JP4031366B2 - アムロジピンの製造方法 - Google Patents
アムロジピンの製造方法 Download PDFInfo
- Publication number
- JP4031366B2 JP4031366B2 JP2002571468A JP2002571468A JP4031366B2 JP 4031366 B2 JP4031366 B2 JP 4031366B2 JP 2002571468 A JP2002571468 A JP 2002571468A JP 2002571468 A JP2002571468 A JP 2002571468A JP 4031366 B2 JP4031366 B2 JP 4031366B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- methyl
- reaction
- amlodipine
- 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 - Fee Related
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
塩素−含有産物は後続のアミン置換反応において非反応性であるため、これに対応するヨード誘導体にあらかじめ転換されなければならない。このようなハロゲン誘導体を用いても、アムロジピンの総収率は22%、またはその以下である。
式(II)のピロール誘導体は新規化合物であり、本発明を実施するにおいて、R1とR2はメチルであることが好ましい。式(II)のピロール誘導体は、[J. Chem. Soc., Perkin Trans. I, 2801,(1984)]に開示された方法に従って高収率で製造でき、下記反応式7に示すように、アミン基がピロールの形態に保護される。
本発明の方法は、ピロール基が強塩基の存在下でも高収率で、たとえば、90%の収率で置換反応を可能にするということに長所がある。そのような塩基条件は一般的なアミン保護基が用いられない。また、前記ピロール基は隣接するエステル保護基に影響を与えなく、ヒドロキシルアミンの作用によってアミンに容易に転換できる。
アミノエタノール30.5g(0.5mol)、アセトニルアセトン57g(0.5mol)および酢酸0.35g(5mmol,触媒量)をトルエン300mlに加えた後、ディーンスターク(Dean-stark)トラップを用いて3時間還流した。反応混合物を室温に冷却し、水200mlと酢酸エチル100mlを加え、30分間撹拌した。有機層をシリカゲルパッド(pad)に通して濾過した後、濾液を減圧蒸留して淡黄色の標題化合物66g(収率:95%)を得た。
テトラヒドロフラン500ml溶液に水素化ナトリウム32g(60%油分散液)を加え、製造例1で得られた2−(2,5−ジメチルピロール−1−イル)エタノール56g(0.4mol)を加えた後室温で1時間撹拌した。反応混合物を0℃に冷却し、これにエチル4−クロロアセトアセテート65.84g(0.4mol)をテトラヒドロフラン200mlに溶かした溶液を2時間にわたって滴加した。混合物を室温で16時間撹拌した後、3N塩酸でpHを6〜7に調整した。これに十分な量の水を加え、残った固体沈殿物を溶解し、酢酸エチル600mlと100mlとで2回抽出した。合わせた酢酸エチル抽出物を無水硫酸マグネシウム上で乾燥し、カーボン処理して脱色した後、減圧蒸留して溶媒を除去して淡黄色油状の標題化合物96.2g(収率:90%)を得た。
(段階a)3−エチル−5−メチル−2−[(2−(2,5−ジメチルピロール−1−イル)エトキシ)−メチル]−4−(2−クロロフェニル)−6−メチル−1,4−ジヒドロ−3,5−ピリジンジカルボキシレートの製造
製造例2で得られたエチル4−[2−(2,5−ジメチルピロール−1−イル)エトキシ]アセトアセテート11.4g(42.6mmol)、2−クロロベンズアルデヒド6g(42.6mmol)およびメチル3−アミノクロトネート4.9g(42.6mmol)をイソプロパノール100mlに加えた後、この混合物を20時間還流した。反応混合物を室温に冷却した後、減圧濃縮して溶媒を除去した。残滓をカラムクロマトグラフィーで精製して淡黄色結晶の標題化合物11g(収率:53%)を得た。
Mass: m/z= 509.11(M+Na)+, 485.94(M+H)+
1H-NMR(300MHz, CDCl3)δ(ppm):7.07〜7.36(m,4H), 6.65(b,1H,NH), 5.86(s,2H), 5.40(s,1H), 4.73(s,2H), 4.03〜4.11(m,4H), 3.74(t,2H, J=5.4Hz), 3.64(s,3H), 2.31(s,6H), 2.27(s,3H), 1.24(t,3H, J=7.1Hz)
IR(KBr): 3377, 2977, 2945, 1692, 1480, 1433, 1305cm-1。
段階1で得られた3−エチル−5−メチル−2−[(2−(2,5−ジチルピロール−1−イル)エトキシ)−メチル]−4−(2−クロロフェニル)−6−メチル−1,4−ジヒドロ−3,5−ピリジンジカルボキシレート7.9g(16.2mmol)、ヒドロキシルアミンヒドロクロリド22.6g(324mmol,20eq)およびトリエチルアミン16.4g(162mmol,10eq)をイソプロパノール60mlと水15mlの混合溶媒に添加した後4.5時間還流した。反応混合物を室温に冷却した後減圧蒸留してイソプロパノールを除去した。残滓に水100mlを加えた後、3N HClでpHを1〜2に調整した後、エチルエーテル50mlで2回洗浄した。水層を1N NaOH水溶液でpHを8〜9に調整した後酢酸エチル100mlで2回抽出した。有機層を飽和塩水で洗浄した後無水硫酸マグネシウムで脱水し、減圧蒸留して溶媒を除去した。残滓をカラムクロマトグラフィーで精製して淡黄色泡(foam)状の標題化合物5.1g(収率:77%)を得た。
Claims (5)
- 段階(a)が有機溶媒中で式(II)の化合物、アミノクロトネートおよび2−クロロベンズアルデヒド0.9〜1.2:1:1モル比の混合物を還流して行われる請求項1に記載の方法。
- 段階(b)が式(V)の化合物に対して15〜25当量比のヒドロキシルアミンヒドロクロリドの存在下で式(V)の化合物を還流して行われる請求項1に記載の方法。
- 段階(b)が式(V)の化合物に対して10当量比の量のトリエチルアミンの存在下で行われる請求項1に記載の方法。
- R1およびR2がメチルである請求項2記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2001-0012858A KR100374767B1 (ko) | 2001-03-13 | 2001-03-13 | 개선된 암로디핀의 제조 방법 |
PCT/KR2002/000434 WO2002072552A1 (en) | 2001-03-13 | 2002-03-13 | Method for preparing amlodipine |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2004523572A JP2004523572A (ja) | 2004-08-05 |
JP4031366B2 true JP4031366B2 (ja) | 2008-01-09 |
Family
ID=19706839
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002571468A Expired - Fee Related JP4031366B2 (ja) | 2001-03-13 | 2002-03-13 | アムロジピンの製造方法 |
Country Status (9)
Country | Link |
---|---|
US (1) | US6492523B2 (ja) |
EP (1) | EP1368315B1 (ja) |
JP (1) | JP4031366B2 (ja) |
KR (1) | KR100374767B1 (ja) |
CN (1) | CN1229348C (ja) |
AT (1) | ATE375979T1 (ja) |
DE (1) | DE60223003T2 (ja) |
ES (1) | ES2291443T3 (ja) |
WO (1) | WO2002072552A1 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100374767B1 (ko) * | 2001-03-13 | 2003-03-03 | 한미약품공업 주식회사 | 개선된 암로디핀의 제조 방법 |
JP5678438B2 (ja) * | 2010-03-05 | 2015-03-04 | 国立大学法人名古屋大学 | ピロールの製造方法 |
CN102070516A (zh) * | 2011-02-22 | 2011-05-25 | 广东东阳光药业有限公司 | 一种制备氨氯地平的方法 |
CN102659673A (zh) * | 2012-05-07 | 2012-09-12 | 山东新华制药股份有限公司 | 氨氯地平自由碱的制备方法 |
CN103044316A (zh) * | 2013-01-23 | 2013-04-17 | 石家庄学院 | 一种以咪唑离子液体为催化剂制备1,4-二氢吡啶的方法 |
CN115536577B (zh) * | 2022-11-09 | 2024-04-30 | 浙江昂利康制药股份有限公司 | 一种氨氯地平碱的制备方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK161312C (da) * | 1982-03-11 | 1991-12-09 | Pfizer | Analogifremgangsmaade til fremstilling af 2-aminoalkoxymethyl-4-phenyl-6-methyl-1,4-dihydropyridin-3,5-dicarboxylsyreestere eller syreadditionssalte deraf samt phthalimidoderivater til anvendelse som udgangsmateriale ved fremgangsmaaden |
US4515799A (en) * | 1983-02-02 | 1985-05-07 | Pfizer Inc. | Dihydropyridine anti-ischaemic and antihypertensive agents |
US5389654A (en) * | 1992-11-26 | 1995-02-14 | Lek, Tovarna, Farmacevtskih In Kemicnih . . . | 3-ethyl 5-methyl(±)2-[2-(N-tritylamino)ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-6-methyl-3,5-pyridinedicarboxylate |
KR100217240B1 (ko) * | 1996-10-31 | 1999-09-01 | 조생현 | 암로디핀 베실레이트의 제조방법 |
KR200151609Y1 (ko) * | 1996-11-30 | 1999-07-15 | 양재신 | 차량용 컴팩트 디스크 박스 |
CN1297016C (zh) * | 1997-01-09 | 2007-01-24 | 日亚化学工业株式会社 | 氮化物半导体元器件 |
HU221810B1 (hu) * | 1997-08-12 | 2003-01-28 | EGIS Gyógyszergyár Rt. | Eljárás amlodipin-bezilát előállítására és az eljárás intermedierjei |
KR100374767B1 (ko) * | 2001-03-13 | 2003-03-03 | 한미약품공업 주식회사 | 개선된 암로디핀의 제조 방법 |
-
2001
- 2001-03-13 KR KR10-2001-0012858A patent/KR100374767B1/ko not_active IP Right Cessation
-
2002
- 2002-03-11 US US10/095,854 patent/US6492523B2/en not_active Expired - Lifetime
- 2002-03-13 ES ES02705570T patent/ES2291443T3/es not_active Expired - Lifetime
- 2002-03-13 AT AT02705570T patent/ATE375979T1/de not_active IP Right Cessation
- 2002-03-13 CN CNB028063767A patent/CN1229348C/zh not_active Expired - Fee Related
- 2002-03-13 EP EP02705570A patent/EP1368315B1/en not_active Expired - Lifetime
- 2002-03-13 DE DE60223003T patent/DE60223003T2/de not_active Expired - Lifetime
- 2002-03-13 WO PCT/KR2002/000434 patent/WO2002072552A1/en active IP Right Grant
- 2002-03-13 JP JP2002571468A patent/JP4031366B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US20020132834A1 (en) | 2002-09-19 |
DE60223003D1 (de) | 2007-11-29 |
KR100374767B1 (ko) | 2003-03-03 |
DE60223003T2 (de) | 2008-02-07 |
CN1229348C (zh) | 2005-11-30 |
ES2291443T3 (es) | 2008-03-01 |
EP1368315A1 (en) | 2003-12-10 |
WO2002072552A1 (en) | 2002-09-19 |
JP2004523572A (ja) | 2004-08-05 |
EP1368315B1 (en) | 2007-10-17 |
CN1496353A (zh) | 2004-05-12 |
EP1368315A4 (en) | 2005-02-09 |
US6492523B2 (en) | 2002-12-10 |
ATE375979T1 (de) | 2007-11-15 |
KR20020072847A (ko) | 2002-09-19 |
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