PROCESS FOR THE PREPARATION OF DIALKYLAMINOETHYLAMINES

(12) PATENT ABRIDGMENT (11) Document no. AU-B-?7496/88 (19) AUSTRALIAN PATENT OFFICE (10) Acceptance No. 606244 (54) Title PROCESS FOR THE PREPARATION OF DIALKYLAMINOETHYLAMINES International Patent Classifications) (51)⁴ C07C 085/12 C07C 085/24 C07C 087/16 (21) Application No.: 27496/88 (22) Application Date : 23.12.88 (3Q) Priority Data (31) Number (32) Date (33) Country 3744506 30.12.87 DE FEDERAL REPUBLIC OF GERMANY (43) Publication Date : 06.07.89 (44) Publication Date of Accepted Application : 31.01.91 (71) Applicant(s) HOECHST AKTIENGESELLSCHAFT (72) Inventor(s) Dr. JURGEN WEBER; Dr. VOLKER FALK; Dr. GERHARDT HORN; Dr. HANSWILHELM BACH; KLAUS MATHIEU; CLAUS KNIEP (74) Attorney or Agent WATERMARK PATENT & TRADEMARK ATTORNEYS, Locked Bag 5, HAWTHORN VIC 3122 (57) Claim 1. A process for the preparation of dialkylamino ethyl-aminesby the. hydro genat ionof dialkylarninoaceto-nitriles in the presence of cobaltcatalysts,charac­terised in that hyd.rQgenation takesplace at 40 to 120^oC and at 4 to 15 MPa on catalystswhich have been obtained by the precipitation of cobaltcarbonate out of the aqueoussolution of ,a cobalt salt with an aqueous alkali metalcarbonatesolution at 20 to 95^ciC, filtration j washingout,optionallysh a;p ingof the catalyst mass and subsequentreduction with, hy'drdgen at temperatures of between 200 and 300^oC, preferably between 220 and 280^oC, •vt/KSt*, j,^ , Form 10COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69COMPLETE SPECIFICATION(ORIGINAL)GlassInt. ClassApplication Number: Lodged:Complete Specification Lodged: Accepted: Published: , Priority: Related Art:K.$me of Applicant: HOECHST AKTIENGESELLS-CHAFT Address of Applicant: 45 Btuningstrasse , D.t-6230 Frankfurt; /Main, Federal Republic of Germany.

Actual Inventor: JURGEN WEBER,. VOLKER FALK, GERHARDT HORN., HANSWILHELM BACH, KLAUS MATHlEU and GLAUS KNIEP.

Address for Service; EDWD. WATERS & SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: PROCESS FOR THE PREPARATION OF DIALKYLAMINOETHYLAMINES The following statement is a full description of this invention, including the best method of performing it known to :• us4gs ^--^^iBS-tsspsy tfn - la -Process for the preparation of dialkyXaminoethylamines The presentinvention relates to a process for the preparationof dialkylaminoethylamines by the hydro- genation ofdialkylaminoacetonitriles on cobalt catalysts.

r 11 \4 » Dialkylaminoethylamines are intermediates in demand in the chemical industry for the preparation of a number of medicines. For example, the diethylaminoethylamine compound is an important starting material for the syntheses of procainamide,ambenohium chloride,meto-clopramide and chinehocain. Dialkylaminoethylamines are accessible by several routes. Oneprocessdescribedin different variations in literature is thereaction of potassiumphthalie acid imide with dialkylaminoet.hyl halides..Alternative­ly, the reaction can also be performed with ammonia or hexamethylene tetramine instead of potassium phthalie acid imide* Disadvantages of theseprocesses are the high amounts of chemicals required and the fact that the effluent is polluted by the reaction pfbdUcts. The use of these processes on an industrial, scale is there­fore limited.

• f < t » I « • • * • * • » « The reaetiOn of ethylene imine with dialkylamines is very cost-effectiye. However, it necessitates the presence of the highly toxic ethylene imine.

" - "-rtW -OT»> 4r ., t,,^ rJ 2 - •t | •« I It** Another route leading to dialkylaminoethylamines is the Mannich reaction of dialkylamines, formaldehyde and alkali metal cyanidewhich produces dialkylaminoaceto-nitriles. The desired diamine is obtained from the acetonitriles by hydrogenation. The conversion of the nitrile group to the amine group can take place with sodium or lithium aluminiumhy­dride. These processes do not have commercial signifi­cance. In industry hydrogenation is performed with hydrogen in the presence of catalysts. According to Winans andAdkins (Am.- Soc. 55, .4167 (193?)) diethylaminoacetonitrile can be hydrogenated on Raneynickelto form diamine in a 37% yield. Apart from the fact that sucha yield is too smallfor a commer­cial process, it was not possibleto readilyreproduce the valuesof WinansandAdkins(cf. Houben-Weyl11/1, page 563). The GB-PS 745 684 describes a process for the prepara­tion of N,M-dialkylaminoethylamine by the catalytic hydrogenation of N,N-dialkylaminoacetonitrileat a pressure above atmospheric pressure and at temperatures below 110⁶C. This process results in a yield of 92% but requires the use of liquid ammonia and Raney cobalt whose production is complicated. Moreover, Raney %: » * * » * * ** * * » t •«* •91 «*I t• t ••« •« * • • * *, r-vfi « rfW" » '"" * -- catalysts cannot be used as fixed bed catalysts but only in suspension. The task was therefore to develop a process which over­comes the afore-mentioned disadvantages of the state of the art and permits the hydrogenation of dialkylamino-acetonitriles with reasoaable technical means producing high yields. The invention consists in a process for the preparation of dialkylaminoethylamines by the hydrogenation tif dialkylaminoacetonitriles in the presence of cobalt catalysts. It is characterised in that hydrogenation takes place at 40 to 120^oC and at 4 to 15 MPa on cata­lysts which have been obtained by the precipitation of cobalt carbonate out of the aqueoussolution of -a' cobalt salt with an aqueousalkali metal carbonate solution at 20 to 95⁰C, filtration, washing out, option­ally shaping of the catalyst mass and subsequent reduc­tion, with hydrogen at temperatures of between 200 and 3.00°C, preferably between 220 and 280^oC. Surprisingly, the new process permits dialkylaminoaeeto-' nitriles to be easily transformed into dialkylamino­ethylamines with a high yield andhigh Selectivity.

A major feature of the invention is the use of cobalt -*t^*K^*m*mm 4 - • m • » catalysts produced in a certain manner for the hydro-genation of the nitriles. In the reduced state these catalysts consist of cobalt, According to a preferred embodiment they also contain 0.25 to 15 % by weight of Si0₂, Mn0₂, Zr0₂, A1₂0₃ or MgO in the form of the oxides, hydroxides or oxide hydrates. These additives are usedsingly or in combi­nations of two or more of the substances. Their amount is preferably 1 to 8 and in particular 2 to 5 % by weight. All afore-mentioned figures in per cent by weight relate to the total catalyst mass in the an­hydrous state before reduction. The above-mentioned formulae merely serve to describe the quantitative composition of the eartalyst mass and they do not necessarily reflect the exact chemical structure of the additives.Apart, ftom as oxides,they can he contained in both the non-reducedandin the reduced catalyst as hydroxides and in particular as oxidehydrates. The mode Of action of the additives has not been clari­fied in all details. Test results indicate that they stabilise the structure of the catalyst, in particular its surface structure, against sintering effects at high tempeirati/res. Moreover;, they also increase the i • * * « •» .aft^KftiW^ 5 - • • • e * » * mechanical stability of the shapes moulded from the catalyst mass. In order to prepare the cobalt catalysts, cobalt car­bonate is precipitated at 20 to 95⁰C out of the aqueous solution of a cobalt salt with an aqueous alkali metal carbonate solution. The term cobalt carbonate simply denotes the reaction product from cobalt salt and alkali metal carbonate under the selected reaction con­ditions and it does not have to correspond to the for­mula CoCCU but, for example,, can also cover basic cobalt carbonates. Suitable cobalt salts are, for example, cobalt nitrate, cobalt chloride, cobalt sul­fate, cobalt acetate. The sodium or potassium compounds are used in particular as alkali metal carbonates. The solutions of the starting materials contain cobalt salt or alkali metal carbonate each in concentrations of 25 to 150 g of Co of alkali metal carbonate per litre of solution. Cobalt sSlt andalkali metal carbonate can be Reacted with each other in equimolaf amounts but it is more appropriate to work with an excess of alkali metal carbonate. 1.1 to 1.5 and in particular 1.2 to 1.3 moles of alkali metal carbonate per tnole of cobalt salt have proved successful. In. drder to prepare cobalt catalysts containing ofie or rtiore additives the cdfresponding substand:es can be • * * * * * * # * * • • * • • • • *• »* • «♦ « r—W •Wrm-'IH »^»£i-«?F* • * • • * ♦ » • ♦ • • • • * * • ♦ « • ♦ «« * 4 suspended in the solution of the cobalt salt or in the alkali metal carbonate solution. However, equally good results can be obtained by adding a soluble salt of the additive to the cobalt salt solution before precipita­tion and precipitating the cobalt carbonate and addi­tive together. Finally, it is also possible to precipi­tate the cobalt carbonate separately and then precipi­tate the additive onto the cobalt carbonate. The performance of the reduction and thus the activa­tion of the catalyst is of major importance for its efficiency. The reduction takesplace m a temperature range which starts at 200^oC, preferably 220^oC and does not exceed 300^oC, preferably 280^oC. It is particularly appropriate to reduce in at least three stages at a temperature whichincreases from stage to stage. Hydrogen is used as a reducingagent. It is passed over the catalyst filling at a space velocity of 200 to 2000 H₀ per 1 catalyst and per hour (200 to 2000 \f_u/\/ . . dHeat h), preferably 300 to 1000 V_u/\/ . . h and in parti- n c a L cular 400 to 700 Vu/V* , . h at normal pressure. n c a "C It has proved successful to set a temperature of 220 to 250^oC, preferably 230 to 240^oC m the first stage and maintain it for 1 to 4, in particular 2 to 3 hours. In the second stage reduction takes place for 1 to 5, in m * • • »* • * * * * • «- • 9 ft • ♦ 3 -s who *»•&#&* s^ iimmm^r^^^³^"""^ ° "**""~"5r*' "*r"* 7 - particular 2 to 3 hours at 245 to 260^oC, preferably 250 to 255⁰C. Subsequently, reduction is completed for a further 1 to 5, in particular 2 to 3 hours at 255 to 280^oC, preferably at 260 to 270^oC.

I * • • • The reduced catalyst is pyrophoric and spontaneously inflammable in air. For better handling it is therefore treated with oxygenheavilydilutedby an inert gas. For example,an N„ stream which containsoxygenin a concentration of about 0.5 to about 1 % by volume is allowed to act on it. This treatment oxidises the catalyst surface; in this condition the catalyst is stable in air up to about 80^oC and is not spontaneously inflammable.

The new pfbces's permits dialkylaminoacetonitriles to be converted into the corresponding dialkylaminoethyl-amines very selectivelyandwith highyields. For hydrogenatiOn thenitriles canbe usedin the commer­cially availableforms; specialpretreatment, e.g. to eliitiinate impurities resultingfrom manufacture,is unnecessary. Hydrogenation itself is conductedat temperatures of 40 to 120°C andat pressures of 4 to 15 MPa. It has proved particularly successful to work at to 110^eC_ppreferably 50 to 80°C andat 6 to 12, preferably 8 to 10 MPa.

The dialkylaminoacetonitriles can be used in substance. However, it is useful to feed them into the hydrogena-tion reactor dissolved in an inert solvent. Aliphatic, cycloaliphatic and aromatic hydrocarbons and aliphatic alcohols can be used as solvents. Suitable solvents are, for example,cyclohexane,toluene, butanol, 2-ethylhexanol. Cyclohexanehasproved particularly successful, the concentration of thedialkylaminoaceto­nitriles in the solution is between 5 and 50 % by weight, preferably 10 to 40 and in particular 15 to 30 % by weight (related in eachcase to the solution). According to a preferred embodiment ammonia is added to the nitrile. This produces an increase in the selecti­vity of the hydrpgenation towards d^ialkylaminoethyl-amines to. over 90%. It has proved successful to use 1 to 20 moles of ammonia per mole of nitrile. Particular­ly good results are achieved if 1.5 to 15 and in particular 2 to 10 moles of ammbriia per mole, of nitrile are contained in the starting mixture. The new process permits dialkylaminoacetonitriles of the general formula N - CH, CN '**^:#r&r-&ti°frtf-tns**- -)§?" ' c « t % to be hydrogenated iato the corresponding diamines, FL and R₂ being the same or different and each denoting unbranched or branched alkyl groups having 1 to 9 carbon atoms. It is particularly suitable for the hydro-genation of alkylaminoacetonitriles in which FL and Rp are the same andeachdenote unbranchedor branched alkyl groups having 1 to 6 carbon atoms, in particular unbranched or branched alkyl groups each having 2 to 4 carbon atoms. Hydrogenation of the dialkylaminpacetonitriles can be performed both discontinuouslyandin particular con­tinuously. With continuous operation the catalyst is located in a tube into which the starting mixture is fed at the bottom, Adequate, preheating of the feed materials is to be provided. It is recommended to set the space velocity to values, of between 0.05 and 1.0, in paftiqular 0.1 to 0.5 volumes of dialkylaminoaceto-nitrile or dialkylaminqacetonitrile solution per volume of catalyst and per hour. The preparation of the claimed catalysts used and the hydrogenation of dialkylaitiinoacetonitriles are described in thefollowing examples,. It is not intended to restrict the invention to these special embodimerrts.

*'»** -fl^sMf ,£ ^^KMft^^^^^r^KWP^**^ -nsr-' "T^r - 10 Example1: Preparation of a cobalt catalyst without additives •• • • «« » • • * •« ** A solution heated to 95⁰C of 1852 g of Co(N0₃)₂ . 6H₂0 C? 375 g of Co) in 7.5 1 of deionised water is poured into a solution heated to 90^oC of 800 g of Na„C0„ in 7.5 1 of deionised water over a period of 2 minutes with vigorous stirring. A suspension of cobalt carbon­ate in water with a pH value of 8.2 to 8.4 is formed. The precipitation product is filtered off and washed thoroughly with roughly 90 1 of condensate water (tem­perature: 70^oC) so that the conductivity cf the rinsing water is less than 100 juS on completion of the washing prccess. The still moist catalyst preliminary product is againsuspendedin deionisedwater and then spray--dried. The mass contains about 53,5 % by weight of cobalt.

t » • « * * * *• * • • * « « • « • * •• • a * ♦ In the reduction process, 200 1 bf Hp/h are passed over 0.5 1 of the dried catalyst mass in a tubular reactor (diameter: 50 mm) at 24,0^oC for 2 hours. Then the tem­perature is increased to 250^PE, reduction is continued for a further 2 hours with 2-OQ 1 of H^/h a,nd completed by treating the catalyst for another 2 hours with 200 1 of Hp/h at 260^oC. For stabilisation purposes the powder is treated at 50 to 70°C with an N- stream containing 0.7 % by vdlDrtii of 0₂andis then pressed into tablets.

^^Hf^Afi-^i ii*.**, *«« firb. > -. r-**. - 11 - i Example 2: Preparation of a cobalt catalyst with additive A solution heated to 9b⁰C of 1852 g of Co(N0₃)₂ . BHpO (=^N 375 g of Co) and85.73 g of Mn (N0₃)₂. 4H₂0 in 7.5 1 of deionised water is steadily poured into a solution heated to 90^oC of 840 g of Na₂C0₃ in 7.5 1 of deionised water over a period of 2 minutes with vigorous stir­ring. A suspensionof cobaltandmanganesecarbonatein water with a pH value of 8.2 to 8.4 is formed. The pre­cipitation product is filtered off andwashedthorough­ly with roughly 90 1 of 70^oC hot condensate water so that the conductivity of the rinsing water is less than irS on completion of thewashingprocess.

«»«i * The still moist catalyst preliminary product is again suspended in peionisedwater andthenspray-dried.The mass contains about 52 % by weight of Co and about 4.1 % by weight of Mn0₉, * i t The reduction of the catalyst takesplace as described in' example 1. Example 3: Hydrogenation of diethylaminoacetonitrile 1,8 1 Of the cobalt catalyst described in example 1 are arranged in the form of tablets 6 mm in diameter as a - 12 fixed bed in a heatable 3 m long double-jacket tube with an inside diameter of 28 mm. The temperature is raised to 70^oC and hydrogen is fed in at a pressure of 8 MPa at the bottom of the reaction tube together with 600 ml of a solution of diethylaminoacetonitrile in cyclohexane(15 % by weight of nitrile related to the solution) via a piston pump continuously per hour. The product dischargingat thereactorheaddoes not con­tain any diethylaminoacetonitrile. In additionto 86.5% of solvent,11% of diethylaminoethylamineare detected by GC. Example4: Hydrogenation of diethylaminoacetonitrile i«W In the reactor of example 3 andusing 1.8 1 of the cata­lyst from example2 at 60^oC andan H„ pressureof 8 MPa diethylaminoacetonitrile in the form of a 30 % by weight; solution (related to thesolution) is reacted to form cyclohexane.At the sametime2.5 moles of NHo/mole of nitrile are fed into the reactor andthe throughput increasedto 900 ml/h. The diethylaminoaceto­nitrile is completely reacted.The GC analysisshows the reaction product to Contain73.2 % of cyclohexane and 25.1 % of the diethylaminoethylamine.

- 13 - Example 5; Hydrogenation of diethylaminoacetonitrile « 4C * • 1 I » * « Undiluted diethylaminoacetonitrile is reacted in the reactor of example 3 at 50°C and a H_? pressure of 8 MPa. 2.5 moles of NH„ are fed into the reactor per mole of nitrile, the throughput is set to 180 ml/h = V/Vh = 0.1. The nitrile is completelyreacted,the GC analysis shows the reaction product to contain 89.7 % of diethyl-aminoethylamine, the r^maxnder beingcleavageproducts. The reaction product is worked up in a column with 24 theoretical plates. Digthylaminoethylamine of more than 99% purity is recovered.

« * * * * i i** ^<jsK?s^-^e_l«&*fe*3W«*jx*¥<**K3^,wv "- -r?- '-"*~« - X4 - THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A process for the preparation of dialkylaminoethyl-amines by the hydrogenation of dialkylaminoaceto-nitnles in the presence of cobalt catalysts, charac­terised in that hydrogenation takes place at 40 to 120^oC and at 4 to 15 MPa on catalysts whxch have been obtained by the precipitation of cobalt carbonate out of the aqueous solution of a cobalt salt with an aqueous alkali metal carbonate solution at 20 to 95⁰C, filtration, washing out, optionally shaping of the catalyst massandsubsequentreduction with hydrogenat temperatures of between 200 and 300^oC, preferably between 220 and 280^oC.

2. A process according to claim 1, characterised in that the catalyst contains in addition 0.25 to 15 % by weight, related to the total catalyst mass, of Si0_?, Mn0_, Zr0_?, Al„0o or MgO singly or as a combination of two of more of these substances in the form of the oxides, hydroxides or oxide hydrates.

3.A process according to claim 2, characterised in that SiOj,, Mn0_?, Zr0„, A1„0„ or MgO is contained in the catalyst in an amount of 1 to 8 andin particular 2 to % by weight,related to the total catalyst mass. 4,A process according to one or more of the claims 1 to 3, characterised in that reduction takesplacein at !IIW*1Vu»i J* - 5tpr-ji~i .i--^*. •"Jas^y^i. JOSijepWWWT • - 15 least three stages at a temperature which increases from stage to stage. 5.A process according to claim 4, characterised in that reduction is performed in the first stageat a tempera­ture of 220 to 250^oC, preferably 230 to 240^oC, in the second stage at 245 to 260^oC₎ preferably 250 to 255⁰C and in the third stageat 255 to 280^oC, preferably 260 to 270^oC. 6.A process according to one or more of theclaims 1 to 5,characterised in that hydrogenation takesplaceat to 100^oC, preferably at 50 to 80^oG. 7.A process according to one or more of the claimsto 6,characterised In' that hydrogenation takesplaceat 6 to 12, preferably 8 to 10 MPa. 8- A process according to one or more of the claims 1 to 7,characterised in that the, dialkylamihoacetOnitfiles are used dissolved in an inert solvent. 9, A process according to claim 8, charaeterised in that the toncentration of dialkylaminoacetonitrile in the solution is 5 to 50 % by weight, preferably 10 to 40 % by weight and in particular 15 to 30 % by weight.

-^^^_r^^_lmimia.^_rr^_irSiim, ^^j^^f^^^a^^iisiaiw*-^^"^-™ -[strike]mnM[/strike]i[strike]rnrjimjmfr[/strike]- 16 - 10. A process according to one or more of the claims 1 to 9, characterised in that hydrogenation takes place in the presence of ammonia, 1 to 20 moles, preferably 1.5 to 15 moles and in particular 2 to 10 moles being used per mole of dialkylaminoacetonitrile.

*«• ♦ * »* t« DATED THIS 22nd day of December, 1988 ► ** * *' •HOECHST AKTIENGESELLSCHAFT t • + • t * » i • * t • * * EDWD. WATERS & SONS, PATENT ATTORNEYS, •"«50 QUEEN STREET, * * « MELBOURNE. VIC. 3000.