JP5463051B2 - Method for producing 1,4-dihydropyridine derivative - Google Patents
Method for producing 1,4-dihydropyridine derivative Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims description 16
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title description 56
- 239000002904 solvent Substances 0.000 claims description 75
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 30
- -1 3-nitrophenyl Chemical group 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 238000002844 melting Methods 0.000 claims description 19
- 230000008018 melting Effects 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 15
- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 claims description 14
- KSZOTXZFYCRWQK-UHFFFAOYSA-N propan-2-yl 2-[(3-nitrophenyl)methylidene]-3-oxobutanoate Chemical compound CC(C)OC(=O)C(C(C)=O)=CC1=CC=CC([N+]([O-])=O)=C1 KSZOTXZFYCRWQK-UHFFFAOYSA-N 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- DCGRISOXIFQLPD-UHFFFAOYSA-N acetic acid;(1-benzhydrylazetidin-3-yl) 3-amino-3-iminopropanoate Chemical compound CC(O)=O.C1C(OC(=O)CC(=N)N)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 DCGRISOXIFQLPD-UHFFFAOYSA-N 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 6
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002334 glycols Chemical class 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims 2
- 239000013078 crystal Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000004811 liquid chromatography Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- GYVCPOZJKBWGLB-UHFFFAOYSA-N acetic acid;(1-benzhydrylazetidin-3-yl) 3,3-diaminoprop-2-enoate Chemical compound CC(O)=O.C1C(OC(=O)C=C(N)N)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 GYVCPOZJKBWGLB-UHFFFAOYSA-N 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000004807 desolvation Methods 0.000 description 4
- 238000005187 foaming Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 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
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- GVIIRWAJDFKJMJ-UHFFFAOYSA-N propan-2-yl 3-oxobutanoate Chemical compound CC(C)OC(=O)CC(C)=O GVIIRWAJDFKJMJ-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、融点１２０〜１２４℃を有する[２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル]（以下、ジヒドロピリジン誘導体と称する）の製造法、特にその単離方法に関するものである。ジヒドロピリジン誘導体は、高血圧症、狭心症等の循環系疾病を治療する医薬として有用である（例えば、特許文献１参照）。 The present invention relates to [2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazeti] having a melting point of 120 to 124 ° C. The present invention relates to a method for producing din-3-yl) ester 5-isopropyl ester] (hereinafter referred to as dihydropyridine derivative), and in particular to a method for isolating the same. The dihydropyridine derivative is useful as a medicine for treating circulatory diseases such as hypertension and angina (see, for example, Patent Document 1).
従来のジヒドロピリジン誘導体は、例えば特許文献１の実施例１に記載された方法に準じて製造される。すなわち、２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステルとアミジノ酢酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩を反応させた後、得られた粗ジヒドロピリジン誘導体をシリカゲルカラムで単離し、次いで、ベンゼン−ｎ−ヘキサンから再結晶することによりジヒドロピリジン誘導体を得ている。しかしながら、この方法はカラム単離を用いており、工業的製造にするには満足する方法ではなかった。また、目的の融点を有する結晶を得るためにベンゼンを用いており安全性の面からも問題があった。また、特許文献２の実施例１に記載された方法に準じて製造されるメタノール付加体は空気中で変質する性質があり安定性に問題があった。 A conventional dihydropyridine derivative is produced according to the method described in Example 1 of Patent Document 1, for example. That is, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester and amidinoacetic acid (1-diphenylmethylazetidin-3-yl) ester acetate were reacted, and then the obtained crude dihydropyridine derivative was isolated on a silica gel column. Then, the dihydropyridine derivative is obtained by recrystallization from benzene-n-hexane. However, this method uses column isolation and is not a satisfactory method for industrial production. In addition, benzene is used to obtain crystals having the target melting point, and there is a problem in terms of safety. In addition, the methanol adduct produced according to the method described in Example 1 of Patent Document 2 has a property of deteriorating in air and has a problem in stability.
本発明は、ジヒドロピリジン誘導体を工業的に有利に製造することを課題とするものである。 This invention makes it a subject to manufacture a dihydropyridine derivative advantageously industrially.
本発明の課題は、２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステルとアミジノ酢酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩を反応させてジヒドロピリジン誘導体を製造する方法において、反応終了後、得られた粗ジヒドロピリジン誘導体をグリコール類、メタノールを除くアルコール類又はジオキサンで再結晶し、ジヒドロピリジン誘導体・溶媒付加体を得た後、必要によりさらに再結晶して精製し、付加した溶媒を酢酸エチルと水の混合溶媒で撹拌、洗浄して除き、アセトン等に溶解させ、シクロヘキサン、メチルシクロヘキサン、ヘプタン、ヘキサン等の有機貧溶媒中に加えるか、またはジヒドロピリジン誘導体・溶媒付加体から溶媒をシクロヘキサン、メチルシクロヘキサン、ヘプタン、ヘキサン等の有機貧溶媒との共沸により除去することを特徴とするジヒドロピリジン誘導体の製造法によって達成される。グリコール類とは、例えばエチレングリコール、プロピレングリコ−ル、プロピレングリコールモノメチルエーテル等である。 An object of the present invention is to provide a method for producing a dihydropyridine derivative by reacting 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester with amidinoacetic acid (1-diphenylmethylazetidin-3-yl) ester acetate. Thereafter, the obtained crude dihydropyridine derivative was recrystallized with glycols, alcohols excluding methanol or dioxane to obtain a dihydropyridine derivative / solvent adduct, and then recrystallized and purified as necessary. Stir in a mixed solvent of ethyl and water, wash and remove, dissolve in acetone, etc., add to an organic poor solvent such as cyclohexane, methylcyclohexane, heptane, hexane or cyclohexane, solvent from dihydropyridine derivative / solvent adduct Methylcyclohexane, heptane, hex It is achieved by the preparation of dihydropyridine derivatives, which comprises removing by azeotropy with an organic poor solvent emissions, and the like. Examples of glycols include ethylene glycol, propylene glycol, and propylene glycol monomethyl ether.
本発明者らは、公知法に替わるジヒドロピリジン誘導体の製造方法、特に単離、精製法について各種の有機溶媒（炭化水素類、ニトリル類、ケトン類、アルコール類、エーテル類、エステル類）を用いて鋭意検討した結果、粗ジヒドロピリジン誘導体に特定の溶媒を加えると、ジヒドロピリジン誘導体のみが溶媒を包接し、ジヒドロピリジン誘導体・溶媒付加体として結晶化することを見い出した。さらに純度を向上させたい場合は付加した溶媒で再結晶を繰り返せばよい。また、付加した溶媒がエチレングリコール、プロピレングリコールの場合は、ジヒドロピリジン誘導体・溶媒付加体がエチレングリコール、プロピレングリコールに溶け難いのでエタノール、イソプロピルアルコールを共存させてもよい。すなわち、粗ジヒドロピリジン誘導体の特定の溶媒による再結晶は、純度、取得率において非常に大きい精製効果をもたらすものである。 The present inventors use various organic solvents (hydrocarbons, nitriles, ketones, alcohols, ethers, esters) for the production method of dihydropyridine derivatives instead of known methods, particularly for isolation and purification methods. As a result of intensive studies, it was found that when a specific solvent was added to the crude dihydropyridine derivative, only the dihydropyridine derivative included the solvent and crystallized as a dihydropyridine derivative / solvent adduct. In order to further improve the purity, recrystallization should be repeated with the added solvent. When the added solvent is ethylene glycol or propylene glycol, the dihydropyridine derivative / solvent adduct is difficult to dissolve in ethylene glycol or propylene glycol, so ethanol and isopropyl alcohol may coexist. That is, recrystallization of the crude dihydropyridine derivative with a specific solvent brings about a very large purification effect in purity and acquisition rate.
さらに、本発明者らは、エチレングリコール、プロピレングリコールが付加したジヒドロピリジン誘導体・溶媒付加体の脱溶媒方法について検討した結果、ジヒドロピリジン誘導体・溶媒付加体を酢酸エチル等の水に難溶性の有機溶媒に溶解、水洗して溶媒付加体から付加している溶媒を除き、アセトン等に溶解後、有機貧溶媒中に加えると融点１２０〜１２４℃を有するジヒドロピリジン誘導体を容易に得ることを見出した。また、ジヒドロピリジン誘導体・溶媒付加体をシクロヘキサン中で共沸留去することでも同様に溶媒付加体から容易に溶媒は除去され、融点１２０〜１２４℃を有するジヒドロピリジン誘導体を高純度・高収率で与えることを見出した。 Furthermore, as a result of studying the desolvation method of dihydropyridine derivatives / solvent adducts to which ethylene glycol or propylene glycol has been added, the present inventors have found that dihydropyridine derivatives / solvent adducts have been made into water-insoluble organic solvents such as ethyl acetate. It has been found that a dihydropyridine derivative having a melting point of 120 to 124 ° C. can be easily obtained by dissolving and washing with water, removing the solvent added from the solvent adduct, dissolving in acetone, and then adding it to an organic poor solvent. Similarly, the azeotropic distillation of the dihydropyridine derivative / solvent adduct in cyclohexane can easily remove the solvent from the solvent adduct, giving a dihydropyridine derivative having a melting point of 120 to 124 ° C. with high purity and high yield. I found out.
本発明によれば、医薬として有用なジヒドロピリジン誘導体を工業的に簡便な方法により、高純度、高収率で得ることができる。 According to the present invention, a dihydropyridine derivative useful as a medicine can be obtained with high purity and high yield by an industrially simple method.
以下に本発明を詳しく説明する。本発明は、例えば反応式（１）によって示すことができる。
本発明の製法における、原料である２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステル（Ｉ）は、例えば、Ｏｒｇ．Ｒｅａｃｔｉｏｎｓ，１５巻、２０４頁（１９６７年）に記載の方法に準じて、３−ニトロベンズアルデヒドとアセト酢酸イソプロピルエステルから脱水縮合させることにより合成される。 In the production method of the present invention, 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester (I), which is a raw material, is described in, for example, Org. According to the method described in Reactions, Vol. 15, p. 204 (1967), the compound is synthesized by dehydration condensation from 3-nitrobenzaldehyde and isopropyl acetoacetate.
本発明の製法における、一方の原料であるアミジノ酢酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩（ＩＩ）は、特開昭６３−２５３０８２号公報に示される方法によって合成される。アミジノ酢酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩は、２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステル１モルに対して、通常０．８〜１．２モル、好ましくは１モルの割合で使用する。 One raw material, amidinoacetic acid (1-diphenylmethylazetidin-3-yl) ester acetate (II), in the production method of the present invention is synthesized by the method disclosed in JP-A-63-253082. Amidinoacetic acid (1-diphenylmethylazetidin-3-yl) ester acetate is usually 0.8 to 1.2 mol, preferably 1 to 1 mol of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester. Used in molar proportions.
本発明の製法において使用される溶媒としては、例えばメタノ−ル、エタノ−ル、イソプロパノ−ル、ｔｅｒｔ−ブタノ−ル等のアルコ−ルを挙げることができるが、イソプロパノ−ルの使用が好ましい。溶媒は、２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステル１モルに対して、通常１〜１０Ｌの量で使用する。 Examples of the solvent used in the production method of the present invention include alcohols such as methanol, ethanol, isopropanol, and tert-butanol. Use of isopropanol is preferred. The solvent is usually used in an amount of 1 to 10 L with respect to 1 mol of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester.
本発明の製法における反応は、原料であるアミジノ酢酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩をフリ−化するための塩基を加えなくても進行するが、反応を速やかに完結させるためには、塩基を使用することが好ましい。塩基としては、例えばナトリウムメチラ−ト、ナトリウムエチラ−ト、ナトリウムイソプロピラ−ト等のアルコラ−ト及び水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基を挙げることができるが、特に、無機塩基の使用が反応収率、取得物純度の面において好ましい。塩基は、２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステル１モルに対して、通常０．５〜１．０倍モルの割合で使用する。 The reaction in the production method of the present invention proceeds without adding a base for freezing the starting material amidinoacetic acid (1-diphenylmethylazetidin-3-yl) ester acetate, but the reaction is completed quickly. For this purpose, it is preferable to use a base. Examples of the base include alcohols such as sodium methylate, sodium ethylate and sodium isopropylate, and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. In particular, the use of an inorganic base is preferable in terms of reaction yield and acquired product purity. The base is usually used at a ratio of 0.5 to 1.0 mole per mole of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester.
本発明の製法における反応温度としては、通常５０℃〜使用溶媒の沸点の範囲が有利であり、反応時間は、反応温度等によって異なるが、通常０．５〜５時間である。
反応終了後、粗ジヒドロピリジン誘導体までは反応混合物を常法に従って、例えば、濃縮、抽出、洗浄、乾燥等の処理をすることによって容易に得ることができる。
The reaction temperature in the production method of the present invention is usually in the range of 50 ° C. to the boiling point of the solvent used, and the reaction time is usually 0.5 to 5 hours, although it varies depending on the reaction temperature and the like.
After completion of the reaction, the reaction mixture can be easily obtained up to the crude dihydropyridine derivative according to a conventional method, for example, by treatment such as concentration, extraction, washing and drying.
以下に、粗ジヒドロピリジン誘導体からジヒドロピリジン誘導体・溶媒付加体を取得する工程（工程（１））について説明する。工程（１）は、（ａ） 粗ジヒドロピリジン誘導体を溶媒による結晶化により、粗ジヒドロピリジン誘導体・溶媒付加体を得る工程と、(ｂ)粗ジヒドロピリジン誘導体・溶媒付加体を、さらに溶媒中で再結晶して精製する工程とからなっている。 Below, the process (process (1)) which acquires a dihydropyridine derivative and a solvent adduct from a crude dihydropyridine derivative is demonstrated. In step (1), (a) a crude dihydropyridine derivative / solvent adduct is obtained by crystallization of the crude dihydropyridine derivative with a solvent, and (b) the crude dihydropyridine derivative / solvent adduct is recrystallized in a solvent. And the process of refining.
(ａ)粗ジヒドロピリジン誘導体・溶媒付加体工程
溶媒は、２−（３―ニトロベンジリデン）アセト酢酸イソプロピルエステル１モルに対して、通常１〜５Ｌ、好ましくは１．８〜３．５Ｌの量で使用する。溶媒としてはグリコール類、メタノールを除くアルコール類又はジオキサンを用いる。
結晶化は、通常、所定量の溶媒を加え、室温付近で約１時間撹拌するか、または加熱し、６０〜６５℃で約１時間撹拌した後、冷却し、５〜１０℃で約１時間撹拌することで実施される。得られた粗ジヒドロピリジン誘導体・溶媒付加体は、濾取した後、乾燥せずに次の再結晶化工程に移ることが好ましい。
(a) Crude dihydropyridine derivative / solvent adduct step The solvent is usually used in an amount of 1 to 5 L, preferably 1.8 to 3.5 L, relative to 1 mol of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester. To do. As the solvent, glycols, alcohols excluding methanol or dioxane are used.
Crystallization is usually carried out by adding a predetermined amount of solvent and stirring at about room temperature for about 1 hour or heating, stirring at 60 to 65 ° C. for about 1 hour, cooling, and cooling at 5 to 10 ° C. for about 1 hour. It is carried out by stirring. The obtained crude dihydropyridine derivative / solvent adduct is preferably filtered and then transferred to the next recrystallization step without drying.
(ｂ) 粗ジヒドロピリジン誘導体・溶媒付加体再結晶工程
前記の粗ジヒドロピリジン誘導体・溶媒付加体工程で得られた湿潤状態の粗ジヒドロピリジン誘導体・溶媒付加体１重量部に対して、付加体を製造するときに用いた溶媒を通常２〜１５倍容量、好ましくは２〜５倍容量使用する。粗ジヒドロピリジン誘導体・溶媒付加体の溶媒がエチレングリコール、プロピレングリコールの場合、粗ジヒドロピリジン誘導体・溶媒付加体がエチレングリコール、プロピレングリコールに溶解し難いためエタノール、イソプロピルアルコールを共存させてもかまわない。この場合、粗ジヒドロピリジン誘導体・溶媒付加体１重量部に対して、エタノール、イソプロピルアルコールを通常１〜１０倍容量、好ましくは２〜５倍容量使用する。再結晶化は、通常、所定量の溶媒を加え加熱し、６０〜６５℃で撹拌溶解した後、約６０℃で熱時濾過し、次いで、その濾液を冷却し、５〜１０℃で約１時間撹拌することで実施される。純度が９９．９％に達しない場合は再結晶を繰り返すことにより達成される。
(b) Crude dihydropyridine derivative / solvent adduct recrystallization step When an adduct is produced with respect to 1 part by weight of the crude dihydropyridine derivative / solvent adduct obtained in the crude dihydropyridine derivative / solvent adduct step. The solvent used in is usually used in a volume of 2 to 15 times, preferably 2 to 5 times. When the solvent of the crude dihydropyridine derivative / solvent adduct is ethylene glycol or propylene glycol, the crude dihydropyridine derivative / solvent adduct is difficult to dissolve in ethylene glycol or propylene glycol, and ethanol or isopropyl alcohol may coexist. In this case, ethanol and isopropyl alcohol are usually used in an amount of 1 to 10 times, preferably 2 to 5 times the volume of 1 part by weight of the crude dihydropyridine derivative / solvent adduct. The recrystallization is usually performed by adding a predetermined amount of solvent and heating, stirring and dissolving at 60 to 65 ° C, followed by hot filtration at about 60 ° C, then cooling the filtrate and cooling to about 1 at 5 to 10 ° C. It is carried out by stirring for a time. When the purity does not reach 99.9%, it is achieved by repeating recrystallization.
ジヒドロピリジン誘導体・溶媒付加体は、再結晶化後、濾取、乾燥により得られる。以上により、ジヒドロピリジン誘導体・溶媒付加体は、９９．９％以上の高純度（ＨＰＬＣ面積百分率）で得られる。 The dihydropyridine derivative / solvent adduct is obtained by recrystallization, filtration and drying. As described above, the dihydropyridine derivative / solvent adduct can be obtained with a high purity (HPLC area percentage) of 99.9% or more.
次に、ジヒドロピリジン誘導体・溶媒付加体から脱溶媒により、融点１２０〜１２４℃を有する[２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル]を取得する工程（工程（２））について説明する。例えばエチレングリコールまたはプロピレングリコールが付加したジヒドロピリジン誘導体・溶媒付加体の脱溶媒方法について検討した結果、ジヒドロピリジン誘導体・溶媒付加体を酢酸エチルと混合し、水で洗浄すると付加していた溶媒は水層に移行し、ジヒドロピリジン誘導体は酢酸エチル層に移行する。濃縮後、アセトンに置換してアセトン溶液とし、有機貧溶媒中に加えることにより融点１２０〜１２４℃を有するジヒドロピリジン誘導体を取得することができる。アセトンの使用量は[２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル]・溶媒付加体に対して０．５〜２倍容量で溶解させる。有機貧溶媒の使用量はアセトンに対して５から１００倍、好ましくは１０から５０倍である。ジヒドロピリジン誘導体は、操作終了後、冷却、濾取、乾燥等の常法により得られる。また、エタノール、ｎ−プロパノール、イソプロパノール、ｔｅｒｔ−ブタノール、ジオキサンが付加したジヒドロピリジン誘導体・溶媒付加体の脱溶媒方法について検討した結果、有機貧溶媒中で共沸させることにより除けることを見出した。本工程はジヒドロピリジン誘導体・溶媒付加体が有機貧溶媒に全く溶解しないため、スラリ−状態である。有機貧溶媒は、ジヒドロピリジン誘導体・溶媒付加体１重量部に対して、通常５〜１００倍容量、好ましくは１０〜２０倍容量の量で使用する。下限値より少ない量では、スラリ−濃度が上がり撹拌に負荷がかかる。上限値より多い量を使用することはできるが、それによる利点はない。溶媒を共沸留去させる操作は、加熱下、常圧又は減圧下に行われるが、速やかに溶媒を留去させるには減圧下に行う方が好ましい。有機貧溶媒とはジヒドロピリジン誘導体をほとんど溶解しない溶媒でありシクロヘキサン、メチルシクロヘキサン、ヘキサン、ヘプタン等を表す。 Next, [2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridine having a melting point of 120 to 124 ° C. is removed from the dihydropyridine derivative / solvent adduct by solvent removal. The step of obtaining dicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester] (step (2)) will be described. For example, as a result of examining the desolvation method of dihydropyridine derivatives / solvent adducts added with ethylene glycol or propylene glycol, the dihydropyridine derivatives / solvent adducts were mixed with ethyl acetate and washed with water. The dihydropyridine derivative moves to the ethyl acetate layer. A dihydropyridine derivative having a melting point of 120 to 124 ° C. can be obtained by concentrating, substituting with acetone to obtain an acetone solution, and adding it to an organic poor solvent. The amount of acetone used is [2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) Ester 5-isopropyl ester] / solvent adduct is dissolved in a volume of 0.5 to 2 times. The amount of the organic poor solvent used is 5 to 100 times, preferably 10 to 50 times that of acetone. The dihydropyridine derivative can be obtained by a conventional method such as cooling, filtration and drying after completion of the operation. Moreover, as a result of examining the desolvation method of the dihydropyridine derivative and solvent adduct added with ethanol, n-propanol, isopropanol, tert-butanol, and dioxane, it was found that it can be removed by azeotropic distillation in an organic poor solvent. This step is in a slurry state because the dihydropyridine derivative / solvent adduct is not dissolved in the organic poor solvent at all. The organic poor solvent is usually used in an amount of 5 to 100 times by volume, preferably 10 to 20 times by volume, based on 1 part by weight of the dihydropyridine derivative / solvent adduct. If the amount is less than the lower limit, the slurry concentration increases and a load is applied to stirring. Larger amounts than the upper limit can be used, but there is no advantage. The operation for distilling off the solvent azeotropically is carried out under heating at normal pressure or under reduced pressure, but it is preferred to carry out under reduced pressure in order to distill off the solvent quickly. The organic poor solvent is a solvent that hardly dissolves the dihydropyridine derivative and represents cyclohexane, methylcyclohexane, hexane, heptane, or the like.
この操作により、ジヒドロピリジン誘導体・溶媒付加体から付加していた溶媒は除去され、シクロヘキサンと共沸留去されるが、共沸終了後、さらに有機貧溶媒をその仕込量の１／１０程度留去させる方が好ましい。溶媒及び有機貧溶媒を留去させる反応温度は、通常５０〜７０℃の範囲であり、その温度になるように減圧度を調節する。
反応時間は、反応温度、減圧度などによって異なるが、所定量の留出量になるまで、通常０．５〜５時間である。
このジヒドロピリジン誘導体を取得する工程では、収率は定量的であり、ジヒドロピリジン誘導体の純度低下も認められない。
以下に実施例を示し、ジヒドロピリジン誘導体・溶媒付加体及びその製造法並びに脱溶媒によるジヒドロピリジン誘導体の製造法についてさらに詳しく説明する。
By this operation, the solvent added from the dihydropyridine derivative / solvent adduct is removed and distilled off azeotropically with cyclohexane, but after completion of the azeotropic distillation, the organic poor solvent is further distilled off by about 1/10 of the charged amount. It is preferable to make it. The reaction temperature for distilling off the solvent and the organic poor solvent is usually in the range of 50 to 70 ° C., and the degree of vacuum is adjusted to reach that temperature.
The reaction time varies depending on the reaction temperature, the degree of vacuum, etc., but is usually 0.5 to 5 hours until a predetermined amount of distillate is reached.
In the step of obtaining the dihydropyridine derivative, the yield is quantitative and no decrease in the purity of the dihydropyridine derivative is observed.
The following examples further illustrate the dihydropyridine derivative / solvent adduct, its production process, and the dihydropyridine derivative production process by desolvation.
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・エチレングリコールの製造
１４．５ｇの２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステルと２０．０ｇの３，３−ジアミノアクリル酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩を２００ｍｌのイソプロピルアルコールと混合した。１．５ｇの水酸化ナトリウムを加えて１時間穏やかに還流した。濃縮後、２００ｍｌの酢酸エチルに溶解し、３回水洗した。無水硫酸マグネシウムで乾燥した。濃縮後、１５０ｍｌのエチレングリコールと混合した。５０℃に加温後、室温で撹拌した。析出した結晶を濾取した。収量３８．８ｇ（Ｗｅｔ）、液体クロマトグラフィーでの面積百分率純度は９９．０％であった。この結晶を５０ｍｌのイソプロピルアルコールと混合し、加温して溶解した。１００ｍｌのエチレングリコールを加えて混合した。室温で撹拌して得られた結晶を濾取した。収量３７．０ｇ（Ｗｅｔ）、液体クロマトグラフィーでの面積百分率純度は９９．９％であった。エタノールで洗浄、乾燥後の融点は１２０〜１２３℃であった。
ＩＲ ＫＢｒｃｍ−１ ３４６４、３３２９、１６９８、１６６７、１４９８、１３４７、１２８６、１２０９、１０７９、７９４、７５５、７０７
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of ethylene glycol 14.5 g 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester and 20.0 g 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate Mixed with isopropyl alcohol. 1.5 g of sodium hydroxide was added and gently refluxed for 1 hour. After concentration, it was dissolved in 200 ml of ethyl acetate and washed three times with water. Dried over anhydrous magnesium sulfate. After concentration, it was mixed with 150 ml of ethylene glycol. After heating to 50 ° C., the mixture was stirred at room temperature. The precipitated crystals were collected by filtration. The yield was 38.8 g (Wet), and the area percentage purity by liquid chromatography was 99.0%. The crystals were mixed with 50 ml of isopropyl alcohol and dissolved by heating. 100 ml of ethylene glycol was added and mixed. Crystals obtained by stirring at room temperature were collected by filtration. The yield was 37.0 g (Wet), and the area percentage purity by liquid chromatography was 99.9%. The melting point after washing with ethanol and drying was 120 to 123 ° C.
IR KBrcm -1 3464, 3329, 1698, 1667, 1498, 1347, 1286, 1209, 1079, 794, 755, 707
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・プロピレングリコールの製造
１．０６ｇの[２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル]を１０ｍｌのイソプロピルアルコールに溶解し、濃縮した。プロピレングリコール１０ｍｌを加えて溶解した。室温で撹拌した。析出した結晶を濾過し、エタノールで洗浄して１．０５ｇの結晶を得た。乾燥後の融点は１１３〜１１６℃であった。
ＩＲ ＫＢｒｃｍ−１ ３４６６、３３２２、１６６８、１５２７、１４９９、１３４６、１２２２、１１７２、１１０３、９２９、７６３、７０７
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of propylene glycol 1.06 g of [2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3 -Yl) ester 5-isopropyl ester] was dissolved in 10 ml isopropyl alcohol and concentrated. 10 ml of propylene glycol was added and dissolved. Stir at room temperature. The precipitated crystals were filtered and washed with ethanol to obtain 1.05 g of crystals. The melting point after drying was 113 to 116 ° C.
IR KBrcm -1 3466, 3322, 1668, 1527, 1499, 1346, 1222, 1172, 1103, 929, 763, 707
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・エタノールの製造
１７．８ｇの２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステルと２４．６ｇの３，３−ジアミノアクリル酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩を２００ｍｌのイソプロピルアルコールと混合した。２．４ｇの水酸化ナトリウムを加えて１時間穏やかに還流した。濃縮後、２００ｍｌの酢酸エチルに溶解し、３回水洗した。無水硫酸マグネシウムで乾燥した。濃縮後、７０ｍｌのエタノールと混合し、加温して溶解した。室温で撹拌すると結晶が析出した。氷水で冷却し、濾取、乾燥した。収量３０．９ｇ、液体クロマトグラフィーでの面積百分率純度は９８．６％であった。この結晶を５０ｍｌのエタノールから再結晶してエタノール付加体２７．６ｇを得た。液体クロマトグラフィーでの面積百分率純度は９９．９％であった。融点は１０７〜１０９℃（発泡）であった。
ＩＲ ＫＢｒｃｍ−１ ３３２０、１６６０、１５３０、１４８０、１３５０、１２２０、１１１０、１０７０、１０３０、７９０、７５０、７１０
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of ethanol 17.8 g 2- (3-Nitrobenzylidene) acetoacetic acid isopropyl ester and 24.6 g 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate in 200 ml isopropyl Mixed with alcohol. 2.4 g of sodium hydroxide was added and refluxed gently for 1 hour. After concentration, it was dissolved in 200 ml of ethyl acetate and washed three times with water. Dried over anhydrous magnesium sulfate. After concentration, it was mixed with 70 ml of ethanol and dissolved by heating. Crystals precipitated upon stirring at room temperature. The mixture was cooled with ice water, filtered and dried. The yield was 30.9 g, and the area percentage purity by liquid chromatography was 98.6%. This crystal was recrystallized from 50 ml of ethanol to obtain 27.6 g of an ethanol adduct. The area percentage purity by liquid chromatography was 99.9%. The melting point was 107-109 ° C. (foaming).
IR KBrcm -1 3320, 1660, 1530, 1480, 1350, 1220, 1110, 1070, 1030, 790, 750, 710
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・ｔｅｒｔ−ブタノールの製造
３．６２ｇの２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステルと５．０ｇの３，３−ジアミノアクリル酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩を５０ｍｌのイソプロピルアルコールと混合した。０．３３ｇの水酸化ナトリウムを加えて１．５時間穏やかに還流した。濃縮後、５０ｍｌの酢酸エチルに溶解し、３回水洗した。無水硫酸マグネシウムで乾燥した。濃縮後、３０ｍｌのｔｅｒｔ−ブタノールと混合し、加温して溶解した。室温で撹拌すると結晶が析出した。氷水で冷却し、濾取、乾燥した。収量７．０ｇ、液体クロマトグラフィーでの面積百分率純度は９５．９％であった。この結晶を１０ｍｌのエタノールと４０ｍｌのｔｅｒｔ−ブタノールの混合溶媒に加温して溶解した。室温で撹拌すると結晶が析出した。氷水で冷却し、濾取、乾燥した。収量６．３８ｇ、液体クロマトグラフィーでの面積百分率純度は９９．５％。であった。融点は１２６〜１２９℃（発泡）であった。
ＩＲ ＫＢｒｃｍ−１ ３４４５、３３２９、１６７６、１４９２、１３４９、１２１６、１０２６、９０６、８０１、７５０、７０３、６９４
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of tert-butanol 50 ml of 3.62 g of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester and 5.0 g of 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate Of isopropyl alcohol. 0.33 g of sodium hydroxide was added and refluxed gently for 1.5 hours. After concentration, it was dissolved in 50 ml of ethyl acetate and washed three times with water. Dried over anhydrous magnesium sulfate. After concentration, it was mixed with 30 ml of tert-butanol and heated to dissolve. Crystals precipitated upon stirring at room temperature. The mixture was cooled with ice water, filtered and dried. The yield was 7.0 g, and the area percentage purity by liquid chromatography was 95.9%. The crystals were dissolved by heating in a mixed solvent of 10 ml of ethanol and 40 ml of tert-butanol. Crystals precipitated upon stirring at room temperature. The mixture was cooled with ice water, filtered and dried. Yield 6.38 g, area percentage purity by liquid chromatography 99.5%. Met. The melting point was 126 to 129 ° C. (foaming).
IR KBrcm -1 3445, 3329, 1676, 1492, 1349, 1216, 1026, 906, 801, 750, 703, 694
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・１，４−ジオキサンの製造
３．６２ｇの２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステルと５．０ｇの３，３−ジアミノアクリル酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩を５０ｍｌのイソプロピルアルコールと混合した。０．３３ｇの水酸化ナトリウムを加えて１．５時間穏やかに還流した。濃縮後、５０ｍｌの酢酸エチルに溶解し、３回水洗した。無水硫酸マグネシウムで乾燥した。濃縮後、３０ｍｌの１，４−ジオキサンと混合し、加温して溶解した。室温で撹拌すると結晶が析出した。氷水で冷却し、濾取、乾燥した。収量５．８ｇ、液体クロマトグラフィーでの面積百分率純度は９８．２％であった。融点は１２７〜１３１℃（発泡）であった。
ＩＲ ＫＢｒｃｍ−１ １７００、１６６０、１５３０、１４９０、１３５０、１２１０、１１２０、１０８０、８７０、７５０、７１０、５２０
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of 1,4-dioxane 3.62 g of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester and 5.0 g of 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate Was mixed with 50 ml of isopropyl alcohol. 0.33 g of sodium hydroxide was added and refluxed gently for 1.5 hours. After concentration, it was dissolved in 50 ml of ethyl acetate and washed three times with water. Dried over anhydrous magnesium sulfate. After concentration, it was mixed with 30 ml of 1,4-dioxane and dissolved by heating. Crystals precipitated upon stirring at room temperature. The mixture was cooled with ice water, filtered and dried. The yield was 5.8 g, and the area percentage purity by liquid chromatography was 98.2%. The melting point was 127 to 131 ° C. (foaming).
IR KBrcm -1 1700, 1660, 1530, 1490, 1350, 1210, 1120, 1080, 870, 750, 710, 520
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・イソプロピルアルコールの製造
３．６２ｇの２−（３−ニトロベンジリデン）アセト酢酸イソプロピルエステルと５．０ｇの３，３−ジアミノアクリル酸（１−ジフェニルメチルアゼチジン−３−イル）エステル酢酸塩を５０ｍｌのイソプロピルアルコールと混合した。０．３５ｇの水酸化ナトリウムを加えて２時間穏やかに還流した。濃縮後、５０ｍｌの酢酸エチルに溶解し、３回水洗した。無水硫酸マグネシウムで乾燥した。濃縮後、２０ｍｌのイソプロピルアルコールと混合し、加温して溶解した。室温で撹拌すると結晶が析出した。氷水で冷却し、濾取、乾燥した。収量４．７ｇ、液体クロマトグラフィーでの面積百分率純度は９８．７％。この結晶を１０ｍｌのイソプロピルアルコールから再結晶して３．５ｇを得た。液体クロマトグラフィーでの面積百分率純度は９９．９％であった。融点は１１０〜１１２℃（発泡）であった。
ＩＲ ＫＢｒｃｍ−１ １６７０、１５３０、１４８０、１３５０、１２２０、１１１０、１０３０、８３０、７９０、７５０、７１０、５２０
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of isopropyl alcohol 50 ml of 3.62 g of 2- (3-nitrobenzylidene) acetoacetic acid isopropyl ester and 5.0 g of 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate Mixed with isopropyl alcohol. 0.35 g of sodium hydroxide was added and gently refluxed for 2 hours. After concentration, it was dissolved in 50 ml of ethyl acetate and washed three times with water. Dried over anhydrous magnesium sulfate. After concentration, it was mixed with 20 ml of isopropyl alcohol and heated to dissolve. Crystals precipitated upon stirring at room temperature. The mixture was cooled with ice water, filtered and dried. Yield 4.7 g, area percentage purity by liquid chromatography 98.7%. This crystal was recrystallized from 10 ml of isopropyl alcohol to obtain 3.5 g. The area percentage purity by liquid chromatography was 99.9%. The melting point was 110 to 112 ° C. (foaming).
IR KBrcm -1 1670, 1530, 1480, 1350, 1220, 1110, 1030, 830, 790, 750, 710, 520
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・プロピレングリコールモノメチルエーテルの製造
１．１３ｇの[２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル]を１０ｍｌのプロピレングリコールモノメチルエーテルに溶解し、濃縮した。室温で撹拌した。析出した結晶を濾過、乾燥して０．５８ｇの結晶を得た。乾燥後の融点は１１３〜１１５℃であった。
ＩＲ ＫＢｒｃｍ−１ ３３０８、２９７７、１６６３、１５２７、１４８１、１３４８、１２８５、１１０５、７９４、７５３、７０６、５１６
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of propylene glycol monomethyl ether 1.13 g of [2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine -3-yl) ester 5-isopropyl ester] was dissolved in 10 ml of propylene glycol monomethyl ether and concentrated. Stir at room temperature. The precipitated crystals were filtered and dried to obtain 0.58 g of crystals. The melting point after drying was 113 to 115 ° C.
IR KBrcm -1 3308, 2977, 1663, 1527, 1481, 1348, 1285, 1105, 794, 753, 706, 516
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル・ｎ−プロピルアルコールの製造
１．００ｇの[２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステル]を１０ｍｌのｎ−プロピルアルコールに溶解し、少し濃縮した。室温で撹拌した。析出した結晶を濾過、乾燥して０．７３ｇの結晶を得た。乾燥後の融点は１１０〜１１６℃であった。
ＩＲ ＫＢｒｃｍ−１ １６６０、１５２０、１４８０、１３５０、１２２０、１１００、１０７０、９１０、８３０、７５０、７１０、５２０
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Preparation of n-propyl alcohol 1.00 g of [2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine -3-yl) ester 5-isopropyl ester] was dissolved in 10 ml n-propyl alcohol and concentrated slightly. Stir at room temperature. The precipitated crystals were filtered and dried to obtain 0.73 g of crystals. The melting point after drying was 110 to 116 ° C.
IR KBrcm -1 1660, 1520, 1480, 1350, 1220, 1100, 1070, 910, 830, 750, 710, 520
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステルの製造
実施例１で得られたエチレングリコール付加体１３４ｇを４００ｍｌの酢酸エチルと１００ｍｌの水と混合した。撹拌して溶解させた。水層を除き、水で２回洗浄した。有機層を無水硫酸マグネシウムで乾燥した。酢酸エチルを濃縮後、アセトン１００ｍｌに溶解した。濃縮後、さらにアセトン５０ｍｌに溶解し、濃縮した。残留物をアセトン５０ｍｌに溶解した。シクロヘキサン９００ｍｌを激しく撹拌し、先のアセトン溶液を３時間かけて滴下した。さらに４時間撹拌した。析出した結晶を濾取、５％のアセトンを含むシクロヘキサンで洗浄した。乾燥して融点１２０〜１２４℃の黄色粉末を８８．９ｇ得た。
ＩＲ ＫＢｒｃｍ−１ ３４４９、３３１７、１６８２、１６５１、１５２３、１４８８、１３４７、１２２４、１０２９、７９５、７４３、７０４
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Production 134 g of the ethylene glycol adduct obtained in Example 1 was mixed with 400 ml of ethyl acetate and 100 ml of water. Stir to dissolve. The aqueous layer was removed and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate. The ethyl acetate was concentrated and dissolved in 100 ml of acetone. After concentration, it was further dissolved in 50 ml of acetone and concentrated. The residue was dissolved in 50 ml of acetone. 900 ml of cyclohexane was vigorously stirred, and the previous acetone solution was added dropwise over 3 hours. The mixture was further stirred for 4 hours. The precipitated crystals were collected by filtration and washed with cyclohexane containing 5% acetone. By drying, 88.9 g of yellow powder having a melting point of 120 to 124 ° C. was obtained.
IR KBrcm -1 3449, 3317, 1682, 1651, 1523, 1488, 1347, 1224, 1029, 795, 743, 704
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステルの製造
実施例３で得たエタノール付加体４．７ｇを５０ｍｌのシクロヘキサンと混合した。６０℃に加温し、減圧にして留去した。冷後、濾取、シクロヘキサンで洗浄した。乾燥して融点１２０〜１２４℃の黄色粉末を４．０５ｇ得た。
ＩＲ ＫＢｒｃｍ−１ １６６０、１５２０、１４８０、１３５０、１２２０、１１００、１０７０、９１０、８３０、７５０、７１０、５２０
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Production 4.7 g of the ethanol adduct obtained in Example 3 was mixed with 50 ml of cyclohexane. The mixture was heated to 60 ° C. and evaporated under reduced pressure. After cooling, it was collected by filtration and washed with cyclohexane. Drying gave 4.05 g of a yellow powder with a melting point of 120-124 ° C.
IR KBrcm -1 1660, 1520, 1480, 1350, 1220, 1100, 1070, 910, 830, 750, 710, 520
２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）―３，５−ピリジンジカルボン酸 ３−（１−ジフェニルメチルアゼチジン−３−イル）エステル ５−イソプロピルエステルの製造
実施例４で得られたｔｅｒｔ−ブタノール付加体２．０ｇを２５ｍｌのシクロヘキサンと混合した。６０℃に加温し、減圧にして留去した。冷後、濾取、シクロヘキサンで洗浄した。融点１２０〜１２４℃の黄色粉末を１．６９ｇ得た。
ＩＲ ＫＢｒｃｍ−１ １６６０、１５２０、１４８０、１３５０、１２２０、１１００、１０７０、９１０、８３０、７５０、７１０、５２０
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Production 2.0 g of the tert-butanol adduct obtained in Example 4 was mixed with 25 ml of cyclohexane. The mixture was heated to 60 ° C. and evaporated under reduced pressure. After cooling, it was collected by filtration and washed with cyclohexane. 1.69 g of a yellow powder having a melting point of 120 to 124 ° C. was obtained.
IR KBrcm -1 1660, 1520, 1480, 1350, 1220, 1100, 1070, 910, 830, 750, 710, 520
本発明は医薬として有用なジヒドロピリジン誘導体の工業的製造方法として有用である。 The present invention is useful as an industrial production method of dihydropyridine derivatives useful as pharmaceuticals.
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| JP2011006379A (en) * | 2009-05-26 | 2011-01-13 | Tokuyama Corp | Method for recrystallizing {2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-3-[1-(diphenylmethyl)azetidin-3-yl]ester-5-isopropyl ester}(azelnidipine), isopropyl alcohol adduct of azelnidipine, and method for producing azelnidipine |
| JP2012020970A (en) * | 2010-07-15 | 2012-02-02 | Tokuyama Corp | Method for producing {3-(1-diphenylmethylazetidin-3-yl)ester-5-isopropyl ester 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate} |
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| US4772596A (en) * | 1986-10-09 | 1988-09-20 | Sankyo Company Limited | Dihydropyridine derivatives, their preparation and their use |
| JPH05230023A (en) * | 1990-10-05 | 1993-09-07 | Teikoku Chem Ind Corp Ltd | 1,4-dihydropyridine derivative, its production and use thereof |
| JP3491506B2 (en) * | 1997-10-14 | 2004-01-26 | 宇部興産株式会社 | Method for producing dihydropyridine derivative |
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| JP7575758B2 (en) | 2021-05-20 | 2024-10-30 | 妙中パイル織物株式会社 | Rectangular pile fabric, support member, and manufacturing method thereof |
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