JPH02225463A - Racemization of n-acetyl-indoline-2-carboxylic acid ester - Google Patents
Racemization of n-acetyl-indoline-2-carboxylic acid esterInfo
- Publication number
- JPH02225463A JPH02225463A JP4627089A JP4627089A JPH02225463A JP H02225463 A JPH02225463 A JP H02225463A JP 4627089 A JP4627089 A JP 4627089A JP 4627089 A JP4627089 A JP 4627089A JP H02225463 A JPH02225463 A JP H02225463A
- Authority
- JP
- Japan
- Prior art keywords
- acetyl
- indoline
- carboxylic acid
- metal
- acid ester
- 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.)
- Pending
Links
- OGMIMMRKTFZDKW-UHFFFAOYSA-N 1-acetyl-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)C)C(C(O)=O)CC2=C1 OGMIMMRKTFZDKW-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 230000006340 racemization Effects 0.000 title claims description 12
- 229910052751 metal Inorganic materials 0.000 claims abstract description 17
- 239000002184 metal Substances 0.000 claims abstract description 17
- 150000004703 alkoxides Chemical class 0.000 claims abstract description 7
- 150000001408 amides Chemical class 0.000 claims abstract description 7
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 229910052987 metal hydride Inorganic materials 0.000 claims abstract description 7
- 150000004681 metal hydrides Chemical class 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 4
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 claims 1
- 125000003047 N-acetyl group Chemical group 0.000 claims 1
- QNRXNRGSOJZINA-UHFFFAOYSA-N indoline-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 4
- -1 sodium ethylate Chemical class 0.000 abstract description 3
- 239000002808 molecular sieve Substances 0.000 abstract description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 abstract description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 abstract description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 abstract description 2
- KXHBYSRUWPZBMF-UHFFFAOYSA-N 1-acetylindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)C)C(C(O)=O)=CC2=C1 KXHBYSRUWPZBMF-UHFFFAOYSA-N 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 239000012046 mixed solvent Substances 0.000 abstract 1
- LVLLGTMKIKQQPF-UHFFFAOYSA-N ethyl 1-acetyl-2,3-dihydroindole-2-carboxylate Chemical compound C1=CC=C2N(C(C)=O)C(C(=O)OCC)CC2=C1 LVLLGTMKIKQQPF-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RNTCWULFNYNFGI-UHFFFAOYSA-N 1-(2,3-dihydroindol-1-yl)ethanone Chemical compound C1=CC=C2N(C(=O)C)CCC2=C1 RNTCWULFNYNFGI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
（イ）産業上の利用分野
本発明は、Ｎ−アセチル−インドリン−２−カルボン酸
エステルのラセミ化法に関するものである。DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a method for racemizing N-acetyl-indoline-2-carboxylic acid ester.
（ロ）従来の技術と発明が解決しようとする問題点
Ｎ−アセチル−インドリン−２−カルボン酸エステルの
ラセミ化が可能であれば、光学活性体Ｄ−インドリンー
２−カルボン酸に対応する（＋）−Ｎ−アセチル−イン
ドリン−２−カルボン酸エステルを有用な光学活性体Ｌ
−インドリンー２−カルボン酸に対応する（−）−Ｎ−
アセチル−インドリン−２−カルボン酸エステルに全て
変換することができる。(b) Problems to be solved by the prior art and the invention If racemization of N-acetyl-indoline-2-carboxylic acid ester is possible, it will correspond to the optically active substance D-indoline-2-carboxylic acid (+ )-N-acetyl-indoline-2-carboxylic acid ester as a useful optically active substance L
-(-)-N- corresponding to -indoline-2-carboxylic acid
All can be converted to acetyl-indoline-2-carboxylic acid ester.
しかし、従来よりＮ−アセチル−インドリン−２−カル
ボン酸エステルがラセミ化できるという知見はなかった
。However, there has been no knowledge that N-acetyl-indoline-2-carboxylic acid ester can be racemized.
（ハ）問題点を解決するための手段
本発明者らは、上記問題点につき鋭意検討した結果、通
常の有機酸無水物（例えば、無水酢酸）の存在下での加
熱ではＮ−アセチル−インドリン−２−カルボン酸エス
テル本化合物はラセミ化しないが、塩基性条件では容易
にラセミ化することを見出し本発明を完成するに至った
。(c) Means for Solving the Problems As a result of intensive study on the above problems, the present inventors found that heating in the presence of ordinary organic acid anhydrides (e.g. acetic anhydride) does not result in N-acetyl-indoline. -2-Carboxylic Acid Ester Although this compound does not racemize, it was found that it easily racemizes under basic conditions, leading to the completion of the present invention.
即ち、本発明は一般式（１）
（式中、Ｒは低級アルキル基、芳香族基を示す、）で表
わされるＮ−アセチル−インドリン−２−カルボン酸エ
ステルを、強塩基性アミン、金属アルコキシド、金属ア
ミド及び金属水素化物から選ばれる化合物の存在下ラセ
ミ化することを特徴とするＮ−アセチノに一インドリン
ー２−カルボン酸エステルのラセミ化法に関するもので
ある。That is, the present invention provides N-acetyl-indoline-2-carboxylic acid ester represented by the general formula (1) (wherein R represents a lower alkyl group or an aromatic group) to a strongly basic amine or a metal alkoxide. The present invention relates to a method for racemizing N-acetino-indoline-2-carboxylic acid ester, which is characterized by racemizing in the presence of a compound selected from metal amides and metal hydrides.
上記−数式（１）のＲとしては低級アルキル基、芳香族
基が挙げられる。R in the above formula (1) includes a lower alkyl group and an aromatic group.
低級アルキル基の具体例としては、メチル基、エチル基
、プロピル基、イソプロピル基、ブチル基、ベンジル基
、ｐ−クロロベンジル基、ｐ−ブロモベンジル基、ｐ−
メチルベンジル基等が挙げられる。Specific examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, benzyl group, p-chlorobenzyl group, p-bromobenzyl group, p-
Examples include methylbenzyl group.
芳香族基の具体例としては、フェニル基、ｐ−クロロフ
ェニルＬ ｐ−トリル基、１−ナフチル基、２−ナフチ
ル基、１−クロロナフチル基等が挙げられる。Specific examples of the aromatic group include phenyl group, p-chlorophenyl L p-tolyl group, 1-naphthyl group, 2-naphthyl group, and 1-chloronaphthyl group.
ラセミ化温度は、通常−５０〜１５０°Ｃの範囲、望ま
しくは０〜１００°Ｃの範囲がよい。The racemization temperature is generally in the range of -50 to 150°C, preferably in the range of 0 to 100°C.
ラセミ化剤としては、強塩基性アミン、金属アルコキシ
ド、金属アミド及び金属水素化物が挙げられる。Racemizing agents include strongly basic amines, metal alkoxides, metal amides, and metal hydrides.
強塩基性アミンの具体例としては、１．８−ジアザビシ
クロ〔５．４．０〕 −７−ウンデセン、１．５ジアザ
ビシクロ〔４．３．０〕 −５−ノネン、１．４ジアザ
ビシクロＣ２，２，２）オクタン等が挙げられる。Specific examples of strong basic amines include 1.8-diazabicyclo[5.4.0]-7-undecene, 1.5diazabicyclo[4.3.0]-5-nonene, and 1.4diazabicycloC2,2. , 2) octane, etc.
金属アルコキシド、金属アミド及び金属水素化物の金属
としては、アルカリ金属、カルシウム等が挙げられる。Examples of the metal in the metal alkoxide, metal amide, and metal hydride include alkali metals, calcium, and the like.
アルカリ金属としてはリチウム、ナトリウム、カリウム
等が挙げられる。Examples of alkali metals include lithium, sodium, potassium, and the like.
金属アルコキシドの具体例としては、ナトリウムエチラ
ート、カリウムも一ブチラード等が挙げられる。Specific examples of metal alkoxides include sodium ethylate, potassium monobutyralate, and the like.
金属アミドの具体例としては、リチウムジイソプロピル
アミド、ナトリウムアミド等が挙げられる。Specific examples of metal amides include lithium diisopropylamide, sodium amide, and the like.
金属水素化物の具体例としては、水素化リチウム、水素
化ナトリウム、水素化カルシウム等が挙げられる。Specific examples of metal hydrides include lithium hydride, sodium hydride, calcium hydride, and the like.
ラセミ化剤の使用量は、Ｎ−アセチル−インドリン−２
−カルボン酸エステル１モルに対して通常０．０１〜１
０モルの範囲、望ましくは０．１〜１モルの範囲がよい
。The amount of racemization agent used is N-acetyl-indoline-2
-Usually 0.01 to 1 per mole of carboxylic acid ester
The range is 0 mol, preferably 0.1 to 1 mol.
ラセミ化に使用される溶媒としては、ジメチルホルミア
ミド、テトラヒドロフラン、イソプロピルエーテル、Ｎ
−アセチル−インドリン−２−カルボン酸エステルのエ
ステル部に対応するアルコール（例えば、エチルエステ
ルの時はエタノール）、ジメトキシエタン等が挙げられ
、これらを混合して使用してもよい。Solvents used for racemization include dimethylformamide, tetrahydrofuran, isopropyl ether, N
Examples include alcohols corresponding to the ester moiety of -acetyl-indoline-2-carboxylic acid ester (for example, ethanol in the case of ethyl ester), dimethoxyethane, etc., and these may be used in combination.
又、Ｎ−アセチル−インドリン−２−カルボン酸エステ
ルの晶出のバランスをとるため非極性のヘキサン、トル
エン等を混合することも可能である。Further, in order to balance the crystallization of N-acetyl-indoline-2-carboxylic acid ester, it is also possible to mix nonpolar hexane, toluene, etc.
上記溶媒はモレキュラーシーブ等で乾燥することが望ま
しい。It is desirable to dry the above solvent using a molecular sieve or the like.
溶媒の使用量としては、Ｎ−アセチル−インドリン−２
−カルボン酸エステル１重量部に対して通常０．２〜５
０重量部の範囲がよい。The amount of solvent used is N-acetyl-indoline-2
-Usually 0.2 to 5 parts by weight of carboxylic acid ester
A range of 0 parts by weight is preferable.
油性の強塩基性アミン等をラセミ化剤として使用する場
合、溶媒を使用しなくてもよい。When an oily strong basic amine or the like is used as a racemizing agent, a solvent may not be used.
（ニ）効果
本発明により、Ｎ−アセチル−インドリン−２−カルボ
ン酸エステルを容易に高い収率でラセミ化することがで
きる。(d) Effects According to the present invention, N-acetyl-indoline-2-carboxylic acid ester can be easily racemized in high yield.
（ホ）実施例
以下、実施例、比較例を挙げ本発明の詳細な説明するが
、本発明はこれらによって限定されるものではない。(e) Examples Hereinafter, the present invention will be explained in detail by giving Examples and Comparative Examples, but the present invention is not limited by these.
実施例１
（−）−Ｎ−アセチル−インドリン−２−カルボン酸エ
チル（（α）ｏ １２３．６° （ｃ＝０．５６、
ＩＥｔｏｌｌ） 、 １００％ｅｅ）７４．３Ｋ、無
水Ｎ、Ｎ−ジメチルホルムアミド０．３７及びヘキサン
で洗浄後乾燥した水素化ナトリウム１０．７ ｍｇと混
合し２２°Ｃで１５分間撹拌した。Example 1 Ethyl (-)-N-acetyl-indoline-2-carboxylate ((α)o 123.6° (c=0.56,
IEtoll), 100% ee) 74.3K, anhydrous N,N-dimethylformamide 0.37g and 10.7 mg of sodium hydride which had been washed and dried with hexane and stirred at 22°C for 15 minutes.
次に、反応液をＯ′Ｃに冷却し、３６重量％塩酸水溶液
１．Ｏｍｌに注ぎ酢酸エチルで抽出し、炭酸水素ナトリ
ウム飽和水溶液５ ｍｌ及び水５ ｍｌを加え洗浄後、
更に水洗した。Next, the reaction solution was cooled to O'C, and a 36% by weight aqueous hydrochloric acid solution was added. After pouring into Oml and extracting with ethyl acetate, adding 5 ml of saturated aqueous sodium bicarbonate solution and 5 ml of water and washing,
It was further washed with water.
得られた溶液を減圧乾燥しＮ−アセチル−インドリン−
２−カルボン酸エチル
（（〔α）、−９，９° （ｃ ＝０．５１ 、 Ｅｔ
ＯＨ） 、 ８％ｅｅ 、 ラセミ化率９２％）６
９．８■を得た。The obtained solution was dried under reduced pressure to obtain N-acetyl-indoline-
Ethyl 2-carboxylate (([α), -9,9° (c = 0.51, Et
OH), 8%ee, racemization rate 92%)6
9.8■ was obtained.
このものがＮ−アセチル−インドリン−２−カルボン酸
エチルであるとは、ガスクロマトグラフィー、核磁気共
鳴吸収スペクトル、質量分析スペクトル等で確認した。It was confirmed by gas chromatography, nuclear magnetic resonance absorption spectrum, mass spectrometry, etc. that this product was ethyl N-acetyl-indoline-2-carboxylate.
実施例２〜４
（−）−Ｎ−アセチル−インドリン−２−カルボン酸エ
チル（〔α）Ｄ １２３．６° （ｃ ＝０．５６、
ＥｔＯＨ） 、 １００％ｅｅ ）を実施例１と同
様に処理し、表１の結果を得た。Examples 2-4 Ethyl (-)-N-acetyl-indoline-2-carboxylate ([α)D 123.6° (c = 0.56,
EtOH), 100%ee) was treated in the same manner as in Example 1, and the results shown in Table 1 were obtained.
実施例５〜７
（＋）−Ｎ−アセチル−インドリン−２−カルボン酸エ
チル（〔α）、＋１２３．６° （ｃ ＝０．５６、
ＥｔＯｌｌ） 、 １００％ｅｅ ）を実施例１と同
様に処理し、表１の結果を得た。Examples 5-7 Ethyl (+)-N-acetyl-indoline-2-carboxylate ([α), +123.6° (c = 0.56,
EtOll), 100%ee) was treated in the same manner as in Example 1, and the results shown in Table 1 were obtained.
実施例８
（＋）−Ｎ−アセチル−インドリン−２−カルボン酸エ
チル（（〔α〕。＋４．４° （Ｃ＝０．６０゜Ｅｔｏ
ｌｌ） 、 ３．６％ｅｅ１２．４０ｇに、１．８−
ジアザビシクロ〔５．４．０〕 −７−ウンデセン１．
０２４ ｇを加え１００〜１０５°Ｃで３時間加熱撹拌
した。Example 8 Ethyl (+)-N-acetyl-indoline-2-carboxylate (([α].+4.4° (C=0.60°Eto
ll), 3.6%ee12.40g, 1.8-
Diazabicyclo[5.4.0]-7-Undecene1.
024 g was added thereto, and the mixture was heated and stirred at 100 to 105°C for 3 hours.
次に、反応液を０°Ｃに冷却し、３５重量％塩酸水溶液
１．０ ｄを加え、実施例工と同様に処理し、Ｎ−アセ
チル−インドリン−２−カルボン酸エチル
（（〔α〕。＋０．６° （Ｃ＝０．４８ 、 Ｅｔ
ＯＨ） 、 ０゜５％ｅｅ、 ラセミ化率８６％）
２．２８ｇを得た。Next, the reaction solution was cooled to 0°C, 1.0 d of 35% by weight aqueous hydrochloric acid solution was added, and treated in the same manner as in the example, to obtain ethyl N-acetyl-indoline-2-carboxylate (([α] +0.6° (C=0.48, Et
OH), 0°5%ee, racemization rate 86%)
2.28g was obtained.
実施例９
（＋）−Ｎ−アセチル−インドリン−２−カルボン酸−
２−ナフチル）（（α〕、→−４６．５° （ｃ＝０．
５１． Ｅｔｏｌｌ） 、 １００％ｅｅ）２９４ｍ
ｇをテトラヒドロフラン９ ｍｌに溶解後、水素化ナト
リウム９．４ ｍｇを添加し２５°Ｃで３時間撹拌した
。Example 9 (+)-N-acetyl-indoline-2-carboxylic acid-
2-naphthyl) ((α), → -46.5° (c=0.
51. Etoll), 100%ee) 294m
g was dissolved in 9 ml of tetrahydrofuran, 9.4 mg of sodium hydride was added, and the mixture was stirred at 25°C for 3 hours.
次に、反応液をＯ′Ｃに冷却し、３６重量％塩酸水溶液
１．０ ｄに加え、実施例１と同様に処理し、Ｎ−アセ
チル−インドリン−２−カルボン酸−２−ナフチル
（’ （Ｃａ 〕 ｂ 二 １８．６ °
（ｃ＝０．５ ５ ４． ＥｔＯ）Ｉ） 。Next, the reaction solution was cooled to O'C, added to 1.0 d of 36% by weight aqueous hydrochloric acid solution, and treated in the same manner as in Example 1 to give 2-naphthyl N-acetyl-indoline-2-carboxylate (' (Ca] b two 18.6 °
(c=0.5 5 4.EtO)I).
４０％ｅｅ、ラセミ化率６０％） ２６２■を得た。40%ee, racemization rate 60%) 262■ was obtained.
実施例１０〜１３
（−）−Ｎ−アセチル−インドリン−２−カルボン酸（
２−ナフチル）（〔α）Ｄ−４６，５°。Examples 10-13 (-)-N-acetyl-indoline-2-carboxylic acid (
2-naphthyl) ([α)D-46,5°.
（’ｃ ＝０．５２． ＥｔＯＨ） 、 １００％ｅ
ｅ） ）を実施例９と同様に処理し、表２の結果を得た
。('c = 0.52.EtOH), 100%e
e) ) was treated in the same manner as in Example 9, and the results shown in Table 2 were obtained.
比較例
（−）−Ｎ−アセチル−インドリン−２−カルボン酸エ
チルエステル６１■を無水酢酸７ ｍｆｌに溶解し５０
°Ｃで２時間加熱したが、旋光度の変化はなくラセミ化
しなかった。更に、１００〜１１０゛Ｃで１．５時間加
熱したが、旋光度の変化はなくラセミ化しなかった。Comparative Example (-)-N-acetyl-indoline-2-carboxylic acid ethyl ester (61 μm) was dissolved in 7 mfl of acetic anhydride.
Although it was heated at °C for 2 hours, there was no change in the optical rotation and no racemization occurred. Further, the mixture was heated at 100-110°C for 1.5 hours, but the optical rotation did not change and racemization did not occur.
（以下、余白）(Hereafter, margin)
Claims (1)
酸エステルを、強塩基性アミン、金属アルコキシド、金
属アミド及び金属水素化物から選ばれる化合物の存在下
ラセミ化することを特徴とするＮ−アセチル−インドリ
ン−２−カルボン酸エステルのラセミ化法。（２）強塩
基性アミンが、１，８−ジアザビシクロ〔５．４．０〕
−７−ウンデセン、１，５−ジアザビシクロ〔４．３．
０〕−５−ノネン、１，４−ジアザビシクロ〔２．２．
２〕オクタンから選ばれる化合物である請求項（１）記
載のＮ−アセチル−インドリン−２−カルボン酸エステ
ルのラセミ化法。 （３）金属アルコキシド、金属アミド及び金属水素化物
の金属がアルカリ金属又はカルシウムから選ばれる金属
である請求項（１）記載のＮ−アセチル−インドリン−
２−カルボン酸エステルのラセミ化法。[Claims] (1) N-acetyl represented by the general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R represents a lower alkyl group or an aromatic group.) - N-acetyl-indoline-2-carboxylic acid ester characterized by racemizing indoline-2-carboxylic acid ester in the presence of a compound selected from strongly basic amines, metal alkoxides, metal amides, and metal hydrides. racemization method. (2) Strongly basic amine is 1,8-diazabicyclo[5.4.0]
-7-undecene, 1,5-diazabicyclo [4.3.
0]-5-nonene, 1,4-diazabicyclo[2.2.
2] The method for racemizing N-acetyl-indoline-2-carboxylic acid ester according to claim (1), which is a compound selected from octane. (3) N-acetyl-indoline- according to claim (1), wherein the metal of the metal alkoxide, metal amide, and metal hydride is a metal selected from alkali metals and calcium.
Racemization method of 2-carboxylic acid ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4627089A JPH02225463A (en) | 1989-02-27 | 1989-02-27 | Racemization of n-acetyl-indoline-2-carboxylic acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4627089A JPH02225463A (en) | 1989-02-27 | 1989-02-27 | Racemization of n-acetyl-indoline-2-carboxylic acid ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02225463A true JPH02225463A (en) | 1990-09-07 |
Family
ID=12742534
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4627089A Pending JPH02225463A (en) | 1989-02-27 | 1989-02-27 | Racemization of n-acetyl-indoline-2-carboxylic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02225463A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013094498A1 (en) * | 2011-12-19 | 2013-06-27 | 住友化学株式会社 | METHOD FOR RACEMIZING α-SUBSTITUTED-β-AMINO ACID ESTER |
| JP2017514832A (en) * | 2014-04-30 | 2017-06-08 | インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ | Methods for preparing JAK1 inhibitors and new forms thereof |
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-
1989
- 1989-02-27 JP JP4627089A patent/JPH02225463A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013094498A1 (en) * | 2011-12-19 | 2013-06-27 | 住友化学株式会社 | METHOD FOR RACEMIZING α-SUBSTITUTED-β-AMINO ACID ESTER |
| CN103998421A (en) * | 2011-12-19 | 2014-08-20 | 住友化学株式会社 | Racemization method of α-substituted-β-amino acid esters |
| US10370387B2 (en) | 2012-11-01 | 2019-08-06 | Incyte Holdings Corporation | Tricyclic fused thiophene derivatives as JAK inhibitors |
| US11161855B2 (en) | 2012-11-01 | 2021-11-02 | Incyte Corporation | Tricyclic fused thiophene derivatives as JAK inhibitors |
| US11851442B2 (en) | 2012-11-01 | 2023-12-26 | Incyte Corporation | Tricyclic fused thiophene derivatives as JAK inhibitors |
| JP2017514832A (en) * | 2014-04-30 | 2017-06-08 | インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ | Methods for preparing JAK1 inhibitors and new forms thereof |
| US10450325B2 (en) | 2014-04-30 | 2019-10-22 | Incyte Corporation | Processes of preparing a JAK1 inhibitor and new forms thereto |
| US11304949B2 (en) | 2018-03-30 | 2022-04-19 | Incyte Corporation | Treatment of hidradenitis suppurativa using JAK inhibitors |
| US12280054B2 (en) | 2018-03-30 | 2025-04-22 | Incyte Corporation | Treatment of hidradenitis suppurativa using JAK inhibitors |
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