.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 4,739,049

« Back to Dashboard

Details for Patent: 4,739,049

Title: Phosphorylation of cyclic amides
Abstract:Compounds of the general formula ##STR1## are reacted with a strong base followed by a phosphorylating agent, such as dicyclicaminophosphinic halide or bis-di-lower alkylaminophosphinic halide to produce an imine of the formula ##STR2## wherein R is dicyclicaminophosphinyloxy or bis-di-lower alkylaminophosphinyloxy. R represents a leaving group which will undergo nucleophilic displacement with nitrogen, oxygen, sulfur and carbon containing nucleophiles, that is, nucleophiles which have, as a reactive site, a nitrogen, oxygen, sulfur or carbon atom, such that, when the cyclic imine undergoes nucleophilic displacement, there is formed C--N, C--O, C--S and C--C bonds between the carbon atom of the cyclic imine and the nucleophilic group. The end products may be utilized as intermediates in the production of pharmaceutically valuable compounds and, in some instances, are pharmaceutically valuable compounds per se.
Inventor(s): Ning; Robert Y. (West Caldwell, NJ), Madan; Pradeep B. (Lake Hiawatha, NJ)
Assignee: Hoffmann-La Roche Inc. (Nutley, NJ)
Filing Date:Aug 15, 1986
Application Number:06/897,456
Claims:1. A process to prepare a compound of the formula ##STR52## wherein A is selected from the group consisting of ##STR53## in which R.sub.5 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, hydroxy lower alkyl and lower alkanoyl; R.sub.4 is selected from the group consisting of phenyl, monohalogen-substituted phenyl, dihalogen-substituted phenyl, pyridyl,, thiophenyl, pyrimidinyl, oxazolyl, thiazolyl and 1-cyclohexenyl; R.sub.6 is selected from the group consisting of hydrogen, lower alkyl, acyl, and lower alkoxycarbonyl; and R.sub.7 is selected from the group consisting of hydrogen, lower alkyl, COO-lower alkyl, a radical of the formula ##STR54## wherein R.sub.8 is lower alkyl and a radical of the formula ##STR55## wherein n is an integer of 2 to 5, which comprises reacting a compound of the formula ##STR56## wherein A R.sub.5, R.sub.4 and R.sub.6 are defined as above, with a strong base followed by a phosphorylating agent selected from the group consisting of dipiperazinophosphinic halides, dipiperidinophosphinic halides, dipyrrolidinophosphinic halides, dimorpholinophosphinic halides and bis-di-lower alkylaminophosphinic halides, and reacting the phosphorylated product with a compound of the formula H.sub.2 NNHCOR.sub.7 wherein R.sub.7 is defined as above.

2. A process for preparing a compound of the formula ##STR57## in which A is selected from the group consisting of ##STR58## wherein R.sub.5 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, hydroxy lower alkyl and lower alkanoyl; R.sub.4 is selected from the group consiting of phenyl, monohalogen-substituted phenyl, dihalogen-substituted phenyl, pyridyl, thiophenyl, pyrimidinyl, oxazolyl, thiazolyl and 1-cyclohexenyl; R.sub.6 is selected from the group consisting of hydrogen, lower alkyl, acyl and lower alkoxycarbonyl; and X is a nucleophilic group selected from the group consisting of amino, monoalkylamino, dialkylamino, anilino, monomethylanilino, morpholino, piperidino, pyrrolidino, hydrazino, 2-hydrazinopyridino, 1,1-dimethylhydrazino, 1,2-dimethylhydrazino, methylhydrazino, 2-hydroxyethylamino, 2-aminoethylamino, methylhydrazinocarboxylate, acetylhydrazido, hydroxylamino, N-methylhydroxylamino and methoxylamino,

which process comprises reacting a compound of the formula ##STR59## in which A and R.sub.5 are as defined above, with a strong base, followed by a phosphorylating agent selected from the group consisting of dipiperazinophosphinic halides, dipiperidino phosphinic halides, dipyrrolidinophosphinic halides, dimorpholinophosphinic halides and bis-di-lower alkylamino phosphinic halides, to produce a compound of the formula ##STR60## in which A and R.sub.5 are as defined above and R is a leaving group of the formula ##STR61## in which R.sub.1 and R.sub.2 independently are lower alkyl or together with the nitrogen atom form pyrrolidino, piperidino, 4-methylpiperidino, piperazino, or morpholino, and nucleophilically displacing the leaving group X in the presence of pyridine or triethylamine.

3. A process for preparing a compound of the formula ##STR62## in which E is ##STR63## wherein R.sub.5 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, hydroxy lower alkyl and lower alkanoyl; and X is a nucleophilic group selected from the group consisting of amino, monoalkylamino, dialkylamino, anilino, monomethylanilino, morpholino, piperidino, pyrrolidino, hydrazino, 2-hydrazinopyridino, 1,1-dimethylhydrazino, 1,2-dimethylhydrazino, methylhydrazino, 2-hydroxyethylamino, 2-aminoethylamino, methylhydrazinocarboxylate, acetylhydrazido, hydroxylamino, N-methylhydroxylamino and methoxylamino, which process comprises reacting a compound of the formula ##STR64## in which B is ##STR65## and R.sub.5 is as defined above, with a strong base, followed by a phosphorylating agent selected from the group consisting of dipiperazinophosphinic halides, dipiperadinophosphinic halides, dipyrrolidinophosphinic halides, dimorpholinophosphinic halides and bis-di-lower alkylamino phosphinic halides, to produce a compound of the formula ##STR66## in which D is ##STR67## R.sub.5 is as defined above and R is a leaving group of the formula ##STR68## in which R.sub.1 and R.sub.2 independently are lower alkyl or together with the nitrogen atom form pyrrolidino, piperidino, 4-methylpiperidino, piperazino, or morpholino, and subsequently nucleophilically displacing the leaving group R with the nucleophilic group X in the presence of pyridine or triethylamine.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc