JPH0575743B2 - - Google Patents
Info
- Publication number
- JPH0575743B2 JPH0575743B2 JP18362687A JP18362687A JPH0575743B2 JP H0575743 B2 JPH0575743 B2 JP H0575743B2 JP 18362687 A JP18362687 A JP 18362687A JP 18362687 A JP18362687 A JP 18362687A JP H0575743 B2 JPH0575743 B2 JP H0575743B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- dihydropyridine
- alkyl group
- represented
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- CUNSUQKHHZVKMU-UHFFFAOYSA-N 1,4-dihydropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CCC=CN1 CUNSUQKHHZVKMU-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 9
- -1 ethyl hydrochloride Chemical compound 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000000304 vasodilatating effect Effects 0.000 description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- JNTMWPCEVGHVML-UHFFFAOYSA-N n-benzyl-2-chloro-n-methylethanamine Chemical compound ClCCN(C)CC1=CC=CC=C1 JNTMWPCEVGHVML-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HFFBRLXQWQCDEX-UHFFFAOYSA-N 1-hydroxy-2h-pyridin-4-ol Chemical class ON1CC=C(O)C=C1 HFFBRLXQWQCDEX-UHFFFAOYSA-N 0.000 description 1
- WOUANPHGFPAJCA-UHFFFAOYSA-N 2-[benzyl(methyl)amino]ethanol Chemical compound OCCN(C)CC1=CC=CC=C1 WOUANPHGFPAJCA-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910020366 ClO 4 Inorganic materials 0.000 description 1
- 238000003445 Hantzsch reaction Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 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
- 229940006460 bromide ion Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910001389 inorganic alkali salt Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Description
＜技術分野＞
本発明は、１，４−ジヒドロキシピリジン誘導
体の製造法に関する。更に詳細には、本発明は、
強力な降圧作用、血管拡張作用等の薬理作用を有
し、かつその薬理作用が長時間持続するという特
徴を持つ、１，４−ジヒドロピリジン誘導体の製
造法に関する。
＜従来技術＞
従来、血圧降下作用、血管拡張作用等の薬理作
用を有する化合物として、多数の１，４−ジヒド
ロピリジン誘導体が知られている。例えば、４−
（２−ニトロフエニル）−２，６−ジメチル−１，
４−ジヒドロピリジン−３，５−ジカルボン酸ジ
メチルエステル（以下ニフエニルジピンと略す）
が冠血管拡張作用などの強力な薬理活性を有する
ことが知られており（米国特許第3644627号明細
書参照）、又４−（３−ニトロフエニル）−２，６
−ジメチル−１，４−ジヒドロピリジン−３，５
−ジカルボン酸メチル−２−（Ｎ−ベンジル−Ｎ
−メチルアミノ）エチル塩酸塩（以下ニカルジピ
ンと略す）が広く知られている（米国特許第
3985758号明細書参照）。
そして、上記の１，４−ジヒドロピリジン誘導
体の製造方法として、いわゆるmodified
Hantzsch反応が開示されている。
又、別の製造方法として１，４−ジヒドロピリ
ジンカルボン酸又はその反応性誘導体とアルコー
ル類とを反応せしめて、１，４−ジヒドロピリジ
ンカルボン酸エステル誘導体を製造する方法が知
られている（例えばＴ，Shibanumaら：Chem.
Pharm.Bull.28，2809−2812（1980）参照）。
本発明者らは、１，４−ジヒドロピリジン誘導
体のうち、側鎖エステル残基が３−アミノエチル
基である場合について、、従来知られていない新
規な方法を見い出し、本発明に到達した。
＜発明の目的＞
本発明の他の目的は、強力な血圧降下作用、血
管拡張作用等の薬理活性を有する１，４−ジヒド
ロピリジン誘導体の製造方法を提供することにあ
る。
更に詳しくは４位に置換フエニル基を有し、５
位にＮ−ジ置換アミノエチルエステル基を有する
１，４−ジヒドロピリジン誘導体又はその酸付加
塩を、緩和な反応条件下、簡便な操作で、且つ高
収率で得られる製造方法を提供することにある。
＜発明の構成及び効果＞
即ち本発明は、下記式［］
<Technical Field> The present invention relates to a method for producing 1,4-dihydroxypyridine derivatives. More specifically, the present invention comprises:
The present invention relates to a method for producing 1,4-dihydropyridine derivatives, which have strong pharmacological effects such as antihypertensive action and vasodilatory action, and are characterized by long-lasting pharmacological actions. <Prior Art> A large number of 1,4-dihydropyridine derivatives have been known as compounds having pharmacological effects such as hypotensive action and vasodilatory action. For example, 4-
(2-nitrophenyl)-2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (hereinafter abbreviated as niphenyldipine)
It is known that 4-(3-nitrophenyl)-2,6 has strong pharmacological activities such as coronary vasodilation (see US Pat. No. 3,644,627)
-dimethyl-1,4-dihydropyridine-3,5
-methyl dicarboxylate-2-(N-benzyl-N
-Methylamino)ethyl hydrochloride (hereinafter abbreviated as nicardipine) is widely known (U.S. Patent No.
3985758). As a method for producing the above-mentioned 1,4-dihydropyridine derivative, so-called modified
A Hantzsch reaction is disclosed. Another production method is known, in which 1,4-dihydropyridinecarboxylic acid or a reactive derivative thereof is reacted with an alcohol to produce a 1,4-dihydropyridinecarboxylic acid ester derivative (for example, T, Shibanuma et al.: Chem.
(See Pharm. Bull. 28 , 2809-2812 (1980)). The present inventors have discovered a novel method previously unknown for 1,4-dihydropyridine derivatives in which the side chain ester residue is a 3-aminoethyl group, and have arrived at the present invention. <Object of the Invention> Another object of the present invention is to provide a method for producing 1,4-dihydropyridine derivatives having pharmacological activities such as strong hypotensive action and vasodilatory action. More specifically, it has a substituted phenyl group at the 4-position, and the 5
To provide a method for producing a 1,4-dihydropyridine derivative having an N-disubstituted aminoethyl ester group or an acid addition salt thereof under mild reaction conditions, with simple operation, and in high yield. be. <Structure and effects of the invention> That is, the present invention provides the following formula []
【化】
〔式中、R1はアルキル基を表わし、Ｘ、Ｙ及
びＺは水素原子、ハロゲン原子、トリフルオロメ
チル基又はニトロ基を表わす。
但し、Ｘ、Ｙ、Ｚが同時に水素原子を表わすこ
とはない。〕
で表わされる１，４−ジヒドロピリジンカルボン
酸と、下記式［］、[In the formula, R 1 represents an alkyl group, and X, Y and Z represent a hydrogen atom, a halogen atom, a trifluoromethyl group or a nitro group. However, X, Y, and Z do not represent hydrogen atoms at the same time. ] 1,4-dihydropyridinecarboxylic acid represented by the following formula [],
【化】
〔式中、R2はアルキル基、R3はアルキル基又
は置換若しくは非置換のアラルキル基を表わし、
Ｌ
は陰イオン残基を表わす。〕
で表わされるアジリジニウム塩とを反応させるこ
とを特徴とする下記式［］、[In the formula, R 2 represents an alkyl group, R 3 represents an alkyl group or a substituted or unsubstituted aralkyl group,
L represents an anionic residue. ] The following formula [], which is characterized by reacting with an aziridinium salt represented by
【化】
〔式中、Ｘ、Ｙ、Ｚ、R1，R2及びR3は前記式
［］及び［］の定義と同じ。〕
で表わされる１，４−ジヒドロピリジン誘導体を
製造する方法である。
本発明の製造法により提供される１，４−ジヒ
ドロピリジン誘導体は、４位に置換フエニル基を
有し、５位にＮ−ジ置換アミノエチル基を有する
カルボン酸エステルという構造上の特徴を有す
る。
本発明によれば、上記式［］で表わされる
１，４−ジヒドロピリジンカルボン酸において、
Ｘ、Ｙ、Ｚは同一若しくは異なつて水素原子；例
えばフツ素原子、塩素原子等のハロゲン原子；ト
ルフルオロメチル基；ニトロ基を表わし、これら
の置換基の種類と置換形式によつて本製造方法は
影響されない。
R1はアルキル基であり、メチル、エチル、ｎ
−プロピル、イソプロピル、ｎ−ブチル、イソブ
チル、sec−ブチル、ｎ−ペンチル等の低級アル
キル基が好ましい。
上記式［］で表わされる１，４−ジヒドロピ
リジンカルボン酸は公知の方法で製製造すること
ができる。例えば、特開昭61−161263号公報にそ
の製造方法が開示されている。
上記式［］で表わされるアジリジニウム塩に
おいて、R2はアルキル基であり、例えばメチル、
エチル、ｎ−プロピル、イソプロピル、ｎ−ブチ
ル等のC1〜C4の低級アルキル基が挙げられる。
R3は、アルキル基又は置換若しくは非置換の
アラルキル基を表わす。アルキル基としては、例
えばメチル、エチル、ｎ−プロピル、ｉ−プロピ
ル、ｎ−ブチル等のC1〜C4の低級アルキル基が
挙げられる。置換若しくは非置換のアラルキル基
としては、例えば置換しくは非置換のベンジル
基、又は置換若しくは非置換のフエネチル基等を
挙げることができる。フエニル基上の置換基とし
ては、例えばハロゲン原子、低級アルキル基、低
級アルキルオキシ基、アミノ基、ニトロ基、低級
アルキルオキシカルボニル基等が挙げられる。
Ｌ
は、陰イオン残基を表わし、例えば塩素イ
オン、臭素イオン、沃素イオン等のハロゲンイオ
ン；メタンスルホネート（CH3SO3 -）、トリフル
オロメタンスルホネート（CF3SO3 -）、トルエン
スルホネート等のスルホネートイオン；過塩素酸
イオン（ClO4 -）；フルオロボレートイオン
（BF4 -）等を挙げることができる。
上記式［］で表わされるアジリジニウム塩は
公知の方法で製造することができる［例えば
Hetetocyclic compounds：vol.42，part1，
p168，Ed.dy A.Hassner，John Wilbey and
Sons（1983）参照］。
本発明によれば、上記式［］で表わされる
１，４−ジヒドロピリジンカルボン酸と上記式
［］で表わされるアジリジニウム塩とを反応せ
しめることによつて上記式［］で表わされる
１，４−ジヒドロピリジン誘導体を製造すること
ができる。
アジリジニウム塩は強い求核性試薬と反応して
開環反応生成物を与えることが知られている
［D.R.Crist and N.J.Leonard：Angew.Chem
Internat Edit.vol8，p962（1969）参照］が、カル
ボン酸と反応せしめてエステルを生成することは
知られていない。
驚くべきことに、本発明によれば、１，４−ジ
ヒドロピリジンカルボン酸（上記式［］）とア
ジリジニウム塩（上記式［］）とを反応せしめ
ると、三員環が開裂し、１，４−ジヒドロピリジ
ンカルボン酸のエステル（上記式［］）が緩和
な条件下で、しかも高収率で得られた。
アジリジニウム塩の開環する位置は、窒素原子
とそれに隣接する炭素原子の結合間である。
本発明の具体的実施態様は以下のとおりであ
る。
上記式［］で表わされる１，４−ジヒドロピ
リジンカルボン酸（１当量）と上記式［］で表
わされるアジリジニウム塩（1.0ないし2.0当量）
とを塩基の存在下溶媒中で、通常の反応温度すな
わち−20℃ないし200℃、好ましくは−10℃ない
し150℃の範囲で通常の反応時間すなわち48時間
以内、多くは24時間程度反応させることによつて
実施することができる。該塩基としては例えばト
リエチルアミン、ジエチルイソプロピルアミン、
ピリジン等のアミン類；苛性ソーダ、苛性カリ、
炭酸カリ等の無機アルカリ塩類；NaH、KH、
CaH2等の水素化金属；ｎ−BuLi等のアルキル金
属等をアジリジニウム塩に対して１ないし２当量
の範囲内で好ましくは用いることができる。
ここで用いられる溶媒としては、水、メタノー
ル、エタノール等のアルコール類；クロロホル
ム、メチレンクロリド等のハロゲン化炭化水素
類；ベンゼン、トルエン等の炭化水素類；エーテ
ル、テトラヒドロフラン等のエーテル類；ジメチ
ルホルムアミド、ジメチルスルホキシド等の非プ
ロトン性極性溶媒等を好ましく用いることができ
る。
かかる反応を実施した後、目的物の単離・精製
は、通常の操作、例えば、抽出、再結晶、クロマ
トグラフイーなどによつて達成することができ
る。
本発明によつて製造される１，４−ジヒドロピ
リジン誘導体又はその酸付加塩として次のように
例示することができる。
しかし、本発明はこれらに限定されるものでは
ない。
参考例 １
＜１−ベンジル−１−メチルアジリジニウムパ
ークロレート＞
無水クロロホルム（15ml）にチオニルクロリド
（1.66g）をとかし氷冷攪拌下２−（Ｎ−ベンジル
−Ｎ−メチルアミノ）−エタノール（1.60g）のク
ロロホルム（15ml）溶液を滴下した。室温にもど
し２時間攪拌後、更に４時間加熱還流した。
溶媒を減圧下に留去し、残留物にトルエンを加
え減圧留去した。残留物をクロロホルムに溶か
し、アルミナカラムクロマトグラフイーに付し、
クロロホルムで溶出される画分を集めるとＮ−
（２−クロロエチル）−Ｎ−メチルベンジルアミン
（1.23g）が得られた。
Ｎ−（２−クロロエチル）−Ｎ−メチルベンジル
アミン（183mg）を無水アセトン（２mg）に溶か
し、氷冷攪拌下AgClO4（248mg）の無水アセトン
（２ml）溶液を滴下した。
２時間攪拌下、生成した沈澱を瀘別し、濾液の
溶媒を留去し、残渣に無水ベンゼンを加え、析出
する結晶を濾取し、クロロホルム−アセトンより
再沈澱して濾取し、真空下乾燥し目的物（150mg）
を得た。
（物性値）
NMR（Aceton−d6）δppm：
2.70（s.3H）3.52（ｓ，4H），3.76（ｓ，2H），7.2
〜7.8（ｍ，5H）
実施例 １
＜２，６−ジメチル−４−（３−ニトロフエニル）
−１，４−ジヒドロピリジン−3.5−ジカルボン
酸メチル２−（Ｎ−ベンジル−Ｎ−メチルアミノ）
エチル＞
無水テトラヒドロフラン（TNF）（２ml）にア
ルゴン雰囲気下Ｏ℃でNaH（23mg）を加えた。氷
冷攪拌下、２，６−ジメチル−４−（３−ニトロ
フエニル）−１，４−ジヒドロピリジン−３−メ
トキシカルボニル−５−カルボン酸（332mg）の
無水TNF溶液（２ml）を加えた。
30分後、参考例１で得られた１−ベンジル−１
−メチルアジリジニウムパークロレート（271mg）
の無水ジメチルホルムアミド溶液（２ml）を加え
た。室温下１時間攪拌後、１夜加熱還流（浴温80
℃）した。
この反応混合物から減圧下に溶媒を留去し、残
留物に氷水を加え、クロロホルムで抽出した。有
機層を水洗、芒硝乾燥し、溶媒を留去し、残渣を
シリカゲルクロマトグラフイーに付し、ｎ−ヘキ
サン−酢酸エチル（６：４）で溶出される画分を
集めると目的物が得られた。
（物性値）
（塩酸塩）
m.p. 168〜170℃（アセトン）
NMR（DMSO−d6）δppm：
2.21（ｓ，3H），2.36（ｓ，6H）2.66（ｔ，2H），
3.53（ｓ，2H），4.21（ｔ，2H），5.18（ｓ，1H），
6.1（brs，1H），7.2〜8.2（ｍ，9H）
実施例 ２
＜２，６−ジメチル−４−（２−フルオロ−５
−ニトロフエニル）−１，４−ジヒドロピリジ
ン−３，５−ジカルボン酸メチル−２−（Ｎ−
ベンジル−Ｎ−メチルアミノ）エチル＞
実施例１と同様な方法により、２，６−ジメチ
ル−４−（２−フルオロ−５−ニトロフエニル）−
１，４−ジヒドロピリジン−３−メトキシカルボ
ニル−５−カルボン酸と、１−ベンジル−１−メ
チルアジリジニウムパークロレートとを反応せし
めて目的物を得た。
（物性値）
NMR（CDCl3）δppm：
8.26〜7.72（ｍ，2H），7.12（ｓ，5H），6.87（dd，
1H，Ｊ＝９Hz），6.37（ｓ，1H），5.23（ｓ，
1H）4.06（ｔ，2H，Ｊ＝６Hz），3.53（ｓ，
3H），3.40（ｓ，2H），2.55（ｔ，2H，Ｊ＝６
Hz），2.26（ｓ，6H），2.12（ｓ，3H）
実施例 ３
＜２，６−ジメチル−４−（３−クロロ−２−
フルオロフエニル）１，４−ジヒドロピリジン
−３，５−ジカルボン酸メチル２−（Ｎ−ベン
ジル−Ｎ−メチルアミノ）エチル＞
２，６−ジメチル−４−（３−クロロ−２−フ
ルオロフエニル）−１，４−ジヒドロピリジン−
３−メトキシカルボニル−５−カルボン酸と、１
−ベンジル−１−メチルアジリジニウムパークロ
レートとを反応せしめて実施例１として目的物を
得た。
（物性値）
NMR（CDCl3）δppm：
2.15（ss，3H），2.26（ｓ，6H），2.60（ｔ，2H），
3.47（ｓ，2H），3.58（ｓ，3H），4.13（ｔ，2H），
5.24（ｓ，1H），5.99（brs，1H），6.85〜7.27
（ｍ，8H）[In the formula, X, Y, Z, R 1 , R 2 and R 3 are the same as defined in the above formulas [] and []. ] This is a method for producing a 1,4-dihydropyridine derivative represented by the following. The 1,4-dihydropyridine derivative provided by the production method of the present invention has a structural feature of being a carboxylic acid ester having a substituted phenyl group at the 4-position and an N-disubstituted aminoethyl group at the 5-position. According to the present invention, in the 1,4-dihydropyridinecarboxylic acid represented by the above formula [],
X, Y, and Z are the same or different and each represents a hydrogen atom; for example, a halogen atom such as a fluorine atom or a chlorine atom; a trifluoromethyl group; or a nitro group; is not affected. R 1 is an alkyl group, methyl, ethyl, n
Lower alkyl groups such as -propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl are preferred. The 1,4-dihydropyridinecarboxylic acid represented by the above formula [] can be produced by a known method. For example, a manufacturing method thereof is disclosed in Japanese Patent Application Laid-open No. 161263/1983. In the aziridinium salt represented by the above formula [], R 2 is an alkyl group, such as methyl,
Examples include C1 to C4 lower alkyl groups such as ethyl, n-propyl, isopropyl, and n-butyl. R 3 represents an alkyl group or a substituted or unsubstituted aralkyl group. Examples of the alkyl group include C1 to C4 lower alkyl groups such as methyl, ethyl, n-propyl, i-propyl, and n-butyl. Examples of the substituted or unsubstituted aralkyl group include a substituted or unsubstituted benzyl group, a substituted or unsubstituted phenethyl group, and the like. Examples of substituents on the phenyl group include a halogen atom, a lower alkyl group, a lower alkyloxy group, an amino group, a nitro group, and a lower alkyloxycarbonyl group. L represents an anionic residue, such as a halogen ion such as a chloride ion, a bromide ion, or an iodide ion; a sulfonate such as methanesulfonate (CH 3 SO 3 - ), trifluoromethanesulfonate (CF 3 SO 3 - ), toluenesulfonate, etc. Ions; perchlorate ion (ClO 4 - ); fluoroborate ion (BF 4 - ), etc. can be mentioned. The aziridinium salt represented by the above formula [] can be produced by a known method [e.g.
Hetetocyclic compounds: vol. 42 , part1,
p168, Ed.dy A.Hassner, John Wilbey and
See Sons (1983)]. According to the present invention, the 1,4-dihydropyridine carboxylic acid represented by the above formula [] is reacted with the aziridinium salt represented by the above formula [], thereby producing 1,4-dihydropyridine represented by the above formula []. Derivatives can be produced. Aziridinium salts are known to react with strong nucleophiles to give ring-opening reaction products [DRCrist and NJLeonard: Angew.Chem
[see Internat Edit. vol. 8, p. 962 (1969)] is not known to react with carboxylic acids to produce esters. Surprisingly, according to the present invention, when 1,4-dihydropyridinecarboxylic acid (formula [] above) and aziridinium salt (formula [] above) are reacted, the three-membered ring is cleaved and the 1,4- An ester of dihydropyridinecarboxylic acid (formula [] above) was obtained under mild conditions and in high yield. The ring opening position of the aziridinium salt is between the bond between the nitrogen atom and the adjacent carbon atom. Specific embodiments of the present invention are as follows. 1,4-dihydropyridinecarboxylic acid (1 equivalent) represented by the above formula [] and an aziridinium salt (1.0 to 2.0 equivalent) represented by the above formula []
and in a solvent in the presence of a base at a normal reaction temperature, i.e., -20°C to 200°C, preferably -10°C to 150°C, and a normal reaction time, i.e., within 48 hours, often about 24 hours. It can be carried out by Examples of the base include triethylamine, diethylisopropylamine,
Amines such as pyridine; caustic soda, caustic potash,
Inorganic alkali salts such as potassium carbonate; NaH, KH,
Hydrogenation metals such as CaH 2 and alkyl metals such as n-BuLi can preferably be used in an amount of 1 to 2 equivalents relative to the aziridinium salt. Solvents used here include water, alcohols such as methanol and ethanol; halogenated hydrocarbons such as chloroform and methylene chloride; hydrocarbons such as benzene and toluene; ethers such as ether and tetrahydrofuran; dimethylformamide, Aprotic polar solvents such as dimethyl sulfoxide can be preferably used. After carrying out such a reaction, isolation and purification of the target product can be achieved by conventional operations such as extraction, recrystallization, chromatography, etc. The 1,4-dihydropyridine derivatives or acid addition salts thereof produced according to the present invention can be exemplified as follows. However, the present invention is not limited thereto. Reference Example 1 <1-Benzyl-1-methylaziridinium perchlorate> Thionyl chloride (1.66 g) was dissolved in anhydrous chloroform (15 ml) and 2-(N-benzyl-N-methylamino)-ethanol ( A solution of 1.60 g) in chloroform (15 ml) was added dropwise. After returning to room temperature and stirring for 2 hours, the mixture was further heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the mixture was distilled off under reduced pressure. The residue was dissolved in chloroform and subjected to alumina column chromatography.
When the fractions eluted with chloroform are collected, N-
(2-chloroethyl)-N-methylbenzylamine (1.23 g) was obtained. N-(2-chloroethyl)-N-methylbenzylamine (183 mg) was dissolved in anhydrous acetone (2 mg), and a solution of AgClO 4 (248 mg) in anhydrous acetone (2 ml) was added dropwise with stirring under ice cooling. While stirring for 2 hours, the formed precipitate was filtered, the solvent of the filtrate was distilled off, anhydrous benzene was added to the residue, the precipitated crystals were collected by filtration, reprecipitated from chloroform-acetone and collected by filtration, and the mixture was filtered under vacuum. Dried target substance (150mg)
I got it. (Physical property values) NMR (Aceton-d 6 ) δppm: 2.70 (s.3H) 3.52 (s, 4H), 3.76 (s, 2H), 7.2
~7.8 (m, 5H) Example 1 <2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3.5-dicarboxylic acid methyl 2-(N-benzyl-N-methylamino)
Ethyl> NaH (23 mg) was added to anhydrous tetrahydrofuran (TNF) (2 ml) at O 0 C under an argon atmosphere. Anhydrous TNF solution (2 ml) of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-methoxycarbonyl-5-carboxylic acid (332 mg) was added under ice-cooling and stirring. After 30 minutes, 1-benzyl-1 obtained in Reference Example 1
-Methylaziridinium perchlorate (271mg)
Anhydrous dimethylformamide solution (2 ml) was added. After stirring at room temperature for 1 hour, heat under reflux overnight (bath temperature 80°C).
℃). The solvent was distilled off from the reaction mixture under reduced pressure, ice water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water, dried with Glauber's salt, the solvent was distilled off, the residue was subjected to silica gel chromatography, and the desired product was obtained by collecting the fractions eluted with n-hexane-ethyl acetate (6:4). Ta. (Physical property values) (Hydrochloride) mp 168-170℃ (acetone) NMR (DMSO-d 6 ) δppm: 2.21 (s, 3H), 2.36 (s, 6H) 2.66 (t, 2H),
3.53 (s, 2H), 4.21 (t, 2H), 5.18 (s, 1H),
6.1 (brs, 1H), 7.2-8.2 (m, 9H) Example 2 <2,6-dimethyl-4-(2-fluoro-5
-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate-2-(N-
Benzyl-N-methylamino)ethyl> 2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-
The desired product was obtained by reacting 1,4-dihydropyridine-3-methoxycarbonyl-5-carboxylic acid with 1-benzyl-1-methylaziridinium perchlorate. (Physical property values) NMR (CDCl 3 ) δppm: 8.26 to 7.72 (m, 2H), 7.12 (s, 5H), 6.87 (dd,
1H, J=9Hz), 6.37 (s, 1H), 5.23 (s,
1H) 4.06 (t, 2H, J=6Hz), 3.53 (s,
3H), 3.40 (s, 2H), 2.55 (t, 2H, J=6
Hz), 2.26 (s, 6H), 2.12 (s, 3H) Example 3 <2,6-dimethyl-4-(3-chloro-2-
2-(N-benzyl-N-methylamino)ethyl> 2,6-dimethyl-4-(3-chloro-2-fluorophenyl) 1,4-dihydropyridine-3,5-dicarboxylate methyl -1,4-dihydropyridine-
3-methoxycarbonyl-5-carboxylic acid and 1
-benzyl-1-methylaziridinium perchlorate to obtain the desired product as Example 1. (Physical property values) NMR (CDCl 3 ) δppm: 2.15 (ss, 3H), 2.26 (s, 6H), 2.60 (t, 2H),
3.47 (s, 2H), 3.58 (s, 3H), 4.13 (t, 2H),
5.24 (s, 1H), 5.99 (brs, 1H), 6.85-7.27
(m, 8H)
Claims (1)
びＺは同一若しくは異なつて、水素原子、ハロゲ
ン原子、トリフルオロメチル基又はニトロ基を表
わす。但し、Ｘ、Ｙ、Ｚが同時に水素原子を表わ
すことはない。〕 で表わされる１，４−ジヒドロピリジンカルボン
酸と、下記式［］、 【化】 〔式中、R2はアルキル基、R3はアルキル基又
は置換若しくは非置換のアラルキル基を表わし、
Ｌ は陰イオン残基を表わす。〕 で表わされるアジリジニウム塩とを反応させるこ
とを特徴とする下記式［］、 【化】 〔式中、Ｘ、Ｙ、Ｚ、R1，R2及びR3は前記式
［］及び［］の定義と同じ。〕 で表わされる１，４−ジヒドロピリジン誘導体又
はその酸付加塩の製造法。[Claims] 1 The following formula [ ], [In the formula, R 1 represents an alkyl group, and X, Y and Z are the same or different and each represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a nitro represents a group. However, X, Y, and Z do not represent hydrogen atoms at the same time. ] 1,4-dihydropyridinecarboxylic acid represented by the following formula [ ], [Formula, R 2 represents an alkyl group, R 3 represents an alkyl group or a substituted or unsubstituted aralkyl group,
L represents an anionic residue. ] [In the formula, X, Y, Z, R 1 , R 2 and R 3 are the above formulas [] and [] Same as definition. ] A method for producing a 1,4-dihydropyridine derivative or an acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18362687A JPS6429358A (en) | 1987-07-24 | 1987-07-24 | Production of 1,4-dihydropyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18362687A JPS6429358A (en) | 1987-07-24 | 1987-07-24 | Production of 1,4-dihydropyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6429358A JPS6429358A (en) | 1989-01-31 |
| JPH0575743B2 true JPH0575743B2 (en) | 1993-10-21 |
Family
ID=16139063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18362687A Granted JPS6429358A (en) | 1987-07-24 | 1987-07-24 | Production of 1,4-dihydropyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6429358A (en) |
-
1987
- 1987-07-24 JP JP18362687A patent/JPS6429358A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6429358A (en) | 1989-01-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0153016B1 (en) | Asymmetrical diesters of 1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid | |
| US5438145A (en) | Process for the preparation of amlodipine benzenesulphonate | |
| UA57722C2 (en) | A process for preparing the salt of 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate and benzosulpho-acid (bezylate amlodipine) | |
| EP0599220B1 (en) | A process for the preparation of amlodipine benzenesulphonate | |
| JP3764386B2 (en) | Method for producing amlodipine benzenesulfonate | |
| JPS6025423B2 (en) | Method for producing 1,4-dihydropyridine | |
| JPH0575743B2 (en) | ||
| EP0063359B1 (en) | 1,4-dihydropyridine derivatives and processes for preparing the same | |
| US4579859A (en) | Vasodilating trinitratoalkyl esters of 2-cyano-1,4-dihydropyridines | |
| US4769465A (en) | Process for the preparation of 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride salt | |
| KR940005016B1 (en) | 1,4-dihydropyridine derivatives | |
| US4419518A (en) | 1,4-Dihydropyridine derivatives | |
| KR930001404B1 (en) | Process for preparing diaryl compounds | |
| JP2552905B2 (en) | N-[(2-oxo-1-pyrrolidinyl) acetyl] piperazine derivative, method for producing the same and senile dementia drug | |
| JPH0527624B2 (en) | ||
| US6207834B1 (en) | Process for producing piperidinecarboxylic acid amide derivatives | |
| EP0079740B1 (en) | Anthraniloyloxyalkanoates | |
| JPH03502688A (en) | Novel 2,3-thiomorpholinedione-2-oxime derivatives, pharmaceutical compositions containing the derivatives, and methods for producing the derivatives | |
| JP3891500B2 (en) | Novel highly selective process for the preparation of enantiomerically pure phenyl-substituted 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives | |
| JPS6323193B2 (en) | ||
| PT88869B (en) | PROCESS FOR THE PREPARATION OF NEW PYRROLIDINES | |
| EP0522176A1 (en) | Dihydropyridine compounds, and process for their preparation | |
| JPH02149562A (en) | Production of 1,4-dihydropyridine derivative using phase-transfer catalyst | |
| JPH03173869A (en) | Preparation of dihydropyridine compound | |
| JPH072774A (en) | Dihydropyridine derivative, its production, medicine composition containing the same and use of the same derivative for producing therapeutic agent for hypertension |