CN1286674A - 制备1-(3,4-二甲氧基苯基)乙醇的方法 - Google Patents
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Abstract
本发明的主题是通过还原式(Ⅱ)的3,4-二甲氧基苯乙酮,制备式(Ⅰ)的1-(3,4-二甲氧基苯基)乙醇的方法,其特征在于,式(Ⅱ)的3,4-二甲氧基苯乙酮的羰基在催化氢化条件下被1摩尔氢还原。
Description
本发明的主题是通过还原式Ⅱ的3,4-二甲氧基苯乙酮,并适合于大规模合成1-(3,4-二甲氧基苯基)乙醇(另一名称为α-甲基藜芦基醇)的多相催化氢化法。
标题化合物是许多重要化合物的原料,对其需求越来越大。例如,它可以用于制备WO97/19040和匈牙利专利申请No3318/95和0893/97中所述的杀虫剂增效剂。因此,需要精心设计一种很经济的技术,其获得的粗产物必须是高纯度的,并且不需要诸如蒸馏之类的纯化操作。被甲氧基取代的1-苯基乙醇就是非常敏感的化合物,该化合物在纯化条件下会造成很大的损失。蒸馏期间热作用和/或痕量酸或碱的作用,会使所述化合物很容易转化为式Ⅲ的双-苯基乙基醚(药物化学通报《Chem.Pharm.Bull.》31,3024(1983);化学会志《J.Chem.Soc.》3158(1957);美国化学会志《J.Am.Chem.Soc.》70,1895(1948)),或通过脱水,它们可形成式Ⅳ的苯乙烯衍生物(美国化学会志《J.Am.Chem.Soc.》106,1361(1984))。
在文献中有两种合成1-(3,4-二甲氧基苯基)乙醇的基本方法。根据第一种方法,该化合物通过3,4-二甲氧基苯甲醛与甲基碘化镁反应制备(药物化学通报《Chem.Pharm.Bull.》31,3024(1983));根据第二种方法,通过还原3’,4’-二甲氧基苯乙酮(另一名称为乙酰藜芦酮)制备。后者的还原可以通过用硼氢化钠(Bull.Soc.Chim.France 1973,2667;J.Chem.Soc.Perkin 2,1994,961;(美国化学会志《J.Am.Chem.Soc.》)86,1186(1964))、氢化三丁基锡(有机化学杂志《J.Org.Chem.》59,7138(1994))、乙醇中的钠(Arch.Pharm(Weinheim Ger.)248,139(1910))、或异丙醇中的异丙醇铝(Ann.1995,677)来进行。考虑到试剂的昂贵成本、特殊的反应条件(例如无水溶剂)、产生的废物以及复杂的操作和纯化工艺,上述方法没有一个适合于大规模生产。
在现有文献中没有提到式Ⅱ的乙酰藜芦酮的多相催化氢化方法。这是出人意料的,因为此途径对于以工业规模制备式Ⅰ化合物来说似乎是最经济的。
羰基的氢化需要活性催化剂。对于苯乙酮的还原,可以使用的催化剂有铂族金属(铂、钯、铑、钌、铱)(Ann.1924,276;有机化学杂志《J.Org.Chem.》24,1885(1959);日本化学会通报《Bull.Chem.Soc.Jpn.》34,32(1961))、镍(美国化学会志《J.Am.Chem.Soc.》52,4349(1930);有机化学杂志《J.Org.Chem.》45,1937,1946(1980))、阮内镍(Raney-nickel)(美国化学会志《J.Am.Chem.Soe.》70,695(1984);J.Chem.Soc.3158(1957);Ann.714,91(1968);Bull.Soc.Chim.France 1972,4324)或亚铬酸铜(美国化学会志《J.Am.Chem.Soc.》53,1090(1931))。但是,这些金属的选择性是不同的。铑催化剂倾向于还将环饱和;根据溶剂和pH,铂可以引起氢解,即出现式Ⅴ的乙苯副产物。对于苯乙酮的催化氢化,文献建议使用10%Pd/C催化剂(Paul Rylander,有机合成中的催化氢化《Catalytic Hydrogenation in organic Synthesis》;103页,学术出版社(Academic Press),1979)。
我们的第一个实验证明不能直接使用已知方法。按照文献建议的工艺,用10%Pd/C作为催化剂,在普通条件(25℃,latm)下,以甲醇为溶剂,式Ⅱ乙酰藜芦酮的氢化不能给出单一的产物:除了预期的1-(3,4-二甲氧基苯基)乙醇之外,还形成大量乙基藜芦醚。酮基的氢化和产物C-O键的水解以类似的速度同时进行,还分离出大量的1-(3,4-二甲氧基苯基)乙基甲基醚副产物。供电子的烷氧基使苄基碳原子活化从而发生亲核取代,因此,后者在给定的条件下,例如在催化剂的表面,可以与亲核物,在我们的发明中是与溶剂(即醇类)反应,但也可以还与还原产物(即α-甲基藜芦基醇)反应。所有这些都增加了所需的式Ⅰ的α-甲基藜芦基醇的敏感性,这使得该方法更加难以实现,也可以解释为什么氢化法没有用于该化合物的制备。
由于所讨论化合物的需求增长,以及催化氢化的成本比较低廉,激励我们不顾上述困难,设计出没有上述缺点的氢化法,即以高产率、高纯度和比前述方法更经济地产生所需的式Ⅰ化合物的方法。
虽然比较少见,但镍和阮内镍也被用于苯酮的氢化,该反应主要在乙醇和甲醇性介质中进行。根据相关文献报道,成功的反应需要相当苛刻的条件(Paul Rylander,有机合成中的催化氢化《Catalytic Hydrogenation in organic Synthesis》;83页,学术出版社,1979)。可以预料,在这些反应中,还会形成1-苯基乙基乙基或甲基醚。如果使用水介质或中性催化剂,这些副产物的形成在理论上可以排除。即使如此,在现有文献中也不能找到给定化合物在水介质中氢化的实施例。其原因可能是原料和产物预期相当难溶于水,其没有进行溶剂化;同时由于极性溶剂化层的存在导致催化剂表面失活(Paul Rylander,有机合成中的催化氢化《CatalyticHydrogenation in Organic Synthesis》;83页,学术出版社,1979),所有这些都将引起还原作用减缓。根据上述情况,反应将会形成副产物。
为了研究这一点,我们计算了乙酰藜芦酮的分配率。令我们惊奇的是,得到了相当低的值(计算的1gp≌122,K(辛醇,水)≌16)。这意味着该物质具有弱亲水特征和适当的极性。随着温度增加,该值将进一步改善,这表明反应有可能进行,并抑制副产物形成。在高于原料熔点(50℃)的温度下进行氢化,可以通过剧烈搅拌水介质中的溶质来保证适当的分散度和溶剂化平衡。实验证实了我们的预测。通过用中性阮内镍催化剂,我们研究了乙酰藜芦酮在20-80℃的氢化。5-48小时后,观察到完全转化,并形成了单一产物。如果反应在50-80℃、6-10巴的氢气压力下进行,实现完全转化的时间要短的多,根据搅拌强度(700-12501/min),反应可在3-7小时内完成。减压蒸发即可从反应混合物得到产物。各种情况下的产率都超过98%。如分析实验(GC,HPLC,VRK)所示,以超过98%纯度的原料作为起始物,产物的纯度高于97%。未反应的起始原料和乙基藜芦醚副产物的总量低至约0.5%。产物的高纯度也可以通过这一现象表现出来:虽然该化合物在以前只知道是一种粘稠的油状物,并且没有披露其熔点,但由本发明方法得到的该化合物放置即结晶。
根据上文所述,本发明的主题是通过还原式Ⅱ的3,4-二甲氧基苯乙酮,制备式Ⅰ的1-(3,4-二甲氧基苯基)乙醇的方法,其特征在于,式Ⅱ的3,4-二甲氧基苯乙酮的羰基在催化氢化条件下用1摩尔氢还原。
所述还原优选采用阮内镍催化剂,在质子性溶剂、优选在含水介质中,在25-100℃、优选在50-100℃的温度下,在1-20巴的压力、优选在5-10巴的压力下进行。
对于阮内镍催化剂,优选地以0.05-0.5重量份使用中性-弱碱性pH7-9促进的阮内镍。
与已知方法相比,本发明的方法具有许多优点:●产率实际上是定量的,●通过过滤,接着简单蒸发,可以分离出产物,而且产物是高纯度的,不需要进一步纯化,●产物为结晶形式,因而更稳定,更易于处理,并可以更好地存贮,●滤出的催化剂可以在接下来的还原中再使用,●考虑到安全性和经济因素,使用水作为溶剂是非常有利的,●该技术具有良好的设备利用率,可以充分利用反应器的容积,而反应时间只有几小时,●不形成废物、副产物。
本发明进一步的细节通过下列实施例说明,但权利要求将不仅限于实施例。实施例1
向装有用于加热和冷却的内盘管、搅拌器、压力计和温度计的10升氢化器中加入3.5kg(19.4mol)3,4一二甲氧基苯乙酮。将0.26kg(0.074份)细粉状阮内镍促进的催化剂浆状物(pH=8-9)加入其中,催化剂用1kg水洗涤。向反应器中加入3.5kg水,用氮气清洗,然后用氢气清洗。在强烈搅拌下(每分钟转速约1420min-1),使混合物在70-85℃与8-10巴的氢气反应。7小时后,氢气停止消耗。关闭氢气阀,将反应后氢化(post-hydrogenated)半小时,然后冷却。滤除催化剂。通过旋转蒸发器在40-50℃水浴中将滤液真空(20乇)浓缩。
产物为黄色粘滞性油状物,重3.48kg(19.1mol,98.5%)。折光率(NaD,25℃)为1.5385;HPLC分析纯度为97.3%;Karl-Fisher法测定水的含量为1.2%。TLC(Kieselgel 60 F254苯-EtAc 7∶3 v/v)显示一个点(Rf=0.28,通过UV和PMA显色)。
一部分产品用1.5倍体积的乙醚-轻汽油(2∶1,v/v)混合物结晶。所得白色晶体的熔点为34-35℃。结构的证实IR(KBr,cm-1)v:3312,3056,3006,2966,2926,2880,2844,1608,1594,1522,
1467,126l,1237,1162,1140,1091,1075,1028,861,814.1H-NMR(200 MHz,CDCl3)δ:1.47(3H,d,J=6.4 Hz,CH3),2.08(1H,s,OH),
3.86和3.88(总共6H,各s,CH3O),4.83(1H,
q,J=6.4 Hz,CHOH),6.79-6.93(3H,m,芳氢)13C-NMR(50MHz,CDCl3)δ:25.05(CH3),55.79和55.89(CH3O),70.10
(ArCH),108.65(C-2),110.98(C-5),117.48(C-6),
138.57(C-1),148.28和149.0(C-3,C-4).文献数据CAS登记号:5653-65-6CA名称:1-(3,4-二甲氧基苯基)-乙醇沸点:145-150(4乇),折光率(Zhur.Obshchei Khim.27,2142(1957),CA 52:8089g)(NaD 20℃)1.5440●1H-NMR(200MHz,CDCl3)δ:1.48(d,J=6.5Hz),3.86和89(s),4.84(q),6.8-6.94(m).●13C-NMR(Ann.1977.588)(50MHz,CDCl3)δ:25.0,55.8,55.9,70.1,108.7,111.1,117.5,138.6,148.4,149.1
实施例2
向装有用于加热和冷却的内盘管、压力计和温度计的氢化器中加入50g(0.278mol)3,4-二甲氧基苯乙酮。将7.5g(0.15重量份)细粉状阮内镍促进催化剂浆状物(pH=8-9)加入其中,催化剂用50ml水洗涤。反应器用氮气清洗,然后用氢气清洗,并在70-85℃下与8-10巴的氢气反应,同时用摇动器搅动。3.5小时后,氢气停止消耗。关闭氢气阀,将反应后氢化半小时。然后冷却,滤除催化剂。通过旋转蒸发器在40-50℃水浴中将水从滤液中真空(20乇)蒸除。产物为黄色粘滞性油状物,重49.6g(0.273mol,98%)。产物的质量与实施例1中所得的产物相似。
Claims (7)
1.通过还原式Ⅱ的3,4-二甲氧基苯乙酮来制备式Ⅰ的1-(3,4-二甲氧基苯基)乙醇的方法,其特征在于:式Ⅱ的3,4-二甲氧基苯乙酮的羰基在催化氢化条件下被1摩尔氢还原。
2.根据权利要求1的方法,其特征在于,该还原用阮内镍催化剂进行。
3.根据权利要求1-2的方法,其特征在于催化剂优选以0.05-0.5重量份的量使用中性-弱碱性pH7-9促进的阮内镍。
4.根据权利要求1-3的方法,其特征在于所述还原在质子性溶剂存在下、优选在含水介质中进行。
5.根据权利要求1-4的方法,其特征在于所述还原在25-100℃、优选在50-100℃的温度下进行。
6.根据权利要求1-5的方法,其特征在于所述还原用氢气在1-20巴的压力、优选在5-10巴的压力下进行。
7.高纯度、结晶的式Ⅰ所示的1-(3,4-二甲氧基苯基)乙醇,其熔点为33-36℃。
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HU9701335A HU219175B (hu) | 1997-07-31 | 1997-07-31 | Eljárás 1-(3,4-dimetoxi-fenil)-etanol előállítására |
HUP9701335 | 1997-07-31 |
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EP (1) | EP1000005B1 (zh) |
JP (1) | JP2002509549A (zh) |
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CN (1) | CN1286674A (zh) |
AT (1) | ATE240922T1 (zh) |
AU (1) | AU8554198A (zh) |
CA (1) | CA2294014C (zh) |
DE (1) | DE69814865D1 (zh) |
EA (1) | EA002328B1 (zh) |
HU (1) | HU219175B (zh) |
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FR2788269B1 (fr) * | 1999-01-08 | 2001-02-09 | Rhodia Chimie Sa | Procede de preparation d'un ether de type benzylique |
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- 1998-07-28 DE DE69814865T patent/DE69814865D1/de not_active Expired - Lifetime
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HUP9701335A3 (en) | 1999-10-28 |
DE69814865D1 (de) | 2003-06-26 |
EA002328B1 (ru) | 2002-04-25 |
HU219175B (hu) | 2001-02-28 |
EA200000177A1 (ru) | 2000-08-28 |
IL133150A0 (en) | 2001-03-19 |
AU8554198A (en) | 1999-02-22 |
WO1999006343A1 (en) | 1999-02-11 |
JP2002509549A (ja) | 2002-03-26 |
ZA986539B (en) | 1999-02-23 |
EP1000005B1 (en) | 2003-05-21 |
KR20010022485A (ko) | 2001-03-15 |
CA2294014C (en) | 2004-05-18 |
HU9701335D0 (en) | 1997-09-29 |
EP1000005A1 (en) | 2000-05-17 |
ATE240922T1 (de) | 2003-06-15 |
US6403843B1 (en) | 2002-06-11 |
HUP9701335A2 (hu) | 1999-05-28 |
CA2294014A1 (en) | 1999-02-11 |
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