CN100338078C - 制备二氨基磷酸酯类化合物的方法 - Google Patents
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Abstract
一种生产二氨基磷酸酯的方法，包括以下步骤：将三卤化磷和二烷基胺在极性溶剂中反应形成中间体化合物。随后接着将该中间体与羟烷基化合物和二烷基胺在非极性助溶剂存在下反应。过滤除去固体副产物之后，两种溶剂分层。上面的非极性溶剂层含有高纯度的二氨基磷酸酯产物时，这是有利的。
Description
技术领域
本发明涉及一种改进的生产二氨基磷酸酯类化合物(phosphorodiamidites)的方法、通过这种方法生产的二氨基磷酸酯类化合物和这种二氨基磷酸酯类化合物的用途。
背景技术
二氨基磷酸酯类化合物的制备在生物技术工业中已经变得越来越重要。二氨基磷酸酯类化合物被用做生产新抗肿瘤剂的中间体。
为了适宜用于这种工业，二氨基磷酸酯类化合物必须是高纯度的。这种二氨基磷酸酯类化合物还必须含有低水平的二氨基磷酸[双-(2-氰乙基)]酯(“二酯”)。
已知该杂质是合成四异丙基二氨基磷酸2-氰乙酯的重要副产物，其是商业上合成低聚核苷酸的重要中间体。
由于二氨基磷酸酯类化合物对空气非常敏感并且热不稳定，目前它们的纯化复杂且昂贵。至今，提取和纯化二氨基磷酸酯类化合物的已知方法经常涉及多步合成步骤，其要求中间体物质的化学分离并且在分离高纯度二氨基磷酸酯产物之前需要大量的纯化步骤。
发明内容
本发明的目的就在于改善生产二氨基磷酸酯的上述缺点。
因此，本发明提供一种生产二氨基磷酸酯的方法，该方法包括以下步骤：将三卤化磷与二烷基胺在极性溶剂中反应形成中间体化合物并且随后将该中间体化合物与羟烷基化合物和二烷基胺在非极性助溶剂存在下反应。
过滤除去固体副产物之后，两种溶剂分层。上面的非极性溶剂层含有高纯度的二氨基磷酸酯产物时，这是有利的。下面极性溶剂层含有被二酯和其它不需要的副产物污染了的不纯产物。然后将上层进行真空汽提来除去溶剂，留下所需要的产物，其纯度大于96％并且含有少于1％的二酯杂质。还可以通过任选再用一些非极性溶剂进行再洗极性溶剂层，得到含有纯产物的非极性溶剂溶液，然后从该溶液中分离高纯度的二氨基磷酸酯的方法来进一步提高产物的产率。
有利地，可以通过使用溶剂纯化方法来提取和纯化被二酯和其它杂质污染的不适于商业用途的不纯产物。二氨基磷酸酯产物优选可溶于非极性助溶剂中，而二酯和其它不需要的极性副产物不溶于非极性助溶剂中而保留在极性溶剂层中。
优选地，三卤化磷是三氯化磷。可选地，三卤化磷是三溴化磷。
二烷基胺优选是二异丙胺。可选地，二烷基胺可以是二甲基胺、二乙基胺、二-正丙胺、二正丁胺、二异丁胺或二叔丁胺。
极性溶剂优选是腈化合物，尤其是乙腈。可选地，极性溶剂可以是丙腈或苄腈。
羟烷基化合物优选是羟丙腈。可选地，羟烷基化合物可以是甲醇、叔丁醇或其它已知适于生产二氨基磷酸酯的羟烷基化合物。
烷烃助溶剂优选是庚烷或己烷。其它合适的C5到C9脂族烃包括戊烷。合适的脂环烃包括例如环己烷。
极性溶剂与非极性溶剂合适的比例是约1∶1。根据本发明的方法提供一种符合式I的二氨基磷酸酯化合物：
(R2N)2-P-O(CH2)n-CN (I)
其中R是C1到C4烷基、羟烷基或氧基烷基基团；并且n是1到4的整数。
根据式I的化合物优选是四异丙基二氨基磷酸2-氰乙酯，其中R是异丙基，并且n＝2。
本发明还提供式I化合物在合成低聚核苷酸中的用途。
现在将仅通过实施例来对本发明作如下描述：
具体实施方式
实施例1
用己烷助溶剂生产四异丙基二氨基磷酸2-氰乙酯
在环境温度下，在1小时内将27.5g三氯化磷加到乙腈(200g)和二异丙胺(121g)的搅拌混合物中。然后在环境温度下，在30分钟内加入200g己烷，再加入14g羟基丙腈。接着将反应混合物搅拌1个小时，并且然后过滤除去固体副产物。将过滤了的反应混合物的上面己烷层分离并进行真空汽提来除去己烷溶剂。这样留下20g四异丙基二氨基磷酸2-氰乙酯，用31P-NMR分析其纯度为96.9％。再用200g己烷搅拌下面乙腈层2小时。通过31P-NMR分析，再提取得到的上面己烷层含有纯度为98％的产物。真空汽提之后，又分离得到11g高纯度的四异丙基二氨基磷酸2-氰乙酯。
实施例2
用庚烷助溶剂生产四异丙基二氨基磷酸2-氰乙酯
在环境温度下，将27.5g三氯化磷加到200g乙腈和121g二异丙胺的搅拌混合物中。然后在环境温度下，在30分钟内向混合物中加入200g庚烷，再加入14.3g羟基丙腈。接着搅拌该反应混合物1个小时并且然后过滤除去固体副产物。然后将上面庚烷层分离并进行真空汽提来除去庚烷溶剂，留下22g四异丙基二氨基磷酸2-氰乙酯，用31P-NMR分析其纯度为96.7％。
实施例3
低纯度四异丙基二氨基磷酸2-氰乙酯的纯化
搅拌10分钟之后将60g低纯度的四异丙基二氨基磷酸2-氰乙酯(用31P-NMR分析其纯度为92％，含有1.3％的二酯)加到200g乙腈和200g庚烷的混合物中，分离上面庚烷层并再用200g庚烷再搅拌下面乙腈层10分钟。然后分离第二庚烷部分并且然后合并两次庚烷部分进行真空汽提来除去庚烷溶剂。得到30g四异丙基二氨基磷酸2-氰乙酯，通过31P-NMR分析其纯度为98.3％。该提取的二氨基磷酸酯化合物中含有少于0.1％的二酯杂质。
Claims (13)
1、一种生产二氨基磷酸酯的方法，该方法包括以下步骤：将三卤化磷与二烷基胺在极性溶剂中反应形成中间体化合物并且接着将该中间体化合物与羟烷基化合物和二烷基胺在非极性助溶剂存在下反应。
2、如权利要求1所要求的方法，其中三卤化磷是三氯化磷。
3、如权利要求1所要求的方法，其中三卤化磷是三溴化磷。
4、根据权利要求1到3中任一项的方法，其中二烷基胺是二异丙胺。
5、如权利要求1到3中任一项所要求的方法，其中二烷基胺选自二甲基胺、二乙基胺、二正丙胺、二正丁胺、二异丁胺或二叔丁胺。
6、如权利要求1到3中任一项所要求的方法，其中极性溶剂是腈化合物。
7、如权利要求6所要求的方法，其中腈化合物是乙腈。
8、如权利要求6所要求的方法，其中极性溶剂是丙腈或苄腈。
9、如权利要求1到3中任一项所要求的方法，其中羟烷基化合物是羟丙腈。
10、如权利要求1到3中任一项所要求的方法，其中羟烷基化合物是甲醇或叔丁醇。
11、如权利要求1到3中任一项所要求的方法，其中烷烃助溶剂是C5到C9脂肪烃。
12、如权利要求1到3中任一项所要求的方法，其中烷烃助溶剂是脂环烃。
13、根据权利要求1到3中任一项的方法，其中极性溶剂和非极性溶剂的比例是1∶1。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0230095.2A GB0230095D0 (en) | 2002-12-24 | 2002-12-24 | Phosphorodiamidite |
| GB0230095.2 | 2002-12-24 | ||
| PCT/GB2003/005544 WO2004058779A1 (en) | 2002-12-24 | 2003-12-18 | Process for preparing phosphorodiamidites |
Publications (2)
| Publication Number | Publication Date |
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| CN1732176A CN1732176A (zh) | 2006-02-08 |
| CN100338078C true CN100338078C (zh) | 2007-09-19 |
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| CNB2003801074642A Expired - Fee Related CN100338078C (zh) | 2002-12-24 | 2003-12-18 | 制备二氨基磷酸酯类化合物的方法 |
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| US (1) | US7276620B2 (zh) |
| EP (1) | EP1583766B1 (zh) |
| JP (1) | JP4511368B2 (zh) |
| KR (1) | KR100889897B1 (zh) |
| CN (1) | CN100338078C (zh) |
| AT (1) | ATE404571T1 (zh) |
| AU (1) | AU2003290281A1 (zh) |
| CA (1) | CA2511609C (zh) |
| DE (1) | DE60322960D1 (zh) |
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| WO (1) | WO2004058779A1 (zh) |
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| US9896463B2 (en) * | 2014-01-15 | 2018-02-20 | Rhodia Operations | Preparation of purified phosphorodiamidite |
| EP3733680A4 (en) | 2017-12-27 | 2021-12-29 | KNC Laboratories Co., Ltd | Production of highly fat-soluble phosphoramidite |
| CN111057108B (zh) * | 2018-10-16 | 2023-08-15 | 中国石油化工股份有限公司 | 一种胺基磷酸酯化合物及其制备方法、用途 |
Citations (1)
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| JPS62212395A (ja) * | 1986-03-11 | 1987-09-18 | Nippon Zeon Co Ltd | リンアミド化合物の製造法 |
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| DE10208828A1 (de) | 2002-03-01 | 2003-09-11 | Bayer Ag | Verfahren zur Reduktion von 3-Heteroaryl-3-oxopropionsäurederivaten |
| US7057062B2 (en) | 2002-04-11 | 2006-06-06 | Isis Pharmaceuticals, Inc. | Process for manufacturing purified phosphorodiamidite |
| JP2005529957A (ja) | 2002-06-13 | 2005-10-06 | ローディア インク． | リン・ジアミダイト合成物を生成する工程 |
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2002
- 2002-12-24 GB GBGB0230095.2A patent/GB0230095D0/en not_active Ceased
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2003
- 2003-12-18 JP JP2004563342A patent/JP4511368B2/ja not_active Expired - Lifetime
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- 2003-12-18 AU AU2003290281A patent/AU2003290281A1/en not_active Abandoned
- 2003-12-18 CN CNB2003801074642A patent/CN100338078C/zh not_active Expired - Fee Related
- 2003-12-18 CA CA2511609A patent/CA2511609C/en not_active Expired - Lifetime
- 2003-12-18 KR KR1020057011547A patent/KR100889897B1/ko active IP Right Grant
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62212395A (ja) * | 1986-03-11 | 1987-09-18 | Nippon Zeon Co Ltd | リンアミド化合物の製造法 |
Non-Patent Citations (1)
| Title |
|---|
| inhibition of HIV -1 replication and activation of RNase L byphosphorothioate/phosphodiester 2,5-oligoadenylatederivatives pfleiderer w et al,Journal of biological chemistry,american society of biological chemists,Vol.270 No.11 1995 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2511609A1 (en) | 2004-07-15 |
| EP1583766B1 (en) | 2008-08-13 |
| KR100889897B1 (ko) | 2009-03-20 |
| WO2004058779A1 (en) | 2004-07-15 |
| US20060128951A1 (en) | 2006-06-15 |
| CA2511609C (en) | 2012-09-25 |
| JP2006512386A (ja) | 2006-04-13 |
| ATE404571T1 (de) | 2008-08-15 |
| US7276620B2 (en) | 2007-10-02 |
| DE60322960D1 (de) | 2008-09-25 |
| AU2003290281A1 (en) | 2004-07-22 |
| KR20050085831A (ko) | 2005-08-29 |
| JP4511368B2 (ja) | 2010-07-28 |
| EP1583766A1 (en) | 2005-10-12 |
| GB0230095D0 (en) | 2003-01-29 |
| CN1732176A (zh) | 2006-02-08 |
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