Superior Catalysts for Preparation of 3-Amino-2,2,4,4-Tetramethylthietane Via the Leuckart Reaction

Europaisches Patentamt 0 337 652 J European Patent Office © Publication number: A1 Office europeen des brevets

EUROPEAN PATENT APPLICATION

C07C 85/08 © Application number: 89303363.9 © int. Cl.4: C07D 331/04 , , B01J 21/02 @ Date of filing: 05.04.89

© Priority: 12.04.88 US 180511 © Applicant: PFIZER INC. 235 East 42nd Street © Date of publication of application: New York, N.Y. 10017(US) 18.10.89 Bulletin 89/42 @ Inventor: Hay, Bruce Allan © Designated Contracting States: 1, High Street AT BE CH DE ES FR GB GR IT LI LU NL SE Mystic Connecticut(US)

© Boric acid or aluminum salts, especially aluminum chloride, aluminum sulfate and aluminum nitrate and hydrates of said salts, are superior catalysts for preparation of 3-amino-2,2,4,4-tetramethylthietane via the Leuckart reaction.

CM If) CO r^ CO

Xerox Copy Centre EP 0 337 652 A1

SUPERIOR CATALYSTS FOR PREPARATION OF 3-AMINO-2,2,4,4-TETRAMETHYLTHIETANE VIA THE LEUC- KART REACTION

This invention relates to an improvement in the version of many carbonyl compounds to amines Leuckart reaction. More particularly it relates to an occurs readily by heating a mixture of the selected improvement in said reaction, especially as it ap- carbonyl compound and the formic acid salt or plies to the preparation of 3-amino-2,2,4,4- formyl derivative of ammonia or the amine to be tetramethylthietane, the improvement comprising 5 alkylated. The addition of various substances as the use of superior catalysts; namely, aluminum catalysts, e.g., formic acid, ammonium formate, salts or boric acid. magnesium chloride or calcium chloride often im- The Leuckart reaction, a process for the reduc- proves the overall yield of a desired amine product tive alkylation of ammonia, primary or secondary and, in some instances, renders an otherwise in- amines with carbonyl compounds has been exten- 70 operable or impractical Leuckart reaction, a sat- sively used to prepare a wide variety of amines isfactory method of alkylation. (Moore, Organic Reactions, V, 301-330 (1949); In the present invention boric acid or aluminum Moelier et al. in Houben-Weyl, Methoden der Or- salts and hydrates thereof function as effective ganischeTT Chemie Xl/I, Georg Thieme, Stuttgart, catalysts for preparation of 3-amino-2,2,4,4- 1956, pp; 648-664). The reduction is effected by 75 tetramethylthietane via the Leuckart reaction. The reacting a carbonyl compound and the formic acid favored aluminum salts are the chloride, sulfate and salt or formyl derivative of ammonia or amine to be nitrate; and the hydrates of said salts. alkylated, e.g. ammonium formate or formamide. The reaction comprises reductive alkylation of The use of magnesium chloride as catalyst for ammonia by the ketone 2,2,4,4-tetramethyl-3-ox- the reaction of benzophenone with formamide was 20 othietane. Alternatively, it can be looked upon as reported by Webers et al., J. Am. Chem. Soc. 70, the reductive amination of the ketone by ammonia. ~~ 1422-1424(1948). When used as catalysts in the reaction de- Bunnett et al., J. Am. Chem. Soc, 71,. 1587- scribed herein, magnesium chloride, calcium chlo- 1589 (1949), rep~ort the results of their investigation ride, cerium chloride, barium chloride, titanium tri- into the use of a variety of substances as catalysts 25 chloride and titanium tetrachloride were found to in the Leuckart reaction, including ferric chloride, produce yields of crude product similar to those zinc chloride, calcium chloride and magnesium produced by the catalysts of this invention. How- chloride. The ferric chloride and zinc chloride were ever, the product quality is significantly poorer than inferior to magnesium chloride in the reaction of p- that produced by the catalysts of this invention. bromoacetophenone with dimethylformamide. Cal- 30 Thus, the catalysts of this invention simplify pu- cium chloride was, however, reported to be a better rification of the crude product and afford improved catalyst in said reaction than magnesium chloride. final yields of the desired pure amine. Zinc chloride It has now been surprisingly found that boric and ferric chloride were ineffective as catalysts in acid or aluminum salts catalyze preparation of 3- said reaction as they were reduced to the metals amino-2,2,4,4-tetramethylthietane via the Leuckart 35 under the reaction conditions used. reaction to provide a product of greatly improved The addition of formic acid, ammonium chlo- quality over that produced by the use of magne- ride or small amounts of water (up to 5%) beyond sium chloride or calcium chloride as catalysts. The that present in the reactants had a negligible effect use of boric acid or aluminum salts and hydrates upon the reaction. thereof as catalysts is of particular advantage in the 40 The favored aluminum salts are desirably and Leuckart reaction when said reaction is used to preferably used in the form of their hydrates, e.g., prepare 3-amino-2,2,4,4-tetramethylthietane of val- AICl3«6H2O, AI(SO+)3»16H2O and AI(NO3)3»9H2O. ue as reactants for preparation of L-aspartyl-D- They and boric acid are used in amounts ranging alanine N-(2,2,4,4-tetramethylthietan-3-yl)amide, a from about 2-20% w/w based upon the carbonyl potent sweetener. 45 compound. A favored amount of catalyst to ketone Although the Leuckart reaction is applicable to compound is 10% w/w. conversion of a wide variety of carbonyl com- The reaction must be run in a vessel that does pounds to amines, it does not, as might be ex- not react with the reactants or products of the pected work equally well with all carbonyl com- Leuckart reaction. Glass or Teflon lined vessels are pounds. In general, for conversion of a given car- so appropriate vessels for the reaction. bonyl compound to a desired amine, reaction con- It is desirable, for reasons of economy, to ditions must be optimized. No set of reaction con- conduct the reaction at the lowest temperature ditions is generally applicable. As described in the which will produce the desired product in the best * review article by Moore (loc. cit.), satisfactory con- yield and purity. Temperatures of from about 1 40 - EP 0 337 652 A1

250° C are used. The reaction time is, of course, a 3-Amino-2,2,4,4-Tetramethylthietane function of the temperature. In general, reaction times ranging from about 20 hours at the lower temperature range to about 4 hours at the upper Formamide (4.0 g, 89 mmol), 2,2,4,4- temperature are sufficient to substantially complete 5 tetramethyl-3-oxothietane (1.0 g, 6933 mmol) and the reaction. The reaction is normally carried out in boric acid (100 mg) were combined in a Teflon a closed system; i.e., under pressure. lined Parr bomb which was heated for 15 hours in The ratio of ketone reactant to formamide is a 175° C oil bath. The reaction was cooled and the not critical. Molar ratios of 1 :4 to 1 :25 are generally light brown mixture taken up in water (40 ml). The used. Lower ratios tend to produce a higher level of w aqueous solution was extracted with methylene by-products. Higher ratios appear to have little ef- chloride (4 x 20 ml) and the combined extracts fect on the reaction. dried (MgSO+) and evaporated under reduced The formyl derivative produced as intermediate pressure to a light brown oil (1.02 g). The residue in the reaction is conveniently hydrolyzed to the was hydrolyzed and the hydrolyzate worked up amine by refluxing with hydrochloric acid of con- 75 according to the procedure of Example 1 to give centration ranging from 1N to 12N (concentrated) the title product 650 mg (65%), verified by its 1H- until hydrolysis is complete. It is generally advanta- NMR spectrum. geous to isolate the intermediate formyl derivative prior to the hydrolysis step in order to obtain a higher quality product than is obtained by 20 EXAMPLE 3 hydrolyzing the reaction mixture. A convenient iso- lation procedure comprises extraction of the reaction with a suitable solvent, e.g., methylene chlo- Repetition of the procedure of Example 1 , but ride, followed by removal of the solvent to provide using the following catalysts in place of aluminum a residue of the formamide derivative. 25 chloride hexahydrate provides 3-amino-2,2,4,4- The invention is further illustrated by the follow- tetramethylthietane: ing examples. AI2(SO03«16H2O AICI3 AI2(NO3)3»9H2O EXAMPLE 1 30 AI2(SO*)3-.

Claims 3-Amino-2,2,4,4-Tetramethylthietane 35 1. An improvement in the process comprising the reductive alkylation of ammonia by 2,2,4,4- Formamide (8.0 g, 178 mmol), 2,2,4 ,4- tetramethyl-3-oxothietane in the Leuckart reaction, tetramethyl-3-oxothietane (1.0 g, 6.933 mmol) and which improvement comprises conducting the re- aluminum chloride hexahydrate (100 mg) were action in the presence of boric acid or an aluminum placed in a Teflon lined Parr bomb and heated at 40 salt as catalyst. 170° C for 18 hours. The reaction was then cooled 2. The process of claim 1 wherein the catalyst and taken up in water (20 ml). The aqueous solu- is boric acid. tion was extracted with methylene chloride (3 x 20 3. The process of claim 1 wherein the alu- ml), the extracts combined and concentrated under minum salt is aluminum chloride, aluminum sulfate, reduced pressure. The residue was refluxed with 45 aluminum nitrate or a hydrate of any one of these. 1 N HCI (20 ml) for 4 hours, the reaction cooled and 4. The process of claim 3 wherein the alu- washed with methylene chloride (2 x 20 ml). It was minum salt is aluminum chloride hexahydrate. then brought to pH 14 by addition of 6N sodium 5. A process for making 3-amino-2,2,4,4- hydroxide and extracted with the methylene chlo- tetramethylthietane which comprises ride (3 x 20 ml). The combined extracts were dried 50 a) reacting formamide with 2,2,4,4- (Na2SO+) and concentrated to give 0.600 g (60%) tetramethyl-3-oxothietane in the presence of boric of title product, verified by its 1H-NMR spectrum. acid or an aluminum salt at a temperature of from 140°-250°C in a closed system until reaction is substantially complete to produce the formamide EXAMPLE 2 55 derivative of 3-amino-2,2,4,4-tetramethyithietane; and, b) hydrolyzing said formamide derivative. EP 0 337 652 A1

6. The process according to claim 5 wherein the catalyst is boric acid. 7. The process according to claim 5 wherein the cataiyst is an aluminum chloride, aluminum sulfate, aluminum nitrate or a hydrate of any one of 5 these. 8. The process according to claim 7 wherein the catalyst is aluminum chloride hexahydrate. 9. A process according to any one of the preceding claims 5 to 8 wherein the formamide w derivative is isolated from the reaction prior to hydrolysis.

55 European Patent Application Number J>) EUROPEAN SEARCH REPORT Office EP 89 30 3363

DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant CLASSIFICATION OF THE Category of relevant passages to claim APPLICATION (Int. CI.4) EP-A-0 034 876 (PFIZER CO.) 1,5 C 07 D 331/04 * 76, example 15 * page C 07 C 85/08 B 01 J 21/02 CHEMICAL ABSTRACTS 1,5 vol. 43, no. 20, 25 October 1949, abstract no. 7920g, Columbus, Ohio, USA; J. F. BUNNETT et al . : "Preparation of tertiary amines by the Leuckart reaction"; & J. Am. Chem. Soc. 71, pages 1587-1589,1949 (Cat. D)

CHEMICAL ABSTRACTS 1,5 vol. 42, no. 18, 20 September 1948, abstract no. 6781b, Columbus, Ohio, US; V. J. WEBERS: "The Leuckart reaction: a study of the mechanism"; & J. Am. Chem. Soc. vol. 70, pages 1422-1424, 1948

CHEMICAL ABSTRACTS 1,5 vol. 42, no. 20, 20- October 1948, abstract no. 7758d, Columbus, Ohio, US; TECHNICAL FIELDS SEARCHED ant. C1.4) F. LEONARD et al . :"2-Thenyl substituted diamines with antihistamic activity"; & C 07 D 331/00 J. Am-. Chem. Soc. 70, pages 2064-2067, 1948 C 07 C 85/08 B 01 J 21/00 THEILHEIMERS SYNTHETIC METHODS OF 1,2,6 ORGANIC CHEMISTRY vol. 41, 1987, page 149, abstract 334, Basel; A. F. FINCH: "Oxazolines from 2-aminoalcohols and carboxylic acids"; & J. Chem. Soc. Partkin Trans I, 1985, pages 1865-1869

The present search report has been drawn up for all claims Place of search Date of completion of the search Examiner BERLIN 05-07-1989 KYRIAKAKOU G

CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons a A : technological background ho O : non-written disclosure & : member of the same patent family, corresponding document a.C P : intermediate document Page 2

European Patent Application Number J EUROPEAN SEARCH REPORT Office EP 89 30 3363

C. FERRI: "Reaktionen der organischen 1,2 Synthese" 1978, G. Thieme Verlag, Stuttgart * page 133 *

BULLETIN OF THE CHEMICAL SOCIETY OF 1,2,6 JAPAN vol. 49, no. 9, September 1976, pages 2485-2490; K. ITO et al . : "Studies on Leuckart-Wallach Reaction Paths" * the whole document *

TECHNICAL FIELDS SEARCHED (Int. C1.4)

The present search report has been drawn up for all claims Place of search Date of completion of the search Examiner BERLIN 05-07-1989 KYRIAKAKOU G CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons a A : technological background O : non-written disclosure & : member of the same patent family, corresponding P : intermediate document document