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(19) United States (12) Patent Application Publication (10) Pub US 20130046111A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0046111 A1 Bobylev (43) Pub. Date: Feb. 21, 2013 (54) METHOD FOR THE HYDROLYSIS OF Publication Classi?cation SUBSTITUTED FORMYLAMINES INTO SUBSTITUTED AMINES (51) Int- Cl C07C 209/62 (2006.01) (71) Applicant: Mikhail Bobylev, Minot, ND (US) (52) US. Cl. ..................................................... .. 564/386 (72) Inventor: Mikhail Bobylev, Minot, ND (US) (57) ABSTRACT An improved method for the synthesis of substituted formy lamines and substituted amines via an accelerated Leuckart (21) APP1~ NOJ 13/657,505 reaction. The Leuckart reaction is accelerated by reacting formamide or N-alkylformamide and formic acid With an (22) F 11 e d, Oct 22 2012 aldehyde or a ketone at a preferred molar ratio that accelerates ' l ’ the reaction. The improved method is applicable to various substituted aldehydes and ketones, including substituted ben Related US. Application Data Zaldehydes. An accelerated method for the hydrolysis of sub . stituted forrnylamines into substituted amines using acid or (63) 51011123113383 ifojfglltcalggnsbgoi 91 gg1882’451’ ?led on base and a solvent at an elevated temperature. The improved ' ’ ’ ' ' ’ ’ ' method is useful for the accelerated synthesis of agrochemi (60) Provisional application No. 60/ 962,739, ?led on Jul. cals and pharmaceuticals such as vanillylamine, amphet 31, 2007. amine and its analogs, and formamide fungicides. US 2013/0046111A1 Feb. 21,2013 METHOD FOR THE HYDROLYSIS OF described in the XIX century, and since that time remained SUBSTITUTED FORMYLAMINES INTO one of the sloWest reactions in organic chemistry. Many SUBSTITUTED AMINES attempts Were made to improve the reaction by using various additives, most commonly formic acid. HoWever, the only BACKGROUND OF THE INVENTION area of improvement appeared to be the yield of the product, [0001] Aldehydes and ketones are valuable building blocks not the processing time. for chemical industry. Reductive amination is a fundamental [0007] In 1996 a signi?cantly shorter reaction time of 30 chemistry process that dramatically expands the application minutes Was achieved through the use of microWave heating of aldehydes and ketones by transforming them into amines. [3]. HoWever, the technique Was successfully applied only to The Leuckart reaction is a unique one step method of reduc a very narroW group of compounds. In addition, the current tive amination. It is a remarkably simple process that includes technical solutions for microWave assisted synthesis do not only tWo components: the carbonyl compound and forma alloW for processing large-scale reactions and therefore can mide. The reaction is completed simply by heating the com not be used in industry. ponents at 160° C. to 185° C. for 6 to 25 hours [1]. The long [0008] In the present invention using the Leuckart reaction processing time seemed to be the only shortcoming of the it Was unexpectedly discovered that the reaction time can be reaction. However, it is associated With a number of serious dramatically decreased by decreasing the concentration of the practical problems. aldehyde or a ketone used in the reaction. Certain speci?c [0002] First, the prolonged exposure of the reaction mix molar ratios of the aldehyde (ketone), formic acid, and for ture to high temperatures inevitably leads to signi?cant ther mamide (alkylformamide) the reaction time can be reduced to mal decomposition of the components, and, consequently, to 30 minutes or loWer Without the use of microWave assistance. loWer yields of the products and di?iculties With their isola Surprisingly it Was found, that in many cases the reaction tion and puri?cation. Second, maintaining high temperatures becomes instant, i.e. fully completed at the moment When it for a long period of time means high consumption of energy reaches the usual reaction temperature of 160-185° C. The and increasing production costs Which make the Leuckart accelerated Leuckart reaction is equally successful if it is reaction unattractive to chemical industry. Third, long pro conducted With conventional or microWave heating. cessing times per se are unattractive to fast paced modern [0009] The unique molar ratio of formamide (N -alkylfor synthetic applications, such as combinatorial chemistry and mamide) to an aldehyde or a ketone is betWeen 150:1 to 5:1 automated parallel synthesis. Thus, the Leuckart reaction as a and most preferably betWeen 100:1 to 10: 1. The speci?c unique one step method of reductive amination became molar ratio of formamide (N-alkylformamide) to formic acid almost completely abandoned in modern synthetic chemistry. is betWeen 20:1 to 6:1 and most preferably 10:1. [0003] Most of the current reductive amination procedures [0010] The speci?c temperature of the accelerated Leuck are currently performed as tWo step combinations of the sepa art reaction is betWeen 150-200° C., and most preferably rate amination and reduction reactions. These tWo step pro 180-190° C., if the reaction is conducted in an open system. It cedures can often take as much time as the traditional Leuck Was found that the speci?c temperature of the accelerated art reaction [2]. They are also quite expensive because they Leuckart reaction is betWeen 150 to 250° C., most preferably require either the use of custom complex hydrides, or pre 190-210° C., if the reaction is conducted in a sealed system. cious metal catalysts and high pres sure equipment. Their only [0011] This accelerated Leuckart reaction can be success advantage over the one step Leuckart reaction is that they are fully applied to the areas Where the traditional Leuckart reac not accompanied by thermal decomposition and as a result tion Was not successful. Speci?cally, it Was believed that the produce cleaner products. Leuckart reaction does not Work on substituted benZalde [0004] Therefore, it is evident that there is a compelling hydes, and that the substituted benZylamines cannot be need for a fast and inexpensive method of reductive amination obtained from the respective benZaldehydes via the Leuckart of aldehydes and ketones equally attractive to industrial and reaction [1]. Further the accelerated Leuckart reaction does laboratory practices. Work on substituted benZaldehydes and that practically any substituted benZylamine can be prepared via the accelerated SUMMARY OF THE INVENTION Leuckart reaction. Speci?cally, it Was found that the reductive amination of vanillin (4-hydroxy-3-methoxybenZaldehyde) [0005] An improved method for the synthesis of substituted can be completed instantly via the accelerated Leuckart reac formylamines via an accelerated Leuckart reaction. The tion. Vanillylamine is an important industrial chemical that is method may also include an accelerated hydrolysis of the used for the synthesis of safe natural painkillers, such as substituted formylamines to substituted amines. The acceler cap saicin and analogs. The neW accelerated Leuckart reaction ated Leuckart reaction is conducted by reacting formamide or comprises the neW method of the synthesis of vanillylamine. N-alkylformamide, formic acid and an aldehyde or a ketone Further, it Was also discovered that the accelerated Leuckart at a speci?c molar ratio and a speci?c temperature. The accel reaction can be successfully applied to 0t,[3-unsaturated alde erated Leuckart reaction is completed Within minutes or sec hydes and ketones, thus comprising a neW method of obtain onds instead of hours. The accelerated hydrolysis is con ing substituted allylamines. ducted in the presence of a speci?c acid and a speci?c solvent [0012] The improved increased reaction rate prevents any at an elevated temperature. The accelerated hydrolysis is also completed Within seconds. substantial thermal deterioration of the reaction mixture. As a result, the ?ltrates obtained after the separation of the reaction products can be repeatedly used as solvents for the next DETAILED DESCRIPTION OF INVENTION rounds of the reaction. The accelerated Leuckart reaction [0006] The improved method of reductive amination of alloWs for the recycling of the reaction ?ltrates thus leading to aldehydes and ketones via an accelerated Leuckart reaction is quantitative yields of the products and minimal amounts of an unanticipated discovery. The Leuckart reaction Was ?rst Wastes. US 2013/0046111A1 Feb. 21,2013 [0013] As a complementary process, it Was shown that reaction mixture con?rmed that the reaction Was complete. substituted formylamines that are obtained as a result of the The reaction mixture Was diluted With 50 ml of Water and Leuckart reaction can be hydrolyzed to substituted amines via extracted With ethyl acetate. The extract Was dried With an accelerated (instant) hydrolysis. Normally, the hydrolysis sodium sulfate and the solvent Was evaporated to produce step that folloWs the Leuckart reaction is a relatively sloW step 1.17 g (77.1%) of 4-hydroxybenZylformamide (IV). that takes about an hour. Surprisingly, in the presence of a speci?c solvent the hydrolysis step also becomes an instant EXAMPLE 3 procedure. As a result, the entire process of obtaining amines from aldehydes and ketones becomes a combination of tWo Reductive amination of 1-(2,4-dichlorophenyl)-4,4 accelerated (instant) reactions, an accelerated (instant) dimethyl-1-propen-3 -one (V) Leuckart reaction and accelerated (instant) hydrolysis. [0014] The present invention is illustrated by the following [0019] One g (3.9 mmol) ofV, 2 ml of formic acid, and 20 examples herein. ml of formamide Were placed in a round bottom ?ask equipped With thermometer, re?ux condenser, and a heating EXAMPLE 1 mantle. The reaction mixture Was heated to 188- 1 90° C. and maintained at this temperature for 10 minutes. The reaction Reductive amination of vanillin (I) mixture Was left to cool to room temperature overnight. The precipitated crystals Were separated by ?ltration, rinsed With [0015] The multi-mode MARS 5 reaction system (CEM Water, and dried With vacuum, producing 70% of N-[1 -(2,4 Corporation) With GreenChem reaction vessels Was used for dichlorophenyl)-4 ,4 -dimethyl-1 -propen-3 -yl] -formamide the synthesis of vanillylformamide (II).
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