JPH0544956B2 - - Google Patents
Info
- Publication number
- JPH0544956B2 JPH0544956B2 JP268788A JP268788A JPH0544956B2 JP H0544956 B2 JPH0544956 B2 JP H0544956B2 JP 268788 A JP268788 A JP 268788A JP 268788 A JP268788 A JP 268788A JP H0544956 B2 JPH0544956 B2 JP H0544956B2
- Authority
- JP
- Japan
- Prior art keywords
- represented
- present
- general formula
- alkyl
- reaction
- 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
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000008065 acid anhydrides Chemical class 0.000 claims description 7
- 150000002466 imines Chemical class 0.000 claims description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- JZZIEZSCFDWFFU-UHFFFAOYSA-N CC(COP(O)=O)=O Chemical class CC(COP(O)=O)=O JZZIEZSCFDWFFU-UHFFFAOYSA-N 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 11
- 238000000034 method Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 5
- -1 benzylidene acetonyl phosphonate derivatives Chemical class 0.000 description 5
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 4
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 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
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- LJODSGRIXRUPTG-UHFFFAOYSA-N 1,4-dihydropyridin-3-ylphosphonic acid Chemical class OP(O)(=O)C1=CNC=CC1 LJODSGRIXRUPTG-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- BWHOZHOGCMHOBV-UHFFFAOYSA-N benzylideneacetone Chemical class CC(=O)C=CC1=CC=CC=C1 BWHOZHOGCMHOBV-UHFFFAOYSA-N 0.000 description 2
- 230000002213 calciumantagonistic effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003218 coronary vasodilator agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 1
- ISLWZBTUAHMAND-UHFFFAOYSA-N 1,3,2-dioxaphosphinan-2-ium 2-oxide Chemical compound O=[P+]1OCCCO1 ISLWZBTUAHMAND-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- MVKRYQSHFZQQQD-UHFFFAOYSA-N 4-(2-nitrophenyl)-3-(2-oxo-1,3,2$l^{5}-dioxaphosphinan-2-yl)but-3-en-2-one Chemical compound O1CCCOP1(=O)C(C(=O)C)=CC1=CC=CC=C1[N+]([O-])=O MVKRYQSHFZQQQD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
（産業上の利用分野）
本発明は、強いカルシウム拮抗性の降圧作用と
冠血管拡張作用を有する１，４−ジヒドロピリジ
ン−５−ホスホネート誘導体を製造するための中
間体として有用な化合物の製造法に関する。
更に詳しくは、本発明は、次の一般式〔〕
で表されるアセトニルホスホネート類と、次の一
般式〔〕
で表されるイミン化合物とを、有機溶媒中で、
（R5CO）2Oで表される酸無水物の存在下に、加熱
縮合することを特徴とする、次の一般式〔〕
で表されるホスホネート誘導体の製造法に関す
る。
式中、R1はアルキル又はアルケニルを表し、
は、環状を形成してもよいことを表しており、更
に環状を形成するときはR1…R1は炭素数が２〜
５であつてそのうちの１以上の炭素はアルキルに
より置換されていてもよい。
R2、R3は、水素、ニトロ、トリフルオロメチ
ル、ハロゲン、又はジフルオロメトキシを表す。
R4は、アルキル又はアラルキルを表す。
R5は、アルキル、ハロアルキル又はフエニル
を表す。
本発明に係る化合物〔〕は、医薬品として有
用な１，４−ジヒドロピリジン−５−ホスホネー
ト誘導体〔特開昭59−161392号公報。Chem.
Pharm.B.ll.35，3898（1987）〕及び、５−環状ホ
スホネート誘導体〔特開昭60−248693号公報。
Chem.Pharm.Bull.35，4144（1987）。Arzneim.
Forsch.，36，1329，1336（1986）。〕に誘導するこ
とができる。これら化合物は、強いカルジウム拮
抗性降圧作用と冠血管拡張作用を有し、高血圧
症、狭心症等の治療剤として有用であることが判
つている。
従つて、本発明は医薬品として有用な化合物の
製造原料を従来法よりも極めて有利に提供するも
のである。
（従来の技術）
従来、本発明に係る一般式〔〕で表される１
−ベンジリデンアセトニルホスホネート誘導体の
製造法として、ホスホネート化合物〔〕とベン
ツアルデヒド類とのクネーベナーゲル
（Knoevenagel）縮合による方法が知られている
（前記文献）。
しかしながら、この反応においては同時にホー
ナー−エモンス（Horner−Emmons）反応
〔Chem.Rev.，74，87（1974）〕が起こり、ベンザ
ルアセトン類が副生して純度と収率の低下を招い
ている。特に環状のホスホネート化合物について
は収率が低い。そのため、純度、収率以外に精製
法についても問題点を含んでおり、工業的生産規
模を考えると著しく不利であつた。
（発明が解決しようとする問題点）
そこで本発明者らは上記欠点を克服する目的で
ホーナー−エモンス反応を起こさないクネーベナ
ーゲル縮合反応を確立することを目指し、高純度
で高収率な本発明化合物〔〕を取得する方法に
ついて鋭意検討を重ねた結果、以下に記載する本
発明に到達した。
（問題点を解決するための手段）
本発明の要旨は、原料物質としてイミン誘導体
〔〕を用いるところにある。
このイミン誘導体〔〕とホスホネート誘導体
〔〕とをクネーベナーゲル縮合することにより、
副反応のホーナー−エモンス反応を起こさずに目
的化合物を取得することができる事実を見出して
本発明は完成されたものである。
以下に本発明を詳細に説明する。
本発明に出発原料として用いるアセトニルホス
ホネート化合物〔〕は、公知化合物であり、公
知の方法によりホスフアイトとハロアセトンとの
反応によつて得ることができる。
〔〕におけるR1で表されるアルキルは、炭
素数１〜６の直鎖又は分枝状のものであつて、例
えば、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、ｎ−ペンチル、
イソペンチル、ｎ−ヘキシル、イソヘキシル等を
挙げることができる。
アルケニルとしては、炭素数３〜５のものが好
ましく、例えば、アリル、イソプロペニル、２−
メタリル、２−ブテニル、３−ブテニル等を挙げ
ることができる。
が、環状を形成するときには、R1…R1は炭素数
２〜５のアルキレンであつてそのうちの炭素は低
級アルキルにより置換されていてもよい。とりわ
け、炭素数が３であつて１〜数個のメチルで置換
されているものが好ましい。
もう一つの出発原料である〔〕は、置換ベン
ツアルデヒドと一級アミン類（R4−NH2）とを
常法により脱水縮合して容易に定量的に得ること
ができ、単離精製することなく縮合物をそのまま
次の反応に用いることができる。
〔〕において、R2、R3として示されるハロ
ゲンとしては、塩素、臭素、フツ素、ヨウ素を挙
げることができる。とりわけ、塩素が好ましい。
R2、R3の置換位置は、フエニル基のオルト位又
はメタ位が好ましく、ジ置換体の場合も両位置が
好ましい。
R4におけるアルキルとしては、炭素数１〜６
のアルキルを挙げることができ、前記にR1の例
として例示したものと同様のものを挙げることが
できる。R4のアラルキルとしては、炭素数７〜
９のものがよく、例えば、ベンジル、フエネチ
ル、フエニルプロピル等を挙げることができる。
とりわけベンジルが好ましい。
本発明の実施にあたつては、〔〕と〔〕と
を適当な溶媒中、酸無水物の存在下に縮合させ
る。この縮合は、通常〔〕を〔〕に対して１
〜２倍当量過剰に用い、使用する酸無水物も
〔〕に対して１〜４倍当量用いるのがよい。
酸無水物として用いる（R5CO）2Oで示される
化合物におけるR5としては、炭素数１〜３の低
級アルキル、ハロゲン化アルキル、又は置換若し
くは無置換のフエニル等を挙げることができる。
とりわけ無水酢酸、無水トリクロル酢酸、無水ト
リフルオロ酢酸等が好ましい。
本発明における溶媒としては、非プロトン性有
機溶媒、例えば、ベンゼン、トルエン、キシレ
ン、アセトニトリル、酢酸エチル、ジオキサン、
テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムア
ミド、ジメトキシエタン、ジエトキシエタン、ク
ロロホルム、トリクロルエチレン等を挙げること
ができる。反応温度は、30〜150℃の間で行うの
がよく、好ましくは60〜120℃で、通常用いる溶
媒の沸点、即ち還流下に反応を行うのが望まし
い。
反応時間は、出発原料、酸無水物、溶媒の種類
やその量及び反応温度によつて異なるが、通常１
〜８時間加熱還流することにより完結する。
本発明において目的化合物は、反応混合物から
濃縮後、有機溶媒による結晶化によつて得られる
が、油状物の場合や結晶であつても、他の通常の
分離精製手段、例えば、抽出、中和、濾過、カラ
ムクロマトグラフイー等の方法によつても単離精
製することができる。
反応混合物中には、ホーナー−エモンス反応成
績体のベンザルアセトンは認められず、目的物の
他はイミン〔〕の合成に用いた一級アミンのＮ
−アシル体が生成したりまた一部原料〔〕の回
収を伴う場合がある。
（実施例）
以下に本発明の実施例を掲げて本発明を更に詳
しく説明する。
実施例 １
２−〔１−（２−ニトロベンジリデン）アセトニ
ル〕−２−オキソ−１，３，２−ジオキサホス
ホリナン
２−ニトロベンツアルデヒド5.89ｇとイソブチ
ルアミン3.42ｇを塩化メチレン20mlに溶解し、２
時間室温で撹拌後、乾操剤（硫酸マグネシウム）
を加えて反応液を乾操し、濾過後濾液を濃縮す
る。残留物（イミン化合物）に２−アセトニル−
２−オキソ−１，３，２−ジオキサホスホリナン
5.34ｇを加え、ベンゼン50mlに溶解し、無水酢酸
6.12ｇを加えて４時間加熱還流する。反応液を減
圧下に濃縮して残留物にエーテルを加えて結晶化
し、目的化合物6.34ｇ（収率68％）を得た。
融点140〜146℃。
元素分析値（C13H14NO6P）
計算値(%) Ｃ：50.17 Ｈ：4.53 Ｎ：4.50
実測値(%) Ｃ：50.21 Ｈ：4.58 Ｎ：4.50
IRνKBr nax：cm-1：1700，1575，1350，1270，1070
NMR：（CDCl3）δ：1.90〜2.04（1H，ｍ），2.20
〜2.45〔1H，ｍと3H，ｓ（2.32と2.61），Ｅ／Ｚ
体：10／１〕，4.10〜4.25と4.48〜4.65（4H，
ｍ），7.23〜7.28（1H，ｍ），7.57〜7.73（2H，
ｍ），7.90（1H，ｄ，Ｊ＝24Hz），8.22〜8.27
（1H，ｍ）
同様にして、以下の化合物を得た。
(Industrial Application Field) The present invention relates to a method for producing a compound useful as an intermediate for producing a 1,4-dihydropyridine-5-phosphonate derivative having strong calcium antagonistic hypotensive action and coronary vasodilator action. . More specifically, the present invention relates to the following general formula [] Acetonyl phosphonates represented by and the following general formula [] and an imine compound represented by, in an organic solvent,
The following general formula [] is characterized by thermal condensation in the presence of an acid anhydride represented by (R 5 CO) 2 O. The present invention relates to a method for producing a phosphonate derivative represented by: In the formula, R 1 represents alkyl or alkenyl, indicates that a ring may be formed, and when forming a ring, R 1 ...R 1 has 2 to 2 carbon atoms.
5, one or more carbons of which may be substituted with alkyl. R 2 and R 3 represent hydrogen, nitro, trifluoromethyl, halogen, or difluoromethoxy. R 4 represents alkyl or aralkyl. R 5 represents alkyl, haloalkyl or phenyl. The compound [ ] according to the present invention is a 1,4-dihydropyridine-5-phosphonate derivative useful as a pharmaceutical [JP-A-59-161392]. Chem.
Pharm.B.ll. 35 , 3898 (1987)] and 5-cyclic phosphonate derivatives [JP-A-60-248693.
Chem.Pharm.Bull. 35 , 4144 (1987). Arzneim.
Forsch., 36 , 1329, 1336 (1986). ]. These compounds have strong calcium antagonistic hypotensive action and coronary vasodilator action, and are known to be useful as therapeutic agents for hypertension, angina pectoris, and the like. Therefore, the present invention provides raw materials for producing compounds useful as pharmaceuticals more advantageously than conventional methods. (Prior art) Conventionally, 1 expressed by the general formula [ ] according to the present invention
- As a method for producing benzylidene acetonyl phosphonate derivatives, a method using Knoevenagel condensation of a phosphonate compound [] and a benzaldehyde is known (see the above-mentioned document). However, in this reaction, the Horner-Emmons reaction [Chem.Rev., 74 , 87 (1974)] occurs at the same time, and benzalacetones are produced as by-products, resulting in a decrease in purity and yield. There is. In particular, the yield is low for cyclic phosphonate compounds. Therefore, in addition to purity and yield, there are also problems with the purification method, which is extremely disadvantageous when considering the scale of industrial production. (Problems to be Solved by the Invention) Therefore, in order to overcome the above-mentioned drawbacks, the present inventors aimed to establish a Knoevenagel condensation reaction that does not cause the Horner-Emmons reaction. As a result of intensive studies on the method of obtaining [], we have arrived at the present invention described below. (Means for Solving the Problems) The gist of the present invention is to use an imine derivative [ ] as a raw material. By performing Knoevenagel condensation of this imine derivative [] and phosphonate derivative [],
The present invention was completed by discovering the fact that the target compound can be obtained without causing the Horner-Emmons reaction, which is a side reaction. The present invention will be explained in detail below. The acetonylphosphonate compound [ ] used as a starting material in the present invention is a known compound, and can be obtained by a known method by reacting a phosphite with a haloacetone. The alkyl represented by R 1 in [] is a straight chain or branched one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n- pentyl,
Isopentyl, n-hexyl, isohexyl and the like can be mentioned. The alkenyl preferably has 3 to 5 carbon atoms, such as allyl, isopropenyl, 2-
Examples include methallyl, 2-butenyl, 3-butenyl, and the like. However, when forming a ring, R 1 ...R 1 is alkylene having 2 to 5 carbon atoms, and one of the carbon atoms may be substituted with lower alkyl. Particularly preferred are those having 3 carbon atoms and substituted with 1 to several methyl groups. Another starting material, [ ], can be easily obtained quantitatively by dehydration condensation of substituted benzaldehyde and primary amines (R 4 -NH 2 ) by a conventional method, without isolation and purification. The condensate can be used as it is in the next reaction. In [], examples of the halogens represented by R 2 and R 3 include chlorine, bromine, fluorine, and iodine. Particularly preferred is chlorine.
The substitution position of R 2 and R 3 is preferably the ortho position or meta position of the phenyl group, and in the case of a di-substituted product, both positions are preferred. Alkyl in R 4 has 1 to 6 carbon atoms.
The same alkyl groups as those exemplified above as examples of R 1 can be mentioned. As aralkyl of R 4 , carbon number is 7 to
9 is preferred, and examples thereof include benzyl, phenethyl, phenylpropyl and the like.
Particularly preferred is benzyl. In carrying out the present invention, [] and [] are condensed in a suitable solvent in the presence of an acid anhydride. This condensation usually converts [ ] to [ ] to 1
It is preferable to use the acid anhydride in excess of 2 to 2 equivalents, and to use 1 to 4 equivalents of the acid anhydride. Examples of R 5 in the compound represented by (R 5 CO) 2 O used as an acid anhydride include lower alkyl having 1 to 3 carbon atoms, halogenated alkyl, substituted or unsubstituted phenyl, and the like.
Particularly preferred are acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, and the like. Solvents used in the present invention include aprotic organic solvents such as benzene, toluene, xylene, acetonitrile, ethyl acetate, dioxane,
Tetrahydrofuran, N,N-dimethylformamide, dimethoxyethane, diethoxyethane, chloroform, trichloroethylene and the like can be mentioned. The reaction temperature is preferably 30 to 150°C, preferably 60 to 120°C, and it is desirable to carry out the reaction at the boiling point of the commonly used solvent, that is, under reflux. The reaction time varies depending on the starting materials, acid anhydride, type and amount of solvent, and reaction temperature, but is usually 1.
Complete by heating to reflux for ~8 hours. In the present invention, the target compound can be obtained by concentrating the reaction mixture and then crystallizing it with an organic solvent, but even if it is an oil or crystal, it can be obtained by other conventional separation and purification methods such as extraction, neutralization, etc. It can also be isolated and purified by methods such as filtration, column chromatography, etc. In the reaction mixture, benzalacetone, a Horner-Emmons reaction product, was not observed, and other than the target product, N of the primary amine used in the synthesis of imine [] was found.
- Acyl bodies may be produced or some raw materials may have to be recovered. (Example) The present invention will be described in more detail below with reference to Examples of the present invention. Example 1 2-[1-(2-nitrobenzylidene)acetonyl]-2-oxo-1,3,2-dioxaphosphorinane 5.89 g of 2-nitrobenzaldehyde and 3.42 g of isobutylamine were dissolved in 20 ml of methylene chloride. ,2
After stirring at room temperature for an hour, drying agent (magnesium sulfate)
is added to dry the reaction solution, and after filtration, the filtrate is concentrated. 2-acetonyl- in the residue (imine compound)
2-oxo-1,3,2-dioxaphosphorinane
Add 5.34g, dissolve in 50ml of benzene, and add acetic anhydride.
Add 6.12g and heat under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was crystallized by adding ether to obtain 6.34 g (yield: 68%) of the target compound. Melting point 140-146℃. Elemental analysis value (C 13 H 14 NO 6 P) Calculated value (%) C: 50.17 H: 4.53 N: 4.50 Actual value (%) C: 50.21 H: 4.58 N: 4.50 IRν KBr nax : cm -1 : 1700, 1575, 1350, 1270, 1070 NMR: ( CDCl3 ) δ: 1.90-2.04 (1H, m), 2.20
~2.45 [1H, m and 3H, s (2.32 and 2.61), E/Z
Body: 10/1], 4.10~4.25 and 4.48~4.65 (4H,
m), 7.23-7.28 (1H, m), 7.57-7.73 (2H,
m), 7.90 (1H, d, J = 24Hz), 8.22-8.27
(1H, m) In the same manner, the following compound was obtained.
【表】
（発明の効果）
本発明の方法の確立により、極めて高収率、高
純度で目的化合物を製造することができる。即
ち、文献記載のベンツアルデヒドを用いるクネー
ベナーゲル縮合反応によるものに比べ、約２〜４
倍の収率を示した。また副反応が起こらず、純度
が高く精製が容易で、工業的製造法としてし極め
て有用である。[Table] (Effects of the Invention) By establishing the method of the present invention, the target compound can be produced with extremely high yield and high purity. That is, compared to the Knoevenagel condensation reaction using benzaldehyde described in the literature, about 2 to 4
It showed twice the yield. Further, it does not cause side reactions, has high purity, and is easy to purify, making it extremely useful as an industrial production method.
Claims (1)
般式〔〕 で表されるイミン化合物とを、有機溶媒中で、
（R5CO）2Oで表される酸無水物の存在下に、加熱
縮合することを特徴とする、次の一般式〔〕 で表されるホスホネート誘導体の製造法。 式中、R1はアルキル又はアルケニルを表し、 は、環状を形成してもよいことを表しており、更
に環状を形成するときはR1…R1は炭素数が２〜
５であつてそのうちの１以上の炭素はアルキルに
より置換されていてもよい。 R2、R3は、水素、ニトロ、トリフルオロメチ
ル、ハロゲン、又はジフルオロメトキシを表す。 R4は、アルキル又はアラルキルを表す。 R5は、アルキル、ハロアルキル又はフエニル
を表す。[Claims] First-order general formula [] Acetonyl phosphonates represented by and the following general formula [] and an imine compound represented by, in an organic solvent,
The following general formula [] is characterized by thermal condensation in the presence of an acid anhydride represented by (R 5 CO) 2 O. A method for producing a phosphonate derivative represented by In the formula, R 1 represents alkyl or alkenyl, indicates that a ring may be formed, and when forming a ring, R 1 ...R 1 has 2 to 2 carbon atoms.
5, one or more carbons of which may be substituted with alkyl. R 2 and R 3 represent hydrogen, nitro, trifluoromethyl, halogen, or difluoromethoxy. R 4 represents alkyl or aralkyl. R 5 represents alkyl, haloalkyl or phenyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP268788A JPH01180890A (en) | 1988-01-08 | 1988-01-08 | Phosphonate derivative and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP268788A JPH01180890A (en) | 1988-01-08 | 1988-01-08 | Phosphonate derivative and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01180890A JPH01180890A (en) | 1989-07-18 |
| JPH0544956B2 true JPH0544956B2 (en) | 1993-07-07 |
Family
ID=11536198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP268788A Granted JPH01180890A (en) | 1988-01-08 | 1988-01-08 | Phosphonate derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01180890A (en) |
-
1988
- 1988-01-08 JP JP268788A patent/JPH01180890A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01180890A (en) | 1989-07-18 |
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