3-Fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone) and some esters. Syntheses and effects in BDF1 mice

Richard W. Pero, Paula Babiarz-Tracy, Thomas P Fondy

Research output: Contribution to journalArticle

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Abstract

1-(Benzoyloxy), 1-(4-nitrobenzoyloxy), and 1-(3,5-dinitrobenzoyloxy) derivatives of 3-fluoro-, 3-chloro-, and 3-bromopropan-2-one were prepared by oxidation of the 1-benzoyloxy-3-halopropan-2-ols in turn prepared from the appropriate benzoyl chloride and 3-halo-1,2-propanediols. 1-Benzoyloxy-3-fluoropropan-2-one was allowed to react with acidic trimethyl orthoformate to yield 1-benzoyloxy-2,2-dimethoxy-3-fluoropropane which upon basic hydrolysis afforded 2,2-dimethoxy-3-fluoropropan-1-ol (fluorohydroxyacetone dimethyl ketal). This was deketalized with aqueous HCl to afford 3-fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone), the title compound. By reacting 1-chloro-3-fluoropropan-2-one and 1,3-dichloropropan-2-one with potassium acetate, 1-acetoxy-3-fluoropropan-2-one and 1-acetoxy-3-chloropropan-2-one (fluoro- and chlorohydroxyacetone acetate, respectively) were obtained. Similarly, sodium benzoate and 1-chloropropan-2-one produced 1-benzoyloxypropan-2-one. Structure-activity relationships are discussed which relate chemical structure, alkylating ability, toxicity, and antitumor effects. Comparative toxicities in mice showed decreasing toxicity, on a molar basis, in the 1-benzoyloxy-3-halopropan-2-one series of bromo > fluoro > chloro. Ketones were much more toxic than the corresponding alcohols. In general the phosphate and benzoyloxy derivatives are more toxic than acetoxy compounds, with nitro-substituted benzoyloxy derivatives being much less toxic.

Original languageEnglish (US)
Pages (from-to)644-647
Number of pages4
JournalJournal of Medicinal Chemistry
Volume20
Issue number5
StatePublished - 1977

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Poisons
Toxicity
Esters
Derivatives
Potassium Acetate
Nitro Compounds
Sodium Benzoate
Propylene Glycol
Structure-Activity Relationship
Ketones
Hydrolysis
Acetates
Phosphates
Alcohols
Oxidation
fluorohydroxyacetone

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

3-Fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone) and some esters. Syntheses and effects in BDF1 mice. / Pero, Richard W.; Babiarz-Tracy, Paula; Fondy, Thomas P.

In: Journal of Medicinal Chemistry, Vol. 20, No. 5, 1977, p. 644-647.

Research output: Contribution to journalArticle

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abstract = "1-(Benzoyloxy), 1-(4-nitrobenzoyloxy), and 1-(3,5-dinitrobenzoyloxy) derivatives of 3-fluoro-, 3-chloro-, and 3-bromopropan-2-one were prepared by oxidation of the 1-benzoyloxy-3-halopropan-2-ols in turn prepared from the appropriate benzoyl chloride and 3-halo-1,2-propanediols. 1-Benzoyloxy-3-fluoropropan-2-one was allowed to react with acidic trimethyl orthoformate to yield 1-benzoyloxy-2,2-dimethoxy-3-fluoropropane which upon basic hydrolysis afforded 2,2-dimethoxy-3-fluoropropan-1-ol (fluorohydroxyacetone dimethyl ketal). This was deketalized with aqueous HCl to afford 3-fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone), the title compound. By reacting 1-chloro-3-fluoropropan-2-one and 1,3-dichloropropan-2-one with potassium acetate, 1-acetoxy-3-fluoropropan-2-one and 1-acetoxy-3-chloropropan-2-one (fluoro- and chlorohydroxyacetone acetate, respectively) were obtained. Similarly, sodium benzoate and 1-chloropropan-2-one produced 1-benzoyloxypropan-2-one. Structure-activity relationships are discussed which relate chemical structure, alkylating ability, toxicity, and antitumor effects. Comparative toxicities in mice showed decreasing toxicity, on a molar basis, in the 1-benzoyloxy-3-halopropan-2-one series of bromo > fluoro > chloro. Ketones were much more toxic than the corresponding alcohols. In general the phosphate and benzoyloxy derivatives are more toxic than acetoxy compounds, with nitro-substituted benzoyloxy derivatives being much less toxic.",
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N2 - 1-(Benzoyloxy), 1-(4-nitrobenzoyloxy), and 1-(3,5-dinitrobenzoyloxy) derivatives of 3-fluoro-, 3-chloro-, and 3-bromopropan-2-one were prepared by oxidation of the 1-benzoyloxy-3-halopropan-2-ols in turn prepared from the appropriate benzoyl chloride and 3-halo-1,2-propanediols. 1-Benzoyloxy-3-fluoropropan-2-one was allowed to react with acidic trimethyl orthoformate to yield 1-benzoyloxy-2,2-dimethoxy-3-fluoropropane which upon basic hydrolysis afforded 2,2-dimethoxy-3-fluoropropan-1-ol (fluorohydroxyacetone dimethyl ketal). This was deketalized with aqueous HCl to afford 3-fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone), the title compound. By reacting 1-chloro-3-fluoropropan-2-one and 1,3-dichloropropan-2-one with potassium acetate, 1-acetoxy-3-fluoropropan-2-one and 1-acetoxy-3-chloropropan-2-one (fluoro- and chlorohydroxyacetone acetate, respectively) were obtained. Similarly, sodium benzoate and 1-chloropropan-2-one produced 1-benzoyloxypropan-2-one. Structure-activity relationships are discussed which relate chemical structure, alkylating ability, toxicity, and antitumor effects. Comparative toxicities in mice showed decreasing toxicity, on a molar basis, in the 1-benzoyloxy-3-halopropan-2-one series of bromo > fluoro > chloro. Ketones were much more toxic than the corresponding alcohols. In general the phosphate and benzoyloxy derivatives are more toxic than acetoxy compounds, with nitro-substituted benzoyloxy derivatives being much less toxic.

AB - 1-(Benzoyloxy), 1-(4-nitrobenzoyloxy), and 1-(3,5-dinitrobenzoyloxy) derivatives of 3-fluoro-, 3-chloro-, and 3-bromopropan-2-one were prepared by oxidation of the 1-benzoyloxy-3-halopropan-2-ols in turn prepared from the appropriate benzoyl chloride and 3-halo-1,2-propanediols. 1-Benzoyloxy-3-fluoropropan-2-one was allowed to react with acidic trimethyl orthoformate to yield 1-benzoyloxy-2,2-dimethoxy-3-fluoropropane which upon basic hydrolysis afforded 2,2-dimethoxy-3-fluoropropan-1-ol (fluorohydroxyacetone dimethyl ketal). This was deketalized with aqueous HCl to afford 3-fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone), the title compound. By reacting 1-chloro-3-fluoropropan-2-one and 1,3-dichloropropan-2-one with potassium acetate, 1-acetoxy-3-fluoropropan-2-one and 1-acetoxy-3-chloropropan-2-one (fluoro- and chlorohydroxyacetone acetate, respectively) were obtained. Similarly, sodium benzoate and 1-chloropropan-2-one produced 1-benzoyloxypropan-2-one. Structure-activity relationships are discussed which relate chemical structure, alkylating ability, toxicity, and antitumor effects. Comparative toxicities in mice showed decreasing toxicity, on a molar basis, in the 1-benzoyloxy-3-halopropan-2-one series of bromo > fluoro > chloro. Ketones were much more toxic than the corresponding alcohols. In general the phosphate and benzoyloxy derivatives are more toxic than acetoxy compounds, with nitro-substituted benzoyloxy derivatives being much less toxic.

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