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(12) Patent Application Publication (10) Pub. No.: US 2016/0304439 A1 Divi Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0304439 A1 Divi Et Al US 20160304439A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0304439 A1 Divi et al. (43) Pub. Date: Oct. 20, 2016 (54) PROCESS FOR THE PREPARATION OF Publication Classification ADVANTAME (51) Int. Cl. (71) Applicant: Divi's Laboratories Limited, Ameerpet CD7C 2.3L/2 (2006.01) (IN) CD7C 45/45 (2006.01) (52) U.S. Cl. (72) Inventors: Murali Krishna Prasad Divi, CPC ............. C07C 231/12 (2013.01); C07C 45/45 Ameerpet (IN); Mysore Aswatha (2013.01) Narayana Rao, Ameerpet (IN); Shaik Nowshuddin, Ameerpet (IN) (57) ABSTRACT (21) Appl. No.: 14/848,533 A novel process for the preparation of N—N-3-(3-hydroxy (22) Filed: Sep. 9, 2015 4-methoxyphenyl)-propyl-L-C.-aspartyl-L-phenylalanine 1-methyl ester is described. It comprises, reacting isovanillin (30) Foreign Application Priority Data or its derivative with vinyl acetate followed by reductive condensation with L-C.-aspartyl-L-phenylalanine-1- Apr. 20, 2015 (IN) ........................... 2019/CHFA2015 methyl ester. US 2016/0304439 A1 Oct. 20, 2016 PROCESS FOR THE PREPARATION OF ADVANTAME MeO O FIELD OF INVENTION NH HO NH 0001. The present invention relates to an improved pro OH cess for the preparation of N—N-3-(3-hydroxy-4- Advantame COOMe methoxyphenyl)propyl-L-C.-aspartyl-L-phenylalanine-1- O methyl ester, known as Advantame, a non-caloric Sweetener. BACKGROUND OF THE INVENTION 0002 Advantame is a novel sweetener developed by 0003. The U.S. Pat. No. 6,794,531 B2, assigned to Aji Ajinomoto Co. It is a derivative of Aspartame, chemically nomoto Co., describes a process for the preparation of N—N-3-(3-hydroxy-4-methoxyphenyl)propyl-L-C.-as Advantame (Scheme 1), involving condensation of 3-(3- partyl-L-phenylalanine-1-methyl ester, having the follow hydroxy-4-methoxyphenyl)-propionaldehyde (III) with ing structure: Aspartame. Scheme 1 MeO H2 MeO \ COOH Catalyst \-co HO HO (I) (II) H2 H2 Catalyst-2 Catalyst-2 MeO COOH Catalyst-1H2 - )- CHO HO HO (IV) (III) NH2 O H MeOOC N OH H2 O Catalyst aspartame MeO NH HO NH OH COOMe Advantame US 2016/0304439 A1 Oct. 20, 2016 0004. The required propionaldehyde derivative (III) was reduced by hydrogenation using catalyst-2 to obtain (IV) prepared by selectively reducing the corresponding cin followed by reduction using catalyst-1. The propionalde namic acid derivative (I) by hydrogenation using catalyst-1 consisting of palladium based catalyst, triaryl phosphine and hyde intermediate (III) was reductively aminated with aspar pivalic acid anhydride to obtain corresponding cinnamalde tame to give advantame. Reduction of carboxylic acid of hyde intermediate (II), followed by a second hydrogenation cinnamic acid intermediate to aldehyde using catalyst-1 was using catalyst-2, which can be any general catalyst based on cumbersome. Ajinomoto reported a related process in its palladium, platinum, nickel etc. Alternatively, (I) was first patent U.S. Pat. No. 6,548,096 B1 (Scheme 2): Scheme 2 NH H MeOOC N MeO NaB(OAc)3H -- O COOBn - He CHO BO (IIa) MeO O NH BO 21 NH BIOOC COOMe (Va) /H2, Pd/C MeO O NH HO NH HOOC COOMe US 2016/0304439 A1 Oct. 20, 2016 0005. In this process, 4-methoxy-3-benzyloxy cinnamal Suffers from a major drawback. Cross aldol condensation dehyde (IIa) was condensed with benzyl protected aspar between acetaldehyde and other carbonyl compound in an tame by reductive amination using Sodium triacetoxyboro alkaline medium generally gives poor yields. This is mainly hydride to obtain (Va). Hydrogenation of (Va) using palladium catalyst resulted in deprotection of benzyl groups because of self-condensation of acetaldehyde enolate with and saturation of the double bond to give Advantame. This unreacted aldehyde resulting in undesirable products and process requires protection and later deprotection of both side reactions (Angew. Chem. Int. Ed. Engl. 1968, 7, 7-14: phenolic group of the cinnamaldehyde and carboxylic acid Synthesis 1979, 633-665). The Ajinomoto process (Scheme of aspartame through benzylation, which increases the num 3) also suffers for similar reasons. The process attempts to ber of steps and cost of the process. Ajinomoto described overcome this problem by slow addition of acetaldehyde to another process in U.S. Pat. No. 7,141,263 B2 (Scheme 3): the alkaline solution of isovanillin. But the addition is Scheme 3 Alkali MeO CHO + CH3CHO -> acetaldehyde BO isovanillin MeO \ H2 MeO CHO Catalyst CHO HO HO (II) (III) NH2 O NH2 O H H MeOOC N MeOOC N OH OH O H2 H2 O Catalyst Catalyst aspartame aspartame MeO O NH HO NH OH COOMe O Advantame 0006. In the scheme-3, the first step is cross aldol con excruciatingly slow taking about 45 hours (up to 96 hours as densation of isovanillin with acetaldehyde in the presence of per Claim-6) making the process duration very long. an alkali to obtain (3-hydroxy-4-methoxy) cinnamaldehyde 0007 Because of the enumerated drawbacks of the above (II). Catalytic hydrogenation of (II) gives (III) which on mentioned processes, there is thus a need for developing an reductive amination with aspartame gives Advantame. improved process. Direct reductive condensation of (II) with aspartame also results in Advantame. By this process (II) is obtained in SUMMARY OF THE INVENTION much purer form compared to other processes where the corresponding cinnamic acid derivative is reduced to obtain 0008 Since acetaldehyde enolate generated from acetal intermediate (II) (Scheme 1). However, Scheme-3 process dehyde in the alkaline medium during aldol condensation US 2016/0304439 A1 Oct. 20, 2016 results in a number of side reactions, it was hypothesized 0013 III. catalytic hydrogenation of (V) or (Vb) to that generating acetaldehyde enolate from a non-aldehyde obtain Advantame. compound may be able to Suppress side reactions during the aldol reaction. Indeed, such was found to be the case when (0014 Junjappa et al (Synlett. 2000, 9, 1345-1347) vinyl acetate was used as a non-aldehyde compound to reported the preparation of cinnamaldehyde by refluxing a generate acetaldehyde enolate. The acetaldehyde enolate tetrahydrofuran solution of benzaldehyde and vinyl acetate obtained from vinyl acetate on condensing with isovanillin using barium hydroxide as a base. Isolation involved dilut resulted in highly pure (4-methoxy-3-hydroxy) cinnamalde ing the reaction mixture with water and extraction with hyde with good yields. chloroform followed by column chromatography for puri 0009. The present invention describes a novel process for fication. No hydroxyl substituted benzaldehyde was Advantame based on vinyl acetate condensation with iso attempted, although other substituted aldehydes were stud vanillin or O-benzylisovanillin followed by reductive ami ied. When 2.5 equivalents of vinyl acetate were used, a nation with Aspartame (Scheme-4): dienal (VI) was obtained in 61%. Scheme 4 O MeO CHO -- us -e-Alkali e 1S vinyl acetate RO isovanillin, R = H BebZylisovanillin, R = Bn MeO \ CHO RO (II), R = H (IIa), R = Bn NH2 O H MeOOC N NaBH4. O N HAc aspartame MeO MeO O O NH HO NH NH RO 21 NH OH OH 22 COOMe COOMe Pd(C O a- O (V), R = H Advantame (Vb), R = Bn DETAILED DESCRIPTION OF THE INVENTION 0010. The present invention describes a process (Scheme 4) for the preparation of Advantame which comprises: (VI) 0011 I. Condensing isovanillin or its O-benzyl deriva- CHO tive with vinyl acetate in the presence of an alkali to N1 N. obtain cinnamaldehyde derivative (II) or (IIa), 0012 II. condensing (II) or (IIa) with aspartame through reductive amination using sodium borohydride and acetic acid to obtain (V) or (Vb). US 2016/0304439 A1 Oct. 20, 2016 00.15 Our initial attempts to prepare (3-hydroxy-4- -continued methoxy) cinnamaldehyde by the method described by Junjappa etal resulted only in the acetylation of the phenolic N CHO N group. (Scheme-5): -- O OH O Scheme-5 2-hydroxycinnamaldehyde coumarin 0019 Surprisingly no reaction was observed when MeO CHO + Ba(OH) or t-BuOK was used as the base. With 3-hydroxy benzaldehyde, corresponding cinnamaldehyde was obtained HO in about 43% yields. With 4-hydroxy benzaldehyde no reaction was observed. The fact that hydroxyl cinnamalde Isovanillin hyde can be obtained without protecting the phenolic group O prompted us to explore further the reaction of isovanillin ls HeTHF, Ba(OH)2 with vinyl acetate. 21 No 0020 Systematic and detailed studies of the reaction conditions such as base, Solvent, temperature and duration of MeO CHO reaction resulted in optimized reaction conditions where (II) was obtained in high yield and purity (>95% yield, >99.5% HPLC). ic--0 0021 Best results were obtained when vinyl acetate was O used in three equivalents to isovanillin and the reaction was conducted in water as solvent at -10+2°C. with 10 equiva Acetylisovanillin lent sodium hydroxide as the base. Formation of impurities was high at room temperature. When Sodium hydroxide was 0016 Change of solvents (acetonitrile, ethanol, metha used in 3 to 6 equivalents, the reaction was incomplete. nol, etc) and bases (NaOH, KOH, EtsNetc), did not improve Similarly, three equivalents of vinyl acetate were required the situation. Hence the phenolic group was protected with for optimum results. It is interesting to note that no dienal benzyl and the resulting O-benzylisovanillin was reacted similar to (IV) was formed as reported by Junjappa et all at with vinyl acetate. No reaction was observed at low or room 2.5 equivalents of vinyl acetate. temperature but significant amount of (IIa) was obtained 0022 Condensation of (II) with aspartame was carried when a solution of O-benzylisovanillin and vinyl acetate in out by reductive amination using sodium borohydride in methanol were autoclaved at 80°C. for 12 hours in presence acetic acid at room temperature.
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