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(12) United States Patent (10) Patent No.: US 8,710,268 B2 Bobylev (45) Date of Patent: *Apr

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(12) United States Patent (10) Patent No.: US 8,710,268 B2 Bobylev (45) Date of Patent: *Apr US008710268B2 (12) United States Patent (10) Patent No.: US 8,710,268 B2 Bobylev (45) Date of Patent: *Apr. 29, 2014 (54) METHOD FOR THE HYDROLYSIS OF (58) Field of Classification Search SUBSTITUTED FORMYLAMINES INTO USPC .................................................. 564/336,386 SUBSTITUTEDAMINES See application file for complete search history. (71) Applicant: Mikhail Bobylev, Minot, ND (US) (56) References Cited (72) Inventor: Mikhail Bobylev, Minot, ND (US) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 8.329,948 B2 * 12/2012 Bobylev ........................ 564,215 patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. This patent is Subject to a terminal dis EP O 518414 * 12/1992 claimer. * cited by examiner (21) Appl. No.: 13/657,505 Primary Examiner — Shailendra Kumar (74) Attorney, Agent, or Firm — James K Petell (22) Filed: Oct. 22, 2012 (57) ABSTRACT (65) Prior Publication Data An improved method for the synthesis of substituted formy US 2013/OO46111A1 Feb. 21, 2013 lamines and Substituted amines via an accelerated Leuckart reaction. The Leuckart reaction is accelerated by reacting formamide or N-alkylformamide and formic acid with an Related U.S. Application Data aldehyde or aketoneata preferred molar ratio that accelerates (63) Continuation of application No. 12/182,451, filed on the reaction. The improved method is applicable to various Jul. 30, 2008, now Pat. No. 8,329,948. Substituted aldehydes and ketones, including Substituted ben Zaldehydes. An accelerated method for the hydrolysis of sub (60) Provisional application No. 60/962,739, filed on Jul. stituted formylamines into Substituted amines using acid or 31, 2007. base and a solvent at an elevated temperature. The improved method is useful for the accelerated synthesis of agrochemi (51) Int. C. cals and pharmaceuticals such as Vanillylamine, amphet CD7C 209/62 (2006.01) amine and its analogs, and formamide fungicides. (52) U.S. C. USPC .......................................................... 564/386 9 Claims, No Drawings US 8,710,268 B2 1. 2 METHOD FOR THE HYDROLYSIS OF ducted in the presence of a specific acid and a specific solvent SUBSTITUTED FORMYLAMINES INTO at an elevated temperature. The accelerated hydrolysis is also SUBSTITUTEDAMINES completed within seconds. CROSS-REFERENCE TO RELATED DETAILED DESCRIPTION OF INVENTION APPLICATION The improved method of reductive amination of aldehydes This application is a continuation application of the prior and ketones via an accelerated Leuckart reaction is an unan application Ser. No. 12/182,451 filed Jul. 30, 2008, now U.S. ticipated discovery. The Leuckart reaction was first described Pat. No. 8,329,948, which claims the benefit to U.S. Provi 10 in the XIX century, and since that time remained one of the sional Patent Application Serial No. 60/962,739 filed Jul. 31, slowest reactions in organic chemistry. Many attempts were 2007, which are hereby incorporated herein by reference in made to improve the reaction by using various additives, most their entirely. commonly formic acid. However, the only area of improve ment appeared to be the yield of the product, not the process BACKGROUND OF THE INVENTION 15 ing time. In 1996 a significantly shorter reaction time of 30 minutes Aldehydes and ketones are valuable building blocks for was achieved through the use of microwave heating 3. How chemical industry. Reductive amination is a fundamental ever, the technique was successfully applied only to a very chemistry process that dramatically expands the application narrow group of compounds. In addition, the current techni of aldehydes and ketones by transforming them into amines. cal solutions for microwave assisted synthesis do not allow The Leuckart reaction is a unique one step method of reduc for processing large-scale reactions and therefore cannot be tive amination. It is a remarkably simple process that includes used in industry. only two components: the carbonyl compound and forma In the present invention using the Leuckart reaction it was mide. The reaction is completed simply by heating the com unexpectedly discovered that the reaction time can be dra ponents at 160° C. to 185° C. for 6 to 25 hours 1). The long 25 matically decreased by decreasing the concentration of the processing time seemed to be the only shortcoming of the aldehyde or a ketone used in the reaction. Certain specific reaction. However, it is associated with a number of serious molar ratios of the aldehyde (ketone), formic acid, and for practical problems. mamide (alkylformamide) the reaction time can be reduced to First, the prolonged exposure of the reaction mixture to 30 minutes or lower without the use of microwave assistance. high temperatures inevitably leads to significant thermal 30 Surprisingly it was found, that in many cases the reaction decomposition of the components, and, consequently, to becomes instant, i.e. fully completed at the moment when it lower yields of the products and difficulties with their isola reaches the usual reaction temperature of 160-185° C. The tion and purification. Second, maintaining high temperatures accelerated Leuckart reaction is equally successful if it is for a long period of time means high consumption of energy conducted with conventional or microwave heating. and increasing production costs which make the Leuckart 35 The unique molar ratio of formamide (N-alkylformamide) reaction unattractive to chemical industry. Third, long pro to an aldehyde or a ketone is between 150:1 to 5:1 and most cessing times per se are unattractive to fast paced modern preferably between 100:1 to 10:1. The specific molar ratio of synthetic applications, such as combinatorial chemistry and formamide (N-alkylformamide) to formic acid is between automated parallel synthesis. Thus, the Leuckart reaction as a 20:1 to 6:1 and most preferably 10:1. unique one step method of reductive amination became 40 The specific temperature of the accelerated Leuckart reac almost completely abandoned in modern synthetic chemistry. tion is between 150-200° C., and most preferably 180-190° Most of the current reductive amination procedures are C., if the reaction is conducted in an open system. It was found currently performed as two step combinations of the separate that the specific temperature of the accelerated Leuckart reac amination and reduction reactions. These two step procedures tion is between 150 to 250° C., most preferably 190-210°C., can often take as much time as the traditional Leuckart reac 45 if the reaction is conducted in a sealed system. tion 2. They are also quite expensive because they require This accelerated Leuckart reaction can be successfully either the use of custom complex hydrides, or precious metal applied to the areas where the traditional Leuckart reaction catalysts and high pressure equipment. Their only advantage was not successful. Specifically, it was believed that the over the one step Leuckart reaction is that they are not accom Leuckart reaction does not work on substituted benzalde panied by thermal decomposition and as a result produce 50 hydes, and that the substituted benzylamines cannot be cleaner products. obtained from the respective benzaldehydes via the Leuckart Therefore, it is evident that there is a compelling need for a reaction 1. Further the accelerated Leuckart reaction does fast and inexpensive method of reductive amination of alde work on substituted benzaldehydes and that practically any hydes and ketones equally attractive to industrial and labora substituted benzylamine can be prepared via the accelerated tory practices. 55 Leuckart reaction. Specifically, it was found that the reductive amination of Vanillin (4-hydroxy-3-methoxybenzaldehyde) SUMMARY OF THE INVENTION can be completed instantly via the accelerated Leuckart reac tion. Vanillylamine is an important industrial chemical that is An improved method for the synthesis of substituted used for the synthesis of safe natural painkillers. Such as formylamines via an accelerated Leuckart reaction. The 60 capsaicin and analogs. The new accelerated Leuckart reaction method may also include an accelerated hydrolysis of the comprises the new method of the synthesis of vanillylamine. substituted formylamines to substituted amines. The acceler Further, it was also discovered that the accelerated Leuckart ated Leuckart reaction is conducted by reacting formamide or reaction can be successfully applied to C.f3-unsaturated alde N-alkylformamide, formic acid and an aldehyde or a ketone hydes and ketones, thus comprising a new method of obtain at a specific molar ratio and a specific temperature. The accel 65 ing Substituted allylamines. erated Leuckart reaction is completed within minutes or sec The improved increased reaction rate prevents any Sub onds instead of hours. The accelerated hydrolysis is con stantial thermal deterioration of the reaction mixture. As a US 8,710,268 B2 3 4 result, the filtrates obtained after the separation of the reaction thermometer, a reflux condenser, a magnetic stirrer and a products can be repeatedly used as solvents for the next heating mantle. The reaction mixture was heated to 189° C. rounds of the reaction. The accelerated Leuckart reaction The heating was immediately turned off; the reaction flask allows for the recycling of the reaction filtrates thus leading to was quickly raised from the heating mantle and allowed to quantitative yields of the products and minimal amounts of 5 cool to room temperature. The TLC conducted on the cold Wastes. reaction mixture confirmed that the reaction was complete. As a complementary process, it was shown that Substituted The reaction mixture was diluted with 50 ml of water and formylamines that are obtained as a result of the Leuckart extracted with ethyl acetate. The extract was dried with reaction can be hydrolyzed to Substituted amines via an accel Sodium sulfate and the solvent was evaporated to produce erated (instant) hydrolysis. Normally, the hydrolysis step that 10 1.17 g (77.1%) of 4-hydroxybenzylformamide (IV). follows the Leuckart reaction is a relatively slow step that takes about an hour.
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