CN1874988B - 用于制备2,3,5-三甲基对苯二酚二酰化物的方法 - Google Patents
用于制备2,3,5-三甲基对苯二酚二酰化物的方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C07C67/00—Preparation of carboxylic acid esters
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- C07—ORGANIC CHEMISTRY
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- C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/16—Acetic acid esters of dihydroxylic compounds
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
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Abstract
本发明涉及2，3，5-三甲基-1，4-对苯二酚二酰化物，所述化合物在甲基三磺酸作为催化剂的存在下通过将2，6，6-三甲基环己-2-烯-1，4-二酮与酰化试剂反应得到。
Description
本发明涉及一种用于制备2，3，5-三甲基对苯二酚二酰化物的方法，该方法在甲烷三磺酸的存在下，将2，6，6-三甲基环己-2-烯-1，4-二酮(ketoisophorone，酮基异佛尔酮)与酰化试剂反应。2，3，5-三甲基对苯二酚二酰化物可用作用于制备2，3，5-三甲基对苯二酚的反应物，其本身是己知的用于制备(all-rac)-α-生育酚的一种有价值的反应物。
已知在强酸性催化剂的存在下，通过酮基异佛尔酮与酰化试剂反应可以生产2，3，5-三甲基对苯二酚二酰化物。对于这个目的，过去已经提出了一些这类催化剂，具体的是质子酸，例如，诸如硫酸的无机酸、诸如对甲苯磺酸的有机酸、强酸性离子交换树脂和诸如氯化锌、三氟化硼、五氟化锑和四氯化钛的Lewis酸(特别参见German Offenlegungsschrift 2149159和欧洲专利公开EP 0916642 A1和EP 1028103 A1)、以及NH-酸性催化剂或CH-酸性催化剂(见PCT公开WO03/051812)。
现在已经发现，通过使用少量甲烷三磺酸，可以以高产率完成酮基异佛尔酮到2，3，5-三甲基对苯二酚二酰化物的转化，并不需使用额外的溶剂。总的来说，从催化剂的稳定性、高产率、选择性和成本来考虑，使用甲烷三磺酸作为催化剂远远优于在该反应中曾使用过的其它催化剂。
因而，本发明涉及一种用于制备2，3，5-三甲基对苯二酚二酰化物的方法，该方法在甲烷三磺酸的存在下，将2，6，6-三甲基环己-2-烯-1，4-二酮与酰化试剂反应。
用在本发明的方法中的酰化试剂可以是通常用在酮基异佛尔酮到2，3，5-三甲基对苯二酚二酰化物的转化中的任何酰化试剂，具体是酸酐、酰卤和烯醇酯。酸酐的实例是直链或支链的链烷酸酐，例如乙酸酐、丙酸酐和丁酸酐。酰卤的实例是直链或支链的链烷酰氯，例如乙酰氯、丙酰氯和丁酰氯。最后，烯醇酯的实例是乙酸异丙烯基酯和丁酸异丙烯基酯。优选的酰化试剂是乙酸酐或乙酰氯，尤其是乙酸酐。
本发明的方法可以在无溶剂的情况下实施。同时酰化试剂与酮基异佛尔酮的比率不是严格控制的，酰化试剂与酮基异佛尔酮的摩尔比率合适的是约1∶1-约10∶1，优选的是约5∶1-约3∶1，最优选的是约3∶1。
催化剂(甲烷三磺酸)的用量(基于酮基异佛尔酮计算)合适的是约0.01-约2.0mol％，优选的是约0.075-约1.5mol％，最优选的是约0.1-约1.0mol％。
本方法便于在约0℃-约140℃下实施，优选的是在约20℃-约90℃下，最优选的是在约20℃-约70℃下。
根据本发明的方法可以分批实施或以连续模式实施。而且，本发明便于在惰性气氛中实施，优选的是在氮气或氩气中。
本反应的过程适于通过在反应期间在不同时段从反应混合物中取出的样品进行气相色谱和质谱分析来监测。
在蒸馏出剩余的酰化试剂和在酰化反应中形成的副产物(例如当乙酸酐作为酰化试剂时，副产物为乙酸)后，所制备的2，3，5-三甲基对苯二酚二酰化物可以通过采用例如甲苯的合适有机溶剂从粗产物混合物中分离出。例如，在利用乙酸酐作为酰化试剂来实现这个过程中，在蒸发出用作萃取溶剂的甲苯以后，得到2，3，5-三甲基对苯二酚二乙酸酯无色晶体。另一分离过程是，在终止反应时，通过冷却并可选添加水到混合物中以促进结晶，使2，3，5-三甲基对苯二酚二酰化物从混合物中结晶。
催化剂可以通过用水或酸-水萃取并浓缩萃取物来回收。或者可选地，催化剂可以通过加入一种两相溶剂体系并从极性相(碳酸酯)中将其析出来回收，其中，两相溶剂体系是，例如碳酸酯(具体的是碳酸乙二酯或碳酸丙二酯)和脂族烃(具体的是庚烷或辛烷)。
通过本发明的方法得到的2，3，5-三甲基对苯二酚二酰化物可以通过酯交换反应(即通过用醇处理，例如如异丙醇或正丁醇的脂族醇)转化成2，3，5-三甲基对苯二酚。取决于醇和催化剂的用量和反应混合物中的温度，酯交换反应产生未酯化的2，3，5-三甲基对苯二酚和所形成的酯作为进一步产物。2，3，5-三甲基对苯二酚可以通过已知的方法，通过与异植醇反应(优选地在两相溶剂体系中)转化成(all-rac)-α-生育酚，例如该溶剂体系包括例如碳酸乙二酯或碳酸丙二酯的极性溶剂和尤其是例如庚烷的脂族烃的非极性溶剂，参见国际申请PCT/EP03/01556。
本发明通过以下实施例来进一步阐明。
实施例1
在装有温度计、用于Ar气吹扫的玻璃管(Ф5mm)、回流冷凝器和磁搅拌棒的50ml四口平底反应瓶中加入甲烷三磺酸(见以下表1)和10.324g(66mmol)酮基异佛尔酮。2分钟内，在快速搅拌下滴加乙酸酐(见以下表1)。在滴加期间，混合物从深黄色最后变成深棕色，并且内部温度升高。在冷却到所希望的反应温度以后，通过油浴来维持温度。取出样品并进行定量GC分析。在一定反应时间(见以下表1)后，将反应混合物冷却到室温，并通过添加3.7g(70mmol)无水碳酸钠使催化剂失活。将反应混合物在40℃/10mbar下蒸馏出乙酸和未反应的酸酐来浓缩。利用角鲨烯作为内标通过GC来分析粗产物。结果和反应条件在以下表1中给出：
表1
| (Ac<sub>2</sub>O) [mmol] | (SO<sub>3</sub>H)<sub>3</sub>CH [mg] | (SO<sub>3</sub>H)<sub>3</sub>CH [mol％] | T [℃] | 时间 [h] | 转化率 [％] | TMHQ-DA [％] |
| 200 | 171.2 | 1.0 | 25 | 4 | 97.2 | 91.8 |
| 333 | 171.2 | 1.0 | 25 | 4 | 99.3 | 91.1 |
| 666 | 171.2 | 1.0 | 25 | 4 | 99.2 | 94.0 |
| 200 | 93.5 | 0.55 | 25 | 22 | 78.6 | 69.0 |
| 200 | 171.2 | 1.0 | 25 | 22 | 100 | 96.6 |
| 200 | 342.4 | 2.0 | 25 | 22 | 100 | 93.2 |
| 200 | 120 | 0.7 | 60 | 4 | 99.1 | 91.5 |
| 200 | 120 | 0.7 | 60 | 4 | 99.3 | 92.9 |
| 200 | 120 | 0.7 | 60 | 4 | 98.9 | 92.3 |
| 200 | 34.2 | 0.2 | 70 | 4 | 83.5 | 72.2 |
| 200 | 94.2 | 0.55 | 70 | 4 | 100 | 92.6 |
| 200 | 154.1 | 0.9 | 70 | 4 | 100 | 94.2 |
[0019]
| 200 | 171.2 | 1.0 | 40 | 4.5 | 98.8 | 88.2 |
| 200 | 342.4 | 2.0 | 40 | 3.5 | 100 | 90.0 |
所给出的数值是几次测试(两次或三次)和两次实验的平均值。
Ac2O：乙酸酐，TMHQ-DA：2，3，5-三甲基-1，4-对苯二酚二乙酸酯[产率]
实施例2
利用230ml反应瓶，改变酮基异佛尔酮和乙酸酐的比率重复实施例1的过程。反应条件和结果在以下表2中给出：
表2
| (Ac<sub>2</sub>O)[mmol] | KIP/Ac<sub>2</sub>O[比率] | T [℃] | 时间 [h] | 转化率 [％] | TMHQ-DA [％] | S(TMHQ-DA) [％] |
| 299 | 1∶2.25 | 45 | 12 | 89.7 | 85.8 | 95.6 |
| 332 | 1∶2.5 | 45 | 12 | 91.9 | 87.2 | 94.9 |
| 398 | 1∶3 | 45 | 12 | 95.6 | 90.9 | 95.1 |
| 663 | 1∶5 | 45 | 12 | 98.6 | 94.5 | 95.8 |
| 1327 | 1∶10 | 45 | 12 | 98.1 | 93.0 | 94.8 |
| 398 | 1∶3 | 25 | 24 | 83.6 | 80.6 | 96.3 |
所给出的数值是几次测试(两次或三次)和两次实验的平均值。
S：选择性
实施例3
与实施例1的过程类似，反应条件利用统计模型(STAVEX)来优化。20.32g(200mmol)乙酸酐在十分钟内加到10.324g(66mmol)酮基异佛尔酮中。结果在以下表3中列出：
表3
| (SO<sub>3</sub>H)<sub>3</sub>CH[mg] | (SO<sub>3</sub>H)<sub>3</sub>CH[mmol] | (SO<sub>3</sub>H)<sub>3</sub>CH[mol％] | T [℃] | 时间 [h] | 转化率 [％] | TMHQ-DA [％] |
| 17.2 | 0.07 | 0.1 | 25 | 4 | 0 | 0 |
| 17.4 | 0.07 | 0.1 | 100 | 4 | 43.2 | 14.8 |
| 172.5 | 0.67 | 1.0 | 100 | 4 | 100 | 83.5 |
| 85.6 | 0.33 | 0.5 | 40 | 14 | 97.6 | 89.7 |
[0032]
| 17.2 | 0.07 | 0.1 | 25 | 24 | 10.8 | 1.0 |
| 85.5 | 0.33 | 0.5 | 55 | 14 | 100 | 90.3 |
| 85.5 | 0.33 | 0.5 | 55 | 22 | 100 | 91.4 |
| 171.4 | 0.67 | 1.0 | 25 | 4 | 83.9 | 75.6 |
| 85.6 | 0.33 | 0.5 | 85 | 14 | 100 | 89.6 |
| 17.1 | 0.07 | 0.1 | 100 | 24 | 45.6 | 16.4 |
| 34.4 | 0.13 | 0.2 | 55 | 14 | 88.7 | 79.0 |
| 85.5 | 0.33 | 0.5 | 55 | 6 | 99.5 | 90.4 |
| 171.1 | 0.67 | 1.0 | 25 | 24 | 99.3 | 92.7 |
| 154.2 | 0.60 | 0.9 | 55 | 14 | 100 | 91.3 |
| 171.4 | 0.67 | 1.0 | 100 | 24 | 100 | 84.6 |
| 171.3 | 0.67 | 1.0 | 60 | 7 | 100 | 91.2 |
| 128.1 | 0.50 | 0.8 | 60 | 10 | 100 | 91.9 |
| 85.5 | 0.33 | 0.5 | 60 | 12 | 100 | 93.5 |
实施例4
基于实施例3的结果，在最优化条件下实施实验。结果总结在表4中。
表4
| (Ac<sub>2</sub>O)[mmol] | KIP/Ac<sub>2</sub>O[比率] | (SO<sub>3</sub>H)<sub>3</sub>CH[mol％] | T [℃] | 时间 [h] | 转化率 [％] | TMHQ-DA [％] | S(TMHQ-DA) [％] |
| 398 | 1∶3 | 0.5 | 60 | 6 | 97.4 | 92.0 | 94.5 |
| 663 | 1∶5 | 1.0 | 25 | 24 | 100 | 96.7 | 96.7 |
Claims (9)
1.一种用于制备2，3，5-三甲基-1，4-对苯二酚二酰化物的方法，所述方法在甲烷三磺酸的存在下，将2，6，6-三甲基环己-2-烯-1，4-二酮与酰化试剂反应。
2.如权利要求1所述的方法，其中，所述反应在基于2，6，6-三甲基环己-2-烯-1，4-二酮0.01mol％-2mol％的甲烷三磺酸的存在下实施。
3.如权利要求1所述的方法，其中，所述反应在基于2，6，6-三甲基环己-2-烯-1，4-二酮0.1mol％-1mol％的甲烷三磺酸的存在下实施。
4.如权利要求1所述的方法，其中，所述酰化试剂与2，6，6-三甲基环己-2-烯-1，4-二酮的摩尔比率为10∶1。
5.如权利要求1所述的方法，其中，所述酰化试剂与2，6，6-三甲基环己-2-烯-1，4-二酮的摩尔比率为为3∶1。
6.如权利要求1所述的方法，其中，所述酰化试剂是乙酸酐。
7.如权利要求1所述的方法，其中，所述反应在0℃-140℃下实施。
8.如权利要求1所述的方法，其中，所述反应在20℃-70℃下实施。
9.一种通过如下制备α-生育酚的方法，将根据权利要求1得到的所述2，3，5-三甲基-1，4-对苯二酚二酰化物通过酯交换转化成2，3，5-三甲基对苯二酚并且通过与异植醇的反应转化成α-生育酚。
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| EP03025513.7 | 2003-11-07 | ||
| EP03025513 | 2003-11-07 | ||
| PCT/EP2004/012058 WO2005044775A1 (en) | 2003-11-07 | 2004-10-26 | Process for the preparation of 2,3,5-trimethylhydroquinone diacylates |
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| US10729469B2 (en) | 2006-01-09 | 2020-08-04 | Roger P. Jackson | Flexible spinal stabilization assembly with spacer having off-axis core member |
| US8353932B2 (en) | 2005-09-30 | 2013-01-15 | Jackson Roger P | Polyaxial bone anchor assembly with one-piece closure, pressure insert and plastic elongate member |
| US10258382B2 (en) | 2007-01-18 | 2019-04-16 | Roger P. Jackson | Rod-cord dynamic connection assemblies with slidable bone anchor attachment members along the cord |
| US7621918B2 (en) | 2004-11-23 | 2009-11-24 | Jackson Roger P | Spinal fixation tool set and method |
| US8066739B2 (en) | 2004-02-27 | 2011-11-29 | Jackson Roger P | Tool system for dynamic spinal implants |
| WO2005092218A1 (en) | 2004-02-27 | 2005-10-06 | Jackson Roger P | Orthopedic implant rod reduction tool set and method |
| US9216041B2 (en) | 2009-06-15 | 2015-12-22 | Roger P. Jackson | Spinal connecting members with tensioned cords and rigid sleeves for engaging compression inserts |
| US8366745B2 (en) | 2007-05-01 | 2013-02-05 | Jackson Roger P | Dynamic stabilization assembly having pre-compressed spacers with differential displacements |
| US10383660B2 (en) | 2007-05-01 | 2019-08-20 | Roger P. Jackson | Soft stabilization assemblies with pretensioned cords |
| US8911477B2 (en) | 2007-10-23 | 2014-12-16 | Roger P. Jackson | Dynamic stabilization member with end plate support and cable core extension |
| JP5716291B2 (ja) * | 2009-04-27 | 2015-05-13 | セントラル硝子株式会社 | 含フッ素レジスト用モノマー類の製造方法 |
| ES2978483T3 (es) * | 2019-12-19 | 2024-09-13 | Dsm Ip Assets B V | Proceso de preparación de hidroquinonas |
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| US3053884A (en) * | 1959-10-09 | 1962-09-11 | Eastman Kodak Co | Esterification by means of methane disulfonic acid and methane trisulfonic acid catalysts |
| DE2149159A1 (de) * | 1970-10-01 | 1972-04-06 | Eastman Kodak Co | Verfahren zur Herstellung von Trimethylhydrochinon |
| US4827021A (en) * | 1988-03-07 | 1989-05-02 | Eastman Kodak Company | Process for the preparation of alkyl 3-alkoxypropionates |
| CN1265390A (zh) * | 1999-02-11 | 2000-09-06 | 底古萨－胡尔斯股份公司 | 2,3,5－三甲基对苯二酚二酯的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| IL41330A (en) * | 1973-01-17 | 1975-07-28 | Imi Inst For Res & Dev | Solid catalyst for heterogeneous reactions |
| ATE204251T1 (de) * | 1996-05-14 | 2001-09-15 | Degussa | Verfahren zur herstellung von trimethylhydrochinon |
| DE69708450T2 (de) * | 1996-12-27 | 2002-05-16 | Daicel Chemical Industries, Ltd. | Methode zum Herstellen von Trimethylhydroquinondiester |
| DE19805690A1 (de) * | 1998-02-12 | 1999-08-19 | Degussa | Verfahren zur Herstellung von Trimethydrochinondiestern und von Trimethylhydrochinon |
| DE19817644A1 (de) * | 1998-04-21 | 1999-10-28 | Degussa | Neues Verfahren zur Herstellung von 2,3,5-Trimethylhydrochinondiestern |
| DE10017494A1 (de) * | 2000-04-07 | 2001-10-11 | Degussa | Verfahren zur Herstellung von Trimethylhydrochinon-Diacetat und Trimethylhydrochinon |
| US7153994B2 (en) * | 2001-12-14 | 2006-12-26 | Dsm Ip Assets B.V. | Manufacture of trimethylhydroquinone diacylates |
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- 2004-10-26 JP JP2006538692A patent/JP4749336B2/ja not_active Expired - Fee Related
- 2004-10-26 DE DE602004014290T patent/DE602004014290D1/de active Active
- 2004-10-26 CN CN2004800323125A patent/CN1874988B/zh active Active
- 2004-10-26 EP EP04790843A patent/EP1680392B1/en not_active Not-in-force
- 2004-10-26 KR KR1020067008782A patent/KR101126908B1/ko active IP Right Grant
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3053884A (en) * | 1959-10-09 | 1962-09-11 | Eastman Kodak Co | Esterification by means of methane disulfonic acid and methane trisulfonic acid catalysts |
| DE2149159A1 (de) * | 1970-10-01 | 1972-04-06 | Eastman Kodak Co | Verfahren zur Herstellung von Trimethylhydrochinon |
| US4827021A (en) * | 1988-03-07 | 1989-05-02 | Eastman Kodak Company | Process for the preparation of alkyl 3-alkoxypropionates |
| CN1265390A (zh) * | 1999-02-11 | 2000-09-06 | 底古萨－胡尔斯股份公司 | 2,3,5－三甲基对苯二酚二酯的制备方法 |
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| US7361781B2 (en) | 2008-04-22 |
| KR101126908B1 (ko) | 2012-03-19 |
| EP1680392A1 (en) | 2006-07-19 |
| WO2005044775A1 (en) | 2005-05-19 |
| JP2007533653A (ja) | 2007-11-22 |
| EP1680392B1 (en) | 2008-06-04 |
| JP4749336B2 (ja) | 2011-08-17 |
| CN1874988A (zh) | 2006-12-06 |
| DE602004014290D1 (de) | 2008-07-17 |
| KR20060107769A (ko) | 2006-10-16 |
| US20070123720A1 (en) | 2007-05-31 |
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