2-Amino acetal hydrochlorides, synthesis

Diethoxy a-hydroxy-benzylphosphonate has been reported to undergo nucleophilic substitution with primary amines to give a-aminophosphonates (Scheme 184) " Primary aromatic amines have been prepared from arylboronic acids in the presence of 0-(2,4-dinitrophenyl)hydroxylamine. " Reaction of iV-t-butanesulfinyl a-haloimines with alkoxides has been reported to give iV-t-butanesulfinyl 2-amino acetals that are precursors for TMSOTf-promoted synthesis of iV-protected a-amino aldehydes and ketones and for the HCl-promoted synthesis of 2-amino acetal hydrochlorides and a-amino ketone and a-amino aldehyde hydrochlorides (Scheme 185). " ... 

An alternative approach to the use of a-aminoketones involves acetals (72JOC221) and pyrazine-2,3-diones have been synthesized by this route (Scheme 58). The acetals are readily available from the phthalimido derivatives via the a-chloroketones. Hemiacetals have also served as a starting point for pyrazine synthesis, although in most cases hemiacetals are too labile to be easily prepared examples are common in the 2-amino-2-deoxy sugar series 2-amino-2-deoxy-D-glucose for example dimerizes to the pyrazine (101) when generated in situ from the hydrochloride salt (68JAP6813469). 

Axenrod and co-workers reported a synthesis of TNAZ (18) starting from 3-amino-l,2-propanediol (28). Treatment of (28) with two equivalents of p-toluenesulfonyl chloride in the presence of pyridine yields the ditosylate (29), which on further protection as a TBS derivative, followed by treatment with lithium hydride in THF, induces ring closure to the azetidine (31) in excellent yield. Removal of the TBS protecting group from (31) with acetic acid at elevated temperature is followed by oxidation of the alcohol (32) to the ketone (33). Treatment of the ketone (33) with hydroxylamine hydrochloride in aqueous sodium acetate yields the oxime (34). The synthesis of TNAZ (18) is completed on treatment of the oxime (34) with pure nitric acid in methylene chloride, a reaction leading to oxidation-nitration of the oxime group to em-dinitro functionality and nitrolysis of the A-tosyl bond. This synthesis provides TNAZ in yields of 17-21 % over the seven steps. 

The synthesis of pazopanib (1) involves sequential animation of 2,4-dichloropyrimidine 25 with 6-amino-2,3-dimethylindazole 24 and 5-amino-2-methyl-benzenesulfonamide 28. The 6-amino-2,3-dimethylindazole 24, on the other hand, was prepared from 2-ethylphenylamine 20 via 5-nitration with fuming nitric acid and concentrated sulfuric acid, followed by treatment with isoamyl nitrite and acetic acid to produce 6-nitro-3-methylindazole 22. The 6-nitro group was reduced with stannous chloride and concentrated HC1 in glyme and subsequently methylated at the C2 position of the indazole ring with trimethyloxonium tetrafluoroborate in acetone to produce 6-amino-2,3-dimethylindazole 24. The resultant indazole 24 was condensed with 2,4-dichloropyrimidine 25 in the presence of sodium bicarbonate in ethanol/THF and subsequent iV-methylation with iodomethane and cesium carbonate to produce 27. The 2-chloro group of pyrimidine was then allowed to react with 5-amino-2-methyl-benzenesulfonamide 28 in catalytic HCl/isopropanol and heated to reflux to deliver pazopanib hydrochloride (1) in good yield. 

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

Oxidation of the dihydropyrazines to pyrazines occurs easily with mild oxidizing agents such as air hydrogen peroxide cupric, ferric, or mercuric ions or with bromine water, bromine in acetic acid, or aqueous nitric acid. The a-(primary amino) carbonyl compounds required for the synthesis of pyrazines may be prepared by a large variety of synthetic methods. The products are usually stable as their salts, for example, hydrochlorides, but the free bases show a strong tendency to undergo self-condensation to the pyrazine and for this reason the amino carbonyl compounds are rarely isolated. 

Neutralization of HCl. Lead hydroxide obtainecT by hydrolysis of the acetate appears to be superior to lead oxide for the liberation of an a-amino acid from its hydrochloride. In the synthesis of a-aminodiethylacetic acid formulated the crude... 

Synthesis of heterocycles [before references]. Hendrickson et al developed a useful general synthesis of heterocycles in which the key step is a Michael addition of the reagent to a substrate of a variety of types having an amino, mercaptan, or hydroxyl group adjacent to an electrophilic center. An example is the reaction of a-aminopropiophenone hydrochloride, and sodium acetate to liberate the amine (1), with dimethyl acetylenedicarboxylate in refluxing methanol. Sodium chloride... 

S.3.3.2 Synthesis from o-glucosamine Allosamizoline (8) has also been synthesized from D-glucosamine (Scheme 3). Methyl 2-amino-4,6-0-benzylidene-3-0-benzyl-2-deoxy-a-D-glucopyranoside" (26), obtained from D-glucosamine hydrochloride (25), was converted into the corresponding M,A -dimethylurea derivative, which underwent hydrolysis with aqueous acetic acid to give the diol 27 (91%). Selective iodination of the primary position and subsequent protection of the secondary hydroxyl group with... 

Pyrrole-based anthranilic acid derivatives have been prepared utilizing a four step sequence starting from arylacetonitriles 4 <04T2267>. Condensation of the latter with ethyl formate followed by treatment with diethylaminomalonate hydrochloride (DEAM-HCl) led to enamine 6. Cyclization and transesterification then gave 3-aminopyrrole-2-carboxylate 7. The acid-mediated cyclocondensation of methylaminoacetaldehyde dimethyl acetal with malonitrile provided a novel synthesis of 2-amino-3-cyanopyrroles, useful building blocks for the preparation ofpyrrolo[2,3- f]pyrimidines <04OL2857>. 

A tremendous upsurge in synthetic activity in this field is evident. A stereoselective synthesis of cis-zeatin (22), whose geometrical isomer was first isolated from Zea mays and shown to be a stimulant of cell division in plant tissue cultures, has been reported (Scheme 2). The Diels-Alder reaction of 1-chloro-l-nitro-socyclohexane (19) with isoprene gave the dihydro-l,2-oxazine hydrochloride (20) in moderate yield. Liberation of the base of (20) followed by zinc-acetic acid reduction gave the required amino-alcohol (21), which upon treatment with 6-chloropurine provided a separable mixture of cis-zeatin (22) and trans-zeatin. Standard tobacco callus bioassay for cytokinin activity showed that the natural trans-zeatin is at least 50 times more active than the synthetic cis-isomer (22). 

The acetoacetyl derivatives are obtained by the reaction of the amine with diketene . In the case of amino acid ester hydrochlorides the presence of one equivalent of sodium methoxide or of a tertiary base is necessary. The group is removed by applying the conditions of the Knorr synthesis of pyrazol derivatives from various /3-keto esters and their derivatives . The protecting group is removed in acetic acid by using an equimolar amount of phenylhydrazine (reaction 3). 

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