An Improved Synthesis of Butyl 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino] -1-piperidineacetate (AU-224).

Abstract

We recently reported the synthesis and gastrointestinal prokinetic activity of novel benzamide derivatives with amphoteric side chains.1) Among them, 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (1a) exhibited the most excellent gastro-and colon-prokinetic activities by intravenous administration to conscious dogs without significant dopamine D 2 receptor antagonist activity. However, 1a showed only weak gastrointestinal prokinetic activity after oral administration due to its low lipophilicity. After the evaluation of several ester prodrugs of 1a, the butyl ester (1b) was consequently selected as a promising gastrointestinal prokinetic agent without significant side effects.As described previously, 1) compound 1b was prepared by esterification of 1a with butyl bromide in a large amount of N,N-dimethylformamide (DMF). The key intermediate 6 was obtained in four steps and an overall yield of 48% from commercially available 4-amino-1-benzylpiperidine (2). A compound 1a was prepared in four steps and an overall yield of 40% from commercially available 4-amino-5-chloro-2-methoxybenzoic acid (7) as shown in Chart 2.Although the previous route was quite adequate for the synthesis with a wide variety of 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinealkanecarboxylic acids or the assorted ester prodrugs of 1a, the overall yield (14%) of 1b from 2 was not sufficient and a number of steps (9 steps) were required. We have therefore developed a new and facile synthetic route for a high overall yield with only short steps. In this paper, we describe a new and efficient route for the synthesis of 1b.In a new synthetic route, the key intermediate, butyl 4-amino-1-piperidineacetate (16), was prepared as shown in Chart 3. The amino group of 2 was protected with di-tertbutyl dicarbonate (Boc 2 O) in acetonitrile (CH 3 CN) to give compound 112) in 90% yield. Debenzylation of 11 with Pearlman's catalyst 3) and cyclohexene in ethyl alcohol (EtOH) afforded a secondary amine (12) 2) in 92% yield. Alkylation of 12 with butyl chloroacetate (14), 4) which was derived from chloroacetyl chloride (13) and butyl alcohol (nBuOH) in 92% yield, was accomplished using triethylamine (Et 3 N) as a base in DMF to give compound 15 in 93% yield. Since the usage of potassium carbonate (K 2 CO 3 ) as a base in this step produced a great deal of the byproduct, butyl 4-tertbutoxycarbonylamino-1-piperidinecarboxylate, we changed the base from K 2 CO 3 to Et 3 N. Next, the deprotection with hydrogen chloride-isopropyl alcohol solution of 15 followed by the removal of acid using Et 3 N gave a primary amine (16) quantitatively. Compound 7 was converted into the activated ester with ethyl chlorocarbonate (ClCO 2 Et) in anhydrous tetrahydrofuran (THF) and then amidated with 16 to give the desired ester (1b) in good (84%) yield.In conclusion, we have established an efficient route for the synthesis of 1b, a novel promising gastro-and colon-prokinetic agent. The new route shortened the total steps of the synthesis of 1b and cons...

Synthesis of Antimicrobial Natural Products Targeting FtsZ: (+)-Totarol and Related Totarane Diterpenes

“…23 Although many conditions have been reported for the solvolysis of dimethyloxazolines related to 13, this substrate proved problematic. 21,24 We found that acidic hydrolysis in ethanol was more consistently high yielding for conversion to ester 14. 25 Reduction to alcohol 15 and conversion to either bromide 16a or chloride 16b were straightforward.…”

“…Regioselective displacement of the ortho methoxy group was achieved in high yield using conditions reported by Myers 23. Although many conditions have been reported for the solvolysis of dimethyloxazolines related to 13 , this substrate proved problematic 21,24. We found that acidic hydrolysis in ethanol was more consistently high-yielding for conversion to ester 14 25.…”

“…Acid 10 was converted to mixed anhydride 10b and then treated with 2-amino-2-methyl-1-propanol to amide 11 21. The resultant amide was cyclized to oxazoline 12 using triethylamine and methanesulfonyl chloride22 in 96% overall yield from 10 .…”

“…Acid 10 was converted to the amide precursor of 12 via the reaction of the mixed anhydride with amide 11. 21 The resultant amide was cyclized to oxazoline 12 using triethylamine and methanesulfonyl chloride 22 in 96% overall yield from 10. Regioselective displacement of the o-methoxy group was achieved in high yield using conditions reported by Myers.…”

“…We initially explored route A by preparing the precursor to 4 in seven steps (Scheme ). Acid 10 was converted to the amide precursor of 12 via the reaction of the mixed anhydride with amide 11 . The resultant amide was cyclized to oxazoline 12 using triethylamine and methanesulfonyl chloride in 96% overall yield from 10 .…”