CN1299363A - 醛的纯化 - Google Patents
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Abstract
本发明涉及4’－氯－4－联苯基甲醛的提纯方法。
Description
本发明涉及从4’-氯-4-联苯基甲醛中除去杂质，4’-氯-4-联苯基甲醛是制备用来抵抗万古霉素抗性感染的糖肽类抗菌素NDISACC-(4-(4-氯苯基)苄基)A82846B的原料。A82846B是从东方无枝酸菌的培养基中分离的发酵产物，该发酵产物产生与共发酵因素密切相关的混合物，A82846B被证明是混合物中的主要抗菌剂。A82846B以4’-氯-4-联苯基甲醛还原性烷基化形成NDISACC-(4-(4-氯苯基)苄基)A82846B。通过降低醛原料中杂质的水平，总产率、纯度和最终抗菌产物的安全性都明显增加。
本发明提供了从合成的4’-氯-4-联苯基甲醛中除去杂质的改进方法。本发明进一步提供了提纯4’-氯-4-联苯基甲醛的方法，该方法包括在乙腈的浓度足以引起亚硫酸氢盐加合物形成沉淀的水/乙腈溶液中以亚硫酸氢钠与4’-氯-4-联苯基甲醛反应，从溶液中分离亚硫酸氢盐加合物沉淀，将分离出的亚硫酸氢盐加合物混合入水/乙腈溶液中，其中水浓度足以使再生的醛沉淀，并将亚硫酸氢盐加合物转变成4’-氯-4-联苯基甲醛。
此亚硫酸氢盐加合物以下式代表：并将在本文中叫做亚硫酸氢盐加合物。
此类型醛的纯化原先是在水/乙醇溶液中进行，见Horning,E.C.,有机合成，CollectiveVol.3,438-440(1995)。乙醇水溶液可以用作本发明的溶剂，但是新的亚硫酸氢盐加合物和再生醛的过滤困难并且在商业生产上不可行。在本发明改进的实施方案中，使用乙腈水溶液。使用此溶剂有利于较好的纯化的醛的产率和纯度。
当4’-氯-4-联苯基甲醛与亚硫酸氢钠反应时，亚硫酸氢钠和4’-氯-4-联苯基甲醛的比例并不重要。亚硫酸氢钠和4’-氯-4-联苯基甲醛的比例范围可以从1∶1至10∶1。此反应优选的亚硫酸氢钠比4’-氯-4-联苯基甲醛范围为约1∶1至约1.3∶1。对溶剂的要求也不苛刻，只要亚硫酸氢盐加合物能形成沉淀。可以使用甲醇水溶液，但是优选使用乙腈水溶液。在此优选实施方案中，在反应中乙腈和水的比例可以从约2∶1至约13∶1。优选约5∶1至约7∶1。此反应对温度的要求也不苛刻，反应温度可以从约0℃-约100℃。反应物典型地在约45℃-约55℃下混合，然后冷却至约15℃-约25℃。
在将分离出的亚硫酸氢盐加合物混合在溶液中并将亚硫酸氢盐加合物转变成4’-氯-4-联苯基甲醛时，对溶剂的要求不苛刻，只要再生的醛形成沉淀。可以使用甲醇水溶液，但是优选使用乙腈水溶液。在此优选实施方案中，在反应中乙腈和水的比例可以从约1∶1至约1∶5。优选约1∶3至约1∶5。此反应典型地在室温下(约15℃-约25℃)进行。反应中溶液的pH可以是酸性(0-3)或碱性(10-14)。优选pH范围是约12-14。
实施例1和2显示了在碱性条件下，在水/乙腈溶液中亚硫酸氢盐加合物转变成4’-氯-4-联苯基甲醛时有很高的醛产率。实施例2和3监测杂质4,4’-二氯联苯(下文称作4,4’-DCBP，定义为多氯化联苯)。实施例3显示了在碱性条件下，在水/乙腈中完全除去4,4’-DCBP。
实施例1
4’-氯-4-联苯基甲醛亚硫酸氢盐加合物的制备
加热下，将0.50g 4’-氯-4-联苯基甲醛溶解在15ml甲醇和2ml水中。加入0.30g亚硫酸氢钠，并在45-50℃下搅拌10分钟。将溶液冷却至0-5℃并搅拌1小时。亚硫酸氢盐加合物形成沉淀，过滤和以5ml甲醇洗涤，然后以10ml丙酮洗涤。产率为97.1％。(a)将0.15g亚硫酸氢盐加合物在10ml水、5ml甲醇中搅拌，加入2N
盐酸调pH为2。将此溶液轻微加热10分钟，并在室温下搅拌20
分钟。形成浆液并滤出固体4’-氯-4-联苯基甲醛。(b)将0.15g亚硫酸氢盐加合物在10ml水、5ml乙腈中搅拌，加入5M
氢氧化钠调节pH为12。将此溶液在室温下搅拌20分钟。形成
沉淀并滤出固体4’-氯-4-联苯基甲醛。
固体的NMR谱显示(b)为纯净的醛和(a)为1.25∶1的亚硫酸氢盐和醛的加合物。
实施例2溶剂和pH比较
将2.8M的亚硫酸氢钠水溶液(相对于醛1.2当量)加到温热的4’-氯-4-联苯基甲醛的有机溶液中(0.46M丙酮和乙腈，0.28M乙醇)。冷却至室温后搅拌1小时，过滤浆液，得到的白色固体进行4,4’-DCBP含量分析。将亚硫酸氢盐加合物转变成醛，然后在酸性条件(pH0.9-1.1，HCl)或碱性条件(pH11-13，NaOH)下，用相同的有机溶剂测定衍生物，反应时间为2-2.2小时。结果显示于表1中。在完成转变后剩余的亚硫酸氢盐加合物量的数据是从分离的产物进行的1H NMR积分谱获得的。在此试验中使用的最初的醛样品含0.64％ 4,4’-DCBP。ACN是乙腈的缩写，IPA是异丙醇的缩写，和3A alc是3A甲醇的缩写。
表1
| 溶剂 | 加合物中的4,4’-DCBP | 剩余的亚硫酸氢盐加合物(％) | 醛产率(％) | 回收的醛中的4,4’-DCBP | |||
| 丙酮甲醇ACN3A alaIPA | 50ppm100ppmNDNDND | HCl1888939494 | NaOH0170167.7 | HCl80.016.38.88.18.0 | NaOH88.590.793.292.486.0 | HCl70ppm70ppmNDNDND | NaOH80ppm100ppmNDNDND |
*ND-于50ppm检测限未检出。
实施例3
醛转变成亚硫酸氢盐加合物的优选方法
在实施例2优选方案中确定的变量是，乙腈中的醛浓度、水中的亚硫酸氢钠浓度和反应时间。干燥的亚硫酸氢盐加合物的产率和残余的4,4’-DCBP的量被评价。结果摘录于表2中。在此试验中使用的最初的醛样品含0.64％4,4’-DCBP。
| 序号 | 醛浓度(M) | NaHSO3浓度(M) | ACN∶H2O | 时间(h) | 亚硫酸氢盐加合物的产率(g) | 4,4＇-DCBP(ppm) |
| ABCDEFGHIJ | 0.380.310.230.310.380.380.310.230.230.38 | 1.72.33.52.33.53.52.31.73.51.7 | 3.86.712.56.73.83.86.76.312.53.8 | 2343423224 | 6.96.86.37.46.55.56.77.17.77.2 | NDND465ND339235NDNDNDND |
| K | 0.23 | 1.7 | 6.3 | 4 | 7.4 | ND |
*ND-于30ppm检测限未检出，每次测定用5g醛。
此研究证明总浓度对于4,4’-DCBP的除去是显著因素。反应物的浓度越浓(E和F)，越不利于4,4’-DCBP除去。最终观察到亚硫酸氢盐加合物的滤过率随乙腈与水的比例的减小而下降。
实施例4
亚硫酸氢盐转变成醛的研究
制备大量的无4,4’-DCBP的亚硫酸氢盐加合物，并在不同的含水量、乙腈的量和室温下的不同反应时间下进行转变。评价的参数是产率和滤过率(+代表有效滤过，一代表难于过滤)。对于每个试验，亚硫酸氢盐加合物(4g)在水和乙腈的混合物中搅拌。加入50％氢氧化钠溶液调节pH为12。试验结果摘录于表3。
表3
| 序号 | H2O(mL) | ACN(mL) | H2O∶ACN | 浓度(M) | 时间(h) | 产率(％) | 滤过率 |
| ABCDEFGHIJK | 2525252545454545353535 | 1010202010102020151515 | 2.52.51.251.254.54.52.252.252.332.332.33 | 0.350.350.280.280.230.230.190.190.250.250.25 | 13131313222 | 90.090.382.081.392.492.391.091.591.791.490.3 | ++++----+++ |
此研究证明要获得高的醛产率，重要的是有相对高的水对乙腈的比例。此外，最稀的反应液导致醛的滤过率低。
实施例5
醛的纯化：除去杂质醛提纯的条件：1．加合物的形成a．0.23M醛溶液b．1.7M亚硫酸氢盐溶液(相对与醛亚硫酸氢盐为1.2摩尔当量)c．通过取等份试样进行NMR分析来监测反应时间d．用高体积的ACN洗涤湿滤饼2．加合物转变成醛a．0.28M浓度的亚硫酸氢盐加合物b．4∶1水比ACNc．在pH12-14反应2小时，取等份试样进行NMR分析证实。此试验以25kg 4’-氯-4-联苯基甲醛开始。在纯化的醛中未检测出4,4’-DCBP，并且相关杂质的总量从0.9％减少至0.3％。纯化的醛的产率是22.2kg(89％)。
Claims (9)
1．一种4’-氯-4-联苯基甲醛与亚硫酸氢钠反应制备亚硫酸氢盐加合物的方法。
2．权利要求1的方法，该方法在水/乙腈溶液中进行，该溶液中乙腈的浓度足以使亚硫酸氢盐加合物形成沉淀。
3．权利要求2的方法，其中乙腈和水的比例是约2∶1-约13∶1。
4．权利要求2的方法，其中亚硫酸氢盐加合物从溶液中分离并混合入水/乙腈溶液中，该溶液中水的浓度足以使再生醛形成沉淀。
5．权利要求4的方法，其中乙腈和水比例是从约1∶3-约1∶5。
6．权利要求4的方法，其中当亚硫酸氢盐加合物转变成4’-氯-4-联苯基甲醛时，溶液的pH为约10-约14。
7．权利要求6的方法，其中当亚硫酸氢盐加合物转变成4’-氯-4-联苯基甲醛时，溶液的pH为约12-约14。
8．一种提纯4’-氯-4-联苯基甲醛的方法，该方法包括：
(1)4’-氯-4-联苯基甲醛与亚硫酸氢钠在水/乙腈溶液中反应，
该溶液中乙腈的浓度足以引起亚硫酸氢盐加合物形成沉
淀，
(2)从溶液中分离出亚硫酸氢盐加合物沉淀，
(3)将分离出的亚硫酸氢盐加合物混合入水/乙腈溶液中，该
溶液中水的浓度足以引起再生的醛形成沉淀，和
(4)亚硫酸氢盐加合物转变成4’-氯-4-联苯基甲醛。
9．通式如下的化合物：
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8429998P | 1998-05-05 | 1998-05-05 | |
| US60/084,299 | 1998-05-05 |
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| Publication Number | Publication Date |
|---|---|
| CN1299363A true CN1299363A (zh) | 2001-06-13 |
| CN1168694C CN1168694C (zh) | 2004-09-29 |
Family
ID=22184070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB99805710XA Expired - Fee Related CN1168694C (zh) | 1998-05-05 | 1999-03-15 | 醛的纯化 |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US6355843B1 (zh) |
| EP (1) | EP1075480B1 (zh) |
| JP (1) | JP2002513794A (zh) |
| KR (1) | KR100624585B1 (zh) |
| CN (1) | CN1168694C (zh) |
| AT (1) | ATE267209T1 (zh) |
| AU (1) | AU748094B2 (zh) |
| BR (1) | BR9911006A (zh) |
| CA (1) | CA2330621A1 (zh) |
| CZ (1) | CZ295089B6 (zh) |
| DE (1) | DE69917445T2 (zh) |
| DK (1) | DK1075480T3 (zh) |
| EA (1) | EA003558B1 (zh) |
| ES (1) | ES2220053T3 (zh) |
| HR (1) | HRP20000749B1 (zh) |
| HU (1) | HUP0101830A3 (zh) |
| ID (1) | ID26405A (zh) |
| IL (1) | IL138636A0 (zh) |
| NO (1) | NO20005529D0 (zh) |
| NZ (1) | NZ507054A (zh) |
| PL (1) | PL191095B1 (zh) |
| PT (1) | PT1075480E (zh) |
| SK (1) | SK285059B6 (zh) |
| TR (1) | TR200003203T2 (zh) |
| UA (1) | UA81595C2 (zh) |
| WO (1) | WO1999057123A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804445A (zh) * | 2013-12-30 | 2014-05-21 | 广州自远生物科技有限公司 | 一种改进的乙酰异戊酰泰乐菌素的制备方法 |
| CN109897020A (zh) * | 2017-12-07 | 2019-06-18 | 中国科学院宁波材料技术与工程研究所 | 一种粗品5-羟甲基-2-呋喃甲醛的精制方法 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2413795A (en) | 2004-05-05 | 2005-11-09 | Cipla Ltd | Process for the preparation of rosiglitazone |
| ES2374379T3 (es) * | 2005-01-14 | 2012-02-16 | Schering Corporation | Síntesis exo y diastereoselectiva de análogos de himbacina. |
| WO2009147068A1 (en) | 2008-06-06 | 2009-12-10 | F. Hoffmann-La Roche Ag | Process for the preparation of halogenated benzoic acid derivatives |
| JP6712991B2 (ja) | 2014-07-17 | 2020-06-24 | ザ メディシンズ カンパニー | 高純度のオリタバンシン及びその製造方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5325530A (en) * | 1976-08-20 | 1978-03-09 | Sumitomo Chem Co Ltd | Purification of aldehydes |
| US4075248A (en) * | 1976-09-07 | 1978-02-21 | Domtar Limited | Production of syringealdehyde from hardwood waste pulping liquors |
| US4065505A (en) * | 1976-11-05 | 1977-12-27 | Shell Oil Company | Oxidation process |
| US5840684A (en) * | 1994-01-28 | 1998-11-24 | Eli Lilly And Company | Glycopeptide antibiotic derivatives |
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1999
- 1999-03-15 PL PL343758A patent/PL191095B1/pl unknown
- 1999-03-15 HU HU0101830A patent/HUP0101830A3/hu unknown
- 1999-03-15 PT PT99911411T patent/PT1075480E/pt unknown
- 1999-03-15 WO PCT/US1999/005666 patent/WO1999057123A1/en active IP Right Grant
- 1999-03-15 CN CNB99805710XA patent/CN1168694C/zh not_active Expired - Fee Related
- 1999-03-15 CA CA002330621A patent/CA2330621A1/en not_active Abandoned
- 1999-03-15 JP JP2000547092A patent/JP2002513794A/ja not_active Withdrawn
- 1999-03-15 EA EA200001153A patent/EA003558B1/ru not_active IP Right Cessation
- 1999-03-15 AT AT99911411T patent/ATE267209T1/de not_active IP Right Cessation
- 1999-03-15 ID IDW20002247A patent/ID26405A/id unknown
- 1999-03-15 BR BR9911006-7A patent/BR9911006A/pt not_active Application Discontinuation
- 1999-03-15 TR TR2000/03203T patent/TR200003203T2/xx unknown
- 1999-03-15 CZ CZ20004082A patent/CZ295089B6/cs not_active IP Right Cessation
- 1999-03-15 UA UA2000116251A patent/UA81595C2/ru unknown
- 1999-03-15 US US09/673,347 patent/US6355843B1/en not_active Expired - Fee Related
- 1999-03-15 AU AU30057/99A patent/AU748094B2/en not_active Ceased
- 1999-03-15 KR KR1020007012278A patent/KR100624585B1/ko not_active IP Right Cessation
- 1999-03-15 DE DE69917445T patent/DE69917445T2/de not_active Expired - Fee Related
- 1999-03-15 NZ NZ507054A patent/NZ507054A/xx unknown
- 1999-03-15 ES ES99911411T patent/ES2220053T3/es not_active Expired - Lifetime
- 1999-03-15 IL IL13863699A patent/IL138636A0/xx not_active IP Right Cessation
- 1999-03-15 DK DK99911411T patent/DK1075480T3/da active
- 1999-03-15 SK SK1632-2000A patent/SK285059B6/sk unknown
- 1999-03-15 EP EP99911411A patent/EP1075480B1/en not_active Expired - Lifetime
-
2000
- 2000-11-02 NO NO20005529A patent/NO20005529D0/no not_active Application Discontinuation
- 2000-11-03 HR HR20000749A patent/HRP20000749B1/xx not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804445A (zh) * | 2013-12-30 | 2014-05-21 | 广州自远生物科技有限公司 | 一种改进的乙酰异戊酰泰乐菌素的制备方法 |
| CN109897020A (zh) * | 2017-12-07 | 2019-06-18 | 中国科学院宁波材料技术与工程研究所 | 一种粗品5-羟甲基-2-呋喃甲醛的精制方法 |
| CN109897020B (zh) * | 2017-12-07 | 2020-12-25 | 中国科学院宁波材料技术与工程研究所 | 一种粗品5-羟甲基-2-呋喃甲醛的精制方法 |
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