Idulian,Unilabo,France,1968
Preparation of 4-aza-5-(N-methyl-4-piperidyl)-10,11-dihydro-5Hdibenzo[
a,d]cycloheptene-5-ol: Add 17.4 g of N-methyl-4-chloropiperidine to a
stirred mixture containing 3.2 g of magnesium, 20 ml of anhydrous
tetrahydrofuran, 1 ml of ethyl bromide and a crystal of iodine. Reflux for two
hours, cool to 30-35°C and add a solution of 13 g of 4-aza-10,11-dihydro-5Hdibenzo[
a,d]cycloheptene-5-one in 25 ml of tetrahydrofuran. Stir for five
hours, remove the solvent by distillation in vacuum and add 250 ml of ether.
Add 100 ml of 10% ammonium chloride solution and extract the mixture with
chloroform. Concentrate the chloroform solution to a residue and recrystallize
from isopropyl ether obtaining 20 g of the carbinol, MP 173-174°C.
Preparation of 4-aza-5-(N-methyl-4-piperidylidene)-10,11-dihydro-5Hdibenzo[
a,d]cycloheptene: Heat 5.4 g of the carbinol and 270 g of
polyphosphoric acid for 12 hours at 140-170°C. Pour into ice water and make
alkaline with sodium hydroxide. Extract with ether. Dry ether solution and
concentrate to a residue. Crystallize from isopropyl ether, MP 124-126°C.
Preparation of 4-aza-5-(N-methyl-4-piperidylidene)-10,11-dihydro-5Hdibenzo[
a,d]cycloheptene dimaleate: To a solution containing 4.3 g of 4-aza-
(N-methyl-4-piperidylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 55
ml of ethyl acetate, add a solution of 3.45 g of maleic acid dissolved in ethyl
acetate. Filter the resulting precipitate and recrystallize the desired product
from an ethyl acetate-methanol mixture to yield 4-aza-5-(N-methyl-4-
piperidylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene dimaleate, MP
152-154°C.
Azatadine maleate, 6,11-dihydro-11-(l-methyl-4-piperidylidene)-5H-benzo-[5,6]cyclo-hepta(1,2-b]pyridine maleate (1:2) (Optimine), is a potent,long-acting antihistaminic with antiserotonin activity. Inearly testing, azatadine exhibited more than three times thepotency of chiorpheniramine in the isolated guinea pigileum screen and more than seven times the oral potency ofchlorpheniramine in protection of guinea pigs against a doublelethal dose of intravenously administered histamine.
