Doxapram

Doxapram Basic information
Product Name:Doxapram
Synonyms:1-Ethyl-4-[2-(4-morpholinyl)ethyl]-3,3-diphenyl-2-pyrrolidinone;2-Pyrrolidinone, 1-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-;ahr619;AHR-619;Dopram;dopream;2-Pyrrolidinone, 1-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl- (7CI, 8CI);2-Pyrrolidinone, 1-ethyl-4-[2-(4-morpholinyl)ethyl]-3,3-diphenyl-
CAS:309-29-5
MF:C24H30N2O2
MW:378.51
EINECS:206-216-3
Product Categories:Pharmaceutical
Mol File:309-29-5.mol
Doxapram Structure
Doxapram Chemical Properties
Melting point 113 - 114°C
Boiling point 506.58°C (rough estimate)
density 1.1056 (rough estimate)
refractive index 1.5620 (estimate)
storage temp. 2-8°C
solubility Chloroform (Slightly), Methanol (Slightly)
form Solid
pka7.30±0.10(Predicted)
color White to Off-White
NIST Chemistry Reference2-Pyrrolidinone, 1-ethyl-4-[2-(4-morpholinyl)ethyl]-3,3-diphenyl-(309-29-5)
Safety Information
Hazardous Substances Data309-29-5(Hazardous Substances Data)
MSDS Information
Doxapram Usage And Synthesis
OriginatorDopram,Robins,US,1965
UsesDoxapram is a central respiratory stimulant.
UsesDoxapram increases the rate and depth of respiration. It is used for post-anesthetic respiratory depression, and for respiratory depression caused by drug use.
UsesDoxapram HCl inhibits TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric channel function with EC50 of 410 nM, 37 μM, 9 μM, respectively - See more at: http://www.selleckchem.com/products/doxapram-hcl.html#sthash.SSt04Hwr.dpuf
DefinitionChEBI: A member of the class of pyrrolidin-2-ones that is N-ethylpyrrolidin-2-one in which both of the hydrogens at the 3 position (adjacent to the carbonyl group) are substituted by phenyl groups, and one of the hydrogens at the 4 position is ubstituted by a 2-(morpholin-4-yl)ethyl group. A central and respiratory stimulant with a brief duration of action, it is used (generally as the hydrochloride or the hydrochloride hydrate) as a temporary treatment of acute respiratory failure, particularly when superimposed on chronic obstructive pulmonary disease, and of postoperative respiratory depression. It has also been used for treatment of postoperative shivering.
Manufacturing Process(A) Preparation of α-(1-ethyl-3-pyrrolidyl)-α,α-diphenylacetonitrile: A suspension of the sodium salt of diphenylacetonitrile was formed by the dropwise addition at 50°C of 193 grams (1.0 mol) of diphenylacetonitrile to a stirred suspension of 43 grams (1.1 mols) of sodium amide in 1 liter of dry toluene. After addition was complete, the mixture was refluxed for 4 hours and then, to the refluxing mixture, 1.0 mol of 1-ethyl-3-chloropyrrolidine was added at a rapid dropwise rate with continuous stirring. After addition was complete, stirring and refluxing were continued for 3 hours. The mixture was then cooled and extracted with one normal hydrochloric acid. The aqueous layer together with an oil layer were separated, made basic with dilute sodium hydroxide, and extracted with ether. The ethereal solution was dried over sodium sulfate and concentrated and the residue was distilled in vacuo. The material crystallized from a 4:1 ethanol-water mixture.
(B) Preparation of 4-(β-chloroethyl)-3,3-diphenyl-1-ethyl-2-pyrrolidinone: A solution of α,α-diphenyl-α-(1-ethyl-3-pyrrolidyl)-acetonitrile in 70% sulfuric acid was heated at 130-140°C for 48 hours, poured onto ice, made basic with sodium hydroxide, and extracted with chloroform. The chloroform solution was acidified with hydrogen chloride gas, dried over sodium sulfate and concentrated. The residue was refluxed in 500 ml of thionyl chloride for 3 hours; the resulting solution was concentrated in vacuo; and the residue wascrystallized from isopropyl ether.
(C) Preparation of doxapram hydrochloride [3,3-diphenyl-1-ethyl-4-(2- morpholino-ethyl)-2-pyrrolidinone hydrochloride monohydrate]: A solution of 25 grams (0.076 mol) of 4-(2-chloroethyl)-3,3-diphenyl-1-ethyl-2- pyrrolidinone and 13.3 grams (0.153 mol) of morpholine in 500 ml of absolute ethanol was heated at 95°-120°C for 21 hours in a closed system and concentrated in vacuo. The residue was dissolved in 300 ml of two normal hydrochloric acid and extracted with 150 ml of ethyl acetate. A solid crystallized (13 g) during the extraction and was removed by filtration. MP 217°-219°C. The acid extracts were made basic with sodium hydroxide and extracted with ether, and the ether solution was concentrated in vacuo and the residue was suspended in six normal hydrochloric acid. Additional crystalline product formed and was recrystallized from two normal hydrochloric acid. Yield, 10 grams; MP 217°-219°C. Total yield, 23 grams (70%).

Therapeutic FunctionRespiratory stimulant
SynthesisDoxapram, 1-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone (8.2.4), is synthesized in the following manner. Diphenylacetonitrile in the presence of sodium amide is alkylated with 1-ethyl-3-chlorpyrrolidine, giving (1-ethyl-3-pyrrolidinyl) diphenylacetonitrile (8.2.1). Acidic hydrolysis of the nitrile group gives (1-ethyl-3 pyrrolidinyl)diphenylacetic acid (8.2.2). Reacting this with phosphorous tribromide (thionyl chloride, thionyl bromide, acetic anhydride) leads to rearrangement with an opening of the pyrrolidine ring and the subsequent closing of the pyrrolidinone ring, forming 1-ethyl-4-(2-bromoethyl)-3,3-diphenyl-2-pyrrolidinone (8.2.3). Substitution of the bromine atom with a morpholine group gives doxapram (8.2.4) [15¨C18].

Synthesis_309-29-5

Doxapram Preparation Products And Raw materials
Raw materialsDiphenylacetonitrile-->Sulfuric acid-->Hydrochloric acid-->1-ethyl-3-chloro-pyrrolidine-->Sodium amide-->Morpholine
N-METHYL-4-MORPHOLIN-4-YLBUTAN-1-AMINE PHENYL RESIN N-Vinyl-2-pyrrolidone Doxapram CHEMBRDG-BB 4011837 ALPHA-PYRIDOIN METHYL-2-PYRROLIDONE DOXAPRAM HYDROCHLORIDE,DOXAPRAM HCL,doxapram hydrochloride monohydrate,Doxapram Hydrochoride 3-PHENYL-2-PYROLLIDINONE PHENYL VALERATE ISOXADIFEN-ETHYL DOXAPRAM IMPURITY B Ethyl acetate N,N-DIETHYL-2-PHENYLACETAMIDE Doxapram Hydrochloride Injection USP N,N-DIMETHYLPIVALAMIDE Phenylacetic acid 1-ethyl-4-(2-morpholinoethyl)-3,3-diphenylpyrrolidin-2-one monohydrochloride

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