CN1187348C - 5-羧基-2-苯并[c]呋喃酮的制备方法 - Google Patents
5-羧基-2-苯并[c]呋喃酮的制备方法 Download PDFInfo
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- CN1187348C CN1187348C CNB008151431A CN00815143A CN1187348C CN 1187348 C CN1187348 C CN 1187348C CN B008151431 A CNB008151431 A CN B008151431A CN 00815143 A CN00815143 A CN 00815143A CN 1187348 C CN1187348 C CN 1187348C
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- furanone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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Abstract
5-羧基-2-苯并[c]呋喃酮可通过包含式(II)表示的对二苯甲酸与多聚甲醛HO(CH2)nH在发烟硫酸中反应的适当的过程,以高纯度和高产率获得。
Description
本发明涉及一种新的制备5-羧基-2-苯并[c]呋喃酮的方法,它作为生产已知的抗抑郁药氰肽氟苯胺即1-[3-(二甲基氨基)丙基]-1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃腈的起始原料。
背景技术
氰肽氟苯胺是一种选择性的5-羟色胺重吸收抑制剂,它作为抗抑郁药已经成功上市几年了。它具有下面的结构:
式I
且它可以按照美国专利US4,650,884中描述的方法制备,即5-氰基-2-苯并[c]呋喃酮经过两个连续的格氏反应,例如分别与4-氟苯基卤化镁和N,N-二甲基氨基丙基卤化镁反应,将所得的二甲醇化合物通过脱水进行闭环反应。5-氰基-2-苯并[c]呋喃酮可以通过5-羧基-2-苯并[c]呋喃酮与脱水剂和分子式为H2N-SO2-R,其中R是NH2,烷氧基,任意取代的苯氧基或取代的苯基的磺胺反应获得,参见我们共同未决的丹麦专利申请PA199801718。
5-羧基-2-苯并[c]呋喃酮已经作为一个在聚合物和油漆工业有用的中间体被描述,然而,目前没有可靠的商业来源可以利用。已知的方法包含催化氢化1,2,4-苯三酸(DE-2630927A1)。该方法提供一种5-和6-羧基-2-苯并[c]呋喃酮的混合物,于是它就要求精细且高费用的纯化,根据《美国有机化学杂志》(J.Org.Chem)1970年第35期第1695-1696页,5-羧基-2-苯并[c]呋喃酮可以通过对苯二甲酸和三氧杂烷在液态SO3中反应合成,在该过程中,三杂氧烷的升华物和沉淀物会堵塞设备。
虽然大量其他方法失败了,但是目前发现了5-羧基-2-苯并[c]呋喃酮可以从对苯二甲酸通过适宜、经济的步骤高产率的制备。
发明详述
本发明提供一种制备5-羧基-2-苯并[c]呋喃酮的方法,
该方法包括将对苯二甲酸
与多聚甲醛(HO(CH2)nH)在发烟硫酸中反应。
通过本发明的方法,可以获得高纯度和高产率(>大约75%)的5-羧基-2-苯并[c]呋喃酮。此外,与现有的文献《美国有机化学杂志》(J.Org.Chem)1970年第35期第1695-1696页记载的方法相比,本发明的方法没有堵塞设备的升华的三杂氧烷沉淀物,例如在冷凝器沉淀。
发烟硫酸为市场上可以获得的发烟硫酸。下面是从Aldrich/Fluka可得到的:
12-17%SO3(发烟硫酸)=15%发烟硫酸
18-24%SO3(发烟硫酸)=20%发烟硫酸
27-33%SO3(发烟硫酸)=30%发烟硫酸
其它来源的20%的发烟硫酸含有20-25%的SO3。
在本发明的方法中,对二苯甲酸与多聚甲醛缩合,同时释放水,并与SO3反应。当反应完成时,5-羧基-2-苯并[c]呋喃酮可以如下所述进行分离:反应混合物用水水解。然后,缩合产物,5-羧基-2-苯并[c]呋喃酮,其中含有可能的二-2-苯并[c]呋喃酮杂质,可以过滤得到,并且5-羧基-2-苯并[c]呋喃酮可以通过调节pH值至约6.7-7.3使其溶解在含水介质中,在固相中留下可能的二-2-苯并[c]呋喃酮杂质。存在的二-2-苯并[c]呋喃酮可以通过过滤除去,而5-羧基-2-苯并[c]呋喃酮可以通过酸化沉淀、过滤、用水洗涤并干燥。
优选1.0-1.33当量的CH2O和1.0-2.5,优选使用1.0-2.0。较优选使用每当量对苯二甲酸1.25-1.5当量的SO3。更优选使用每当量对苯二甲酸大约1.37当量(相当于大约3.3kg20-25%发烟硫酸/kg对苯二甲酸。
对苯二甲酸与多聚甲醛的反应在升高的温下进行,适宜的温度大约为50-148℃,优选115-125℃或138-148℃。反应时间没有限制且本领域技术人员可以很容易地确定,在115-125℃一批210kg的反应时间优选为17-21小时。反应时间随温度的升高减少。
调节pH值至6.3-7.3是为了溶解形成的5-羧基-2-苯并[c]呋喃酮,可以用NaOH调节,例如大约10%的NaOH水溶液。
酸化是为了沉淀5-羧基-2-苯并[c]呋喃酮,可以通过加硫酸至pH=2实现。
作为起始原料使用的对苯二甲酸是市场上可以获得的。
实施例
本发明通过下面的实施例进一步说明。
实施例1
5-羧基-2-苯并[c]呋喃酮
将对苯二甲酸(10kg)加入反应器中。加入发烟硫酸酸(20%(18-24%SO3);6kg/kg对二苯甲酸),然后加入多聚甲醛(1.33当量,0.24kg/kg对二苯甲酸)。该混合物在125℃搅拌17小时。加入水(13kg/kg对二苯甲酸和助滤剂,温度调节到大约70℃。过滤沉淀,用水洗涤并悬浮在水中。悬浮液的pH值用NaOH调节到大约7,加入活性炭,0.07kg/kg对二苯甲酸,然后过滤混合物,用水漂洗沉淀。滤液的温度调节到大约65℃并且用50%的硫酸将pH值调节到大约2。5-羧基-2-苯并[c]呋喃酮沉淀通过过滤分离,洗涤并干燥。产率为83%。
实施例2
5-羧基-2-苯并[c]呋喃酮
将发烟硫酸(20-25%SO3,43kg)加入反应器中。加入对二苯甲酸(13kg),然后加入多聚甲醛(3.8kg)。该混合物在138-148℃搅拌4.5小时。加入水(87L),温度调节到大约100℃。过滤沉淀,用水洗涤并悬浮在水中。悬浮液的pH值用NaOH(大约10%)调节到大约7,加入0.5kg活性炭,然后过滤混合物,用水漂洗沉淀。滤液的温度调节到大约85℃并且用96%的硫酸将pH值调节到大约2。5-羧基-2-苯并[c]呋喃酮沉淀通过过滤分离洗涤并干燥。产率为82%。
Claims (5)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DKPA199901569 | 1999-11-01 | ||
DKPA199901569 | 1999-11-01 |
Publications (2)
Publication Number | Publication Date |
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CN1391567A CN1391567A (zh) | 2003-01-15 |
CN1187348C true CN1187348C (zh) | 2005-02-02 |
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CNB008151431A Expired - Fee Related CN1187348C (zh) | 1999-11-01 | 2000-10-19 | 5-羧基-2-苯并[c]呋喃酮的制备方法 |
Country Status (13)
Country | Link |
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US (2) | US6403813B1 (zh) |
EP (1) | EP1235819A1 (zh) |
JP (1) | JP2003513084A (zh) |
CN (1) | CN1187348C (zh) |
AR (1) | AR026063A1 (zh) |
AU (1) | AU7902400A (zh) |
BR (1) | BR0015471A (zh) |
CA (1) | CA2389379C (zh) |
HK (1) | HK1052702A1 (zh) |
HR (1) | HRP20020405A2 (zh) |
IT (1) | IT1319251B1 (zh) |
MX (1) | MXPA02004313A (zh) |
WO (1) | WO2001032642A1 (zh) |
Families Citing this family (20)
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TR200102957T2 (tr) | 1999-04-14 | 2004-12-21 | H. Lundbeck A/S | Sitalopram hazırlanması için metod. |
ITMI991581A1 (it) * | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
AR026063A1 (es) * | 1999-11-01 | 2002-12-26 | Lundbeck & Co As H | Metodo para la preparacion de 5-carboxiftalida. |
IL150335A0 (en) | 1999-12-28 | 2002-12-01 | Lundbeck & Co As H | Method for the preparation of citalopram |
PT1246813E (pt) | 1999-12-30 | 2004-02-27 | Lundbeck & Co As H | Metodo para a preparacao de citalopram |
KR100660802B1 (ko) * | 2000-01-14 | 2006-12-26 | 하. 룬트벡 아크티에 셀스카브 | 5-시아노프탈리드의 제조 방법 |
IT1317729B1 (it) * | 2000-01-18 | 2003-07-15 | Norpharma S P A | Procedimento per la preparazione della 5-carbossiftalide. |
NL1017417C1 (nl) | 2000-03-03 | 2001-03-16 | Lundbeck & Co As H | Werkwijze voor de bereiding van Citalopram. |
GB0005477D0 (en) | 2000-03-07 | 2000-04-26 | Resolution Chemicals Limited | Process for the preparation of citalopram |
HUP0300274A2 (hu) | 2000-03-13 | 2003-06-28 | H. Lundbeck A/S | Eljárás citalopram előállítására |
IES20010206A2 (en) | 2000-03-13 | 2002-03-06 | Lundbeck & Co As H | Method for the preparation of citalopram |
JP2003527385A (ja) * | 2000-03-13 | 2003-09-16 | ハー・ルンドベック・アクチエゼルスカベット | 5−置換された1−(4−フルオロフェニル)−1,3−ジヒドロイソベンゾフランの段階的アルキル化法 |
PL360107A1 (en) | 2000-03-14 | 2004-09-06 | H.Lundbeck A/S | Method for the preparation of citalopram |
ES2159271B1 (es) * | 2000-03-16 | 2002-05-01 | Lundbeck & Co As H | Metodo para la preparacion de 5-ciano-1-(4-fluorofenil)-1,3-dihidroisobenzofuranos |
AR032455A1 (es) | 2000-05-12 | 2003-11-12 | Lundbeck & Co As H | Metodo para la preparacion de citalopram, un intermediario empleado en el metodo, un metodo para la preparacion del intermediario empleado en el metodo y composicion farmaceutica antidepresiva |
WO2004083197A2 (en) * | 2003-03-21 | 2004-09-30 | H. Lundbeck A/S | Intermediates for the preparation of citalopram and escitalopram |
TR200504022T1 (tr) * | 2003-03-24 | 2006-08-21 | Hetero Drugs Limited | (S)-sitalopram oksalatın yeni sıvı kristal formları. |
WO2006090409A1 (en) * | 2005-02-28 | 2006-08-31 | Kekule Pharma Ltd., | An improved process for the preparation of 5 - carboxyphthalide |
CN106632183A (zh) * | 2016-12-07 | 2017-05-10 | 万全万特制药(厦门)有限公司 | 一种草酸艾司西酞普兰杂质的制备方法 |
CN112062741A (zh) * | 2019-06-11 | 2020-12-11 | 太仓市茜泾化工有限公司 | 一种5-羧酸苯酞的制备方法 |
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US3607884A (en) * | 1969-03-11 | 1971-09-21 | Mobil Oil Corp | Preparation of 5-carboxyphthalide in liquid sodium trioxide |
DE2242007A1 (de) * | 1972-08-26 | 1974-03-14 | Basf Ag | Verfahren zur herstellung von phthalimidinen |
GB1526331A (en) | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
DE2630927A1 (de) * | 1976-07-09 | 1978-01-19 | Basf Ag | Verfahren zur herstellung von phthalidcarbonsaeure-(5) |
GB8419963D0 (en) | 1984-08-06 | 1984-09-12 | Lundbeck & Co As H | Intermediate compound and method |
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DE59003859D1 (de) | 1989-08-23 | 1994-01-27 | Alusuisse Lonza Services Ag | Sterilisierfähiger Verpackungsbehälter aus Kunststoff-Metall-Kunststoff-Verbundmaterial und Verfahren zu dessen Herstellung. |
US5296507A (en) | 1990-09-06 | 1994-03-22 | H.Lundbeck A/S | Treatment of cerbrovascular disorders |
DE19626659A1 (de) * | 1996-07-03 | 1998-01-08 | Basf Ag | Verfahren zur Herstellung von Phthaliden |
DE19627697A1 (de) * | 1996-07-10 | 1998-01-15 | Basf Ag | Verfahren zur Herstellung von Phthaliden |
CA2291067C (en) | 1997-07-08 | 2002-07-30 | H. Lundbeck A/S | Method for the preparation of citalopram |
UA62985C2 (en) | 1997-11-10 | 2004-01-15 | Lunnbeck As H | A method for the preparation of citalopram |
WO1998019512A2 (en) | 1997-11-11 | 1998-05-14 | H. Lundbeck A/S | Method for the preparation of citalopram |
IL142346A0 (en) | 1998-10-20 | 2002-03-10 | Lundbeck & Co As H | Method for the preparation of citalopram |
CZ300408B6 (cs) | 1998-12-23 | 2009-05-13 | H. Lundbeck A/S | Zpusob výroby 5-kyanoftalidu |
AR022329A1 (es) | 1999-01-29 | 2002-09-04 | Lundbeck & Co As H | Metodo para la preparacion de 5-cianoftalida |
TR200102957T2 (tr) | 1999-04-14 | 2004-12-21 | H. Lundbeck A/S | Sitalopram hazırlanması için metod. |
ITMI991581A1 (it) | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
ITMI991579A1 (it) | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | Metodo per la preparazione di citalopram |
AU742554B2 (en) | 1999-10-25 | 2002-01-03 | H. Lundbeck A/S | Method for the preparation of citalopram |
US6310222B1 (en) | 1999-11-01 | 2001-10-30 | Sumika Fine Chemicals Co., Ltd. | Production method of 5-phthalancarbonitrile compound, intermediate therefor and production method of the intermediate |
AR026063A1 (es) | 1999-11-01 | 2002-12-26 | Lundbeck & Co As H | Metodo para la preparacion de 5-carboxiftalida. |
AU1130901A (en) | 1999-11-01 | 2001-05-14 | H. Lundbeck A/S | Method for the preparation of 5-carboxyphthalide |
IT1317729B1 (it) | 2000-01-18 | 2003-07-15 | Norpharma S P A | Procedimento per la preparazione della 5-carbossiftalide. |
US6433196B1 (en) | 2000-02-17 | 2002-08-13 | Sumika Fine Chemicals Co., Ltd. | Production method of citalopram, intermediate therefor and production method of the intermediate |
IES20010143A2 (en) | 2000-02-24 | 2001-07-25 | Lundbeck & Co As H | Method for the preparation of citalopram |
NL1017415C1 (nl) | 2000-02-24 | 2001-05-18 | Lundbeck & Co As H | Werkwijze voor de bereiding van Citalopram. |
GB0005477D0 (en) | 2000-03-07 | 2000-04-26 | Resolution Chemicals Limited | Process for the preparation of citalopram |
IL144817A0 (en) | 2000-08-18 | 2002-06-30 | Lundbeck & Co As H | Method for the preparation of citalopram |
PL353369A1 (en) | 2000-12-28 | 2003-11-17 | H.Lundbeck A/S | Process for the preparation of pure citalopram |
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2000
- 2000-10-17 AR ARP000105451A patent/AR026063A1/es unknown
- 2000-10-19 MX MXPA02004313A patent/MXPA02004313A/es unknown
- 2000-10-19 JP JP2001534793A patent/JP2003513084A/ja not_active Withdrawn
- 2000-10-19 BR BR0015471-7A patent/BR0015471A/pt not_active IP Right Cessation
- 2000-10-19 CA CA002389379A patent/CA2389379C/en not_active Expired - Fee Related
- 2000-10-19 WO PCT/DK2000/000585 patent/WO2001032642A1/en active Application Filing
- 2000-10-19 CN CNB008151431A patent/CN1187348C/zh not_active Expired - Fee Related
- 2000-10-19 AU AU79024/00A patent/AU7902400A/en not_active Abandoned
- 2000-10-19 EP EP00969234A patent/EP1235819A1/en not_active Withdrawn
- 2000-10-19 US US09/692,653 patent/US6403813B1/en not_active Expired - Fee Related
- 2000-10-27 IT IT2000MI002342A patent/IT1319251B1/it active
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- 2002-05-06 US US10/140,361 patent/US6888009B2/en not_active Expired - Fee Related
- 2002-05-10 HR HR20020405A patent/HRP20020405A2/hr not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
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CN1391567A (zh) | 2003-01-15 |
MXPA02004313A (es) | 2002-11-07 |
WO2001032642A1 (en) | 2001-05-10 |
CA2389379A1 (en) | 2001-05-10 |
BR0015471A (pt) | 2002-07-09 |
CA2389379C (en) | 2007-04-10 |
AU7902400A (en) | 2001-05-14 |
JP2003513084A (ja) | 2003-04-08 |
ITMI20002342A1 (it) | 2002-04-27 |
HRP20020405A2 (en) | 2004-02-29 |
US6888009B2 (en) | 2005-05-03 |
IT1319251B1 (it) | 2003-09-26 |
US6403813B1 (en) | 2002-06-11 |
US20020165403A1 (en) | 2002-11-07 |
EP1235819A1 (en) | 2002-09-04 |
HK1052702A1 (en) | 2003-09-26 |
AR026063A1 (es) | 2002-12-26 |
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