123482-22-4 Usage
Originator
Zatosetron
maleate,Eli-Lilly
Uses
Antimigraine.
Manufacturing Process
A mixture of 5-chloromethyl salicylate, 3-chloro-2-methylpropene, potassium
carbonate, and acetone was heated at reflux overnight. After cooling, the
mixture was extracted with diethyl ether and ethyl acetate. The organic
extracts were combined, washed twice with a 10% sodium chloride solution
and water, dried over sodium sulfate, and concentrated in vacuum. The
resulting liquid was vacuumed distilled. The fraction collected and the desired
5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid, methyl ester was obtained.
The 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid, methyl ester was
heated at reflux for 6 h in 1-methyl-2-pyrrolidinone. The mixture was then
vacuum distilled and the fraction collected and the desired 2-hydroxy-5-
chloro-3-(2-methyl-2-propenyl)benzoic acid, methyl ester was obtained.
A mixture of the 2-hydroxy-5-chloro-3-(2-methyl-2-propenyl)benzoic acid,
methyl ester and 1 L of methanol was saturated with 90% formic acid and
then refluxed overnight. The solution was concentrated in vacuum, added to
water, and extracted with ethyl acetate. The organic layer was washed with
water, dried over sodium sulfate, and concentrated in vacuum, providing the
desired 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid,
methyl ester as an oil.
The 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, methyl
ester were heated at reflux with sodium hydroxide and water for 2-3 h. After
cooling, the mixture was extracted with diethyl ether and ethyl acetate. The
aqueous layer was acidified with hydrochloric acid and again extracted with
ethyl acetate and diethyl ether. These latter organic extracts were combined
and washed with water, dried over sodium sulfate, and concentrated in
vacuum. Crystallization of the resulting solid from ethyl acetate/hexane
provided the desired 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7-
carboxylic acid, 71% yield, melting point 158.5°-160°C.
A mixture of 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid
and thionyl chloride was heated at reflux for 3 h. After the mixture was
3522 Zatosetron maleate
concentrated in vacuum and azeotroped with toluene, dry toluene was added
and the solution cooled to 5°C. A solution of N-methyl-tropamine in toluene
was added in dropwise fashion and the reaction heated at reflux overnight.
After cooling, the mixture was added to ice water, made basic, and extracted
with diethyl ether/ethyl acetate. The organic layer was washed twice with 6 N
hydrochloric acid. The combined aqueous extracts were cooled, made basic
with sodium hydroxide solution, and extracted with ethyl acetate. The ethyl
acetate solution was washed twice with water, dried over sodium sulfate, and
concentrated in vacuum providing of the endo-5-chloro-2,3-dihydro-2,2-
dimethyl-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl-7-benzofurancarboxamide,
free base, as an oil.
In practice it is usually used as maleate salt.
Therapeutic Function
Serotonin antagonist
Check Digit Verification of cas no
The CAS Registry Mumber 123482-22-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,3,4,8 and 2 respectively; the second part has 2 digits, 2 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 123482-22:
(8*1)+(7*2)+(6*3)+(5*4)+(4*8)+(3*2)+(2*2)+(1*2)=104
104 % 10 = 4
So 123482-22-4 is a valid CAS Registry Number.
InChI:InChI=1/C19H25ClN2O2/c1-19(2)10-11-6-12(20)7-16(17(11)24-19)18(23)21-13-8-14-4-5-15(9-13)22(14)3/h6-7,13-15H,4-5,8-10H2,1-3H3,(H,21,23)
123482-22-4Relevant articles and documents
Zatosetron, a Potent, Selective, and Long-Acting 5HT3 Receptor Antagonist: Synthesis and Structure-Activity Relationships
Robertson, David W.,Lacefield, William B.,Bloomquist, William,Pfeifer, William,Simon, Richard L.,Cohen, Marlene L.
, p. 310 - 319 (2007/10/02)
Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin.Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse.Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists.Simple benzoyl derivatives of tropine and 3α-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats.Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity.The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclooct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate).The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR.Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50=0.86 μg/kg iv).Low oral doses of zatosetron (30 μg/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats.Moreover, this compound did not produce hemodynamic effects after iv administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors.Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
