C1=CC=C2C(C(C(O)=O)C)=CC=CC2=C1 VKCNNDPZFOVURD-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
- CMWTZPSULFXXJA-UHFFFAOYSA-N 2-(6-methoxy-2-naphthalenyl)propanoic acid Chemical compound C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 11
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 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 7
- 239000002904 solvent Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011437 continuous method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は２−（６−メトキシ−２−ナフチル）
プロピオン酸４−メチルピペリジン塩による
（±）−２−（６−メトキシ−２−ナフチル）プロ
ピオン酸の光学分割法に関する。更に詳しくは本
発明は工業的に有利な光学分割法としての優先晶
出法における２−（６−メトキシ−２−ナフチル）
プロピオン酸４−メチルピペリジン塩の利用に関
する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2-(6-methoxy-2-naphthyl)
This invention relates to a method for optical resolution of (±)-2-(6-methoxy-2-naphthyl)propionic acid using propionic acid 4-methylpiperidine salt. More specifically, the present invention relates to 2-(6-methoxy-2-naphthyl) in a preferential crystallization method as an industrially advantageous optical resolution method.
This invention relates to the use of 4-methylpiperidine propionate salt.
２−（６−メトキシ−２−ナフチル）プロピオ
ン酸の（＋）−体は抗炎症、鎮痛および解熱作用
等を有する化合物であるが、通常有機合成法によ
つて得られる２−（６−メトキシ−２−ナフチル）
プロピオン酸は光学的に不活性な（±）−体であ
り、従つて有用な（＋）−体を得るにはこれを光
学分割する必要がある。（±）−２−（６−メトキ
シ−２−ナフチル）プロピオン酸の光学分割方法
としては多数の方法が提案されているが、そのす
べては（±）−体に光学分割剤すなわちキラール
（chiral）な物質を作用させ、生成したジアステ
レオマーの溶解度差等を利用して分割する方法で
ある。しかしながら、これらの従来法は高価な光
学活性体を用いる点に難点がある。一方、優先晶
出法は（±）−体の過飽和溶液に一方の光学活性
体を加えて所望の光学活性体を晶析させる方法で
あり、その操作方法それ自体は周知である。しか
しながら、現在のところいかなる化合物がこの操
作の適用により光学分割可能であるか全く予測す
ることができない。そこで、工業的に有利な優先
晶出法が可能かどうか（±）−２−（６−メトキシ
−２−ナフチル）プロピオン酸自体および（±）
−２−（６−メトキシ−２−ナフチル）プロピオ
ン酸の各種有機および無機塩について鋭意研究を
重ねた結果、（±）−２−（６−メトキシ−２−ナ
フチル）プロピオン酸を４−メチルピペリジン塩
とすることによつて初めて高能率に光学分割でき
ることを見い出し、本発明を完成するに至つた。 The (+)-isomer of 2-(6-methoxy-2-naphthyl)propionic acid is a compound that has anti-inflammatory, analgesic, and antipyretic effects. -2-naphthyl)
Propionic acid is an optically inactive (±)-form, and therefore it is necessary to optically resolve it to obtain a useful (+)-form. A large number of methods have been proposed for the optical resolution of (±)-2-(6-methoxy-2-naphthyl)propionic acid, but all of them have been proposed for the optical resolution of (±)-isomer, i.e., chiral. This is a method of separating the diastereomers by applying a substance to the diastereomers and making use of differences in solubility between the diastereomers. However, these conventional methods have a drawback in that they use expensive optically active substances. On the other hand, the preferential crystallization method is a method in which a desired optically active substance is crystallized by adding one of the optically active forms to a supersaturated solution of the (±)-isomer, and its operation method itself is well known. However, it is currently impossible to predict which compounds can be optically resolved by applying this procedure. Therefore, whether an industrially advantageous preferential crystallization method is possible (±)-2-(6-methoxy-2-naphthyl)propionic acid itself and (±)
As a result of intensive research on various organic and inorganic salts of -2-(6-methoxy-2-naphthyl)propionic acid, we found that (±)-2-(6-methoxy-2-naphthyl)propionic acid was converted into 4-methylpiperidine. They discovered that highly efficient optical resolution can be achieved for the first time by converting it into a salt, leading to the completion of the present invention.
すなわち、本発明は式
で示される２−（６−メトキシ−２−ナフチル）
プロピオン酸４−メチルピペリジン塩および
（±）−２−（６−メトキシ−２−ナフチル）プロ
ピオン酸４−メチルピペリジン塩の過飽和溶液に
光学活性の２−（６−メトキシ−２−ナフチル）
プロピオン酸４−メチルピペリジン塩の結晶を存
在せしめ、該光学活性体と同種の光学活性２−
（６−メトキシ−２−ナフチル）プロピオン酸４
−メチルピペリジン塩を選択的に晶出させた後、
固液分離して光学活性塩を取得する（±）−２−
（６−メトキシ−２−ナフチル）プロピオン酸の
光学分割法である。 That is, the present invention is based on the formula 2-(6-methoxy-2-naphthyl) represented by
Optically active 2-(6-methoxy-2-naphthyl) was added to a supersaturated solution of 4-methylpiperidine propionate salt and (±)-2-(6-methoxy-2-naphthyl) propionate.
Crystals of 4-methylpiperidine propionate salt are present, and the same type of optically active 2-
(6-methoxy-2-naphthyl)propionic acid 4
- After selectively crystallizing the methylpiperidine salt,
Obtain optically active salt by solid-liquid separation (±)-2-
This is an optical resolution method for (6-methoxy-2-naphthyl)propionic acid.
以下に本発明方法を具体的に説明する。まず、
２−（６−メトキシ−２−ナフチル）プロピオン
酸４−メチルピペリジン塩の調製方法としては、
適当な溶媒中に２−（６−メトキシ−２−ナフチ
ル）プロピオン酸と４−メチルピペリジンを加え
て２−（６−メトキシ−２−ナフチル）プロピオ
ン酸４−メチルピペリジン塩を結晶として分離す
ればよい。塩の調製に当つて２−（６−メトキシ
−２−ナフチル）プロピオン酸と４−メチルピペ
リジンは必ずしも当モルである必要はない。 The method of the present invention will be specifically explained below. first,
The method for preparing 2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt is as follows:
If 2-(6-methoxy-2-naphthyl)propionic acid and 4-methylpiperidine are added to a suitable solvent, 2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt is separated as crystals. good. In preparing the salt, 2-(6-methoxy-2-naphthyl)propionic acid and 4-methylpiperidine do not necessarily have to be in equimolar amounts.
次に優先晶出操作方法を具体的に説明する。実
施するに当つて使用する（±）−２−（６−メトキ
シ−２−ナフチル）プロピオン酸４−メチルピペ
リジン塩の過飽和溶液は、常法により（±）−２
−（６−メトキシ−２−ナフチル）プロピオン酸
４−メチルピペリジン塩またはいずれか一方の光
学活性体塩を過剰に含有する塩の混合物を適当な
溶媒に加熱して溶解し、そして得られる溶液を冷
却あるいは濃縮して調製する。また、（±）−２−
（６−メトキシ−２−ナフチル）プロピオン酸お
よび４−メチルピペリジンのジメチルアセトアミ
ド等の溶媒に対する溶解度はそれらの塩の溶解度
よりも大きいから、適当な濃度の（±）−２−（６
−メトキシ−２−ナフチル）プロピオン酸および
４−メチルピペリジンの溶液を混合することによ
り、（±）−２−（６−メトキシ−２−ナフチル）
プロピオン酸４−メチルピペリジン塩の過飽和溶
液を調製することもできる。かくして調製した
（±）−体塩の過飽和溶液に光学活性体塩を接種す
ることにより同種の光学活性体塩を優先的に晶出
させることができる。接種に使用する種晶の光学
純度は高いことが必要であるが、接種量は溶質量
の0.1〜１％程度で充分である。また、過飽和溶
液に一方の光学活性体塩が過剰に含有されている
場合には接種量はもつと少量でもよく、更には全
く接種しなくとも過剰に含有されている光学活性
体塩の起晶が自然に発生し、接種した場合と同様
に光学活性体塩を晶出させることもできる。晶出
温度は任意に選択できるが、室温付近が便利であ
る。優先晶出操作に用いられる溶媒としては、
（±）−２−（６−メトキシ−２−ナフチル）プロ
ピオン酸４−メチルピペリジン塩が適当な溶解度
を示すことが好ましく、ヘキサメチルホスホルア
ミド、ジメチルスルホキシド、ジメチルアセトア
ミド、ジメチルホルムアミド、アセトン、メチル
エチルケトン、メチルイソブチルケトン、エチレ
ングリコールジメチルエーテル、ジオキサン、酢
酸エチル、イソプロパノール等の単独溶媒および
これらの有機溶媒の適当な組合せからなる混合溶
媒が挙げられる。特に、代表的な非プロトン性極
性溶媒であるジメチルアセトアミド等のアミド系
溶媒、ジメチルスルホキシド、アセトン等の単独
溶媒およびこれらの適当な組合せからなる混合溶
媒が好ましい。 Next, the preferential crystallization operation method will be specifically explained. A supersaturated solution of (±)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt used in the implementation is prepared by a conventional method.
-(6-Methoxy-2-naphthyl)propionate 4-methylpiperidine salt or a mixture of salts containing an excess of optically active salt of either one is heated and dissolved in an appropriate solvent, and the resulting solution is dissolved. Prepare by cooling or concentrating. Also, (±)-2-
Since the solubility of (6-methoxy-2-naphthyl)propionic acid and 4-methylpiperidine in solvents such as dimethylacetamide is greater than the solubility of their salts, appropriate concentrations of (±)-2-(6
(±)-2-(6-methoxy-2-naphthyl) by mixing solutions of -methoxy-2-naphthyl)propionic acid and 4-methylpiperidine.
Supersaturated solutions of propionic acid 4-methylpiperidine salt can also be prepared. By inoculating the optically active salt into the thus prepared supersaturated solution of the (±)-form salt, the optically active salt of the same type can be preferentially crystallized. Although it is necessary that the seed crystals used for inoculation have high optical purity, an amount of inoculation of about 0.1 to 1% of the amount of solute is sufficient. In addition, if the supersaturated solution contains an excess of one of the optically active salts, the amount of inoculation may be as small as possible; furthermore, the optically active salt contained in excess may be crystallized without inoculation at all. occurs naturally, and the optically active salt can also be crystallized in the same way as when it is inoculated. Although the crystallization temperature can be selected arbitrarily, it is convenient to set it around room temperature. Solvents used in preferential crystallization operations include:
Preferably, (±)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt exhibits appropriate solubility, such as hexamethylphosphoramide, dimethylsulfoxide, dimethylacetamide, dimethylformamide, acetone, methyl ethyl ketone. , methyl isobutyl ketone, ethylene glycol dimethyl ether, dioxane, ethyl acetate, isopropanol, etc., and mixed solvents consisting of appropriate combinations of these organic solvents. Particularly preferred are typical aprotic polar solvents such as amide solvents such as dimethylacetamide, single solvents such as dimethylsulfoxide and acetone, and mixed solvents consisting of appropriate combinations thereof.
前記操作により一方の光学活性体を晶析させた
母液中には反対の光学活性を有する対掌体が過剰
に溶存しているので、この母液について前回と同
様の操作をくり返せば対掌体を選択的に晶出させ
ることができる。例えば、（±）−体塩を追加溶解
した後、冷却して再び過飽和溶液を調製し、これ
に適量の対掌体を接種し同様な操作を繰返して各
対掌体塩を取得することができる。また、本発明
方法は前述のようなバツチ法ばかりでなく、例え
ば活性体晶析槽と対掌体晶析槽とを並列または直
列に連結し、それぞれの晶析槽に種晶を存在させ
て連続的に分割晶出を行う周知の連続方式によつ
ても実施できる。 Since an excess of the enantiomer with the opposite optical activity is dissolved in the mother liquor obtained by crystallizing one optically active substance by the above operation, repeating the same operation as before for this mother liquor will yield the enantiomer. can be selectively crystallized. For example, after additionally dissolving the (±)-isomer salt, it is cooled to prepare a supersaturated solution again, and an appropriate amount of the enantiomer is inoculated into this, and the same operation is repeated to obtain each enantiomer salt. can. Furthermore, the method of the present invention is not limited to the batch method as described above, but also includes, for example, connecting an active substance crystallization tank and an enantiomer crystallization tank in parallel or in series, and allowing seed crystals to exist in each crystallization tank. It can also be carried out by a well-known continuous method in which split crystallization is carried out continuously.
かくして得られた光学活性体塩は常法により適
当な溶媒を用いて再結晶することにより高い光学
純度の塩とすることができる。この塩を常法によ
る中和あるいは、イオン交換樹脂処理等により、
４−メチルピペリジンと分離し、高純度の光学活
性２−（６−メトキシ−２−ナフチル）プロピオ
ン酸を取得することができる。 The optically active salt thus obtained can be recrystallized using a suitable solvent in a conventional manner to obtain a salt with high optical purity. This salt is neutralized by conventional methods or treated with ion exchange resin, etc.
By separating it from 4-methylpiperidine, highly pure optically active 2-(6-methoxy-2-naphthyl)propionic acid can be obtained.
なお本発明において使用する２−（６−メトキ
シ−２−ナフチル）プロピオン酸４−メチルピペ
リジン塩は新規な化合物であり、ちなみに光学活
性２−（６−メトキシ−２−ナフチル）プロピオ
ン酸４−メチルピペリジン塩の融点は130〜135℃
である。 The 4-methylpiperidine 2-(6-methoxy-2-naphthyl)propionic acid salt used in the present invention is a new compound; The melting point of piperidine salt is 130-135℃
It is.
次に実施例を挙げて本発明を詳細に説明する。 Next, the present invention will be explained in detail with reference to Examples.
実施例 １
（＋）−２−（６−メトキシ−２−ナフチル）プ
ロピオン酸3.19g〔〔α〕25 D＝＋64.7゜（ｃ＝１、クロ
ロホルム）〕をメチルエチルケトン172mlに加え、
これに４−メチルピペリジン1.37gを添加し加熱
溶解した。これを徐々に冷却し、30℃になつたと
ころで析出した結晶を別し、少量のメチルエチ
ルケトンで洗浄した後乾燥して（＋）−２−（６−
メトキシ−２−ナフチル）プロピオン酸４−メチ
ルピペリジン塩3.96g（収率86.8％）を得た。Example 1 Add 3.19 g of (+)-2-(6-methoxy-2-naphthyl)propionic acid [[α] 25 D = +64.7° (c = 1, chloroform)] to 172 ml of methyl ethyl ketone,
1.37 g of 4-methylpiperidine was added to this and dissolved by heating. This was gradually cooled, and when the temperature reached 30°C, the precipitated crystals were separated, washed with a small amount of methyl ethyl ketone, and dried (+)-2-(6-
3.96 g (yield: 86.8%) of 4-methylpiperidine methoxy-2-naphthyl)propionic acid salt was obtained.
比旋光度〔α〕29 D＝−7.5゜（ｃ＝１、メタノール）
融点 130.4〜131.4℃
元素分析値
Ｃ％ Ｈ％ Ｎ％
測定値：72.83 8.26 4.21
計算値：72.92 8.26 4.25
実施例 ２
（±）−２−（６−メトキシ−２−ナフチル）プ
ロピオン酸15.38gをジメチルアセトアミド165ml
に加え、これに４−メチルピペリジン6.63gを添
加し、加熱溶解した。これを徐々に冷却し30℃に
なつたところで析出した結晶をろ別し、少量のア
セトンで洗浄した後、乾燥して（±）−２−（６−
メトキシ−２−ナフチル）プロピオン酸４−メチ
ルピペリジン塩16.06g（収率73.0％）を得た。Specific optical rotation [α] 29 D = -7.5° (c = 1, methanol) Melting point 130.4 - 131.4°C Elemental analysis value C% H% N% Measured value: 72.83 8.26 4.21 Calculated value: 72.92 8.26 4.25 Example 2 (± )-2-(6-methoxy-2-naphthyl)propionic acid (15.38 g) to 165 ml of dimethylacetamide
In addition to this, 6.63 g of 4-methylpiperidine was added and dissolved by heating. This was gradually cooled and when the temperature reached 30℃, the precipitated crystals were filtered out, washed with a small amount of acetone, and dried (±)-2-(6-
16.06 g (yield: 73.0%) of 4-methylpiperidine methoxy-2-naphthyl)propionic acid salt was obtained.
融点 120.4〜122.7℃
元素分析値
Ｃ％ Ｈ％ Ｎ％
測定値：72.90 8.27 4.18
計算値：72.92 8.26 4.25
実施例 ３
（±）−２−（６−メトキシ−２−ナフチル）プ
ロピオン酸４−メチルピペリジン塩1.47gおよび
実施例１で得られた（＋）−２−（６−メトキシ−
２−ナフチル）プロピオン酸４−メチルピペリジ
ン塩0.03gをジメチルアセトアミド24mlとアセト
ン６mlの混合溶媒に加熱して溶解させゆるく撹拌
しながら徐々に冷却する。43℃で実施例１で得ら
れた（＋）−２−（６−メトキシ−２−ナフチル）
プロピオン酸４−メチルピペリジン塩の結晶
0.01gを添加し２時間かけて37℃まで冷却した後、
析出した結晶を別し、少量のアセトンで洗浄し
てから、乾燥して（＋）−２−（６−メトキシ−２
−ナフチル）プロピオン酸４−メチルピペリジン
塩〔〔α〕29 D＝−6.5゜（ｃ＝１、メタノール）光学純
度87％〕0.12gを得た。Melting point 120.4-122.7℃ Elemental analysis C% H% N% Measured value: 72.90 8.27 4.18 Calculated value: 72.92 8.26 4.25 Example 3 4-Methylpiperidine (±)-2-(6-methoxy-2-naphthyl)propionic acid 1.47 g of salt and (+)-2-(6-methoxy-
0.03 g of 4-methylpiperidine 2-naphthylpropionic acid salt is dissolved in a mixed solvent of 24 ml of dimethylacetamide and 6 ml of acetone by heating, and the mixture is gradually cooled while stirring gently. (+)-2-(6-methoxy-2-naphthyl) obtained in Example 1 at 43°C
Crystals of 4-methylpiperidine propionate salt
After adding 0.01g and cooling to 37℃ over 2 hours,
The precipitated crystals were separated, washed with a small amount of acetone, and dried to give (+)-2-(6-methoxy-2
0.12 g of 4-methylpiperidine -naphthyl)propionic acid salt [[α] 29 D = -6.5° (c = 1, methanol), optical purity 87%] was obtained.
実施例 ４
（±）−２−（６−メトキシ−２−ナフチル）プ
ロピオン酸４−メチルピペリジン塩1.47gおよび
（−）−２−（６−メトキシ−２−ナフチル）プロ
ピオン酸４−メチルピペリジン塩〔〔〔α〕29 D＝＋
7.3゜（ｃ＝１、メタノール）光学純度97％〕0.03g
をジメチルアセトアミド30mlに加熱して溶解さ
せ、ゆるく撹拌しながら徐々に冷却する。42℃で
前記の（−）−２−（６−メトキシ−２−ナフチ
ル）プロピオン酸４−メチルピペリジン塩の結晶
0.01gを添加し、４時間かけて34℃まで冷却した
後、析出した結晶を別し、少量のアセトンで洗
浄してから乾燥して（−）−２−（６−メトキシ−
２−ナフチル）プロピオン酸４−メチルピペリジ
ン塩〔〔α〕29 D＝＋6.3゜（ｃ＝１、メタノール）光学
純度84％〕0.10gを得た。Example 4 1.47 g of (±)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt and (-)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt [[[α] 29 D = +
7.3゜(c=1, methanol) optical purity 97%〕0.03g
Heat and dissolve in 30 ml of dimethylacetamide, and gradually cool while stirring gently. Crystallization of the above (-)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt at 42°C.
After cooling to 34°C over 4 hours, the precipitated crystals were separated, washed with a small amount of acetone, and dried to give (-)-2-(6-methoxy-
0.10 g of 2-naphthyl)propionic acid 4-methylpiperidine salt [[α] 29 D = +6.3° (c = 1, methanol), optical purity 84%] was obtained.
実施例 ５
（±）−２−（６−メトキシ−２−ナフチル）プ
ロピオン酸４−メチルピペリジン塩1.47gおよび
実施例１で得られた（＋）−２−（６−メトキシ−
２−ナフチル）プロピオン酸４−メチルピペリジ
ン塩0.04gをジメチルアセトアミド30mlに加熱し
て溶解させ、ゆるく撹拌しながら徐々に冷却す
る。42℃で前記の（＋）−２−（６−メトキシ−２
−ナフチル）プロピオン酸４−メチルピペリジン
塩の結晶0.01gを添加し、４時間かけて34℃まで
冷却した後、析出した結晶を別し少量のアセト
ンで洗浄してから乾燥して（＋）−２−（６−メト
キシ−２−ナフチル）プロピオン酸４−メチルピ
ペリジン塩〔〔α〕29 D＝−6.5゜（ｃ＝１、メタノー
ル）光学純度87％〕0.13gを得た。Example 5 1.47 g of (±)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt and (+)-2-(6-methoxy-
0.04 g of 4-methylpiperidine 2-naphthyl)propionic acid salt is dissolved in 30 ml of dimethylacetamide by heating, and the mixture is gradually cooled with gentle stirring. The above (+)-2-(6-methoxy-2
- After adding 0.01 g of crystals of 4-methylpiperidine naphthylpropionate salt and cooling to 34°C over 4 hours, the precipitated crystals were separated, washed with a small amount of acetone, and dried (+)- 0.13 g of 4-methylpiperidine 2-(6-methoxy-2-naphthyl)propionic acid salt [[α] 29 D = -6.5° (c = 1, methanol), optical purity 87%] was obtained.
次に析出した結晶を別した母液に（±）−２
−（６−メトキシ−２−ナフチル）プロピオン酸
４−メチルピペリジン塩0.13gを添加して再び加
熱溶解させる。次いで徐々に冷却し、42℃で
（−）−２−（６−メトキシ−２−ナフチル）プロ
ピオン酸４−メチルピペリジン塩〔〔α〕29 D＝＋
7.3゜（ｃ＝１、メタノール）光学純度97％〕の結
晶0.01gを添加する。４時間かけて34℃まで冷却
してから析出した結晶を別し、少量のアセトン
で洗浄後、乾燥して（−）−２−（６−メトキシ−
２−ナフチル）プロピオン酸４−メチルピペリジ
ン塩〔〔α〕29 D＝6.6（ｃ＝１、メタノール）光学純
度88％〕0.11gを得た。 Next, the precipitated crystals are separated from the mother liquor by (±)−2
Add 0.13 g of 4-methylpiperidine -(6-methoxy-2-naphthyl)propionic acid salt and heat to dissolve again. Then, it was gradually cooled and heated to 42°C to form (−)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt [[α] 29 D =+
Add 0.01 g of crystals of 7.3° (c=1, methanol) with optical purity of 97%. After cooling to 34°C over 4 hours, the precipitated crystals were separated, washed with a small amount of acetone, and dried to give (-)-2-(6-methoxy-
0.11 g of 2-naphthyl)propionic acid 4-methylpiperidine salt [[α] 29 D = 6.6 (c = 1, methanol), optical purity 88%] was obtained.
実施例 ６
（±）−２−（６−メトキシ−２−ナフチル）プ
ロピオン酸４−メチルピペリジン塩3.90gおよび
実施例１で得られた（＋）−２−（６−メトキシ−
２−ナフチル）プロピオン酸４−メチルピペリジ
ン塩0.10gをジメチルアセトアミド40mlに加熱し
て溶解させ、ゆるく撹拌しながら徐々に冷却す
る。55℃で前記の（＋）−２−（６−メトキシ−２
−ナフチル）プロピオン酸４−メチルピペリジン
塩の結晶0.01gを添加し、3.6時間かけて46℃まで
冷却した後、析出した結晶を別し、少量のアセ
トンで洗浄してから乾燥して（＋）−２−（６−メ
トキシ−２−ナフチル）プロピオン酸４−メチル
ピペリジン塩〔〔α〕30 D＝−6.0（ｃ＝１、メタノー
ル）光学純度80％〕0.48gを得た。Example 6 3.90 g of (±)-2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt and (+)-2-(6-methoxy-
0.10 g of 4-methylpiperidine 2-naphthyl)propionic acid salt is dissolved in 40 ml of dimethylacetamide by heating, and the mixture is gradually cooled with gentle stirring. The above (+)-2-(6-methoxy-2
- Add 0.01 g of crystals of 4-methylpiperidine (naphthyl)propionate salt, cool to 46°C over 3.6 hours, separate the precipitated crystals, wash with a small amount of acetone, and dry (+) 0.48 g of -2-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt [[α] 30 D =-6.0 (c=1, methanol), optical purity 80%] was obtained.
次いで得られた粗（＋）−２−（６−メトキシ−
２−ナフチル）プロピオン酸４−メチルピペリジ
ン塩の0.31gをジメチルアセトアミド3.1mlに加熱
溶解させ、徐々に冷却し、30℃で析出した結晶を
別して高純度の（＋）−NPA・４−MP塩0.24g
（回収率77.4％）を得た。その0.20gを水15mlに溶
解し、水酸化ナトリウム0.03gを加えて塩を分解
し、25mlのエーテルで３回押出して４−メチルピ
ペリジンを除去した後、水溶液を塩酸酸性として
から酢酸エチルで抽出し、酢酸エチル層を水洗
後、飽和食塩水で脱水し、さらに硫酸マグネシウ
ムで乾燥した後、酢酸エチルを減圧下に留去させ
て（＋）−２−（６−メトキシ−２−ナフチル）プ
ロピオン酸の結晶〔〔α〕25 D＝＋64.2（ｃ＝１、ク
ロロホルム）〕0.14gを得た。 Then, the obtained crude (+)-2-(6-methoxy-
0.31 g of 4-methylpiperidine 2-naphthyl)propionate salt was dissolved in 3.1 ml of dimethylacetamide by heating, gradually cooled, and the precipitated crystals were separated at 30°C to obtain high-purity (+)-NPA 4-MP salt. 0.24g
(recovery rate 77.4%). Dissolve 0.20g of it in 15ml of water, add 0.03g of sodium hydroxide to decompose the salt, extrude with 25ml of ether three times to remove 4-methylpiperidine, acidify the aqueous solution with hydrochloric acid, and then extract with ethyl acetate. After washing the ethyl acetate layer with water, dehydrating it with saturated brine and further drying over magnesium sulfate, ethyl acetate was distilled off under reduced pressure to give (+)-2-(6-methoxy-2-naphthyl)propion. 0.14 g of acid crystals [[α] 25 D =+64.2 (c=1, chloroform)] was obtained.
Claims (1)
プロピオン酸４−メチルピペリジン塩の過飽和溶
液に光学活性の２−（６−メトキシ−２−ナフチ
ル）プロピオン酸４−メチルピペリジン塩の結晶
を存在せしめ、該光学活性体と同種の光学活性２
−（６−メトキシ−２−ナフチル）プロピオン酸
４−メチルピペリジン塩を選択的に晶出させ、そ
してその後固液分離して光学活性塩を取得するこ
とを特徴とする、（±）−２−（６−メトキシ−２
−ナフチル）プロピオン酸の光学分割法。1 (±)-2-(6-methoxy-2-naphthyl)
Crystals of optically active 4-methylpiperidine 2-(6-methoxy-2-naphthyl)propionate are present in a supersaturated solution of 4-methylpiperidine propionate, and optically active 2
-(6-methoxy-2-naphthyl)propionic acid 4-methylpiperidine salt is selectively crystallized, and then solid-liquid separation is performed to obtain an optically active salt, (±)-2- (6-methoxy-2
- Optical resolution method of (naphthyl)propionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17456882A JPS5965075A (en) | 1982-10-06 | 1982-10-06 | Optical resolution of (+-)-2-(6-methoxy-2-naphthyl)propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17456882A JPS5965075A (en) | 1982-10-06 | 1982-10-06 | Optical resolution of (+-)-2-(6-methoxy-2-naphthyl)propionic acid |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11513990A Division JPH02288843A (en) | 1990-05-02 | 1990-05-02 | 4-methylpiperidine salt of 2-(6-methoxy-2-naphthyl) propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5965075A JPS5965075A (en) | 1984-04-13 |
| JPH0259817B2 true JPH0259817B2 (en) | 1990-12-13 |
Family
ID=15980830
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17456882A Granted JPS5965075A (en) | 1982-10-06 | 1982-10-06 | Optical resolution of (+-)-2-(6-methoxy-2-naphthyl)propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5965075A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1222013B (en) * | 1987-07-10 | 1990-08-31 | Chimica Profarmaco Spa Ind | OPTIC RESOLUTION PROCESS OF PROPIONIC ACID 2 (6 METHOXES 2 NAFTIL) |
| JP5536869B2 (en) * | 2009-03-26 | 2014-07-02 | ポクセル・エスアーエス | Method for the separation of enantiomers of dihydro-1,3,5 triazine racemate using a preferential crystallization method |
-
1982
- 1982-10-06 JP JP17456882A patent/JPS5965075A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5965075A (en) | 1984-04-13 |
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