CN102267958A - 芳族化合物的单硝化 - Google Patents

芳族化合物的单硝化 Download PDF

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CN102267958A
CN102267958A CN2011101571533A CN201110157153A CN102267958A CN 102267958 A CN102267958 A CN 102267958A CN 2011101571533 A CN2011101571533 A CN 2011101571533A CN 201110157153 A CN201110157153 A CN 201110157153A CN 102267958 A CN102267958 A CN 102267958A
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M·赛迪洛特
T·P·克利里
P·张
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Abstract

本发明提供了一种制备下式化合物4的方法：该方法包括(a)使下式化合物5与硫酸反应，并且在用水稀释后，(b)用碱处理溶液，使溶液pH值大于10。

Description

芳族化合物的单硝化
本申请是申请号为200780015189.X的发明专利申请的分案申请，原申请的申请日为2007年04月17日，发明名称为“芳族化合物的单硝化”。
本发明涉及含至少一个碱性氮原子的底物的硝化。该方法进一步包括由底物和硝酸生成的硝酸盐的生成和分离，以及在此之后在酸性条件下对该盐的硝化。因此概括而言，本发明涉及带有碱性氮原子的芳族化合物的通用单硝化方法，以及在一个更具体的实施方案中涉及一种制备4-吗啉代-2-硝基苯甲醚的方法。
在有机化学中，芳核的硝化是最基本的反应之一，并广泛用于制备硝基芳族化合物。但是，鉴于几个原因，该反应不为人所称赞，多数医药生产商都不愿在内部进行大规模的硝化。主要是出于安全问题。有两个主要因素造成此反应在安全方面的问题。第一个因素是此反应本身。最常用的硝化试剂为浓硝酸和硫酸的混合物。二者都是强氧化剂。尽管有替代的硝化试剂，但其中多数都会原位生成硝酸或其它具有高度反应性的中间产物。硝化反应通常为强放热反应，方法操作不当或设备出故障时失控至爆炸的危险性很大。第二个因素是硝化产物。多数硝化产物都具有较低的热和/或冲击稳定性，且分解时释放大量的能量(例如TNT，即三硝基甲苯，是一种威力强大的炸药)。因此，进行硝化时必须采取额外的预防措施，包括采用特殊设备(如带防护板的反应器)和对人员进行强化培训。除安全问题外，还有副反应问题。例如，硝化试剂过量供给时，会发生过硝化。位置异构体的生成和侧链上的反应很常见。因此，开发可使硝化过程更为安全、化学控制更佳的新硝化方法仍是一个重要的研究目标。
根据本发明，发现本方法适用于很多种类的化合物。理论上说，可使用本方法硝化任何可在常规条件下硝化并含有碱性氮原子的芳族化合物。表1至表4中列出了一些实例。对于表1至表4中列出的所有实例，硝化都是通过将硝酸盐溶液或悬浮液加至约10当量的浓硫酸中来进行的。本发明包括的底物归纳为以下各组。
A.具有一般结构6的苯胺衍生物，其中Ar为可硝化的芳族环，R1和R2为氢、烷基或芳族基团。表1列出了一些实例。
Figure BDA0000067817450000021
B.具有一般结构7的芳族化合物，其中Ar为可硝化的芳族环，R1、R2、R3和R4为氢、烷基或芳族基团，n是1到12的整数。表2列出了一些实例。
Figure BDA0000067817450000022
C.具有一般结构8的芳族化合物，其中Ar为可硝化的芳族环，G为合适的原子或基团(如CR1R2、O、S、SO、SO2等)，R为带有碱性氮原子的杂环或其它基团。表3列出了一些实例。
Figure BDA0000067817450000023
D.具有一般结构9的稠环芳族化合物，其中苯环与带有碱性氮原子的杂环稠合，R1、R2和R3可以是氢或是可以耐受常规硝化条件的其它基团。表4列出了一些实例。
Figure BDA0000067817450000024
表1
Figure BDA0000067817450000025
Figure BDA0000067817450000031
Figure BDA0000067817450000041
表2
Figure BDA0000067817450000042
Figure BDA0000067817450000051
表3
表4
Figure BDA0000067817450000061
表1-4的底物的盐通常可以通过在＜20℃下向底物溶液加入1.0当量70％硝酸制得。采用TBME(叔丁基甲醚)作为可溶于其中的底物的反应溶剂。对于在TBME中溶解性较差的底物，加入第二种溶剂帮助溶解。用于反应的溶剂组合包括TBME/THF(四氢呋喃)、TBME/乙腈、TBME/乙酸乙酯等。对于生成盐时从溶液中析出的盐，通过过滤和在室温下真空干燥实现分离。对于不完全从溶剂中析出的盐，加入乙腈直到形成均匀溶液。然后，此溶液经过MgSO4干燥、过滤并浓缩以提供固态盐。
盐的硝化通过在＜10℃下将盐溶液或悬浮液加入过量硫酸来进行。反应所用溶剂包括二氯甲烷、硝基甲烷和其它对反应混合物惰性的溶剂。反应完成后，在＜20℃下通过向水中加入酸层稀释混合物。然后，通过加入碱，如氨水、碳酸钾水溶液、碳酸钠水溶液或碳酸氢钠水溶液等，将稀释后的混合物碱化到pH为6-11。多数情况下，此时产物析出。固态产物经过滤、水洗，然后在50℃左右真空干燥过夜，以得到硝化产物。析出的产物为油时，用溶剂(如二氯甲烷、乙酸乙酯等)萃取混合物。然后对该有机溶液进行水洗、经过MgSO4干燥、过滤并浓缩以得到粗产物。
通过应用该硝化方法，产生了一种制备4-吗啉代-2-硝基苯甲醚(4)的新方法的发明，4-吗啉代-2-硝基苯甲醚(4)是正在开发中的抗抑郁药的关键中间产物(WO 01/97786)。该方法概括于方案1。
该新方法与上述申请中公开的原有方法相比有几个主要优点，包括：
1)一种简化方法。5直接从第一步骤中的粗产物萃取液中析出，可以免除分离5的游离碱。
2)稳定性更高。盐5包括比例精确为1∶1的底物(5的游离碱)和硝酸。因此，不会生成二硝化杂质。该方法消除了准确称量和加入硝酸的必要性，因此减轻了工艺操作的负担。
3)安全性提高。该方法消除了向浓硫酸中加入5的固态游离碱的操作(由于该过程为强放热，大规模生产时为非常危险的操作)。取而代之向硫酸中加入5在二氯甲烷中的溶液。此加入过程可容易控制，从而避免产生过量的热。该方法还消除了将70％硝酸与浓硫酸混合的操作。
4)废物的形成减少，处理能力提高。此方法中使用5，从而可减少60％的硫酸加入量，这可使本方法中产生的废物减少40％，生产能力提高30％。
5)产率显著提高。用本新方法得到的总体产率为92％，而用原有方法的产率仅为58％，产率提高了59％。
关于芳族基团，考虑为芳基。
“芳基”指一价、单环或双环的芳族碳环烃基，优选为6-10元芳族环体系。优选的芳基包括但不限于苯基、萘基、甲苯基和二甲苯基。
“杂环基”指取代或未取代的5-8元单环或双环芳族或非芳族烃，其中1-3个碳原子被选自氮、氧或硫原子的杂原子取代。实例包括吡咯烷-2-基、吡咯烷-3-基、咪唑-4-基、吡唑-3-基、吗啉-4-基等。
“杂原子”指选自N、O或S的原子。
“烷基”一词指含1-约20个碳原子的直链或支链饱和烃基，包括具有1-约7个碳原子的基团。在某些实施方案中，烷基取代基可以是低级烷基取代基。“低级烷基”一词指含1-6个碳原子的烷基，在某些实施方案中为含1-4个碳原子的烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和仲戊基。
本发明的方法可按以下方案所示进行。
方案1
Figure BDA0000067817450000081
盐的硝化也可在不同条件下进行。例如，此反应可通过向硝酸盐的二氯甲烷溶液中加入乙酰氯进行。在一些情况下，用不同方法得到不同的产物。例如，在将5的溶液加入硫酸中对5进行硝化时，产物为4(方案1)。但是，当通过在5的乙酸溶液中加入2.0当量的乙酰氯进行硝化时，分离出产物10的产率为91％。另一实例如方案2所示。这些实例表明，通过选择不同的条件，可以控制苯胺衍生物的硝酸盐硝化的位置选择性。
方案2
方案3
Figure BDA0000067817450000083
除了硫酸，也可以用其它酸来硝化硝酸盐。这通过使用三氟乙酸、甲磺酸的二氯甲烷溶液以及纯甲磺酸硝化S-1来示例说明。结果总结于表5。
表5
Figure BDA0000067817450000091
本发明涉及一种硝化选自如下的芳族化合物的方法：
Figure BDA0000067817450000092
其中
Ar为可硝化的芳族环，
R1、R2、R3和R4为氢、烷基或芳族基团，
G选自CR1R2、O、S、SO或SO2，
R为杂环或其它带有碱性氮原子的基团，和
n为1-12的整数，
该方法包括在原料与硝酸反应后生成和分离原料的硝酸盐，以及在此之后向酸中加入该硝酸盐溶液或悬浮液。分离的硝酸盐由比例为1∶1的硝酸和胺底物构成。因此，硝化过程中可以容易地防止过硝化和硝化不足，这在大规模生产过程中难以控制。
关于芳族环/基团，考虑为芳基。
提供以下实施例和参考资料是为了更好地理解本发明，实际范围在所附权利要求中限定。
实施例1
吗啉代苯甲醚，硝酸盐(5)
Figure BDA0000067817450000093
在一个干燥、清洁、配有机械搅拌器和氮气入口的1L 4颈圆底烧瓶中加入20g(162.3mMol)对氨基苯甲醚、48g(336mMol)2-氯乙醚、1.04g(3.2mMol)溴化四丁基铵和77g 42％氢氧化钠溶液。在110℃左右将混合物回流约8h。确认反应完成后，将混合物冷却至20℃，并分别用50mLTBME和50mL乙酸乙酯萃取。合并的有机溶液用80mL水洗涤。将此有机溶液冷却至0±5℃并缓慢向其中加入14.6g(162.3mMol)70％HNO3。加入的后期阶段产生重沉淀物。加入后将该批料陈化至少1h。将固体过滤，用40mL TBME洗涤，然后在45℃温度下真空干燥过夜，得到40.2g(97％)褐色固体5。
实施例2
4-吗啉代-2-硝基苯甲醚(4)
Figure BDA0000067817450000101
在一干燥、清洁、配有机械搅拌器和氮气入口的250mL 4颈圆底烧瓶中加入80g(815mMol)95％硫酸。将酸冷却至约0℃。将20g(78mMol)5在125mL二氯甲烷中的溶液缓慢加入酸中，同时保持批料温度在0±5℃。加入后将混合物搅拌30分钟。停止搅拌，将底部酸层分离。将酸溶液缓慢加入到200mL水中，同时保持温度＜10℃。然后在保持温度＜10℃的同时向此稀酸溶液中缓慢加入190mL 28％NH4OH溶液。加入结束后，混合物的pH值应高于10。在5±5℃下将该批料陈化1h。将固体过滤，用50mL水洗涤，然后在45℃下真空干燥过夜，得到17.5g(94％产率)橙色固体4。
实施例3
苯胺，硝酸盐(S-11)
将苯胺(10g，107mMol)在100mL TBME中的溶液冷却至0±5℃。保持温度＜20℃的同时向此溶液中加入70％硝酸(9.7g，107mMol)。加入后在0±5℃下将混合物搅拌约1h。将固体过滤，用TBME洗涤，然后在室温下低真空(house vacuum)干燥过夜，得到16.4g(98％)标题化合物。
化合物S-9、S-12、S-14、S-15、S-16、S-22采用相同步骤制备。
实施例4
对氨基苯甲醚，硝酸盐(S-10)
Figure BDA0000067817450000111
将对氨基苯甲醚(10g，81.2mMol)在80mL TBME和20mL THF中的溶液冷却到0±5℃。保持温度＜20℃的同时向此溶液加入70％硝酸(7.3g，81.2mMol)。加入后在0±5℃下将混合物搅拌约1h。将固体过滤，用TBME洗涤，然后在室温下低真空干燥过夜，得到14.6g(97％)标题化合物。
化合物S-19、S-21采用相同的步骤制备。
实施例5
N，N-二甲基苄胺，硝酸盐(S-13)
Figure BDA0000067817450000112
将N，N-二甲基苄胺(10g，74mMol)在80mL TBME和20mL THF中的溶液冷却至0±5℃。保持温度＜20℃的同时向此溶液加入70％硝酸(6.7g，74mMol)。加入后在0±5℃下将混合物搅拌约1h。向反应混合物加入乙腈直到形成均匀溶液。将溶液经过MgSO4干燥、过滤并浓缩，得到14.7g(100％)标题化合物。
化合物S-1、S-2、S-3、S-4、S-5、S-6、S-7、S-8、S-17采用相同的步骤制备。
实施例6
苯基-2-咪唑啉，硝酸盐(S-18)
Figure BDA0000067817450000121
将2-苯基-2-咪唑啉(10g，68.4mMol)在100mL TBME和50mL乙腈中的悬浮液冷却至0±5℃。保持温度＜20℃的同时向此悬浮液加入70％硝酸(6.2g，68.4mMol)。加入后在0±5℃下将混合物搅拌约1h。将固体过滤，用TBME洗涤，然后在室温下低真空干燥过夜，得到13.4g(91％)标题化合物。
化合物S-20、S-23、S-24采用相同的步骤制备。
实施例7
4，N，N-三甲基-3-硝基苯胺(N-1)
Figure BDA0000067817450000122
将S-1(3g，15.1mMol)在25mL二氯甲烷中的溶液缓慢加入到95％冷硫酸(14.8g，151mMol)中，同时保持批料温度在0±5℃。加入后在0±5℃温度下将混合物搅拌约3h。停止搅拌，并在保持温度＜20℃的同时将底部酸层缓慢地转移到30mL水中。在＜20℃下向稀释的反应混合物缓慢加入氢氧化铵溶液，直到pH值＞10。生成沉淀物。在＜20℃下将该混合物陈化约1h。将固体过滤、水洗并在约45℃下低真空干燥过夜，得到2.54g(93％)标题化合物。
化合物N-3、N-6、N-4/N-5、N-8/N-9、N-10/N-11、N-17、N-32/N-33采用相同的步骤制备。
实施例8
2-(4-硝基苯基)咪唑(N-28)
Figure BDA0000067817450000123
将S-20(4g，19.3mMol)在30mL二氯甲烷中的悬浮液缓慢加入到95％冷硫酸(18.9g，193mMol)中，同时保持批料温度在0±5℃。加入后在0±5℃下将混合物搅拌约3h。停止搅拌，并在保持温度＜20℃的同时将底部酸层缓慢地转移到40mL水中。在＜20℃下向稀释的反应混合物中缓慢加入氢氧化铵溶液，直到pH值＞10。沉淀物生成。在＜20℃下将该混合物陈化约1h。将固体过滤、水洗并在约45℃温度下低真空干燥过夜，得到3.5g(96％)标题化合物。
化合物N-24、N-26、N-27、N-34、N-35采用相同的步骤制备。
实施例9
甲氧基-3-硝基-N-甲基苯胺(N-12)
将S-9(4g，20mMol)在40mL二氯甲烷中的溶液缓慢加入到95％冷硫酸(20g，200mMol)中，同时保持批料温度在0±5℃。加入后在0±5℃下将混合物搅拌约3h。停止搅拌，并在保持温度＜20℃的同时将底部酸层缓慢地转移到40mL水中。在＜20℃下向稀释的反应混合物中缓慢加入氢氧化铵溶液，直到pH值约为7。用二氯甲烷将混合物萃取两次。将合并的有机溶液用盐水洗涤、经MgSO4干燥、过滤并浓缩，得到3.46g(95％)标题化合物。
化合物N-9采用相同的步骤制备。
实施例10
甲氧基-3-硝基苯胺(N-13)
将S-10(4g，21.5mMol)在40mL二氯甲烷中的悬浮液缓慢加入到95％冷硫酸(21g，215mMol)中，同时保持批料温度在0±5℃。加入后在0±5℃下将混合物搅拌约3h。停止搅拌，并在保持温度＜20℃的同时将底部酸层缓慢地转移到40mL水中。在＜20℃下向稀释的反应混合物中缓慢加入氢氧化铵溶液，直到pH值为6-11。用二氯甲烷将混合物萃取两次。将合并的有机溶液用盐水洗涤、经MgSO4干燥、过滤并浓缩，得到3.3g(91％)标题化合物。
化合物N-2、N-9、N-14/N-15/N-16、N-29/N-30/N-31、N-22/N-23、N-21采用相同的步骤制备。
实施例11
吗啉代-3-硝基苯甲醚(10)
Figure BDA0000067817450000141
在室温下向5(2g，7.8mMol)在5mL乙酸中的溶液中缓慢加入乙酰氯(1.6g，15.6mMol)。将混合物搅拌约30min。在＜20℃下向反应混合物中缓慢加入冷氢氧化铵溶液。然后将混合物陈化约1h。将固体过滤，水洗并在45℃下真空干燥过夜，得到1.7g(91％产率)10。
实施例12
4，N，N-三甲基-2-硝基苯胺(11)
Figure BDA0000067817450000142
在0℃左右向S-1(2g，10.1mMol)在10mL二氯甲烷中的溶液中缓慢加入乙酰氯(1.6g，15.6mMol)。将混合物搅拌约2h。在＜20℃下通过加入氢氧化铵溶液将反应混合物碱化到pH值＞10。用二氯甲烷将混合物萃取两次。将合并的有机溶液用盐水洗涤、经MgSO4干燥、过滤并浓缩，得到1.7g(93％)11。
实施例13
S-1在三氟乙酸中的硝化
将S-1(4g，20.2mMol)在45g二氯甲烷中的溶液缓慢加入三氟乙酸(23g，202mMol)中，同时保持批料温度在0±5℃。加入后在0±5℃下将混合物搅拌约1h。在保持温度＜20℃的同时将混合物缓慢地转移到40mL水中。在＜20℃下向此混合物中缓慢加入28％氢氧化铵溶液，直到pH值＞10。将有机相分离，并将水相用48g二氯甲烷萃取。将合并的有机溶液用盐水洗涤，然后在旋转蒸发仪上浓缩至干燥，得到3.44g(94％)11。
实施例14
S-1在甲磺酸的二氯甲烷溶液中的硝化
将S-1(4g，20.2mMol)在22g二氯甲烷中的溶液缓慢加入到19g甲磺酸和22g二氯甲烷的混合物中，同时保持批料温度在0±5℃。加入后在0±5℃下将混合物搅拌约4h。在保持温度＜20℃的同时将混合物缓慢地转移到40mL水中。在＜20℃下向此混合物中缓慢加入28％氢氧化铵溶液，直到pH值＞10。将有机相分离，并将水相用55g二氯甲烷萃取。将合并的有机溶液用盐水洗涤，然后在旋转蒸发仪上浓缩至干燥，得到3.41g(92％)产物，为11和N-1的混合物，两者比例约为93∶7。
实施例15
S-1在甲磺酸中的硝化
将固态S-1(4g，20.2mMol)缓慢加入到19g甲磺酸中，同时保持批料温度在17±5℃。加入后在17±5℃下将混合物搅拌约1h。在保持温度＜20℃的同时将混合物缓慢地转移到40mL水中。在＜20℃下向此混合物中缓慢加入28％氢氧化铵溶液，直到pH值＞10。将混合物用43g二氯甲烷萃取。将有机相分离，并将水相用29g二氯甲烷萃取。将合并的有机溶液用盐水洗涤，然后在旋转蒸发仪上浓缩至干燥，得到3.22g(91％)产物，为11和N-1的混合物，两者比例约为75∶25。

Claims (1)

1.一种制备下式化合物的方法：
Figure FDA0000067817440000011
该方法包括
(a)使下式化合物与硫酸反应：
Figure FDA0000067817440000012
并且在用水稀释后
(b)用碱处理溶液，使溶液pH值大于10。
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