2) United States Patent oy ow ~ wo en @ 6s) @) (6) or Bobylev METHOD FOR THE HYDROLYSIS OF SUBSTITUTED FORMYLAMINES INTO. SUBSTITUTED AMINES, Applicant: Mikhail Bobylev, Minot, ND (US) Inventor: Mikhail Bobylev, Minot, ND (US) Notice: Subject to any disclaimer, the term ofthis, pateat is extended or adjusted under 3 USC. 154(b) by O days This patent is subject to a terminal dis- claim, Appl. Now 13/687,505 Filed: Oct. 22,2012 Prior Publication Data S 20130046111 AL Feb. 21,2013 Related U.S. Application Data Continuation of application No, 12/182,481, filed on Jul. 30, 2008, now Pat. No. 8,329,948. Provisional application No. 60'962,739, filed on Ju 31, 2007 Int. core 20902 (2006.01) S648 'US008710268B2 US 8,710,268 B2 *Apr. 29, 2014 (10) Patent No. 4s) Date of Patent: (58) Field of Classification Search usec 564/336, 386 ‘See application ile for complete search history References Cited US. PATENT DOCUMENTS 60) 329.948 2* 122012 Botyler soars PORPIGN PATENT DOCUMENTS fa osisas © wie * cited by examiner Shailenda Kumar James K Petell Primary Examiner (74) Attornes, Agent, or Firm on ABSTRACT An improved method forthe synthesis of substituted form’ Jamines and substituted amines via aa accelerated Leuckart reaction, The Levckart revction is accelerated By reacting Tormamide or N-ikylformamide and formic acid with an ldeyde or aketone ata preferred molar rato that accelerates the reaetion, The improved method is applicable to various substited aldehydes and ketones, including substituted ben: ‘aldehydes. An agcelerated method forthe hydrolysis of sub- stituted formylamines ino substituted amines using acid or base and a solvent at an elevated temperature, The improved ‘method is usefil forthe accelerated synthesis of agrochemi- cals and pharmaceuticals such as vanillylamine, amphet- mine and its analogs, and formamide fungicides. 9 Claims, No DrawingsUS 8,710,268 B2 1 METHOD FOR THE HYDROLYSIS OF SUBSTITUTED FORMYLAMINES INTO. SUBSTITUTED AMINES, (CROSS-REPERENCE TO RELATED APPLICATION This application is a continuation application of the prior application Ser. No, 12/182,451 filed Jul. 30, 2008, now US. Pat. No. 8,329,948, which claims the benefit to U.S. Prov sional Patent Application Serial No. 60/962,739 filed Ju. 31, 2007 , which are hereby incorporated herein by reference in their cate BACKGROUND OF THE INVENTION Aldehydes and Ketones are valusble building blocks for ‘chemical industry. Reductive amination is @ fundamental ‘chomisiry process that dramatically expands the application ‘of aldehydes and ketones by transforming them into amines The Leuckart reaction is unique one step method of redue~ tiveamination Itisa remarkably simple process hat includes ‘only two components: the carbonyl compound and forma mide, The reaction is completed simply by heating the com- ponents at 160°C. to 185° C, for 6 35 hours [1]. The long processing time seemed to be the only shortcoming of the reaction, However its associated with a number of serious practical problems, First the prolonged exposure ofthe reaction mixture t0 high temperatures inevitably leads to significant thermal ‘decomposition of the components, and, consequently, (0 lower yiels ofthe products and difiulties with their isola- tion and purification. Second, maintaining high temperatures or long period of time meuas high consumption of energy ‘and increasing production costs which make the Leuckart reaction unattractive o chemical industry. Thid, Jong. pro- ‘cessing times per se are unattractive to fast paced modern synthetic appliations, such as combinatorial chemist and somated parallel synthesis. Thus, he Levckart reaction as unique one step method of reductive amination became almost completely abandoned in moder synthetic chemistry. ‘Most of the current reduetive amination procedures are ‘curently performed as two step combinations of the separate ‘amination and redvtion reactions. These two step procedures ‘can often take as mich time asthe traditional Leva reac~ tion [2] They are also quite expensive because they require ther the use of custom complex hydrides, or previous metal ‘catalysts and high pressure equipment. Their only advantage ‘over the one step Leuckart reaction isthat they are not accom- panied by thermal decomposition and as a result produce ‘leaner products, “Therefor, its evident that ther isa compelling need for 3 {ast nd inexpensive method of reductive amination of alde- hydes and ketones equally attractive to industrial and fabora- tory practices SUMMARY OF THE INVENTION An improved method for the synthesis of substituted formylamines via an accelerated Levckart reaction. ‘The method may also include an accelerated hydrolysis of the substituted farmylamines to substituted amines. The acceler ated Levckar reaction is conducted by reacting formamide oF N-alkylformamide, formic acd and an aldehyde or a ketone ‘ata specific molar rato and a specific temperature. The accel= ‘erated Levckart reaction is completed within minttes or sc ‘onds instead of hours. The accelerated hydrolysis is con 0 o 2 ‘ducted in the presence ofa specific aid anda specific solve atan elevated temperature. The aocelerated hydrolysis isa ‘completed within seconds DETAILED DESCRIPTION OF INVENTION ‘The improved method of reductive amination of aldehydes ‘and Ketones via an accelerated Leuckart reaction isan una- ticipated discovery. The Leuckar reaction ws fist desribed in the XIX century, and since that time remained one ofthe slowest reaetions in organie chemistry: Many attempts were made to improve the reaetion by using variousadditives, most ‘commonly formic acid, However, the only ea of improve- ‘meat appeared tobe the yield ofthe product, not the process- ing time. 2 1996. significantly shorter reaction time of 30 minutes ‘was achieved through the use of microwave heating [3] ow ever, the technique was successflly applicd only to a very ‘arrow group of compounds. In addition, the current techni- cal solutions for microwave assisted synthesis do not allows or processing large-scale reactions and therefore cannot be sed in inst ‘Inthe present invention using the Leuckart reaction it was ‘unexpectedly discovered that the reaction time ean he dr- matically decreased by decreasing the concentration of the faldeiyde or a ketone Used in the reaction. Certain specific ‘molar ratios of the aldehyde (ketone), formic acid, and for ‘mamide (alkyformamide) the reaetion time can be reduced to $30minutes or lower without the use of microwave assistance. Surprisingly it was found, that in many eases the reaction ‘becomes instant. filly completed atthe moment when it reaches the usual retin temperature of 160-185° C. The accelerated Levckart reaction is equally suecessfl if i is ‘ondcted With conventional or microwave heat The unique molar ratio of formamide (N-allkylfonmaide) to an aldehyde ora ketone is between 15041 1 S:1 and most preferably between 100:1 to 10:1, Thespecifie molar ratio of formamide (Nealkyiformamide) to formic acid is between 20:1 to 6:1 and most preferably 10e1 The specific temperature ofthe accelerated TL euckar eae tion is between 150-200" ., and most preferably 180-190 CC, ifthereaetionisconducted inanopen system. twas found thatthe specific temperature of the accelerated Leuckar reac- sion is between 150% 250° C., most preferably 190-210" C., it the reaction is conducted in'a sealed system ‘This accelerated Leuckart reaetion can be successilly applied to the areas where the traditional Leuckart reaction ‘was not sueeessfil, Specifically, it was believed that the TLevekart reaction does not work on substituted benzalde- hnydes, and that the substituted benzylamines cannot be ‘oblaitd from the respective benzaldebydes va the Leuckart reaction [1]. Further the accelerated Leuckart reaction does ‘Work on substituted benvaldehydes and that practically any substituted benzylamine ean be prepared va the accelerated Leuekart reaction. Specifically, twas found that the reductive amination of vanilin (4-hydnoxy'3-methoxybenzaldehyde) ‘can be completed instantly via the accelerated Leuckar reae- ‘ion, Vanillytamine isan important industrial chemical that is ‘used for the syuthesis of safe natural paakillers, seh as capsaicin and analogs. The new accelerated Leuckar reaction comprises the new method ofthe syathesis of vanily amine Tuner, it was also discovered that the accelerated | euckart reaction ean be successfully applied to unsaturated alde- Fhydes andl ketones, thus comprising anew method of obtain- ing substituted allylaines “The improved increased reaction mate prevents any sab- stantial thermal deterioration of the reaction mixture. AS aUS 8,710,268 B2 3 result, the filtrates obtained ater the separation ofthe react products can be repeatedly used as solvents for the next rounds of the reaction, The accelerated Leueckart reaction allows forthe recycling ofthe reaction filtrates thus leading 0 ‘quantitative yields ofthe products and minimal amounts of ‘wate, ‘Asacomplementary proces, twas shown that substituted ormylamines that are obiained as a result of the Leuckart reaction can heiydrolyzed to subslitited amines ia an aocel- ‘erated (instant hydrolysis. Normally, the hydrolysis step that follows the Leuckart reaction is a relatively slow stp that takes about an hour Surprisingly, inthe presence of aspecific solvent the hydrolysis step albo becomes an instant proce- ‘dure. Asa result the entire process of obtaining amines fom aldehydes and ketones becomes a combination of two accel- ‘erated (instant) reactions, an accelerated (instant) Leuckaet reaction and accelerated (instant) hydrolysis The present invention is illueated by the following ‘examples herein. EXAMPLE 1 Reductive amination of vanillin (1) “The multimode MARS 5 eeetion system (CEM Corpo- ration) With GreenChem reaction vessels Was used for the synthesis of vanilly formamide. 1.52 z 10mm of 1,20 til formamide nd I ml of formic aid were placed inthe ‘Groen hem rection vessel. The Greenhem reaction vessel ‘was placedinto the MARS 5 reaction system adh ection Inixtre was quickly heated o 20? C. The reaetion mixtite svat kept a 200°C. for 3 minutes ad then cooled to 100°C The GresaChem resction vessel was removes from the MARS 5 system, the residual pressure was released, andthe reaction vessel was opened. TLC shoved that the rection twas complete The reaction mixture wasdted With Om] of ‘water and extracted with ethyl acetate. The exact was died ‘with sodiom sulfate and the solvent was evaporated. The residue was purified by column chromstography (lea ue, (CHCl, CH,O11201 vi and yield 137 g(73%) of Novae nis formamide (I), mp. 88. C. (benzene). NMR Dr seston): 821s (1, HC—0), 7.60 (1, NED, 7.58 brs GH, OF), 695 (LH, aromatc), 676 2H, aromatic), 432 A QH,CH), 3805 GEC). NCNMR (De acetone): 61.9 (C0), 1987, 147.4, 13LT, 121.6, 16.1, 1126 (aromatic ceubons), $6.6 (CH), 423 (CH), IR (act erst, ATR, fom) 3296 (NED, 3213 (OH), 1643 (C—O). Cyl, NOs alulated, eC $9.66; 1, 6.125N, 7.73. Found, 6259.90, 598, H, 613, 612, N, 774,773, “The resetion Was repeated With 4.56 p 0 mao! of van- iin and reaction time of 1 min. TLC showed thatthe reaction was complete. The reaction mixture Was extracted fl purified the sae way prdcing 3.29 g (40%) aN nillytomamide The reaction was repeated with 1.52 (10 mmol) of vane iin and conventional eating a 190°C, for L minute. The reaction mixture was extracted and pried the same Way producing 146 y (80%) of N-vanilyfommanide (1, EXAMPLE2 Instant reductive amination of 4+-hydroxybenzaldehyde IIT) 4-hydroxybenzaldchyde (1.22 g oF 10 mmol), Formanside (22.72 g0¢ 20.03 ml.) and formic acid (2.43 gor 2m.) were placed into a 50 ml. round bottom Mask equipped with @ 0 o 4 thermometer, a reflux condenser, a magnetic ster and a heating mantle, The reaction mixture was heated to 189° C. ‘The heating was immediately tumed off; the reaction flask ‘vas quickly raised from the heating mantle and allowed ¢0 «oo! fo rom temperature. The TLC condueted on the cokd ‘action mixture confirmed thatthe reaction was complete The reaction mixture was diluted with 50 ml of water and extracted with ethyl acetate, The extrct was dried with sodium sulfate and the solvent was evaporated produce 117 277.1%) of 4-hydroxybeneylormamie (IV), EXAMPLE 3 Reductive amination of 1(2,4-dichlorophenyl)-4.4- sdimethyl-l-propen3-one (V) (One g (3.9 mmol) of ¥, 2 ml of formic acid, and 20 ml of. formamide were placed in a rnd bottom Haske egpipped with thermometer, rfiux condenser, and a heating mantle The reaction mixture was heated to I88-19P C. aad maine tained at this temperature for 10 minutes. The reaction mix- ture was left to cool to mom temperature overnight. The precipitated erystals were separated by filtration, rinsed with ‘Water, and dried with vacuum, producing 70% of N-[1-2.4- {ichloropheny!)-44-cimethyI-1-propen-3-l]-formamide wD. EXAMPLE Reductive amination of benzoplienone (VID) ‘The reaction procedure for V was repeated with 5 g of benzophenone and te reetion time of 15 mites. The reae- tion produced 95% of henrhydryformaide (VII) (isolated yield). EXAMPLES Instant hydrolysis of N-[1-2.4-dichloropheny)44- «dimethyl I-propen-3-yl}formamide (V1) One g of VI, 10 ml of concentrated hydrochloric acd, and 10 ml of methanol were placed in the GreenChem reaction vessel. The GreenCihem reaction vessel was placed into the MARS 5 revetion system and the reaction mixture was {quickly beated to 120°C. The microwave heating was imme- diately tuned offand he reaction mixture wasquickly cooled 0 60° C. The GreenChem reaction vessel was removed rom the MARS 5 system, the residual pressure was released, and the reaction vessel was opened. TEC show tha the reac was complete, The reaction mixture was cooled 10 roe ‘emperature; the precipitated crystals were separated by fi ‘waton, The filtrate was dried with vacuum and produced an ‘addtional amount of the product. The yield of N-[1-24- ichlocophenyD)-44-dimethyl-I-propen-3-ylj-amine hydeo- chloride (IX) is quantitative EXAMPLE 6 Instant hydrolysis of benzhydey formamide (VIII) ‘The reaction procedure for VIwas repeated with | gofVIIL and prodaced quantitative yield of benziydrylamine hydeo- chloride (%),US 8,710,268 B2 5 EXAMPLET Instant hydrolysis of vanilly formamide (ID) ‘The reaction procedure for VI was repeated with 1 g of TL and produced quantitative yield of vanillylamine hydrochlo- ride (XD, EXAMPLES Reductive amination of 2.4,6.timethoxybenzaldebyde (XI) with reeyeling of the filtrate 1.96 (10 mmol) of XII, 20 ml of formamide, and 2 ml of Jormic acid were placed in the GreenChem reaction vessel ‘The Green hem reaction vessel was placed into the MARS- reaction system andthe reaction mixture was quickly heated to 200° C. The reaction mixture was kept st 200° C. for 3 ‘minutes and then cooled to 100°C. The GreenChem reati vessel was removed from the MARS § system, the residual pressure wat released, and the reaction vessel was opened. ‘TLC showed that the reaction was complete, The reaction mixture was cooled to room temperature the precipitated cysts were separated by ration, rinsed with water and > “died with vacuum. The filtrate was used as solvent inthe next reaction, The reaction was repeated 10 times. The total of 9.6402 g of formic acid, and 34.5680 g of formamide were added to the rection mixture over te ten cycles to compen- sate the losses. The total yield of 2,6trimethoxsbenzy Hor mamide (XII) is quantitative Other Embodiments ‘The description ofthe spevific embodiments ofthe inven- tion is presented for the parpose of illastraton, It is not intended to he exhaustive nor to Timi the scape of the inven- tion to the specific forms described herein, Although the invention has been described with reference to several 6 embodiments it ill be understood by one of ordinary skill {heart that various modifications can be made without depat- ing {rom the spirit and the seope ofthe invention, asset orth intheclaims. Al patents, patent applications and publications referenced herein are hereby incorporated by reference, (Other embodiments are within the claims “The invention claimed is 1. A method for the accelerated hydrolysis of the subst ‘uted formylamine into a substituted amine, comprising ‘a, mixing the substituted formylamine with a volume of ‘acid oF base and alcoho in sealed reaction system; bs. maising the tempersture of the reaction mixture to a reaction temperature system between 100°C. and 160° Cand «maintaining the mixture to reat at the reaction tempera lure for a ime between O seconds to 60 minutes. 2. The method ot claim I; wherein the acid is hydrochloric acid 3. The method of claim 1; wherein the base is sodium hydroxide 4 Themethod of claim 1, wherein the reaction temperature is mised or maintained by Conventional heating or by micro- wave heating. 8. The method ofclaim 1, further comprising cooling the ‘mixture to room temperature and removing precipitated cry tals by filteaton, 6. The method ofelaim I; wherein the substituted sine is ‘asubstitutedallylamine, amphetamine or substituted aniphet- 77. The method of claim 6, wherein the subsiuted amphet- amine includes N-methylamphotamine, m-tifiuoromethy- Jamphetamine, and N-ety-avttluceomeshs amphetamine 8, The method of claim 1, wherein the substituted formy- Jamine is a substituted allyformamide, N-formylamphet- amine and substituted N-formylamphetamine. '9. The method of 1, wherein once the reetion tem is reached, the heat is tuned of