309-29-5 Usage
Description
Doxapram is a central and respiratory stimulant belonging to the class of pyrrolidin-2-ones. It is an N-ethylpyrrolidin-2-one derivative with specific substitutions on the phenyl groups and a 2-(morpholin-4-yl)ethyl group. Doxapram has a brief duration of action and is commonly used in its hydrochloride or hydrochloride hydrate form.
Uses
Used in Pharmaceutical Industry:
Doxapram is used as a respiratory stimulant for the treatment of acute respiratory failure, particularly when it is superimposed on chronic obstructive pulmonary disease (COPD). It is also used for postoperative respiratory depression and postoperative shivering.
Used in Anesthesia:
Doxapram is used as a treatment for post-anesthetic respiratory depression, helping to increase the rate and depth of respiration in patients who have undergone anesthesia.
Used in Drug Development:
Doxapram HCl inhibits TASK-1, TASK-3, and TASK-1/TASK-3 heterodimeric channel function with EC50 values of 410 nM, 37 μM, and 9 μM, respectively. This makes it a potential candidate for drug development targeting these channels for various therapeutic applications.
Originator
Dopram,Robins,US,1965
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 Function
Respiratory stimulant
Synthesis
Doxapram, 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) [15–18].
Check Digit Verification of cas no
The CAS Registry Mumber 309-29-5 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 3,0 and 9 respectively; the second part has 2 digits, 2 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 309-29:
(5*3)+(4*0)+(3*9)+(2*2)+(1*9)=55
55 % 10 = 5
So 309-29-5 is a valid CAS Registry Number.
InChI:InChI=1/C24H30N2O2/c1-2-26-19-22(13-14-25-15-17-28-18-16-25)24(23(26)27,20-9-5-3-6-10-20)21-11-7-4-8-12-21/h3-12,22H,2,13-19H2,1H3
309-29-5Relevant articles and documents
Novel Methods for Preparation of (+)-1-ethyl-4-[2-(4-morpholinyl)ethyl)-3,3-diphenyl-2-pyrrolidinone
-
Paragraph 0084, (2013/05/09)
The present invention includes a method of preparing a composition comprising (+)-doxapram or a salt thereof, wherein the composition is essentially free of (?)-doxapram or a salt thereof.
