CN100361967C - 2-氰基-3-羟基-n-(苯基)丁-2-烯酰胺的制备方法 - Google Patents
2-氰基-3-羟基-n-(苯基)丁-2-烯酰胺的制备方法 Download PDFInfo
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- -1 but-2-ene amide Chemical class 0.000 claims abstract description 12
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
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- 239000011630 iodine Substances 0.000 description 1
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- 238000012544 monitoring process Methods 0.000 description 1
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- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
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- 239000010935 stainless steel Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/26—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and singly-bound oxygen atoms bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/27—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and doubly-bound oxygen atoms bound to the carbon skeleton
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及获得氰基-3-羟基-N-(苯基)丁-2-烯酰胺的方法,通过该方法,苯基取代的2-氰基-N-(苯基)乙酰胺在一种碱、乙酸酐及至少一种溶剂的存在下发生转化,所得2-氰基-3-羟基-N-(苯基-衍生物)丁-2-烯酰胺通过酸化结晶。
Description
本发明涉及由2-氰基-N-(苯基)乙酰胺制备2-氰基-3-羟基-N-(苯基)丁-2-烯酰胺的方法,特别涉及由2-氰基-N-(4-三氟甲基苯基)乙酰胺制备2-氰基-3-羟基-N-[(4-三氟甲基)苯基]丁-2-烯酰胺的方法。
化合物2-氰基-3-羟基-N-[(4-三氟甲基)苯基]丁-2-烯酰胺是已知的(US5,679,709)。2-氰基-3-羟基-N-[(4-三氟甲基)苯基]丁-2-烯酰胺的制备方法在例如US 5,519,042或US 5,700,822中有所叙述。该已知方法的缺点是产率低和纯度低。
现已发现:在乙酸酐和氢氧化钠的存在下,2-氰基-3-羟基-N-(苯基)丁-2-烯酰胺可由2-氰基-N-(苯基)乙酰胺来制备。
因此,本发明涉及式I化合物的制备方法,
其中,R1为a)-CF3,
b)-O-CF3,
c)-S-CF3,
d)-OH,
e)-NO2,
f)卤素,
g)苄基,
h)苯基,
i)-O-苯基,
k)-CN,
l)-O-苯基,该基团被下述基团单取代或多取代:
1)-(C1-C4)-烷基,
2)卤素,
3)-O-CF3,或
4)-O-CH3,且
R2为a)-(C1-C4)-烷基,
b)卤素,或
c)氢原子,
该方法包括使式II化合物
其中R1和R2如上定义,
在至少一种碱、乙酸酐及至少一种溶剂的存在下发生反应,然后分离所得式I化合物。
本发明还涉及式III化合物的制备方法,
其中,使式IV化合物
在水、氢氧化钠、乙酸酐及另外一种溶剂的存在下发生反应,然后分离反应产物式III化合物。
在式I化合物的制备中,可按下述方法进行步骤:首先,将式II化合物(或2-氰基-N-(4-三氟甲基苯基)乙酰胺)置于溶剂中,并将所得溶液或混悬液冷却。然后加入氢氧化钠水溶液和乙酸酐,再将所得反应混合物在冷却下搅拌或振摇。
反应适当时间后,用酸将式I化合物沉淀出来。将式I化合物分离,例如使用乙酸乙酯或甲苯例如通过结晶或萃取使之分离。可通过冷却混悬液或进一步蒸发溶剂促进结晶。
术语“溶剂”用于表示例如水,有机溶剂,例如:
酮溶剂,例如丙酮、甲基乙基酮或甲基异丁基酮;
卤代烃,例如二氯甲烷;
醇,例如乙醇、异丙醇或正丁醇;
醚,例如二异丙醚、二乙氧基甲烷或二乙二醇二甲醚;
烃,例如甲苯;
酯,例如乙酸乙酯;
疏质子溶剂,例如二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜或N-甲基吡咯烷酮;或
所述溶剂的混合物,或者
可以使用相转移催化剂,例如季铵盐或盐,例如二甲基双十四烷基溴化铵、苄基三乙基氯化铵、Alliquat336(3-甲基三辛基氯化铵)、四丁基硫酸氢铵或四丁基氯化;
冠醚或穴状配体,例如18-冠-6或穴状配体222 [=4,7,13,16,21,24-六氧杂-1,10-二氮杂双环-(8.8.8)二十六烷];或
聚乙二醇,当为与水微混溶的溶剂如甲苯时是特别有利的。
术语“碱”用于表示碱金属氢氧化物,例如氢氧化钠或氢氧化钾、固体苛性钠或不同浓度的苛性钠碱液;碱金属氢化物及碱土金属氢化物,例如氢化钠、氢化钙;酰胺,例如氨基钠;醇盐,例如甲醇钠、叔丁醇钾;有机金属化合物,例如正丁基锂;或胺,例如二乙基异丙胺;或者所述有机碱的混合物。碱液中存在的水参与计算反应混合物的制备。
术语“卤素”用于表示氟、氯、溴和碘。
术语“-(C1-C4)-烷基”用于表示烃基,例如甲基、乙基、丙基、正丁基或异丁基。
适宜的酸例如是盐酸、硫酸、硝酸或磷酸,或所述酸的混合物。
对于本发明的反应,优选每100mol式II或式IV化合物使用150mol至300mol乙酸酐和100mol至550mol氢氧化钠。
溶剂的用量通常为每kg式II或IV化合物使用3kg至11kg,优选为4kg至6kg。
反应时间通常为数分钟至24小时,优选为1至3小时,这取决于混合物的组分和所选择的温度范围。
反应温度为-5℃至50℃,优选为0℃至30℃,特别为10℃。
在分离所得的2-氰基-3-羟基-N-[(4-三氟甲基)-苯基]丁-2-烯酰胺中,初始底物式II化合物或2-氰基-N-(4-三氟甲基苯基)乙酰胺的残留量减少至低于0.5%。
对于本发明的反应,初始底物可根据文献如DE 1 900 947中已知的方法来制备。
加工产物(process product)具有生物活性,适于例如治疗类风湿性关节炎或多发性硬化症。
本发明的方法的有利特征是反应时间非常短、省去了额外的纯化步骤、产率高且所制备产物的纯度高。本发明的方法的优点为基本完全反应生成式I化合物或2-氰基-3-羟基-N-[(4-三氟甲基)苯基]丁-2-烯酰胺且副产物总含量低于1%。
实施例1
2-氰基-3-羟基-N-[(4-三氟甲基)苯基]丁-2-烯酰胺的制备
称取2.5g 2-氰基-N-(4-三氟甲基苯基)乙酰胺和0.127g-二甲基双十四烷基溴化铵,置于带有玻璃料(frit)的Teflon反应器中。向反应器中充入氩气,加入15ml二乙氧基甲烷。开启振摇,将内容物冷却至15℃。手工加入1.73ml50%浓度的NaOH水溶液,在5-20分钟内加入总量为2.12ml的乙酸酐。然后通过HPLC反复监测反应混合物。加入乙酸酐后将混悬液另外振摇8.5小时。
然后将反应器冷却至5℃。在10分钟内各加入3.20ml水和2.90ml37%HCl,反应器内部温度保持在5℃。在此温度下将内容物振摇1小时。随后向每个反应器中加入13.0ml水,加热至10℃,振摇1小时。用氩气喷射白色混悬液。残余固体用水洗涤3次,每次15.0ml,于45℃和150mbar干燥至恒重,称重,用HPLC进行分析。
2-氰基-3-羟基-N-[(4-三氟甲基)苯基]丁-2-烯酰胺的HPLC法
检测技术: 液相色谱法(欧洲药典)
仪器: 液相色谱仪:
Waters Alliance Separations Module 2690
色谱柱: 材料:不锈钢
长度:100mm
内径:4.6mm
固定相: Waters Symmetry-C18
粒径3.5μm
流动相: 乙腈:350ml
水:650ml
三乙胺:5ml
用85%H3PO4调pH至6.0
进样体积: 10μl
上样器温度: 12℃
柱温: 20℃
流速: 0.8ml/分钟
运行时间: 45分钟
检测: UV/Vis,210nm
标准品溶液: 将14.0mg参比标准品置于2ml乙腈中超声,制成20ml。
供试品溶液: 将12.5mg物质用乙腈R溶解至25ml。
保留时间(分钟): 绝对 相对
2-氰基-3-羟基-N-[(4-三氟甲基)-苯基]丁-2-烯酰胺: 6.4±10% 1.0
2-氰基-N-(4-三氟甲基苯基)-乙酰胺: 12.8±10% 2.0±10%
4-三氟甲基苯胺: 14.1±10% 2.2±10%
计算:
AB=供试品溶液色谱图中各副产物的峰面积
∑A=供试品溶液色谱图中除溶剂峰之外的所有峰面积总和
实施例2-7
表1中的实验在与实施例1相似的方法下进行。
表1:各种溶剂混合物
实施例 | PTC<sup>(1)</sup> | 溶剂 | 体积(ml) | PTC摩尔当量 | 产率(理论值的%) |
2 | 二甲基双十四烷基溴化铵 | 甲苯 | 30 | 0.1 | 48.3 |
3 | 二甲基双十四烷基溴化铵 | 甲苯 | 30 | 0.05 | 53.6 |
4 | 二甲基双十四烷基溴化铵 | 二乙氧基甲烷 | 25 | 0.1 | 65.4 |
5 | 苄基三乙基氯化铵 | 二乙氧基甲烷 | 30 | 0.05 | 73.7 |
6 | 二甲基双十四烷基溴化铵 | 二乙氧基甲烷 | 30 | 0.05 | 79.4 |
7 | 苄基三乙基氯化铵 | 二乙氧基甲烷 | 15 | 0.1 | 77.8 |
(1)PTC表示相转移催化剂
实施例8
将2.5g 2-氰基-N-(4-三氟甲基苯基)乙酰胺和15ml丙酮加入带有玻璃料的Teflon反应器中。开启振摇,将混合物冷却至15℃。手工加入1.73ml 50%浓度的NaOH水溶液,在5至20分钟内加入2.12ml乙酸酐,取样,HPLC反复监测。加入乙酸酐后将混悬液另外振摇8.5小时,冷却至5℃。在10分钟内各加入3.20ml水和2.90ml 37%HCl,反应器内部温度保持在5℃。在此温度下将内容物振摇1小时。随后加入13.0ml水,将混合物温热至10℃,振摇1小时。用氩气喷射白色混悬液。残余固体用去离子水洗涤3次,每次15.0ml,于45℃和150mbar干燥至恒重,称重,用HPLC进行分析。产量:2.76g(理论值的92%,HPLC纯度为98.3)。
实施例9
称取9.1g 2-氰基-N-(4-三氟甲基苯基)乙酰胺置于200ml四颈烧瓶中,然后加入49ml甲基异丁基酮使之混悬(微黄色低粘度混悬液),然后冷却至10℃。在此温度下由量筒直接加入17.8ml 33%浓度的NaOH。在此过程中温度升至12℃,并形成难以搅拌的奶油色混悬液。将其剧烈搅拌10分钟。然后在1小时20分钟内,于7至12℃逐滴加入9.7ml乙酸酐。在此过程中粘稠的混悬液转变为略微混浊的橙色溶液,逐滴加入50分钟(约逐滴加入7ml)后,有固体从该溶液中结晶淅出,结果观察到温度自发升高(最大值高于12℃)。取样,HPLC分析,仍然发现在反应混合物中初始物质2-氰基-N-(4-三氟甲基苯基)乙酰胺的峰面积约为1.29%。继续逐滴加入。1小时20分钟后,在逐滴加入的终点,根据HPLC分析可知已达到完全转化(2-氰基-N-(4-三氟甲基苯基)乙酰胺的峰面积约为0.13%)。将混合物另外搅拌50分钟,冷却至3至5℃。然后在此温度下,于10分钟内逐滴加入11.5ml水;混合物的pH为7.1。在1小时内逐滴加入16ml 37%浓度的HCl,结果在恒温下pH达1.1。另外搅拌25分钟后,pH仍为1.1(加入约7ml HCl后即形成奶油色不均匀的可搅拌混悬液)。在接下来的20分钟内,逐滴加入47.5ml水,温度升至10℃。pH升至1.7。将混合物另外搅拌40分钟。然后抽吸除去混悬液,残余物用30ml水洗涤5次至不含氯化物。于40℃减压干燥,得到奶油色固体。产量:9.8g(理论值的91%,HPLC纯度为99.0)。
表2的反应在与实施例8和9相似的方法下进行。
表2
实施例 | 溶剂 | 乙酸酐当量 | NaOH当量 | 产率(理论值的%) | 产物(HPLC纯度) |
10 | 正丁醇 | 1.5 | 2.25 | 47 | 66.7 |
11 | 异丙醇 | 1.5 | 2.25 | 63 | 69.3 |
12 | 丙酮 | 1.5 | 2.25 | 92 | 98.3 |
13 | 甲基异丁基酮 | 1.5 | 2.25 | 74 | 93.8 |
14 | 甲基异丁基酮 | 1.5 | 2.26<sup>*</sup> | 54 | 84.1 |
15 | 甲基异丁基酮 | 2.5 | 5.00<sup>**</sup> | 91 | 99.0 |
16 | N-甲基吡咯烷酮 | 1.5 | 2.26 | 58 | 66.5 |
*30%浓度的NaOH **33%浓度的NaOH
Claims (22)
2.如权利要求1所要求的方法,其中所述的碱金属氢氧化物为氢氧化钠或氢氧化钾、固体苛性钠或苛性钠碱液。
3.如权利要求1所要求的方法,其中所述的酰胺为氨基钠。
4.如权利要求1所要求的方法,其中所述的醇盐为甲醇钠或叔丁醇钾。
5.如权利要求1所要求的方法,其中所述的有机金属化合物为正丁基锂。
6.如权利要求1所要求的方法,其中所述的酮溶剂为丙酮、甲基乙基酮或甲基异丁基酮。
7.如权利要求1所要求的方法,其中所述的卤代烃为二氯甲烷。
8.如权利要求1所要求的方法,其中所述的醇为乙醇、异丙醇或正丁醇。
9.如权利要求1所要求的方法,其中所述的醚为二异丙醚、二乙氧基甲烷或二乙二醇二甲醚。
10.如权利要求1所要求的方法,其中所述的烃为甲苯。
11.如权利要求1所要求的方法,其中所述的酯为乙酸乙酯。
12.如权利要求1所要求的方法,其中所述的疏质子溶剂为二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜或N-甲基吡咯烷酮。
13.如权利要求1所要求的方法,其中所述的相转移催化剂为季铵盐或盐。
14.如权利要求13所要求的方法,其中所述的相转移催化剂为二甲基双十四烷基溴化铵、苄基三乙基氯化铵、3-甲基三辛基氯化铵、四丁基硫酸氢铵或四丁基氯化。
15.如权利要求1至14中任一项所要求的方法,其中式III化合物用酸沉淀出来。
16.如权利要求15所要求的方法,其中所述的酸是盐酸、硫酸、硝酸或磷酸,或这些酸的混合物。
17.如权利要求1至14中任一项所要求的方法,其中每100mol式IV化合物使用150mol至300mol乙酸酐和100mol至550mol氢氧化钠。
18.如权利要求1至14中任一项所要求的方法,其中溶剂的用量基于1kg式IV化合物计为3kg至11kg。
19.如权利要求18所要求的方法,其中溶剂的用量基于1kg式IV化合物计为4kg至6kg。
20.如权利要求1至14中任一项所要求的方法,其中反应温度为-5℃至50℃。
21.如权利要求1至14中任一项所要求的方法,其中反应温度为0℃至30℃。
22.如权利要求1至14中任一项所要求的方法,其中反应温度为10℃。
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