CN1170804C - 邻位取代的苯甲醛、它的制备方法和用途 - Google Patents
邻位取代的苯甲醛、它的制备方法和用途 Download PDFInfo
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- 150000002641 lithium Chemical class 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- HTZGVHYSMVGNOV-UHFFFAOYSA-N lithium;dicyclohexylazanide Chemical compound [Li+].C1CCCCC1[N-]C1CCCCC1 HTZGVHYSMVGNOV-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/55—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2323/00—Functional layers of liquid crystal optical display excluding electroactive liquid crystal layer characterised by chemical composition
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Abstract
式(I)的化合物它是通过在溶剂或溶剂混合物中、在-60℃以下的温度下，将式(II)卤代苯与有机锂化合物反应，然后与式(III)甲酰基等同物反应来制备的，该化合物可用作制备农用化学品、电子材料和药品的起始原料。
Description
技术领域及背景技术
在化学文献中对作为用于活性物质合成的起始原料(例如，EP-A-0174 131，EP-A-0 271 240，EP-A-0 289 942，FR-A-1 514 517，US-A-3856 504，US-A-3 982 020US-A-4 902 814)或一般作为中间体(DE-A 3310 953)的、有邻位卤素取代基或有总共至多5个取代基的苯甲醛进行了广泛的描述。以2-氯-6-氟苯甲醛，2-溴-6-氟苯甲醛和2-氟-6-碘苯甲醛形式存在的、在一个邻位上具有氯、溴或碘取代基和在另一个邻位上具有氟取代基的醛是已知的。然而，对具有多个氟取代基和其它官能团的化合物存在着需求，因为氟化或不同程度的氟化通过改变亲油性和/或偶极距经常会增强农用化学品或药品的活性(Kanie等人，Bull.Chem.Soc.Jpn.(日本化学协会简报)2000，73，471)。
具有多个氟取代基-其中一个与醛官能团相邻-和邻位卤素取代基(不是氟)的苯甲醛是未知的，尽管这些化合物中的一些能够从上述参考文献的通式中得出。
发明内容
因此本发明提供了式(I)的邻位取代苯甲醛：
其中X1，X2和Y具有以下含义：
X1＝H或F
X2＝H或F
Y＝Cl，Br或I。
优选下面的化合物：
a)X1和X2是H
Y是Cl或Br；或
b)X1是F，X2是H
Y是Cl或Br；或
c)X1和X2是F
Y是Cl或Br；
尤其为
2-氯-5，6-二氟苯甲醛
2-氯-5，6-二氟苯甲醛
2-氯-4，5，6-三氟苯甲醛
2-溴-4，5，6-三氟苯甲醛。
本发明而且提供了制备式(I)化合物的方法，它包括，在溶剂或溶剂混合物中、在不促进阿林(arine)形成的温度下，使其中Y，X1和X2如式(I)所定义的式(II)的卤代苯与有机锂化合物反应。锂化合物与起始原料(II)的摩尔比优选是1∶1-1.2∶1，所得到的锂化合物然后再次在不促进阿林(arine)形成的温度下与式(III)的甲酰基等同物反应，随后水解得到(I)。(II)与(III)的摩尔比优选是1∶1-1∶2
在(III)中，R1具有1-6个碳原子的烷基，三甲基甲硅烷基或(取代或未取代的)苯基，R2是具有1-6个碳原子的烷基，三甲基甲硅烷基或(取代或未取代的)苯基，和R3是-CH(＝O)或-CH(OR4)2；R1和R2与氮原子一起还可以是五元到七元环的一部分。R4是具有1-4个碳原子的烷基。
式(II)化合物与有机锂化合物的反应优选在-60℃以下的温度下，尤其优选在-70℃以下的温度下，更尤其在-70℃到-110℃的温度下进行。典型的反应时间是1-8小时。当反应结束时(例如可通过DC或GC检测)，将反应混合物缓慢升温到-25℃到-15℃，仔细用水进行水解。使用盐酸将混合物酸化到pH为1-5，并用适合的溶剂(例如，叔丁基甲基醚，二氯甲烷，乙酸乙酯，甲苯)萃取。合并有机相的提取物，例如用硫酸钠进行干燥。在减压下除去溶剂，以得到所需的式(III)邻位取代的苯甲醛，如果需要，产物能够通过液相色谱法、蒸馏或结晶或它们的结合来纯化。典型的收率是在50-80％的范围内，基于(II)计。有机锂化合物优选是仲胺的锂化合物，尤其具有大的取代基。尤其优选二异丙基氨基化锂，2，2，6，6-四甲基哌啶锂，二环己基氨基化锂，环己基异丙基氨基化锂或双(三甲基甲硅烷基)氨基化锂。尤其，优选2，2，6，6-四甲基哌啶锂。对于那些其中Y是Cl的式(II)化合物，有机锂化合物是烷基锂化合物或仲胺的锂化合物；优选正丁基锂。如果需要，可以加入叔丁醇钾以改善活化。
在优选的实施方案中，式(II)中的Y是Br。理想的是，将活化剂或选择性改性剂加到反应混合物中，例如四甲基乙二胺或叔丁醇钾(后者对于那些其中Y是Cl的式(II)化合物是优选的)。
式(III)的甲酰基等同物优选是N，N-二甲基甲酰胺，N，N-二乙基甲酰胺，N，N-二乙基甲酰胺，N，N-二丙基甲酰胺，N，N-二异丙基甲酰胺，N，N-二丁基甲酰胺，N-甲酰基吡咯烷酮，N-甲酰基吗啉，N-甲酰基哌啶，二甲基甲酰胺二烷基乙酰，N-甲基甲酰苯胺，N-乙基甲酰苯胺或N，N-双(三甲基甲硅烷基)甲酰胺。
式(III)的甲酰基等同物尤其优选N，N-二甲基甲酰胺。
用于本发明的适合溶剂是质子惰性溶剂，例如醚如四氢呋喃、1，2-二甲氧基乙烷、1，4-二噁烷、乙醚，或者烃如己烷、环己烷、庚烷、戊烷或这些质子惰性溶剂的混合物。
(II)与有机锂化合物的反应也能够在化合物(III)的存在下进行，以便从(II)原位形成的锂衍生物能够直接与(III)反应。为此，在-60℃以上，例如在-20到+25℃的范围内进行反应是必要和理想的。
本发明而且提供了式(I)的化合物作为制备农用化学品，电子材料，尤其液晶，以及药品的起始原料的用途。式(I)的化合物尤其适合于这些目的，因为醛官能团(例如，经Witting反应，还原得到苄基醇，与C-H、N-H或S-H化合物缩合)和卤素官能团(这里指取代基Y的官能团)(例如经Suzuki偶联，Grignard反应，Heck反应)可为反应所利用，以及有可能在其中X1是F的那些化合物或由它衍生的产物的情况下，更尤其在其中X1和X2是F的那些化合物或由它衍生的产物的情况下的特定条件下，可利用二氟芳族化合物(例如，经邻位金属取代)或三氟芳族化合物(例如，经邻位金属取代或芳族亲核取代)或四氟芳族化合物(例如，经芳族亲核取代)的反应活性。
实施例：
实施例1 2-溴-5，6-二氟苯甲醛
152mmol的2，2，6，6-四甲基哌啶和152mmol的正丁基锂(在正己烷中的1.6M溶液)在280ml干燥四氢呋喃中的溶液在-75℃下与145mmol的1-溴-3，4-二氟苯混合。保持该温度4小时，然后滴加174mmol的DMF。然后缓慢解冻该反应混合物，用水在-20℃下水解，使用盐酸酸化，和用叔丁基甲基醚萃取。用饱和氯化钠溶液洗涤所合并的有机萃取物，并使用硫酸钠干燥。在减压下除去该溶剂，粗产物通过液相色谱法在硅胶上纯化(洗脱剂：二氯甲烷/正庚烷1∶1)和从正庚烷中重结晶，得到呈微黄色晶体的18g(56％)2-溴-5，6-二氟苯甲醛。熔点：40-43.5℃。1H-NMR(400MHz，CDCl3/TMS)：
δ＝10.31(dd，4J(HF)＝2Hz，5J(HF)＝1.5Hz，1H，CHO)，7.45(ddd，3J(HH)＝9Hz，4J(HF)＝4Hz，5J(HF)＝2Hz，1H，Har)，7.28(ddd，3J(HF)＝9Hz，4J(HF)＝8Hz 1H，Har)。19F-NMR(376.5MHz，1H宽带去耦，CDCl3/CFCl3)：δ＝-136.4(d，3J＝19.2Hz)，-139.2(d，3J＝19.2Hz)。
实施例2
2-溴-4，5，6-三氟苯甲醛能够以与实施例1相似的方式从1-溴-3，4，5-三氟苯起始来获得。1H-NMR(400MHz，CDCl3/TMS)：δ＝10.24(dd，4J(HF)＝1.5Hz，5J(HF)＝1Hz，1H，CHO)，7.38(ddd，3J(HH)＝9Hz，4J(HF)＝6Hz，5J(HF)＝2Hz，1H，Har)，19F-NMR(376.5MHz，1H宽带去耦，CDCl3/CFCl3)：δ＝-123.4(dd，3J＝20Hz和13Hz)，-135.9(dd，3J＝19Hz和13Hz)，-158.0(dd，3J＝19Hz和13Hz)。
实施例3
2-氯-5，6-二氟苯甲醛能够与实施例1相似从1-氯-3，4-二氟苯起始来获得。
实施例4
2-溴-3，4，5，6-四氟苯甲醛能够与实施例1相似从1-溴-2，3，4，5-四氟苯起始来获得。
实施例5
2-氯-3，4，5，6-四氟苯甲醛能够与实施例1相似从1-氯-2，3，4，5-四氟苯起始来获得。
实施例6
2-碘-5，6-二氟苯甲醛能够与实施例1相似从3，4-二氟苯起始来获得。
应用实施例1
根据Kumar，有机化学期刊1997，62，8535-8539页中所述，将2-溴-5，6-二氟苯甲醛与4-戊基苯基硼酸在Pd催化剂的存在下反应，以得到3，4-二氟-4’-戊基二苯基-2-羧醛(carbaldehyde)。该化合物根据Kumar，上文所述与三甲基碘化锍反应，以得到3，4-二氟-2-(环氧乙烷-1-基)-4’-戊基联苯。无需进一步纯化，该化合物在BF3醚合物的存在下被转化为1，2-二氟-7-戊基菲。粗产品通过一般用于这种液晶材料的工序来纯化(参考DE-A 195 00 768)，产生呈无色晶体的1，2-二氟-7-戊基菲。
Claims (4)
1、式(I)的化合物：
其中X1，X2和Y具有以下含义：
X1＝H或F，
X2＝H或F，
Y＝Cl，Br或I。
2、权利要求1所要求的化合物，其中：
a)X1和X2是H
Y是Cl或Br；或
b)X1是F，X2是H
Y是Cl或Br；或
c)X1和X2是F，
Y是Cl或Br。
3、制备权利要求1或2所要求的化合物的方法，其特征在于，在正己烷和四氢呋喃的溶剂混合物中、在低于-60℃的温度下，使其中Y为Cl、Br或I，X1为H或F和X2为H或F的式(II)卤代苯与有机锂化合物为2，2，6，6-四甲基哌啶锂反应，然后与甲酰基等同物为二甲基甲酰胺或二乙基甲酰胺反应，随后水解。
4、权利要求1或2所要求的化合物作为用于制备液晶混合物的组分的起始原料的用途。
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| DE10022661.2 | 2000-05-10 | ||
| DE10022661A DE10022661A1 (de) | 2000-05-10 | 2000-05-10 | Ortho-substituierte Benzaldehyde, Verfahren zu ihrer Herstellung und ihre Verwendung |
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| EP (1) | EP1153909B1 (zh) |
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| DE10225048B4 (de) * | 2001-06-07 | 2015-03-12 | Merck Patent Gmbh | Fluorierte (Dihydro)phenanthrenderivate und deren Verwendung in flüssigkristallinen Medien |
| DE10145780B4 (de) | 2001-09-17 | 2012-10-04 | Merck Patent Gmbh | Fluorierte Cyclopenta[a]naphthaline und ihre Verwendung in Flüssigkristallmischungen und Displays |
| DE10145779B4 (de) * | 2001-09-17 | 2012-11-15 | Merck Patent Gmbh | Fluorierte Cyclopenta[b]naphthaline und ihre Verwendung in Flüssigkristallmischungen |
| US6677479B2 (en) | 2001-11-13 | 2004-01-13 | Clariant Finance Lbvi Limited | Substituted fluoroaromatics, process for preparing them and their use |
| DE102004022728B4 (de) * | 2004-05-07 | 2018-08-23 | Merck Patent Gmbh | Fluorierte Phenanthrene und ihre Verwendung in Flüssigkristallmischungen |
| CN102659544A (zh) * | 2012-05-02 | 2012-09-12 | 上海中新裕祥化工有限公司 | 2，3-二氟苯甲醛的制备方法 |
| CN102659546A (zh) * | 2012-05-03 | 2012-09-12 | 江苏泰特尔化工有限公司 | 一种新型的液晶中间体4-溴-2,3-二氟苯甲醛 |
| CN104447250A (zh) * | 2014-12-24 | 2015-03-25 | 常熟市新华化工有限公司 | 一种由对氯甲苯合成对氯苯甲醛的方法 |
| CN105967974B (zh) * | 2016-05-06 | 2018-08-31 | 蚌埠中实化学技术有限公司 | 一种2-甲基-3,4,5-三氟溴苯的制备方法 |
| CN111018892A (zh) * | 2020-01-03 | 2020-04-17 | 烟台盛华液晶材料有限公司 | 一种芳烃氟邻位金属化的制备方法 |
| CN115010574B (zh) * | 2022-06-06 | 2024-01-05 | 爱斯特（成都）生物制药股份有限公司 | 1-溴-2-氯-4-氟-2碘苯的合成方法 |
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| CH471196A (de) * | 1966-04-06 | 1969-04-15 | Basf Ag | Verfahren zur Herstellung eines orangen Pigmentfarbstoffs |
| FR1514517A (fr) | 1967-03-08 | 1968-02-23 | Ile De France | Procédé de préparation de dérivés de n-substitués benzamides |
| US3982020A (en) * | 1970-03-17 | 1976-09-21 | Sandoz, Inc. | Substituted benzylidene hydrazines for treating hyperglycemia, obesity and inflammation |
| US3856504A (en) * | 1971-06-08 | 1974-12-24 | Hercules Inc | Use of certain n-(2,6-dihalobenzylidene)-benzylamines and certain n-(2,6-dihalobenzylidene)phenylethylamines to increase crop yield |
| DE3310953A1 (de) * | 1983-03-25 | 1984-09-27 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von benzalchloriden |
| EP0174131A3 (en) | 1984-09-01 | 1989-06-07 | FISONS plc | Dihydropyridines, processes and intermediates for their production, and pharmaceutical formulations containing them |
| AU6042686A (en) * | 1985-07-29 | 1987-02-05 | American Home Products Corporation | 1,4,5,6,7,8-hexahydro-(substituted) phenyl-1,7- napthyridine-3-carboxylic acid derivatives |
| GB8617649D0 (en) * | 1986-07-18 | 1986-08-28 | Ici Plc | Fluorobenzyl esters |
| GB8629806D0 (en) | 1986-12-12 | 1987-01-21 | Ici Plc | Fluorobenzyl esters |
| DE3882167T2 (de) | 1987-05-08 | 1994-04-07 | Ihara Chemical Ind Co | Verfahren zur Herstellung von Fluorbenzaldehyden. |
| US5340833A (en) * | 1992-05-01 | 1994-08-23 | Eisai Co., Ltd. | Urokinase inhibitors |
| US5648021A (en) * | 1994-01-17 | 1997-07-15 | Hoechst Aktiengesellschaft | Phenanthrene derivatives and their use in liquid-crystalline mixtures |
| DE19500768C2 (de) | 1994-01-17 | 2003-11-20 | Aventis Res & Tech Gmbh & Co | Phenanthren-Derivate und ihre Verwendung in flüssigkristallinen Mischungen |
| UA56185C2 (uk) * | 1996-09-30 | 2003-05-15 | Пфайзер Інк. | Аралкіл- та аралкіліденгетероциклічні лактами та іміди, фармацевтична композиція та спосіб лікування |
| GB0005789D0 (en) * | 2000-03-11 | 2000-05-03 | Knoll Ag | Therapeutic agents |
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- 2001-05-10 US US09/852,552 patent/US6811832B2/en not_active Expired - Fee Related
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| EP1153909B1 (de) | 2004-10-13 |
| US20010050352A1 (en) | 2001-12-13 |
| CN1339428A (zh) | 2002-03-13 |
| EP1153909A2 (de) | 2001-11-14 |
| EP1153909A3 (de) | 2002-07-24 |
| US6811832B2 (en) | 2004-11-02 |
| JP2001316323A (ja) | 2001-11-13 |
| KR20010104657A (ko) | 2001-11-26 |
| DE50104070D1 (de) | 2004-11-18 |
| KR100758518B1 (ko) | 2007-09-14 |
| DE10022661A1 (de) | 2001-11-15 |
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