CN1028995C - 制备酰氨基甲烷膦酸及酰氨甲基次膦酸的方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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Abstract
酰氨基甲烷膦酸及式I的酰氨甲基亚膦酸是制备生物活性化合物的有价值的中间体。这些化合物是式II化合物与式III化合物在至少有与式II化合物等摩尔量的乙酸酐存在下进行反应制备的。
式中R1为羟基，C1-C4-烷基或苯基。R2为氢，C1-C6-烷基，苄基或苯基，苯基上或者未被取代，或者被一个或多个如下基团取代：C1-C4-烷基，C1-C4-烷氧基和卤素其中式I中R1不是羟基的化合物是新化合物。
R2-CO-NH-CH2-P(O)(OH)R1 (I)
R2-CO-NH-CH2-OH (III)
H-P(O)(OH)R1
Description
酰氨基甲烷膦酸是制备具有工业意义的氨基甲烷膦酸的有价值的中间体。特别是作为中间体与乙醛酸反应（参见US-A-4851159）也宜于制备有除草作用的N-膦酰甲基甘氨酸。迄今酰氨基甲烷膦酸是例如将N-羟甲基酰胺与三氯化磷反应，后用盐酸水解得到的，（US-A-2304156;US-A-2328358）。该法的突出缺点是生成不希望的副产物双氯甲醚，它是致癌物。双氯甲醚于水解步骤经甲醛与盐酸反应生成，甲醛是在水解反应条件下以痕量含于N-羟甲基酰氨之中，完全除去双氯甲醚需要费事的纯化步骤。因此，本发明目的是提供能避免生成双氯甲醚和工业上可行的方法。
本发明内容是制备式Ⅰ化合物的方法，
式中R1为羟基，C1-C4-烷基或苯基，R2为氢，C1-C6-烷基（最好是C1-C3-烷基），苄基或苯基，苯基或者不被取代，或被一个或多个如下基团取代：C1-C4-烷基，C1-C4-烷氧基和卤素，该方法之特征是，在至少有与式Ⅱ化合物等摩尔量乙酸酐存在下，将式Ⅱ化合物与式Ⅲ化合物反应
式中R2和R1的意义如前述。
本发明还涉及上述式Ⅰ的酰氨甲基次膦酸，式中R1和R2的意义同前述，只是R1为羟基除外。这些化合物是制备具有生物活性的氨基甲基次膦酸的有价值的中间体（S.LMaier于“氨基膦酸的化学进展”，于“磷与硫”14，195.322（1983），及其中引用的文献），在式Ⅰ中，R1和R2为优选的上述基团的酰氨甲基膦酸是优选的化合物。
用于本发明方法的起始化合物例如可考虑有：N-羟甲基甲酰胺，N-羟甲基乙酰胺以及尤其是N-羟甲基苯甲酰胺。通式Ⅲ的酸例如是亚磷酸，甲烷亚磷酸和苯基亚磷酸，式Ⅱ和式Ⅲ的化合物一般为已知的，可以买到或按已知方法易于制取的。
各组分之间的摩尔比对于收率的提高有特殊意义。通式ⅡN-羟甲基酰胺、通式Ⅲ的酸和乙酸酐等原料的摩尔比优选为1∶1∶1.5到1∶（1-1.1）∶8，尤以1∶1∶1.5到1∶1∶4的摩尔比为好，乙酸酐还可以过量。
式Ⅱ和式Ⅲ的反应必要时可在有机溶剂中进行。
作为溶剂例如可以考虑用极性质子性溶剂和非质子性有机溶剂。如乙酸，乙腈，四氢呋喃或二噁烷，乙酸是优选的溶剂，也可不用溶剂。
该方法宜于这样进行：式Ⅱ和式Ⅲ和乙酸酐等反应组分在5～60℃温度范围内，进行混合必要时加以冷却。而且，各组分的加入次序並不重要。例如，可在有机溶剂如乙酸中将通式Ⅲ的酸溶液定量加到乙酸酐中，然后将通式Ⅱ的N-羟甲基酰胺（必要时溶解于溶剂中）分次或连续加到上面制得的混合物中。混合结束后必要时还需再次搅拌，例如在10～60℃温度范围，然后最好加热回流，反应毕，在反应混合物中含有的过量的乙酸酐先加入水再加热水解，然后最好将前面的反应物中必要时加入的有机溶剂除去，例如用蒸留方法，必要时减压蒸除。反应物也可例如以结晶形式自有机溶剂中过滤分离出。
该方法最好这样进行：乙酸酐和式Ⅱ和式Ⅲ的反应组分于5～60℃温度下（必要时加以冷却）混合，然后加热回流直到反应完全。
产物处理可按常规方法进行。例如，有可能首先真空蒸除易挥发的物质。沉出的剩余物然后可必要时与水共热，或用其它溶剂浸渍，如丙酮、乙腈、乙酸、甲醇、乙醇或异丙醇。然后分离出析出的结晶性产物，並可用常规方法进一步精制。此外，在反应混合物中含有的过量的乙酸酐在进一步处理之前进行水解是有利的。使用N-羟甲基苯甲酰胺时，在冷却时就已部分地结晶析出终产物。
粗产物可简便地用结晶方法进一步精制。本法的一个特点是，沉出的R2不是甲基的式Ⅰ的终产物可能含有一部分R2为甲基的式Ⅰ化合物作为副产物。为了进一步处理终产物，按照US-A-4851159的方法，该副产物部分与本发明方法的主成分有同样的价值。需要时该副产物可按常规分离方法加以分离。
实施例1
302g（2.0mol）N-羟甲基苯甲酰胺加到200ml乙酸中，冷却到10℃。然后在搅拌和冷却下于10℃和15分钟内滴入146g（2.0mol）亚磷酸溶于200ml乙酸的溶液。将近滴加终了时，溶液几近澄明。然后将521g（5.11mol）乙酸酐迅速滴入，但需冷却，使温度不超过53℃然后加热回流2.5小时。冷却到室温后，冷却下加入56g（3.1mol）水，最后回流30分钟，减压蒸除大约110ml乙酸，剩余的反应溶液搅拌过夜，吸滤。得到340g（约理论量的80%）结晶性混合物，大约是70%苯甲酰氨基甲烷膦酸，大约20%乙酰氨基甲烷膦酸和一些磷酸（根据31P-NMR谱），混合物的熔点为156～163℃。水中重结晶后，得纯净的苯甲酰氨基甲烷膦酸，熔点176～177℃。
实施例2
561g（5.5mol）乙酸酐冷至10℃。搅拌並冷却下一小时内滴入164g（2.0mol）亚磷酸和300ml乙酸的溶液，然后冷却下于10-15℃、50分钟内分次加入302g（2.0mol）N-羟甲基苯甲酰胺。于10℃搅拌20分钟，然后将反应混合物维持回流2.5小时，冷却，在搅拌和冷却下，于25～30℃滴入61g（3.39mol）水，再加热回流，冷却后搅拌过夜，吸滤，得320g（约75%的理论量）苯甲酰氨基甲烷膦酸的粗品，从母液中还可回收些粗品。
实施例3
43.3g（0.424mol）乙酸酐冷却至10℃，搅拌和
冷却下滴入16g（0.2mol）甲烷次膦酸溶于40ml乙酸的溶液，加毕，于10分钟内分次加入30.2g（0.2mol）N-羟甲基苯甲酰胺，撤去冷却浴，使内温升到32℃，加热回流2.5小时，冷却。减压浓缩至内温95℃，剩余物为46.7g粗产品。将其热溶于水中，热吸滤，滤液减压浓缩至温度95℃，得到38.3g结晶性剩余物，水中重结晶得24g（56%理论量）（苯甲酰氨甲基）-（甲基）次膦酸，mp.144-146℃，CHNP分析结果如下：
C9H12NO3P计算值：50.70%C，5.67%H，6.57%N，14.53%P
（213） 实测值：51.2%C，5.8%H，6.5%N，14.2%P
实施例4
43.2g（0.424mol）乙酸酐冷却至10℃，搅拌並冷却下于15℃滴入28.2g（0.2mol）苯亚膦酸溶于40ml乙酸的溶液，然后于10分钟内冷却下于15℃分次加入30.2g（0.2mol）N-羟甲基苯甲酰胺，撤除冷却浴，使内温升到35℃，加热回流3小时后冷却。加入175ml水，此时温度升至35℃，再加热回流，搅拌下冷却，结晶后共得40g（73%理论量）苯甲酰氨甲基苯次膦酸，mp.158～160℃，CHNP分析结果如下：
C14H14NO3P 计算值：61.09%C，5.13%H，5.09%N，11.25%P
（275） 实测值：61.2%C，5.2%H，5.3%N，10.7%P
实施例5
40.8g（0.4mol）乙酸酐冷却至10℃，于搅拌和冷却下，5分钟内加入16.4g（0.2mol）亚磷酸，然后于10℃在10分钟内滴入17.8g（0.2mol）N-羟甲基乙酰胺。加毕，先于室温，后加热回流2.5小时，冷却后，分次加入10ml水，再回流1小时，再加入10ml乙酸及1.5ml水的混合物，搅拌，结晶后，吸滤得16.3g（53%理论量）乙酰氨基甲烷膦酸，mp.188-194℃。
Claims (16)
1、式Ⅰ化合物的制备方法：
式中R1为羟基，C1-C4-烷基或苯基，R2为氢，C1-C6-烷基，苄基或苯基，苯基上或者未被取代，或被一个或多个如下基团取代：C1-C4-烷基，C1-C4-烷氧基和卤素，该方法的特征是，将式Ⅱ的化合物与式Ⅲ化合物，在至少有与式Ⅱ化合物等摩尔量的乙酸酐存在下进行反应，
式中R2和R1的意义同前述。
2、按权利要求1的方法，其特征是R1为羟基。
3、按权利要求1的方法，其特征是R1为甲基，乙基或苯基。
4、按权利要求1的方法，其特征是R2为氢，C1-C3-烷基，苄基或苯基。
5、按权利要求1的方法，其特征是R2为苯基。
6、按权利要求1的方法，其特征是式Ⅱ和Ⅲ化合物及乙酸酐按摩尔比为1∶1∶1.5到1∶（1-1.1）∶8进行反应。
7、按权利要求6的方法，其特征是摩尔比为1∶1∶1.5到1∶1∶4。
8、按权利要求6的方法，其特征是将反应后过量的乙酸酐水解。
9、按权利要求1的方法，其特征是式Ⅱ和或Ⅲ化合物的反应是在有机溶剂存在下进行的。
10、按权利要求9的方法，其特征是溶剂为乙酸。
11、按权利要求2的方法，其中R2是苯基。
12、按权利要求3的方法，其中R2是苯基。
13、按权利要求1的方法，其中R2是甲基。
14、按权利要求2的方法，其中R2是甲基。
15、按权利要求3的方法，其中R2是甲基。
16、按权利要求11-15的任一项的方法，其中，式Ⅱ和式Ⅲ化合物的反应是在一种有机溶剂存在下进行的。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4026026A DE4026026A1 (de) | 1990-08-17 | 1990-08-17 | Acylaminomethyl-phosphinsaeuren und verfahren zur herstellung von acylaminomethanphosphonsaeuren und acylaminomethyl-phosphinsaeuren |
| DEP4026026.7 | 1990-08-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1059147A CN1059147A (zh) | 1992-03-04 |
| CN1028995C true CN1028995C (zh) | 1995-06-21 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91105717A Expired - Fee Related CN1028995C (zh) | 1990-08-17 | 1991-08-16 | 制备酰氨基甲烷膦酸及酰氨甲基次膦酸的方法 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US5432291A (zh) |
| EP (1) | EP0543850B1 (zh) |
| JP (1) | JP3236612B2 (zh) |
| CN (1) | CN1028995C (zh) |
| AT (1) | ATE131485T1 (zh) |
| AU (1) | AU8310091A (zh) |
| CA (1) | CA2089652C (zh) |
| DE (2) | DE4026026A1 (zh) |
| DK (1) | DK0543850T3 (zh) |
| ES (1) | ES2082220T3 (zh) |
| IE (1) | IE912919A1 (zh) |
| IL (1) | IL99202A (zh) |
| PT (1) | PT98699B (zh) |
| WO (1) | WO1992003450A1 (zh) |
| ZA (1) | ZA916503B (zh) |
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| WO2014012986A1 (en) | 2012-07-17 | 2014-01-23 | Straitmark Holding Ag | Method for the synthesis of n-phosphonomethyliminodiacetic acid |
| US9676799B2 (en) | 2012-07-17 | 2017-06-13 | Straitmark Holding Ag | Method for the synthesis of N-(phosphonomethyl)glycine |
| RU2674022C9 (ru) | 2012-07-17 | 2019-01-24 | МОНСАНТО ТЕКНОЛОДЖИ ЭлЭлСи | Способ синтеза альфа-аминоалкиленфосфоновой кислоты |
| RU2694047C2 (ru) | 2012-07-17 | 2019-07-09 | МОНСАНТО ТЕКНОЛОДЖИ ЭлЭлСи | Способ синтеза аминоалкиленфосфоновой кислоты |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3824961A1 (de) * | 1988-07-22 | 1990-01-25 | Basf Ag | Verfahren zur herstellung von bis(aminomethyl)-phosphinsaeure oder deren sauren oder basischen salzen |
| HU203360B (en) * | 1988-11-25 | 1991-07-29 | Monsanto Co | Process for producing n-acylamino methylphosphonates |
-
1990
- 1990-08-17 DE DE4026026A patent/DE4026026A1/de not_active Withdrawn
-
1991
- 1991-08-07 DE DE59107093T patent/DE59107093D1/de not_active Expired - Fee Related
- 1991-08-07 EP EP91914144A patent/EP0543850B1/de not_active Expired - Lifetime
- 1991-08-07 AU AU83100/91A patent/AU8310091A/en not_active Abandoned
- 1991-08-07 DK DK91914144.0T patent/DK0543850T3/da active
- 1991-08-07 CA CA002089652A patent/CA2089652C/en not_active Expired - Fee Related
- 1991-08-07 ES ES91914144T patent/ES2082220T3/es not_active Expired - Lifetime
- 1991-08-07 WO PCT/EP1991/001495 patent/WO1992003450A1/de active IP Right Grant
- 1991-08-07 JP JP51316891A patent/JP3236612B2/ja not_active Expired - Fee Related
- 1991-08-07 AT AT91914144T patent/ATE131485T1/de not_active IP Right Cessation
- 1991-08-15 IL IL9920291A patent/IL99202A/en not_active IP Right Cessation
- 1991-08-16 ZA ZA916503A patent/ZA916503B/xx unknown
- 1991-08-16 PT PT98699A patent/PT98699B/pt not_active IP Right Cessation
- 1991-08-16 CN CN91105717A patent/CN1028995C/zh not_active Expired - Fee Related
- 1991-08-16 IE IE291991A patent/IE912919A1/en unknown
-
1993
- 1993-02-11 US US07/969,167 patent/US5432291A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE59107093D1 (de) | 1996-01-25 |
| ZA916503B (en) | 1992-04-29 |
| IL99202A0 (en) | 1992-07-15 |
| AU8310091A (en) | 1992-03-17 |
| DE4026026A1 (de) | 1992-02-20 |
| IL99202A (en) | 1995-10-31 |
| WO1992003450A1 (de) | 1992-03-05 |
| PT98699B (pt) | 1999-01-29 |
| IE912919A1 (en) | 1992-02-26 |
| CN1059147A (zh) | 1992-03-04 |
| EP0543850A1 (de) | 1993-06-02 |
| PT98699A (pt) | 1992-07-31 |
| JP3236612B2 (ja) | 2001-12-10 |
| CA2089652A1 (en) | 1992-02-18 |
| CA2089652C (en) | 2001-09-18 |
| ES2082220T3 (es) | 1996-03-16 |
| ATE131485T1 (de) | 1995-12-15 |
| JPH06501925A (ja) | 1994-03-03 |
| DK0543850T3 (da) | 1996-03-11 |
| EP0543850B1 (de) | 1995-12-13 |
| US5432291A (en) | 1995-07-11 |
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