JPH0686413B2 - Process for producing oxaloamino acid derivative - Google Patents
Process for producing oxaloamino acid derivativeInfo
- Publication number
- JPH0686413B2 JPH0686413B2 JP2162365A JP16236590A JPH0686413B2 JP H0686413 B2 JPH0686413 B2 JP H0686413B2 JP 2162365 A JP2162365 A JP 2162365A JP 16236590 A JP16236590 A JP 16236590A JP H0686413 B2 JPH0686413 B2 JP H0686413B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- oxaloamino
- group
- producing
- 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 - Lifetime
Links
- 239000002253 acid Substances 0.000 title claims description 26
- 125000003111 oxaloamino group Chemical group C(=O)(C(=O)O)N* 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 5
- -1 oxalate compound Chemical class 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- FKHGAFIKZYQKRR-UHFFFAOYSA-N 2-[(4-methoxy-4-oxobutyl)amino]-2-oxoacetic acid Chemical compound COC(=O)CCCNC(=O)C(O)=O FKHGAFIKZYQKRR-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 239000011968 lewis acid catalyst Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- LMHHFZAXSANGGM-UHFFFAOYSA-N 2-aminoindane Chemical compound C1=CC=C2CC(N)CC2=C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- KVQGGLZHHFGHPU-UHFFFAOYSA-N methyl 4-aminobutanoate Chemical compound COC(=O)CCCN KVQGGLZHHFGHPU-UHFFFAOYSA-N 0.000 description 1
- AQZTVRSXYOQPOA-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)formamide Chemical compound C1=CC=C2CC(NC=O)CC2=C1 AQZTVRSXYOQPOA-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- RLPQQBNSTHRHEK-UHFFFAOYSA-M potassium;2-ethoxy-2-oxoacetate Chemical compound [K+].CCOC(=O)C([O-])=O RLPQQBNSTHRHEK-UHFFFAOYSA-M 0.000 description 1
- SJNHYWHFXPPTJJ-UHFFFAOYSA-M potassium;2-methoxy-2-oxoacetate Chemical compound [K+].COC(=O)C([O-])=O SJNHYWHFXPPTJJ-UHFFFAOYSA-M 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 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
- 239000003769 thromboxane A2 receptor blocking agent Substances 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、オキサロアミノ酸誘導体の新規製法に関す
る。TECHNICAL FIELD The present invention relates to a novel method for producing an oxaloamino acid derivative.
オキサロアミノ酸エステル及びインダン−５−イルオキ
サロアミノ酸等のオキサロアミノ酸誘導体は、各種医薬
化合物の合成中間体として有用である。例えば、オキサ
ロアミノ酸エステルは、２−アミノインダンとの縮合反
応により（２−アミノインダン−５−イル）オキサロア
ミノ酸化合物とすることができ、該化合物はさらに還元
後、アミノ基上にベンゼンスルホニル基を導入すること
により、トロンボキサンA2拮抗剤として有用なＮ−
｛〔２−（ベンゼンスルホニルアミノ）インダン−５−
イル〕アセチル｝アミノ酸を製造することができる（特
願昭63-323884号）。Oxaloamino acid esters and oxaloamino acid derivatives such as indan-5-yl oxaloamino acid are useful as synthetic intermediates for various pharmaceutical compounds. For example, an oxaloamino acid ester can be converted to a (2-aminoindan-5-yl) oxaloamino acid compound by a condensation reaction with 2-aminoindan, and the compound is further reduced to form a benzenesulfonyl group on the amino group. The introduction of N-, which is useful as a thromboxane A 2 antagonist,
{[2- (benzenesulfonylamino) indan-5-
[Ill] acetyl} amino acid can be produced (Japanese Patent Application No. 63-323884).
本発明は、合成中間体として有用なかかるオキサロアミ
ノ酸誘導体を、簡便な操作で収率良く製造する新規製法
を提供するものである。The present invention provides a novel method for producing such an oxaloamino acid derivative, which is useful as a synthetic intermediate, with a simple operation and a high yield.
本発明によれば、一般式 （式中、R2は低級アルコキシカルボニル低級アルキル基
を表す。） で示されるオキサロアミノ酸エステルは、一般式 （式中、R1は低級アルキル基、Ｚは酸で容易に除去しう
るカルボキシル基の保護基を表す。） で示されるシュウ酸エステル化合物と、一般式 H2N−R2 （III） （式中、記号は前記と同一意味を有する。） で示される化合物とを反応させて一般式 （式中、記号は前記と同一意味を表す。） で示される化合物とし、次いで該生成物を酸で処理して
カルボキシル基の保護基を除去して製造することができ
る。According to the invention, the general formula (In the formula, R 2 represents a lower alkoxycarbonyl lower alkyl group.) The oxaloamino acid ester represented by the general formula (In the formula, R 1 represents a lower alkyl group, Z represents a protecting group of a carboxyl group which can be easily removed with an acid.), And an oxalic acid ester compound represented by the general formula H 2 N—R 2 (III) ( In the formula, the symbols have the same meanings as described above.) (Wherein the symbols have the same meanings as described above), and then the product is treated with an acid to remove the protecting group for the carboxyl group.
また、一般式 （式中、R3はアミノ基の保護基、他の記号は前記と同一
意味を表す。） で示されるインダン−５−イルオキサロアミノ酸化合物
は、上記反応で得たオキサロアミノ酸エステルをハロゲ
ン化後、該生成物と一般式 （式中、記号は前記と同一意味を表す。） で示されるインダン化合物とを、ニトロベンゼンの存在
下縮合反応させて製造することができる。Also, the general formula (In the formula, R 3 is a protecting group for an amino group, and other symbols have the same meanings as described above.) Is an indan-5-yl oxaloamino acid compound obtained by halogenating the oxaloamino acid ester obtained by the above reaction. , The product and the general formula (In the formula, symbols have the same meanings as described above.) The compound can be produced by subjecting the indane compound represented by the formula to a condensation reaction in the presence of nitrobenzene.
本発明方法において、カルボキシル基及びアミノ基の保
護基としては、慣用のものをいずれも用いることができ
る。例えば、カルボキシル基の保護基Ｚとしては、酸
（ハロゲン化水素、トリフルオロ酢酸等）で容易に除去
しうる、ｔ−ブチル基、ベンズヒドリル基等の保護基
を、また、アミノ基の保護基R3としては、例えばホルミ
ル基、ベンジルオキシカルボニル基、トリフルオロアセ
チル基等をいずれも適宜用いることができる。In the method of the present invention, as the protecting group for the carboxyl group and the amino group, any conventional one can be used. For example, as the protecting group Z for a carboxyl group, a protecting group such as a t-butyl group or a benzhydryl group which can be easily removed with an acid (hydrogen halide, trifluoroacetic acid, etc.), or a protecting group for an amino group R As 3 , for example, any of formyl group, benzyloxycarbonyl group, trifluoroacetyl group and the like can be appropriately used.
シュウ酸エステル（II）と化合物（III）との反応は、
無溶媒又は適当な溶媒中、脱酸剤の存在又は非存在下で
実施できる。脱酸剤としては、例えば、トリ低級アルキ
ルアミン、ピリジン等を適宜使用できる。The reaction between the oxalate ester (II) and the compound (III) is
It can be carried out without solvent or in a suitable solvent in the presence or absence of a deoxidizing agent. As the deoxidizing agent, for example, tri-lower alkylamine, pyridine and the like can be used appropriately.
つづく酸で容易に除去しうるカルボキシル基の保護基
（Ｚ）の除去は、無溶媒又は適当な溶媒中、適当な酸
（ハロゲン化水素又はトリフルオロ酢酸等）で処理して
実施することができる。Subsequent removal of the protecting group (Z) for the carboxyl group, which can be easily removed with an acid, can be carried out by treating with a suitable acid (hydrogen halide, trifluoroacetic acid, etc.) in the absence of solvent or a suitable solvent. .
またかくして得たオキサロアミノ酸エステル（Ｉ）のハ
ロゲン化反応は、無溶媒又は適当な溶媒中、ハロゲン化
剤で処理して実施することができる。この場合、ハロゲ
ン化剤としては、例えば、オキサリルハライド、チオニ
ルハライド等慣用のものをいずれも使用することができ
る。The halogenation reaction of the thus-obtained oxaloamino acid ester (I) can be carried out by treating with a halogenating agent in the absence of solvent or a suitable solvent. In this case, as the halogenating agent, for example, any conventional one such as oxalyl halide or thionyl halide can be used.
オキサロアミノ酸エステル（Ｉ）のハロゲン化物と化合
物（VI）との縮合反応は、ニトロベンゼンの存在下、適
当な溶媒中で実施できる。この縮合反応は、ルイス酸触
媒の存在下に実施するのが好ましく、ルイス酸触媒とし
ては、例えば、塩化アルミニウムを好適に用いることが
できる。The condensation reaction between the halide of oxaloamino acid ester (I) and compound (VI) can be carried out in the presence of nitrobenzene in a suitable solvent. This condensation reaction is preferably carried out in the presence of a Lewis acid catalyst, and as the Lewis acid catalyst, for example, aluminum chloride can be preferably used.
上記本発明の各反応において、溶媒としては例えば、塩
化メチレン、ジクロロエタン、クロロホルム等を好適に
使用でき、また各反応は、いずれも冷却〜加温下で好適
に進行する。In each reaction of the present invention described above, for example, methylene chloride, dichloroethane, chloroform and the like can be preferably used as a solvent, and each reaction suitably proceeds under cooling to heating.
実施例１ （１）シュウ酸エチルエステルモノカリウム塩10gをク
ロロホルム50mlに懸濁し、ピリジン10.14gとt-ブチルア
ルコール9.50gを加える。該懸濁液に、オキシ塩化リン1
1.79gを５〜15℃にて２時間かけて滴下した後、室温で2
4時間攪拌する。反応終了後、反応液を洗浄、乾燥し、
減圧濃縮して、シュウ酸t-ブチルエチルエステル10.42g
を油状物として得る。Example 1 (1) 10 g of oxalic acid ethyl ester monopotassium salt was suspended in 50 ml of chloroform, and 10.14 g of pyridine and 9.50 g of t-butyl alcohol were added. To the suspension, phosphorus oxychloride 1
1.79g was added dropwise at 5 ~ 15 ℃ over 2 hours, then at room temperature for 2
Stir for 4 hours. After the reaction is completed, the reaction solution is washed and dried,
Concentrated under reduced pressure to give 10.42 g of oxalic acid t-butyl ethyl ester.
As an oil.
収率93.5％ 沸点58〜64℃（2mmHg） NMRδ（CDCl3）:4.32（q,J=7,2H）,1.56（s,9H）,1.37
（t,J=7,3H） （２）本品5.22gをエタノール40mlに溶解させ、４−ア
ミノ酪酸メチル・塩酸塩6.91gを加えた後、10℃にてト
リエチルアミン5.0gを５分間かけて滴下する。該混合液
を室温で16時間攪拌した後、エタノールを減圧留去す
る。残渣を塩化メチレンに溶解し、洗浄、乾燥後、減圧
濃縮して４−（t-ブチルオキサリルアミノ）−ｎ−酪酸
メチルエステル7.03gを油状物として得る。Yield 93.5% Boiling point 58-64 ℃ (2mmHg) NMR δ (CDCl 3 ): 4.32 (q, J = 7,2H), 1.56 (s, 9H), 1.37
(T, J = 7,3H) (2) Dissolve 5.22 g of this product in 40 ml of ethanol, add 6.91 g of methyl 4-aminobutyrate / hydrochloride, and then add 5.0 g of triethylamine for 5 minutes at 10 ° C. Drop it. The mixture is stirred at room temperature for 16 hours and then ethanol is distilled off under reduced pressure. The residue is dissolved in methylene chloride, washed, dried, and concentrated under reduced pressure to give 7.03 g of 4- (t-butyloxalylamino) -n-butyric acid methyl ester as an oil.
収率95.6％ NMRδ（CDCl3）:7.25-7.40（br,1H）,5.69（s,3H）,3.3
7（q,J=7,2H）,2.40（t,J=7,2H）,1.80-2.00（m,2H）,
1.56（s,9H） （３）本品5.6gと13％塩化水素−ジオキサン溶液56mlの
混合物を室温で３時間攪拌した後、減圧濃縮する。残渣
を酢酸エチル10mlに溶解後、ｎ−ヘキサン30mlを加え結
晶化させ、10℃以下に冷却後析出晶をろ取し、乾燥させ
て４−（オキサロアミノ）−ｎ−酪酸メチルエステル4g
を無色プリズム晶として得る。Yield 95.6% NMR δ (CDCl 3 ): 7.25-7.40 (br, 1H), 5.69 (s, 3H), 3.3
7 (q, J = 7,2H), 2.40 (t, J = 7,2H), 1.80-2.00 (m, 2H),
1.56 (s, 9H) (3) A mixture of 5.6 g of this product and 56 ml of a 13% hydrogen chloride-dioxane solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 10 ml of ethyl acetate, 30 ml of n-hexane was added for crystallization, the mixture was cooled to below 10 ° C., and the precipitated crystals were collected by filtration and dried to give 4- (oxaloamino) -n-butyric acid methyl ester 4 g.
Is obtained as colorless prism crystals.
収率91.8％ m.p.68−72℃ 実施例２ （１）シュウ酸メチルエステルモノカリウム塩より実施
例１−（１）と同様にして、シュウ酸t-ブチルメチルエ
ステルを油状物として得る。Yield 91.8% mp 68-72 [deg.] C. Example 2 (1) Oxalic acid t-butyl methyl ester was obtained as an oily substance from oxalic acid methyl ester monopotassium salt in the same manner as in Example 1- (1).
収率91.6％ NMRδ（CDCl3）:3.87（s,3H）,1.56（s,9H） （２）本品より実施例１−（２）及び（３）と同様にし
て、４−（オキサロアミノ）−ｎ−酪酸メチルエステル
を得る。Yield 91.6% NMR δ (CDCl 3 ): 3.87 (s, 3H), 1.56 (s, 9H) (2) From this product, 4- (oxaloamino) was prepared in the same manner as in Examples 1- (2) and (3). ) -N-butyric acid methyl ester is obtained.
実施例３ （１）４−（オキサロアミノ）−ｎ−酪酸メチルエステ
ル40g、塩化メチレン260ml及びジメチルホルムアミド0.
11gの混合物に、氷冷撹拌下、オキサリルクロリド33.6g
を滴下する。室温で２時間撹拌後、溶媒を留去して４−
（クロロオキサリルアミノ）−ｎ−酪酸メチルエステル
43.9gを得る。Example 3 (1) 40 g of 4- (oxaloamino) -n-butyric acid methyl ester, 260 ml of methylene chloride and dimethylformamide.
33.6 g of oxalyl chloride was added to a mixture of 11 g under ice cooling.
Is dripped. After stirring at room temperature for 2 hours, the solvent was distilled off and 4-
(Chlorooxalylamino) -n-butyric acid methyl ester
Get 43.9g.
（２）塩化アルミニウム167.2gの1,2−ジクロロエタン8
2ml懸濁液に、ニトロベンゼン45mlを加えた後、２−ホ
ルミルアミノインダン30.7gの1,2−ジクロロエタン200m
l溶液を８〜13℃にて、30分間かけて滴下する。該混合
物に、４−（クロロオキサリルアミノ）−ｎ−酪酸メチ
ルエステル43.9gの1,2−ジクロロエタン41ml溶液を８〜
12℃にて１時間かけて滴下し、室温で2.5時間撹拌後、
氷水中に注入する。有機層を分取し、さらに1,2−ジク
ロロエタン480mlで水層を２回抽出後、有機層を洗浄、
乾燥後、溶媒を留去する。残渣にトルエン186mlを加
え、加熱溶解させた後冷却して４−〔（２−ホルミルア
ミノインダン−５−イル）オキサリルアミノ〕−ｎ−酪
酸メチルエステル51.4gを無色プリズム晶として得る。(2) Aluminum chloride 167.2 g of 1,2-dichloroethane 8
After adding 45 ml of nitrobenzene to the 2 ml suspension, 2-formylaminoindan 30.7 g of 1,2-dichloroethane 200 m
The solution is added dropwise at 8-13 ° C over 30 minutes. To the mixture, a solution of 4-3.9 g of 4- (chlorooxalylamino) -n-butyric acid methyl ester in 4 ml of 1,2-dichloroethane in 41 ml of 8 to 8 was added.
After dropping at 12 ° C for 1 hour and stirring at room temperature for 2.5 hours,
Pour into ice water. Separate the organic layer, extract the aqueous layer twice with 480 ml of 1,2-dichloroethane, and wash the organic layer.
After drying, the solvent is distilled off. To the residue was added 186 ml of toluene, and the mixture was heated and dissolved and then cooled to obtain 51.4 g of 4-[(2-formylaminoindan-5-yl) oxalylamino] -n-butyric acid methyl ester as colorless prism crystals.
収率81.3％ m.p.100−102℃ 〔発明の効果〕 本発明の方法によれば、安価なシュウ酸ジエチルエステ
ルのモノアルカリ金属塩から一工程で得られるシュウ酸
エステル（II）を原料化合物とし、中間生成物を全く単
離・精製することなく、簡便な操作でオキサロアミノ酸
エステル（Ｉ）を製造することができる。Yield 81.3% mp100-102 ° C [Effect of the Invention] According to the method of the present invention, an oxalate ester (II) obtained in one step from an inexpensive monoalkali metal salt of oxalic acid diethyl ester is used as a starting compound, and an intermediate The oxaloamino acid ester (I) can be produced by a simple operation without completely isolating and purifying the product.
また本発明方法によれば、オキサロアミノ酸エステル
（Ｉ）のハロゲン化物とインダン化合物（VI）との縮合
反応を、ニトロベンゼンの存在下で実施することによ
り、インダン−５−イルオキサロアミノ酸化合物（Ｖ）
とルイス酸との錯体が流動性を有し、該錯体を水に加え
る等の簡便な操作で高純度の該化合物（Ｖ）を高収率で
得ることができるという利点も得られる。Further, according to the method of the present invention, the condensation reaction between the halide of oxaloamino acid ester (I) and indane compound (VI) is carried out in the presence of nitrobenzene to give indan-5-yloxaloamino acid compound (V).
There is also an advantage that the complex of Lewis acid with Lewis acid has fluidity and the compound (V) of high purity can be obtained in high yield by a simple operation such as adding the complex to water.
Claims (2)
るカルボキシル基の保護基を表す。） で示されるシュウ酸エステル化合物と、一般式 H2N−R2 （式中、R2は低級アルコキシカルボニル低級アルキル基
を表す。） で示される化合物とを反応させた後、生成物を酸で処理
してカルボキシル基の保護基（Ｚ）を除去することを特
徴とする一般式 （式中、記号は前記と同一意味を表す。） で示されるオキサロアミノ酸エステルの製法。1. A general formula (In the formula, R 1 represents a lower alkyl group, Z represents a protecting group of a carboxyl group which can be easily removed with an acid.), And an oxalate compound represented by the general formula H 2 N—R 2 (wherein R 2 represents a lower alkoxycarbonyl lower alkyl group), and then the product is treated with an acid to remove the protecting group (Z) of the carboxyl group. (In the formula, symbols have the same meanings as described above.) A process for producing an oxaloamino acid ester represented by the formula:
を表す。） で示されるオキサロアミノ酸エステルをハロゲン化後、
該生成物と一般式 （式中、R3はアミノ基の保護基を表す。） で示されるインダン化合物とを、ニトロベンゼンの存在
下で縮合反応させることを特徴とする一般式 （式中、記号は前記と同一意味を表す。） で示されるインダン−５−イルオキサロアミノ酸化合物
の製法。2. General formula (In the formula, R 2 represents a lower alkoxycarbonyl lower alkyl group.) After halogenating the oxaloamino acid ester represented by
The product and the general formula (In the formula, R 3 represents an amino-protecting group.) An indane compound represented by the formula is subjected to a condensation reaction in the presence of nitrobenzene. (In the formula, symbols have the same meanings as described above.) A method for producing an indan-5-yloxaloamino acid compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2162365A JPH0686413B2 (en) | 1990-06-20 | 1990-06-20 | Process for producing oxaloamino acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2162365A JPH0686413B2 (en) | 1990-06-20 | 1990-06-20 | Process for producing oxaloamino acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0454159A JPH0454159A (en) | 1992-02-21 |
| JPH0686413B2 true JPH0686413B2 (en) | 1994-11-02 |
Family
ID=15753182
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2162365A Expired - Lifetime JPH0686413B2 (en) | 1990-06-20 | 1990-06-20 | Process for producing oxaloamino acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0686413B2 (en) |
-
1990
- 1990-06-20 JP JP2162365A patent/JPH0686413B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0454159A (en) | 1992-02-21 |
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