JPS5865269A - 4-substituted-(2s,3s,4s)-2-carboxypyrrolidine-3-acetic acid and its ester - Google Patents
4-substituted-(2s,3s,4s)-2-carboxypyrrolidine-3-acetic acid and its esterInfo
- Publication number
- JPS5865269A JPS5865269A JP16217381A JP16217381A JPS5865269A JP S5865269 A JPS5865269 A JP S5865269A JP 16217381 A JP16217381 A JP 16217381A JP 16217381 A JP16217381 A JP 16217381A JP S5865269 A JPS5865269 A JP S5865269A
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- group
- compound
- ester
- acetic acid
- butoxycarbonyl
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- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
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Abstract
Description
【発明の詳細な説明】
本発明は、下記一般式[11で表わされる新規な4置換
(28,38,48) −2−カルボキシピロリジン−
3−酢酸およびそのエステルに関する。Detailed Description of the Invention The present invention provides novel 4-substituted (28,38,48)-2-carboxypyrrolidine-
Regarding 3-acetic acid and its ester.
ことで R1は、水素、又は、1ニーブトキシカルボニ
ル基、ベンゾキシカルボニル基、アセチル基トリフルオ
ロアセチル基、ベンゾイル基等のイミノ基の保護基を表
わし、R2及びR1ば、それぞれ、水素又は低級アルキ
ル基を表わし R4は、アルデヒド基、又は環状もしく
は非環状のアセタール基を表わす。R1 represents hydrogen or a protecting group for an imino group such as 1-nibutoxycarbonyl group, benzoxycarbonyl group, acetyl group, trifluoroacetyl group, benzoyl group, and R2 and R1 each represent hydrogen or lower alkyl group. R4 represents an aldehyde group or a cyclic or acyclic acetal group.
動物の神経系には、多くの遊離型アミノ酸が存在し、種
々の代謝過程に関与するとともに、細胞内外の水分やイ
オン分布の調節に関与していることは、よく知られた事
実である。神経組織内に分布するアミノ酸のなかで、あ
る種のものは、とのよう外代謝的・生理機能維持的な意
義のほかに、神経伝達物質としての役割をもつものがあ
り、このようなアミノ酸として、γ−アミノ酪酸、L−
グルタミン酸、グリシン、L−アスパラギン酸等があげ
られている。It is a well-known fact that many free amino acids exist in the nervous system of animals and are involved in various metabolic processes as well as regulating the distribution of water and ions inside and outside of cells. Among the amino acids distributed in nervous tissues, some have a role as neurotransmitters in addition to having metabolic and physiological function maintenance significance. as, γ-aminobutyric acid, L-
Examples include glutamic acid, glycine, and L-aspartic acid.
本発明者らは、カイニン酸が、L−グルタミン酸の類似
作用体として約100倍の効力を有することに着目して
、カイニン酸の類似化合物についで鋭意研究を行った結
果、カイニン酸とは若干具なるL−グルタミン酸の類似
作イ牧して約100倍の効力を有する新規化合物である
( 28,3S、4N−2−カルボキシ−4−(1−メ
チル−5−カルボキシ基IZ、3E−へキサジェニル)
ピロリジン−3−酢酸の合成に成功し、その合成過程で
、本発明に到達したものである。The present inventors focused on the fact that kainic acid has approximately 100 times the potency as a similar agent of L-glutamic acid, and as a result of conducting intensive research on similar compounds of kainic acid, we found that kainic acid is slightly different from kainic acid. It is a new compound that has about 100 times the potency of similar L-glutamic acid (28,3S,4N-2-carboxy-4-(1-methyl-5-carboxy group IZ, 3E- xagenil)
The present invention was achieved through the successful synthesis of pyrrolidine-3-acetic acid.
(2S、3S、4s)−2−カルボキシ−4−(1−メ
チル−5−カルボキシ−IZ、3に一ヘキサジェニル)
ピロリジン−3−酢酸の合成は、次のような方法によっ
て行われる。(2S,3S,4s)-2-carboxy-4-(1-methyl-5-carboxy-IZ, 3-hexadienyl)
Synthesis of pyrrolidine-3-acetic acid is carried out by the following method.
イミノ基がt−ブトキシ−)yルボニル基等で保護され
ているピログルタミン酸[21を出発原石とし、遊離の
カルボキシ基をメチロール基に還元しシロキシ化して保
護した後、フェニルセレニルクロリド及びオゾン等を反
応させることにより二重結合を導入し、N−カルボニル
−2−シロキシメチルピロリジン−3−エン−5オン[
3] %: 4) ル。Starting from pyroglutamic acid [21, in which the imino group is protected with a t-butoxy-)y carbonyl group, etc., the free carboxyl group is reduced to a methylol group and protected by siloxylation, followed by phenylselenyl chloride and ozone, etc. A double bond is introduced by reacting N-carbonyl-2-siloxymethylpyrrolidin-3-ene-5one [
3] %: 4) Le.
この化合物[3]に、2−1−リメチルシロキシー1゜
3−ペンタジェンを付加し、中間体[4]を得、これを
オゾン酸化し、2,2−エチレンジオキシブタン[51
を作用させて、(2s、3s、 4s) −N−カルボ
ニル−2−シロキシメチル−4−(1−メチル−2,2
−工fレンジオキシエチル)ピロリジン−5−オン−3
−酢酸エステル[61を得る。To this compound [3], 2-1-limethylsiloxy 1°3-pentadiene was added to obtain intermediate [4], which was oxidized with ozone and 2,2-ethylenedioxybutane [51
(2s, 3s, 4s) -N-carbonyl-2-siloxymethyl-4-(1-methyl-2,2
-dioxyethyl)pyrrolidin-5-one-3
-Acetate ester [61 is obtained.
1j)42−Q)12
この化合物[61のケトン基をメチレン基に、エステル
基をメチロール基に還元し、シロキシ基を外してヒドロ
キシ基とした後、二つのメチロール基を酸化して、本発
明に係る化合物の−っである(2S、3E!、4S)−
N−カルボニル−2−アルコキシカルボニル−4−(1
−メチル−2,2−エチレンジオキシエチル)ピロリジ
ン−3−酢酸、エステル[71を得る。また、との化合
物[7]を加熱して、本発明に係る化合物の他の−っで
ある(2s、38゜4S)−N−カルボニル−2−アル
コキシカルボニル−4−(1−ホルミルエチル)ヒロI
J IJ 、)ノー3−酢酸エステル[81を得る。1j) 42-Q) 12 The ketone group of this compound [61 is reduced to a methylene group, the ester group is reduced to a methylol group, the siloxy group is removed to form a hydroxy group, and the two methylol groups are oxidized to obtain the present invention. - of the compound related to (2S, 3E!, 4S) -
N-carbonyl-2-alkoxycarbonyl-4-(1
-Methyl-2,2-ethylenedioxyethyl)pyrrolidine-3-acetic acid, ester [71 is obtained. In addition, by heating the compound [7], another compound according to the present invention (2s, 38°4S)-N-carbonyl-2-alkoxycarbonyl-4-(1-formylethyl) Hiro I
J IJ ,) no 3-acetic acid ester [81 is obtained.
との化合物[81にメトキシメチルトリフェニルホスホ
リルクロリドを反応させ、更にフェニルセレニルクロリ
ドを反応させた後、N−ブロモスクシンイミドで酸化し
て、(28,3S、48) −N−カルボニル−2−
アルコキシカルボニル−4−(1−メチル−2Z及び2
E−ホルミルエチニル)−ピロリジン−3−酢酸エステ
ル[91および叫の約2:1の混合物を得る。The compound [81 was reacted with methoxymethyltriphenylphosphoryl chloride and further reacted with phenylselenyl chloride, and then oxidized with N-bromosuccinimide to form (28,3S,48) -N-carbonyl-2-
Alkoxycarbonyl-4-(1-methyl-2Z and 2
An approximately 2:1 mixture of E-formylethynyl)-pyrrolidine-3-acetic acid ester [91 and E-formylethynyl] is obtained.
このシス化合物[9]に2R−メチル−3−ヒドロキシ
プロピルトリフェニルホスホリルプロミド[旬を反応さ
せて、(2s、3+s、4s)−N−カルボニル−2−
アルコキシカルボニル−4−(1−メチル−5−メチロ
ール−12,3E−へキサジェニル)ピロリジン−3−
酢酸エステルを4!) 、そのメチロール基をカルボキ
シ基に酸化し、二つのエステル基をカルボキシ基に加水
分解し、イミノ基の保護基Rを外して、所期の(28,
3’S、41−2−カルボキシ−4−(1−メチル−5
−カルボキシ−12,3F−ヘキサジェニル)ピロリ酢
酸−3−酢酸圏を得る。This cis compound [9] was reacted with 2R-methyl-3-hydroxypropyltriphenylphosphoryl bromide [(2s, 3+s, 4s)-N-carbonyl-2-
Alkoxycarbonyl-4-(1-methyl-5-methylol-12,3E-hexagenyl)pyrrolidine-3-
Acetate ester 4! ), the methylol group is oxidized to a carboxy group, the two ester groups are hydrolyzed to the carboxy group, the protecting group R of the imino group is removed, and the desired (28,
3'S, 41-2-carboxy-4-(1-methyl-5
-carboxy-12,3F-hexagenyl)pyrroliacetic acid-3-acetate is obtained.
本発明に係る化合物は、この合成過程における中間体で
ある(2s、38,4S)−2−アルコキシカルボニル
−4−(1−メチル−2,2−エチレンジオキシエチル
)ピロリジン−3−酢酸エステル[7]および(28,
3El、 4S) −2−アルコキシ力/L/ ホ=ル
ー4−(1−ホルミルエチル)ピロリシン−3−酢酸エ
ステル[8)を含む4置換(28,38゜48)−2−
カルボキシピロリジン−3−酢酸およびそのエステル[
11であり、本発明者らによって初めて合成された新規
の化合物であって、最終目的化合物である(2s、3s
、4s)−2−カルボキシ−4−(1−メチル−5−カ
ルボキシ−IZ、3B−へキサジェニル)ピロリジン−
3−酢酸叩の合成中間体として重要であるだけでなく、
カイニン酸等の他の化合物の合成中間体としても重要で
ある。また、この化合物自体も、若干の神経的作用を有
し、実験動物に特定の病気を発生させるのにも有用であ
る。The compound according to the present invention is an intermediate in this synthesis process, (2s, 38,4S)-2-alkoxycarbonyl-4-(1-methyl-2,2-ethylenedioxyethyl)pyrrolidine-3-acetic ester. [7] and (28,
3El, 4S) -2-alkoxy power/L/ 4-substituted (28,38°48)-2- containing ho=4-(1-formylethyl)pyrrolisine-3-acetic acid ester [8]
Carboxypyrrolidine-3-acetic acid and its ester [
11, is a new compound synthesized for the first time by the present inventors, and is the final target compound (2s, 3s
, 4s)-2-carboxy-4-(1-methyl-5-carboxy-IZ, 3B-hexagenyl)pyrrolidine-
It is not only important as a synthetic intermediate for 3-acetic acid production, but also
It is also important as a synthetic intermediate for other compounds such as kainic acid. The compound itself also has some neurological effects and is useful in inducing certain diseases in laboratory animals.
次に本発明に係る化合物に属する代表的な化合物の物性
を示す。Next, the physical properties of typical compounds belonging to the compounds according to the present invention will be shown.
(1) (2s、 3s、 48 ) −N −t−ブ
トキシカルボニル−2−メトキシカルボニル−4−(1
−メfルー2.2−エチレンジオキシエチル)ピロリジ
ン−3−酢酸メチル
分子骨 401.4
性状 無色油状物質
旋光度 1αID −7,0°(C!=0.5 an
a]3)工R(neat、[−’) 1740.169
0’ H−NMR(cDc13.δ) 4.68.4.
67 (l T(、a、 J=2.5Hz)、 4.2
2.4,32(IH,S)、 3.75(3H,El)
、 1.47゜1.40 (9H,S )、 0.95
(3H,d、 、T=6.5Hi(2)(28,3s
、 4s)−N−t−ブトキシカルボニル−2−メトキ
シカルボニル−4−(1−ホルミルエチル)ピロリジン
−3−酢酸メチル
分子量 357.4
性状 無色油状物質
IR(neat、m’) 2700.1730.16.
.90’H−NMR(CD(!13.8 ) 9.56
(L H,a、 J=2.5Hz )。(1) (2s, 3s, 48) -N-t-butoxycarbonyl-2-methoxycarbonyl-4-(1
-Mef-2.2-ethylenedioxyethyl)pyrrolidine-3-methyl acetate molecular bone 401.4 Properties Colorless oil Optical rotation 1αID -7,0° (C!=0.5 an
a] 3) Engineering R (neat, [-') 1740.169
0' H-NMR (cDc13.δ) 4.68.4.
67 (l T(,a, J=2.5Hz), 4.2
2.4,32(IH,S), 3.75(3H,El)
, 1.47°1.40 (9H,S), 0.95
(3H,d, ,T=6.5Hi(2)(28,3s
, 4s) -Nt-butoxycarbonyl-2-methoxycarbonyl-4-(1-formylethyl)pyrrolidine-3-methyl acetate Molecular weight 357.4 Properties Colorless oil IR (neat, m') 2700.1730.16 ..
.. 90'H-NMR (CD(!13.8) 9.56
(LH,a,J=2.5Hz).
1.15 (3H+ a、+ J−6Hz )次に、本
発明に係る化合物に属する代表的な化合物の具体的製造
例について述べる。1.15 (3H+a, +J-6Hz) Next, specific production examples of typical compounds belonging to the compounds according to the present invention will be described.
t −ブトキシカルボニル−(−)−ピログルタミン酸
5.0gをテトラハイドロフランに溶解し、−10℃に
冷却し、クロル炭酸エチル2.439と、次いで、トリ
エチルアミン2.32gとを加え、撹拌した。40分後
、溶媒を0°Cで減圧留去した。反応混合物を90チ工
タノール100+mlに浴解し、−10℃で水素化はう
素す) IJウム1.60gを少量づつ加え1時間撹拌
した。それに水30m1 を加え、10%塩酸でPH4
とし、溶媒を減圧留去し、酢酸エチルで抽出し、硫酸マ
グネシウム上で乾燥し、溶媒を減圧留去して油状物質を
え、とれをシリカゲルカラムクロマトグラフにかけ、エ
チルエーテルで展開し、アセトン・ヘキサンに溶解し、
再結晶させ、N −t−ブトキシカルボニル−2−ヒド
ロキシメチルピロリジン−5−オン2.2g を得た。5.0 g of t-butoxycarbonyl-(-)-pyroglutamic acid was dissolved in tetrahydrofuran, cooled to -10°C, and 2.439 g of ethyl chlorocarbonate and then 2.32 g of triethylamine were added and stirred. After 40 minutes, the solvent was removed under reduced pressure at 0°C. The reaction mixture was dissolved in 100+ml of 90% titanol, and 1.60g of IJium (hydrogenated) was added little by little at -10°C and stirred for 1 hour. Add 30ml of water to it and adjust the pH to 4 with 10% hydrochloric acid.
The solvent was distilled off under reduced pressure, extracted with ethyl acetate, dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oily substance, and the residue was subjected to silica gel column chromatography, developed with ethyl ether, and extracted with acetone. Dissolved in hexane,
Recrystallization yielded 2.2 g of N-t-butoxycarbonyl-2-hydroxymethylpyrrolidin-5-one.
このものの旋光度は、(a) ”o =63.9°(0
=0.55.0TTe1.3)であった。The optical rotation of this object is (a) ”o = 63.9° (0
=0.55.0TTe1.3).
この化合物2.196gとイミダゾール166gのジメ
チルホルムアミドの溶液15me に、0℃で、t−ブ
チルジメチルシリルフロリド1.85gのジメチルホル
ムアミド溶液5 mlを加える。0℃で45分、室温で
45分反応後、反応液を冷水中に注ぎ、エーテル・塩化
メチレン(10:1)で抽出し、硫酸マグネシウムで乾
燥後、溶媒を減圧留去し、シリカゲルカラムクロマトグ
ラムに」ニリN−t−フ゛トキシカルボニルー2−t−
ブチルジメチルシロキシメチルピロリジン−5−オン[
:15) 3.23 gを得た。To 15 ml of a solution of 2.196 g of this compound and 166 g of imidazole in dimethylformamide, 5 ml of a solution of 1.85 g of t-butyldimethylsilyl fluoride in dimethylformamide is added at 0°C. After reacting for 45 minutes at 0°C and 45 minutes at room temperature, the reaction solution was poured into cold water and extracted with ether/methylene chloride (10:1). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the mixture was subjected to silica gel column chromatography. 2-t-
Butyldimethylsiloxymethylpyrrolidin-5-one [
:15) 3.23 g was obtained.
0H3C!I(3
Ca 片=60.6 (0−1,1+ 0HQ13)I
R(crrL−’): 1780,174.0.17
1ONMR(6):4..16(]、H,m)、3.9
3(LH,ad。0H3C! I (3 Ca piece = 60.6 (0-1,1+ 0HQ13) I
R(crrL-'): 1780,174.0.17
1ONMR(6):4. .. 16(], H, m), 3.9
3 (LH, ad.
J=4. 12Hz) 3.68 (1,H,dd、
J=2. 12Hz)。J=4. 12Hz) 3.68 (1,H,dd,
J=2. 12Hz).
1、.54(9■(、S)、0.89(9H,s)、0
.05(3H。1. 54(9■(,S), 0.89(9H,s), 0
.. 05 (3H.
S)、0.04(3H,5)
一78°Cで調整したジイソプロピルアミン1.5F!
inl。S), 0.04 (3H, 5) - diisopropylamine 1.5F adjusted at 78°C!
inl.
n−ブチルリチウム6.95m1をテトラヒドロフラン
25mJ に溶解した溶液に、この化合物(15)3.
2.9のテトラヒドロフラン溶液5ゴを、窒素気流中、
−78°Cで滴下し、−78℃で30分撹拌後、フェニ
ルセレニルフロリド2.05,9’のテトラヒドロフラ
ン溶液5 alを加えた。5分後飽和塩化アンモニウム
水溶液を加え、室温に戻し、エーテルで抽出し、硫酸マ
グネシウム上で乾燥し、シリカゲルカラムクロマトグラ
にかけ、N−t−ブトキシカルボニル−2−t−ブチル
ジメチルシロキシメチル−4−フェニルセレノピロリジ
ン−5−オン全得り。This compound (15) 3.
2.9 of the tetrahydrofuran solution in a nitrogen stream,
It was added dropwise at -78°C, and after stirring at -78°C for 30 minutes, 5 al of a solution of phenylselenyl fluoride 2.05,9' in tetrahydrofuran was added. After 5 minutes, a saturated aqueous ammonium chloride solution was added, the temperature was returned to room temperature, extracted with ether, dried over magnesium sulfate, and subjected to silica gel column chromatography to obtain N-t-butoxycarbonyl-2-t-butyldimethylsiloxymethyl-4- All phenylselenopyrrolidin-5-one obtained.
この化合物3.2gを80WLlの無水塩化メチレンに
溶解し一78℃でオゾン酸化を行い、次に無水酢酸ナト
リウム6.6gを加え、0°Cにした。40分後、水洗
し、硫酸ナトリウム−にで乾燥し、5ili−cCC−
7カラムクロマトグラフにかけ、エーテル・ヘキサン(
1:4)で展開し、白色結晶として、N −t −フ)
キシカルボニル−2−t−ブチルジメチルシロキシメチ
ルピロリジン−3−エン−5−オン(16) 1.73
g を得た。3.2 g of this compound was dissolved in 80 WLl of anhydrous methylene chloride and subjected to ozone oxidation at -78°C, then 6.6 g of anhydrous sodium acetate was added and the temperature was brought to 0°C. After 40 minutes, it was washed with water, dried with sodium sulfate, and 5ili-cCC-
7 column chromatography, ether/hexane (
1:4) and as white crystals, N-t-f)
Oxycarbonyl-2-t-butyldimethylsiloxymethylpyrrolidin-3-en-5-one (16) 1.73
I got g.
H3CH3
(α):= −175,6(0=0.9.0Hc13)
工R(fi−1) 1,780. 1,740. 1
71ONMR(6) 7.06 (IH,d、d、、
J=2.5.7H2)、 6.1−2(LH,dd、、
T:2.0.7H2)、4.60(IH,m)。H3CH3 (α):= -175,6 (0=0.9.0Hc13)
Engineering R (fi-1) 1,780. 1,740. 1
71ONMR(6) 7.06 (IH, d, d,,
J=2.5.7H2), 6.1-2(LH, dd,,
T: 2.0.7H2), 4.60 (IH, m).
4.15 (1,H,dd、、 J=4.1.0H2)
、 3.71 (LH。4.15 (1,H,dd,, J=4.1.0H2)
, 3.71 (LH.
da、、 J=5. l0Hz)、 1.58(9H,
s)、 0.89(9H,El)、0.05(3H,S
)、0.045(3H,S)この化合物(1−6) 4
40mgと2−トリメチルシロキシー1,3−ペンタジ
ェン1.2TIを封管中で、135℃に加熱し、4日間
反応を行った。得られた油状物質から未反応の2−トリ
メチルシロキシ−1゜3−ペンタジェンを減圧留去後、
塩化メチレン30ゴに溶解し、−78°Cに冷却しオゾ
ン酸化を行った。da,, J=5. 10Hz), 1.58(9H,
s), 0.89 (9H, El), 0.05 (3H, S
), 0.045 (3H,S) This compound (1-6) 4
40 mg of 2-trimethylsiloxy 1,3-pentadiene 1.2TI were heated to 135° C. in a sealed tube and reacted for 4 days. After removing unreacted 2-trimethylsiloxy-1°3-pentadiene from the obtained oily substance under reduced pressure,
It was dissolved in 30 g of methylene chloride, cooled to -78°C, and ozone oxidized.
反応液にジメチルスルフィド5 mlを加え、−78°
Cで4時間、室温で14時間撹拌し、溶媒を減圧留去後
、エーテル5 mlに溶解し、ジアゾメタンのエーテル
溶液を反応液が黄色になるまで加え、室温で15分静置
後、エーテルを減圧留去し、ベンゼン4m/!、 2
. 2−エチレンジオキシブタン4 ml及びP−トル
エンスルホン酸2 mgを加え、窒素気流中4時間室温
で撹拌する。反応液に重炭酸す) IJウム粉末20m
gを加え、溶媒を減圧留去し、シリカゲルカラムクロマ
トグラフにかけ、エーテル・ヘキサン(2:3)で展開
し、油状物質として、(2s、 3s、 4.s )
−N −t−ブトキシカルボニル−2−ブチルジメチル
シロキシメチル−4−(1−メチル−2,2−エチレン
ジオキシエチル)ピロリジン−5−オン−3−酢酸メチ
ル(17)250mgH3CH3
[α翻=−39,3°(0=0.56. anc:+、
)工R(cm−’)1780,1,735.170ON
MR(δ)5.54(IH,d、J=4Hz)、3.6
9(3H,S)1.58,1..53(9T(、s)、
0.88(9H,日)、0.06(3HI S)+
0.04 (3I(、S )この化合物〔17〕24
0mgのテトラヒドロフラン溶液2 mlに、窒素気流
中、はう素・ジメチルスルフィド・コンプレックス21
9mgを加え、60〜65℃で8時間反応し、反応液を
0℃に冷却し、過剰の試薬を氷片を加えて分解し、エー
テルで抽出し、硫酸ナトリウム上で乾燥し、シリカゲル
カラムクロマトグラフにかけ、エーテル・ヘキサン(2
:1)で展開し、(28,3ET、4S) −N−t−
ブトキシカルボニル−2−t−ブチルジメチルシロキシ
メチル−4−(1−メチル−2,2−エチレンジオキシ
エチル)ピロリジン−3−エチルアルコール(18)1
50mg を得た。Add 5 ml of dimethyl sulfide to the reaction solution and heat to -78°
After stirring at C for 4 hours and at room temperature for 14 hours, the solvent was distilled off under reduced pressure, dissolved in 5 ml of ether, an ether solution of diazomethane was added until the reaction mixture turned yellow, and after standing at room temperature for 15 minutes, ether was added. Distilled under reduced pressure to remove 4 m/! of benzene! , 2
.. Add 4 ml of 2-ethylenedioxybutane and 2 mg of P-toluenesulfonic acid, and stir at room temperature for 4 hours in a nitrogen stream. Add bicarbonate to the reaction solution) IJum powder 20m
The solvent was distilled off under reduced pressure, and the mixture was subjected to silica gel column chromatography and developed with ether/hexane (2:3) to form an oily substance (2s, 3s, 4.s).
-N -t-Butoxycarbonyl-2-butyldimethylsiloxymethyl-4-(1-methyl-2,2-ethylenedioxyethyl)pyrrolidin-5-one-3-methyl acetate (17) 250mgH3CH3 [αtranslation=- 39.3° (0=0.56. anc:+,
) Engineering R (cm-') 1780, 1,735.170ON
MR (δ) 5.54 (IH, d, J=4Hz), 3.6
9 (3H, S) 1.58, 1. .. 53(9T(,s),
0.88 (9H, Sun), 0.06 (3HIS)+
0.04 (3I(,S) this compound [17]24
Boron dimethyl sulfide complex 21 was added to 2 ml of 0 mg of tetrahydrofuran solution in a nitrogen stream.
9 mg was added, the reaction was carried out at 60-65°C for 8 hours, the reaction solution was cooled to 0°C, the excess reagent was decomposed by adding ice chips, extracted with ether, dried over sodium sulfate, and subjected to silica gel column chromatography. Ether hexane (2
:1) and expand (28,3ET,4S) -Nt-
Butoxycarbonyl-2-t-butyldimethylsiloxymethyl-4-(1-methyl-2,2-ethylenedioxyethyl)pyrrolidine-3-ethyl alcohol (18) 1
50 mg was obtained.
H3CH3
四せ=−30°(c=1.0. cuc13)IR(1
−’)3450.1’68O
NMR(6) 4.70(IH,d、 J:3Hz)、
1.52.1.55(9)I、 El)、 0.90
(9)I、 S)、 0.06(61(、S)この化合
物(18) 130.qrgをメタノールに溶解し、F
−)ルエンスルホン酸を加え、室温で2時間撹拌し、重
炭酸ナトリウム粉末20m9を加え、メタノールを減圧
留去後、cc−7カラムクロマトグラフにかけ、エーテ
ルで展開し、油状物質として、(2s、3s、4s)−
N−t−ブトキシカルボニル−2−メチロール−4−(
1−メチル−2,2−エチレンジオキシエチル)ピロリ
ジン−3−3−エチルアルコール(19)86mgを得
た。H3CH3 4th = -30° (c = 1.0. cuc13) IR (1
-') 3450.1'68O NMR (6) 4.70 (IH, d, J: 3Hz),
1.52.1.55(9)I, El), 0.90
(9)I, S), 0.06(61(,S)) Dissolve 130.qrg of this compound (18) in methanol, F
-) Add luenesulfonic acid, stir at room temperature for 2 hours, add 20 m9 of sodium bicarbonate powder, remove methanol under reduced pressure, apply CC-7 column chromatography, develop with ether, and obtain (2s, 3s, 4s)-
N-t-butoxycarbonyl-2-methylol-4-(
86 mg of 1-methyl-2,2-ethylenedioxyethyl)pyrrolidine-3-3-ethyl alcohol (19) was obtained.
[α慴=−23,7(O二0.57. CH(!13)
工R(cm−’)3400.1675
NMR(δ) 4.70(IH,d、 J:=3Hz)
、 1.45(9H,S)。[α = -23,7 (O2 0.57. CH (!13)
Engineering R (cm-') 3400.1675 NMR (δ) 4.70 (IH, d, J: = 3Hz)
, 1.45 (9H,S).
0.95 (3H,d、 J:6Hz)この化合物[:
19) 75mg、 ピリジニウムジクロメート97
8mgをジメチルホルムアミド2.5mlに溶解し、3
5℃で3日間反応し、反応液にエーテル50m1、次に
、無水硫酸マグネシウムを加えて、隠退し、濾液から溶
媒を減圧留去し、エーテル2 mlに溶解し、これにジ
アゾメタンのエーテル溶液4 mlを加え、溶媒を減圧
留去して油状物質を得、これをシリカゲルクロマトグラ
フにかけ、エーテル・ヘキサン(3:2)で展開し、本
発明に係る化合物の一つである(2S、38.48)−
N−t−プトキジカルボニル−2−メトキシカルボニル
−4−(1−メチル−2,2−エチレンジオキシエチル
)ピロリジン−3−酢酸メチル(:1−3) 55mg
を得た。0.95 (3H, d, J: 6Hz) This compound [:
19) 75mg, pyridinium dichromate 97
Dissolve 8 mg in 2.5 ml of dimethylformamide,
The reaction was carried out at 5°C for 3 days, 50 ml of ether and then anhydrous magnesium sulfate were added to the reaction solution, the solution was evaporated, the solvent was distilled off from the filtrate under reduced pressure, the solution was dissolved in 2 ml of ether, and 4 ml of an ether solution of diazomethane was added to the reaction solution. ml and the solvent was distilled off under reduced pressure to obtain an oily substance, which was subjected to silica gel chromatography and developed with ether/hexane (3:2), which is one of the compounds according to the present invention (2S, 38. 48)-
N-t-butoxycarbonyl-2-methoxycarbonyl-4-(1-methyl-2,2-ethylenedioxyethyl)pyrrolidine-3-methyl acetate (:1-3) 55mg
I got it.
また、この化合物(13’l 530mgを60係酢酸
に溶解し、60℃で20時間反応させ、溶媒を減圧留去
して、シリカゲルカラムクロマトグラフにかけ、エーテ
ル・ヘキサノ(3:2)で展開し、油状物質として、本
発明に係る化合物の他の一つである(2s、3s、4s
)−N−t−ブトキシカルボニル−2−メトキシカルボ
ニル−4−(1−ホルミルエチル)ピロリジン−3−酢
r(12メチル〔14〕300mgを得た。In addition, 530 mg of this compound (13'l) was dissolved in 60% acetic acid, reacted at 60°C for 20 hours, the solvent was distilled off under reduced pressure, and the mixture was subjected to silica gel column chromatography and developed with ether/hexano (3:2). , which is another one of the compounds according to the present invention as an oily substance (2s, 3s, 4s
)-Nt-butoxycarbonyl-2-methoxycarbonyl-4-(1-formylethyl)pyrrolidine-3-acetic acid r(12methyl[14]) (300 mg) was obtained.
Claims (1)
2−カルボキシピロリジン−3−酢酸およびそのエステ
ル ここで、丘1は、水素、又は、t−ブトキシカルボニル
基、ベンゾキシカルボニル基、アセチル基、トリフルオ
ロアセチル基、ベンゾイル基等のイミノ基の保護基を表
わし、R2及びR3は、それぞれ、水素又は低級アルキ
ル基を表わし R4は、アルデヒド基、又は、環状もし
くは非環状のアセタール基を表わす。[Claims] 4-substituted (2s, 3s, 4s) represented by the following general formula -
2-Carboxypyrrolidine-3-acetic acid and its ester where Hound 1 is hydrogen or a protecting group for imino groups such as t-butoxycarbonyl group, benzoxycarbonyl group, acetyl group, trifluoroacetyl group, benzoyl group, etc. , R2 and R3 each represent hydrogen or a lower alkyl group, and R4 represents an aldehyde group or a cyclic or non-cyclic acetal group.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16217381A JPS5865269A (en) | 1981-10-12 | 1981-10-12 | 4-substituted-(2s,3s,4s)-2-carboxypyrrolidine-3-acetic acid and its ester |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16217381A JPS5865269A (en) | 1981-10-12 | 1981-10-12 | 4-substituted-(2s,3s,4s)-2-carboxypyrrolidine-3-acetic acid and its ester |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS5865269A true JPS5865269A (en) | 1983-04-18 |
Family
ID=15749400
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16217381A Pending JPS5865269A (en) | 1981-10-12 | 1981-10-12 | 4-substituted-(2s,3s,4s)-2-carboxypyrrolidine-3-acetic acid and its ester |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5865269A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4661512A (en) * | 1984-10-31 | 1987-04-28 | S. A. Panmedica | Adamantanamine derivatives, processes for their preparation and drugs in which they are present |
-
1981
- 1981-10-12 JP JP16217381A patent/JPS5865269A/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4661512A (en) * | 1984-10-31 | 1987-04-28 | S. A. Panmedica | Adamantanamine derivatives, processes for their preparation and drugs in which they are present |
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