CAS号 [402-13-1] 生产工艺  3-氨基三氟甲苯-4-甲酸

CAS名: Benzoic acid, 2-amino-4-(trifluoromethyl)- 历史参考文献:

用途: 医药中间体（糖尿病用药）。反应类别: -CN à -CONH₂ à -COOH, 加氢还原（-NO₂ à -NH₂）。

生产工艺文献: 按本人手头资料整理如下：

BIOS 1153, 157-160.（胶卷PB 85687）3-Aminobenzotrifluoride-4-carboxylic acid.（Hoechst）英国人译自德文。抄录如下。

（4-Trifluoromethylanthranilic acid）考虑到CAS号，现分项抄录。反应式: 本人有加注，译者未说明资料来源。
 

Stage 2: 3-Nitrobenzotrifluoride-4-carboxylic acid. (“Nitrocarbonsaeure”) 反应式：略。本人暂未找到德文原件！

135 g. “Nitril” 100%. 750 g. monohydrate. 47.5 g. sodium nitrite.

The “Nitril” is added to the monohydrate at about 50⁰C., and heated for 2 hours at 75-80⁰C. stirring all the time.

The conversion to the amide is complete when a test sample diluted with water gives a crystalline precipitate. The temperature must definitely not exceed 80⁰C.

After cooling to 70⁰C., the finely powdered sodium nitrite is added fradually, taking care that the temperature does not rise above 85⁰C. It is then cooled down and slowly poured into water, again taking care that the temperature remains below 85⁰C. After this it is diluted further to 1¹/₂ l., cooled to 10-15^oC., filtered and washed with a little ice water.

Yield = 132 g. 100% = 92% of theory.  M. Pt. 130-135⁰C.

Stage 3: 3-Aminobenzotrifluoride-4-carboxylic acid. (“CF₃ anthranilsaeure” ) 

44.65 kg. “Nitrocarbonsaeure” 100%. 450 l. Water. 23.03 kg. Caustic soda, 30%.

These are dissolved by stirring together for ¹/₂ hour and run into the reaction vessel. The solution must be alkaline to Delta paper. Nickel catalyst corresponding to 800 g. “Ni” is added and the reaction vessel closed. The air is flushed out with nitrogen and 15 atmospheres of hydrogen pumped in. On heating up, the hydrogen absorption begins at about 50⁰C. but the temperature is raised to 60-80⁰C. maintaining a hydrogen pressure of 15 atmospheres. During 2-3 hours the theoretical amount of hydrogen (12.78 cu. m.) should be consumed. If this is the case, and the pressure no longer falls, it is stirred a further 2 hours and a sample examined. This should be colourless and have a M. Pt. of 176⁰C. after working up. If this is satisfactory the catalyst is filtered off in a small press.

The yield (as solution is 37 kg. = 95% theoretical.

Further figures obtained were:

Nitrocarbonsaeure 100% 132 kg. Caustic soda   22.5 kg. Nickel catalyst at 100% Ni  2.7 kg.

Compressed hydrogen  58 cu.m.  Pure nitrogen  11 cu.m.  Yield = 103.5 kg. “CF₃ Anthranilsaeure” 

张澍声 编译。《精细化工中间体工业生产技术》 1996年。P. 68.  译自BIOS 1153,157. 抄录如下。

（二）3-硝基三氟甲苯-4-甲酸:  在约50⁰C将135 g 100% “氰化物”加到750 g硫酸一水合物中，在75-80⁰C加热2小时，同时不断搅拌。取样用水稀释，得到结晶沉淀，则酰胺的转化完全（抄注： -CN à -CONH₂）。温度必须不超过80⁰C。

冷却到70⁰C，缓缓加入47.5 g亚硝酸钠粉，小心不使温度超过85⁰C。然后冷却，缓缓倾入冰中，小心保持温度在85⁰C以下，过滤，用少量水洗涤。

得到132 g 100% 3-硝基三氟甲苯-4-甲酸，熔点13-135⁰C，收率92%。

（三）3-氨基三氟甲苯-4-甲酸:  将44.65 kg 3-硝基三氟甲苯-4-甲酸，450 L水，23.03 kg 30%氢氧化钠溶液，在反应釜中混合搅拌0.5小时。将相当于800 g镍的镍催化剂加入，密闭反应釜。用氮气冲洗去空气，压入15巴的氢。加热后在约50⁰C开始吸收氢，将温度升至60-80⁰C,保持氢压为15巴。于2-3小时内消耗掉理论量的氢（12.78立方米），并且压力不再下降，再搅拌2小时。取样检验，应为无色，处理后熔点176⁰C。检验满意后，过滤出催化剂。

得到37 kg 3-氨基三氟甲苯-4-甲酸的溶液，收率95%。

进一步所取得的数据：

3-硝基三氟甲苯-4-甲酸 100% 132 kg. 苛性钠 22.5 kg.  镍催化剂（以100%镍计）2.7 kg.

高压氢  58立方米。 纯氮  11立方米。  得量 = 103.5 kg 3-氨基三氟甲苯-4-甲酸。

加注:  为了说明特种文献的特点，现将Sandoz公司发表的专利资料抄录如下：

GB 2019214. 1979年10月31日。= US 4307113. 1981年12月22日。

Example 1. 2-amino-α,α,α-trifluoro-p-toluic acid (4-trifluoromethylanthranilic acid)

Step A: Preparation of 2-amino-α,α,α-trifluoro-p-toluamide (4-trifluoromethylanthranilic acid amide)

49 g. of 2-nitro-4-trifluoromethylbenzonitrile is dissolved in 200 ml. of anhydrous methanol and the resultant solution is hydrogenated in the presence of 1.5 g. of hydrogenation catalyst (10% Pd on active charcoal). After the theoretical uptake of hydrogen is achieved, the reaction mixture is filtered to remove the palladium and the solvent is removed on a rotary evaporator. The resultant residue is filtered and dried in vacuo to yield 2-amino-α,α,α-trifluoro-p-toluamide (-trifluoromethylanthranilic acid amide), m.p. 147-149⁰C.

A larger quantity of the amide compound is obtained by combining the ethyl ether washes and evaporating the combined washes in vacuo to dryness to 2-amino-α,α,α-trifluoro-p-toluamide, m.p. 147-149⁰C.

Step B:  Preparation of 2-amino-α,α,α-trifluoro-p-toluic acid (4-trifluoromethylanthranilic acid)

Into 160 ml. of water containing 9.6 g. of sodium hydroxide is suspended 16 g. of 2-amino-α,α,α-trifluoro-p-toluamide. The solution is refluxed 5 hours, then cooled, poured onto ice and acidified to a pH of 6 with concentrated hydrochloric acid. The resultant precipitate is filtered, washed with water and dried in vacuo to yield 2-amino-α,α,α-trifluoro-p-toluic acid (4-trifluoromethylanthranilic acid), m.p. 175-177⁰C.

抄注:  本人看完专利，未发现专利中提及德文历史资料。同时我査了Beilstein手册和美国CA，也未发现有记载！本人在这里再次提出，如果，这一历史资料还有用，请读者加以利用吧！这里应该是医药合成和生产科技人员的看法？

考虑到环保，国内经常提到加氢还原工艺，这一历史资料也算是提供参考，问题之一是氢源，其次是催化剂的选择。

陈忠源  2017年7月5日          于 无锡   明辉国际。