(2) oy 6) wo en @ 6s) 66) United States Patent Bobyley METHOD FOR THE SYNTHESIS OF SUBSTITUTED FORMYLAMINES AND. SUBSTITUTED AMINES, Inventor: Mikhail Bobylev, Minot, ND (US) Notice: Subject to any disclaimer, the term ofthis patent is extended ot adjusted under 35 USC. 154(b) by 1004 days Appl. Now 12/182,481 Filed: Jul, 30,2008, Prior Publication Data US 200910143622.A1 Jun, 4, 2009 Related US. Application Data Provisional application No. 60'962,739, filed on Ju 31, 2007 "eC. core us (2006.01) us.cl. 36472 Field of Classification Seate! 564/259, 564/336 ‘64/215, 564/289, 336 ‘See application file for complete search history. References Cited US. PATENT DOCUMENTS SAS5A67 A 101992 Pinchot 'US008329948B2 (10) Patent No. 4s) Date of Patent: US 8,329,948 B2 Dee. 11, 2012 FOREIGN PATENT DOCUMENTS ep sisit 6/1904 (OTHER PUBLICATIONS PCT Intemational Search Report date Ost, 16, 2008 Bobyler et al. "Mictowaveassited Symbesis of Novack Iylormamide” Mar 25-29, 207, ACS 253nd National Meting ad Exponiion, PICOGRAM v.72 and Abstracts KRAM"Reldealfstonof a Major Input a lit Amphetamine, 1 Forensic Chemistry 1979, vol 24, pp. 596-59, Discusion, Primary Examiner — Shailendea Kunsae (74) Attorney, Agent, or Firm — James K Petel on An improved method fo the synthesis of substituted foemy. lamines and substituted amines via an accelerated Leuckart reaction, The Levckart reaction is accelerated by reacting formamide oF N-lylformamide and formic acid with an aldehyde ora ketone ata prefered molar ratio that accelerates the reaction, The improved method is applicable to various substituted aldehydes and ketones including substituted be: ‘aldehydes. An accelerated method forthe hydrolysis of sub- Stated formylamines into substituted amines using acid oF base and a solvent at an elevated temapemtue, The improved method is usefl forthe accelerated synthesis of agrochemi- cals and pharmaceuticals such as vanillylamine, amphet- amine and its analogs, and foemamide fungicides. ABSTRACT 9 Claims, No DrawingsUS 8,329,948 B2 1 METHOD FOR THE SYNTHESIS OF SUBSTITUTED FORMYLAMINES AND SUBSTITUTED AMINES, ‘This application claims benefit o 60962,739, filed Jul 31 2000. BACKGROUND OF THE INVENTION Aldehydes and Ketones are valusble building blocks for ‘chemical industry. Reductive amination is @ fundamental ‘chomistry process that dramatically expands the application ‘of aldehydes and Ketones by translorming them inte amines. ‘The Leuckart reaction is a unique one stop method of rede tiveamination lisa remarkbly simple process that 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 1 25 hours [1]. The long processing time seemed to be the only shortcoming of the reaction, However, itis associated With a aumber of serious practical problems. Tint, the prolonged exposure of the rection mixture 10 high temperatures inevitably leeds to significant thermal ‘decomposition of the components, and, consequently, to lower yields ofthe products and difficulties with their isol tion and purification. Second, maintaining high temperatures {or long period of time means high consumption of encrsy ‘and ineresking production costs which make the Leuckatt reaction unattractive to chemical industry. Third, long pro- ‘cessing times per se are unatiractive to fast paced modern symhetic applications, such as combinatorial chemistry and automated parallel synthesis. Ths, the Levekar reaction asa ‘unique one step method of reductive amination became ‘almost completely abandoned in modern synthetic chemistry ‘Most of the current reductive amination procedures are ‘currently performed as two step combinations of the separate mination and reduction reactions, These twostep procedures ‘can often take as mc time asthe taditional Leuekat reae= tion [2]. They are also quite expensive because they require «ther the use of eustom complex hydrides, or precious metal ‘catalysts and high pressure equipment. Theironly advantage ‘overthe one step Levckart reaction isthatthey are not accom pranicd by thermal decomposition and as a result produce ‘leaner products Therefore itis evident that there isa compelling need for ‘stand inexpensive method of reductive amination of alde- hhydes and ketones equally attractive w industrial and labors tory practices SUMMARY OF THE INVENTION An improved method for the synthesis of substituted formylamines via an accelerated Tevckart reaction, The mcthod may also inchide an accelerated hydrolysis of the substituted formylamines o substituted amines. The aeceler- ated [cuekart reaction is conducted by escting formamide or Nealkyformamide, formic aed and an aldebyde or a ketone ‘aspecifc molar ratio anda specific temperature. The wcccl- ‘erated Leuckaet reetion is completed within minutes or see~ ‘onds instead of hours. The accelerated hydrolysis is con “ducted inthe presence ofa specific acid anda specific solvent ‘tan elevated temperature. The accelerated hydrolysis also ‘completed within seconds DETAILED DESCRIPTION OF INVENTION ‘The improved method of redctive amination of aldehydes ‘and ketones via an secelerated Leuckart reaction is an unan 0 o 2 ticipated discovery. The Leuekart reaction was fist desribed in the XIX century, and since that time remained one ofthe slowest reaetions in organie chemistry: Many attempts were ‘mado to improve the reaction by using variousadditives, most ‘commonly formic acid, However, the only ea of improve- ‘ment appeared tobe the yield of the procic, not the process ing time. a 196 a sigaificsnlly shorter reaction time of 30 minutes ‘was achieved through the use of microwave heating [3] How ever the technique was successflly applicd only to a very ‘narrow group of compounds. In addition, the current techn cal solutions for microwave assisted synthesis do not allows {or processing largescale evetions and therefore cannot be sed in inst ‘In the present invention using the Leuckart reaction it was ‘unexpectedly discovered that the reaction time ean he dr- ‘matically decreased by decreasing the concenteation of the aldehyde or a ketone used in the reaction. Certain specific ‘molar ratios of the aldeyde (ketone, formie acid, and for ‘mumide alkyformamide) the reaction time can be reduced to $30minstes or lower without the use of microwave assistance. Surprisingly it was found, that in many eases the reaction bbocomes instant ic filly completed a the moment when it reaches the usual rection temperature of 160-185° C. The accelerated Levckart reaction is equally soccessil if itis ‘onucted With conventional or microwave heat ‘Te unique molar ratio of formamide (N-alkyl formamide) to an aldehyde ora ketone is between 15041 0 5:1 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 10:1 The specific temperature ofthe accelerated Leuckart reac tion is between 150-200" Cand most preferably 180-190 , ifthereactionis conducted inanopen system. Itwas found thatthespevific temperature ofthe accelerated Levckar reac- ‘ion is between 150% 250° C., most preferably 190-210" C., if the reaction is conducted in a sealed system ‘This accelerated Leuckart reaction can be successilly applic to the areas where the traditional Levckart reaction ‘was not sees, Specifically, it was believed that the TLeuekart reaction dees not work on substituted benzalde- hnydes, and that the substituted benzylamines cannot be ‘oblaitd from the respective benzaldebydes va the Leuckart rwaetion [1], Further the accelerated Levekart reaction does work on substituted benvaldehydes and that practically any substituted benzylamine ean be prepared via the acelerated Levelt reaction. Specifically, twas found that theredetive mination of vanillin (4hydroxy-3-methoxybenzaldehyde) can be completed instantly via the accelerated Leuckarreae- ‘ion, Vanillytamine isan important industrial chemical that is vwsed forthe syatheris of sale natural painkillers, such as capsaicin and analogs. The new sceelerated Leuckar reaction ‘comprises the new method of the syathess of vanililamine, unter, twas 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 allylamines The improved increased reaction rate prevents any sub- stantial thermal deterioration ofthe reaction mixture, AS a result, the filtrates obtained afer the separation ofthe reaction products can be repeatedly used as solvents forthe next rounds of the resction, The accelerated Leuekart reaction allows forthe reveling ofthe reaction iltrates thus leading 0 {quantitative yields of the products and minimal amounts of Wastes “As a complementary proces, its shown tha substituted ormylamines that ae obtained as a result of the LeuckartUS 8,329,948 B2 3 reaction can belydrolyzed to substituted amines via an aecel- ‘erated (instant hydrolysis. Normally, he hydrolysis step that Tollows the Leuckart reaction is a relatively slow step that takes about an hour Surprisingly, inthe presence of a specific solvent the hydrolysis step albo becomes an instant proce- ‘dure. Asa result the entire process of obtaining amines fom aldehydes and ketones becomes combination of two aocel- ‘erated (instant) reactions, an accelerated (instant) Leuckat reaction and accelerated (instant) hydrolysis The present invention is illutated by the following ‘examples herein, EXAMPLE 1 Reduetive Amination of Vaillia (1) “The multi-mode MARS 5 reetion system (CEM Compo- ration) with GroonChem reaction vessels was used for the synthesis of vanilly formamide (1.1.52 (10 mmol) fT, 20 ml of formamide, and | ml af formic acid were placed in the ‘Green hem reaction vessel, The GreenChem reaction vessel ‘was placed into the MARS 5 reaction system andthe reaction mixture was quickly heated to 200° C. The reaction mixture twas kept at 200° C. for 3 minutes and then cooled to 100°C. ‘The GreenChem reaction vessel was removed from the MARS 5 system, the residual pressure was released, and dhe reaction vessel was opened. TLC showed thatthe reaction was complete. The reaction mixture was diluted with 0m of ‘water and extracted with ethyl acetate. The extract was dried ‘with sodium sulfate and the solvent was evaporsted. The residue was purified by column chromatography (sles wel (CH, Cl:CH,OH 20:1 vi) and yielded 137 g (75%) of N- nillymamide (I), m.p.83.5° C (benzene). NMR (D6- ‘acetone): 8.21 s (1H, HC—O), 7.60 s (LH, NH), 7.35 brs, (IH, OF) 6.98 (1H, aromatic, 676 s (2H, aomate), 432 ‘d2H.CH,),3.808GH,CHy)."CNMR(D6-aeetone}: 161.9 (C=O), 148.7, 147.1, 131.7, 121.6, 116.1, 112.6 (aromatic ‘carbons), 56.6 (CH), 423 (CH). IR (neat exystals, ATR, ‘em”"): 3296 (NH), 3213 (OH), 1643 (C=O). C,H NOx, ‘aleulated, % C, $9.66; 1, 6.12:N, 7.73. Found, %: C59.50, 59.89, H 6.13, 612;N7.74,773. “The reation was repeated with 4.56 g (30 mmol) of van- ill and a resction time of 1 min. TLC showed that the reaction was complete. The reaction mixture was extracted fan purified the same way producing 3.29 g (60%) af N- aillyformamide (ID, The reaction was repeated with 1.52 g (10 mmol) of van iin and couventional heating at 1907 C. for 1 minute. The reaction mixture was extracted and purified the same way producing 1-46 g (80%) of N-vanillyormanide (ID, EXAMPLE2 Instant Reductive Amination of “Ehydroxyhenzaldehyde 1 4-hydroxybenzaldchyde (1.22 g oF 10 mmol), Formanside (22.72 g0F 20.03 mL) and formic acid (2.43 g or mi.) were placed into a 50 ml. round bottom Mask equipped with @ thermometer, a rellux condenser, a magnetic stier and & heating mantle, The reaction mixture was heated to 189° C. ‘The heating was immediately tamed off; the reation flask ‘ak quickly raised from the heating mantle and allowed 10 ‘cool to room temperature, The TLC conducted on the cold reaction mixture confirmed that the reaction was complete. ‘The reaction mixture was dilted with 50 ml of water and cextracied with ethyl acetate, The extract was dried with 0 o 4 sodium sulfate and the solvent was evaporated 0 produce 117 207.1%) of 4-hydroxybenylormamide (IV), EXAMPLES Reductive Amination of 142,4-dichlorophenyD)-4.4 ‘dimethyl-I-propen-3-one (V) One g 3.9 mmol) of V, 2 ml of formic aeid, and 20 ml of {formamide were placed in a round bottom ilask equipped With thermometer, reflux condenser, and a heating mantle ‘The reaction mixture was heated to 188-190° Cand main- tained at this temperature for 10 minutes. The reaction mix- ture was left to cool to mom tempersture overnight. The precipitated crystals were separated by filtration, rinsed with ‘water, and dried with vacuum, producing 70% of N-[1-24- ichlorophenyl)-44-dimethyl-I-propen-3-l]-formamide WD. EXAMPLE Reductive Amination of Benzophenone (VID) ‘The reaction procedure for V was repeated with § g of ‘benzophenone and te resetion time of TS minutes. Thereac- tion produced 95% of henehydylformamnide (VII) Gsolated yield). EXAMPLES Instant Hydrolysis of N-[1-(2-4-lichlorophenyl)-4.4- . mixing the aldehyde ora ketone ata 1:100t0 1:10 molar ratio to the formamide «step a and step b are not order dependent; raising temperature of said mixture to reaction tem- perature of at least 180° Cand «iainlining the mixture a the reaction temperstue fora Time between 0 40 80 minutes, 2. The method of claim 1, wherein the formamide is aa substituted formamide or a N-slky formamide. 3. Themethod of claim 2, wherein he N-alkyormamideis selected from a group consisting of Nemethy formamide and Neethylformamige, “4. The method of claim 1, wherein the system is an open system and the reaction temperature of the Leuekar reaction is raised to between 180° C. and 190° C, 5. The method of elsim 1 wherein the system is sealed system andthe reaction temperature of the Leuckar reaction is raised to between 190° C. and 210° C. 6. The method of claim 1, wherein the temperature ofthe Leueckart reaction is mised or maintained by conventional beating or by microwave heating. 7. The method of ela 1, wherein the substituted benzyl. formamide is. vanilylformamide, 4-hydroxybenzylforma- side, and 24,6-rimethoxybenzy formamide. '8. The method of claim 1, wherein the subsite benza éehyde is vanillin, 4-hydroxyborzaldehyde, and 24,6-1 methoxybenzaldehyde '9. The method of claim I, further comprising an soccler- ated hydrolysis of the substituted benzylformamide into a substitited benzylamine,