Aminoketone hydrochloride

Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords aminoketone hydrochloride salt 3.20. Such aminoketones are often isolated as the corresponding salts because the free aminoketones are prone to dimerisation, having both nucleophilic and electrophilic centres. (For a common alternative preparation of aminoketones, see the Knorr pyrrole synthesis, Chapter 2.) Liberation of the free base of 3.20 in the presence of the acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester hydrolysis then affords the biologically-active carboxylic acid 3.23. 

Ketones of the selenophene series are aminomethylated to give aminoketone hydrochlorides, which with phenylhydrazine form N-phenylpyrazolines.115 Kishner reduction of acyl selenophenes has led to various 2-alkylselenophenes the Clemmensen technique proved inapplicable for this purpose.116... 

In the laboratory of E.B. Pedersen, several 2-methylsulfanyl-1H-imidazoles were prepared and tested for their activity against HIV-1 These compounds can be regarded as novel non-nucleoside reverse transcriptase inhibitors. The required a-aminoketone hydrochloride building blocks were prepared using the Dakin-West reaction. L-Cyclohexylalanine was dissolved in excess pyridine and propionic anhydride and was kept at reflux overnight. The resulting a-propionylamino ethyl ketone was hydrolyzed with concentrated hydrochloric acid and the a-aminoketone hydrochloride was heated with one equivalent of potassium thiocyanate in water to afford 4-cyclohexylmethyl-5-ethyl-1,3-dihydroimidazole-2-thione. This material was then advanced to 4-cyclohexylmethyl-1-ethoxymethyl-5-ethyl-2-methylsulfanyl-IH-imidazole. 

As an extension of this study, Hamada s group applied these conditions to the asymmetric hydrogenation of aromatic a-aminoketone hydrochlorides. Surprisingly, no reaction took place under similar conditions. However, it was discovered that the presence of a catalytic amount of NaBARF in addition to sodium acetate in toluene was essential for this hydrogenation catalysed by the same homogeneous nickel catalyst. In these adapted conditions, the synthesis of a series of anti jS-aminoalcohol hydrochlorides was achieved with moderate to high yields, almost complete anti diastereoselectivity in all cases of substrates and high enantioselectivities of up to 96% ee, as shown in Scheme 2.70. 

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). 

Aminolevulinic acid HC1 for topical solution, 20%, contains the hydrochloride salt of aminolevulinic acid, an endogenous 5-carbon aminoketone. The stick for topical application is a two-component system consisting of a plastic tube containing two sealed glass ampules and an applicator tip. One ampule contains 1.5 mL of solution vehicle comprising alcohol (ethanol content = 48% v/v),... 

Arylmorphans were prepared first by the NIH group(23) following a route similar to atetralone synthesis for benzomorphans (Scheme 5.1). Alkylation of 2-(3-methoxyphenyl)cyclohexanone by 2-chlorodimethylaminoethane and sodamide afforded the aminoketone (2), which was converted to 2-methyl-5-phenylmorphan (5). Yields of 5 were relatively low, due largely to the formation of O-alkylated material (4) (75%). Improvement of the yield of N-alkyl product to 40% was achieved(4) by performing the reaction in DMF/NaH with chlorethylamine hydrochloride rather than the volatile base. 

Since hydrochloride hydrate 5 crystallized from the reaction mixture, an additional step was necessary to obtain the desired ortho-ketoaniline 6. The free base was obtained by treatment of 5 with NaOAc in a pH range of 4.0-6.0, which had to be carefully adjusted during the reaction. Hydrate formation of ketones is a reversible process in solution, and the equilibrium fraction of o-aminoketone 6 was continuously extracted from the aqueous layer until removal of hydrating water was complete. The extraction was carried out on a 3,000 g scale. 

Mannich reaction of acetophenone with formaldehyde and piperidine results into the formation of an aminoketone, which on grignardization with bicyclic halide and subsequent neutralization with HCl affords the offieial eompound biperiden hydrochloride. 

Since the 1950 s, the synthesis of DALA has undergone continuous improvements and a variety of starting materials have been tested, including levulinic acid. The following is an overview of successful synthetic approaches that have been described in both the scientific and patent literature. Note that throughout the text the acronym DALA will be used for both the hydrochloride salt and the free DALA. The free DALA is a very unstable compound (1,2-aminoketone) that undergoes spontaneous dimerization to form a stable pyrazine 2 after oxidation of the intermediate dihydropyrazine 1 (Figure 1) (70). 

Stereospecific reduction. NaBH4 added with stirring at 25° to a soln. of 9a-fluoro -16a- methyl -17,20 20,21- bis (methylenedioxy) -11- oxopregn -4- eno [3,2-c] -pyrazole in dimethylformamide containing water, after 4 hrs. ice-cooled, excess reagent decomposed with N HCl, and the product converted to its hydrochloride 9a-fluoro-ll) -hydroxy-16a-methyl-17,20 20,21-bis (methylenedioxy)-pregn-4-eno[3,2-c] pyrazole hydrochloride. Y 86.2%. R. Hirschmann et al., J. Med. Chem. 7, 352 (1964) aminoalcohols s. T. Chiemprasert, H.-J. Rimek, and F. Zymalkowski, A. 685, 141 (1965) stereospecific reduction of a-aminoketones s. A. Ichihara et al.. Bull. Chem. Soc. Japan 38, 1158 (1965). 

A subsequent X-ray structure determination (21) of 6-epimesembranol methiodide (16) which had been obtained from (—)-mesembrine confirmed the assignment of the absolute configuration. A more recent (22) X-ray structure determination of (—)-mesembrane hydrochloride has provided further substantiation that the absolute configuration proposed on the basis of the CD work which assumed normal Octant behavior is correct. This result is of some interest, as it is in apparent violation of the rules suggested by Hudec 2J), who has proposed that axial jS-aminoketones should exhibit anti-Octant behavior. 

Despite the powerful potential of the Neber rearrangement, it has been scarcely utilized in the total synthesis of complex natural products. The earliest such application was in Woodward s total synthesis of lysergic acid. Although not utilized in the successful route to this alkaloid, an early approach to the a-aminoketone (24) exploited the Neber rearrangement on compound 22. Preparation of the oxime (23) followed by rearrangement provided the amine hydrochloride 24 in good yield however, this compound was unstable as a free base and could not be processed further en route to lysergic acid. 

The original Mannich reaction consisted in the reaction of a compound containing at least one active hydrogen atom (ketones, nitroalkanes, p-ketoesters, P-cyano acids etc.) with formaldehyde and primary or secondary amine or ammonia (in the form of its hydrochloride) to give products, p-aminoketone derivatives, known as mannich base (Scheme 153). ... 

Dimethylamino - a - methylpropiophenone and dibenzoyl - (—) - tartaric acid monohydrate dissolved in acetone, stirred until crystallization begins and for an additional 18 hrs., the solid collected and washed with acetone, the combined filtrate coned, with repeated collection of additional product ( —)-j -di-methylamino-a-methylpropiophenone acid dibenzoyltartrate (Y 94%) treated with aq. NHg, extracted with ether, dried with anhydrous MgS04, and acidified with dry HCl ( —)-/ -dimelhylamino-a-methylpropiophenone hydrochloride (Y 94%).—Concentration of the filtrate from the resolution causes racemization of the soluble diastereoisomeric salt and affords a nearly quantitative yield of the insoluble salt. Dibenzoyl-( + )-tartaric acid yields the insoluble salt with the ( + )-aminoketone. A. Pohland, L. R. Peters, and H. R. Sullivan, J. Org. Ghem. 28, 2483 (1963) cf. W. Theilacker, P. Braune, and G. G. Strobel, B. 97, 880 (1964). 

Aldehydes of different types can be conveniently prepared from the next lower halides through carbinols which are split by dia-zotized sulfanilic acid Aliphatic aldehydes in particular can be easily obtained from carboxylic acids through N-acylethylenimi-es Aldehydes, in turn, can be converted directly into nitriles with hydroxylamine hydrochloride Ketones can be efficiently prepared from ethylene derivatives via boranes and, in high purity, from labile alcohols by oxidation in an aq.-ethereal two-phase medium Heating aliphatic acids with reduced iron powder proved to be an excellent method for the prepn. of sym. straight-chain ketones /5-Aminoketones unobtainable by Mannich reaction may be prepared via halogenomagnesium enolates... 

Pyrroles. Equimolar amounts of a-aminopropiophenone hydrochloride, dimethyl acetylenedicarboxylate, and Na-acetate refluxed 10 min. in methanol then 30 min. in the presence of a little HGl dimethyl 5-methyl-4-phenyl-pyrrole-2,3-dicarboxylate. Y 81%.—A weak base is used as catalyst for the Michael addition to prevent dimerization of the a-aminoketone. F. e., also isolation of the intermediate, and quinolines, s. J. B. Hendrickson and R. Rees, Am. Soc. 83, 1250 (1961). 

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