124937-51-5 Usage
Chemical Properties
Pale Yellow Gel
Originator
Detrol,Pharmacia and Upjohn
Uses
A muscarinic receptor antagonist. Used in the treatment of urinary incontinence.
Manufacturing Process
Trans-cinnamic acid (100 g, 675 mmol) is added to a 1 L 4-neck round bottom
flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet.
Para-cresol (76.6 g, 708 mmol) is preheated in a water bath at 60°C and
added to the cinnamic acid followed by concentrated sulfuric acid (13.0 ml,
243 mmol). The reaction is immediately heated to a set point of 122.5°C and
stirred at 120°-125°C until judged to be complete by HPLC analysis. When the
reaction is complete the mixture is cooled to 100°C and added to a
prewarmed separatory funnel (500 ml). The bottom layer containing the
sulfuric acid is removed and toluene (280 ml), water (50 ml) and potassium
carbonate (47%, 10 ml) are added to the separatory funnel containing the
crude product. The pH of the aqueous layer is adjusted to between 5-8 with
additional 47% potassium carbonate. The layers are separated and the
organic layer is then washed once with water (50 ml). The organic layer is
concentrated to a final volume of approximately 150 ml under reduced
pressure. Isopropanol (350 ml) is then added, and distillation is continued to
a volume of 350 ml. Isopropanol (150 ml) is again added and again distilled
to 350 ml (2 times). The mixture is then cooled to 30°-40°C with rapid
stirring until the product crystallizes. The rapid stirring is continued after
crystallization. The product is cooled to 0°-5°C and held at this temperature
for 1 h, filtered and washed with isopropanol (200 ml) cooled to 0°-5°C. If the
last portion of the wash is colored the wash is continued until no more color is
removed. The solids are then dried at 60°C under reduced pressure to give
the 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, melting point
(uncorrected) 83°-85°C.
3,4-Dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (100.0 g, 420.2 mmol)
is added to toluene (500 ml). The mixture is degassed by purging alternately
with vacuum and nitrogen and then cooled to -21°C. Diisobutylaluminum
hydride in toluene solution (DIBAL, 1.5 M, 290 ml, 435 mmol) is then slowly
added over 2 h via add funnel while maintaining the reaction temperature at -
20°-25°C. The reaction is usually done when the DIBAL add is completed. If the reaction is not done additional DIBAL can be added in increments. When
the reaction is done (<1% lactone) ethyl acetate (45 ml) is added at -20°-
25°C via add funnel. Very little exotherm is observed. Next, citric acid (23%,
500 ml) is added. The mixture is stirred at 45°-50°C for 1 h (or stirred
overnight at 20°-25°C), the phases are separated, the organic phase is
washed with water (2 times 300 ml). The organic phase is concentrated to
250 ml under reduced pressure. Methanol (500 ml) is added, and the mixture
is concentrated to 250 ml. The methanol addition and distillation is repeated
to give the 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol in methanol
solution.
3,4-Dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol in methanol (500 ml) is
slowly added to palladium on carbon (5%, 22 g, 1.5 mmol) while maintaining
a slight nitrogen purge. If 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol
is added too quickly without a nitrogen purge the catalyst will ignite the
methanol. Diisopropylamine (147.0 ml, 1.05 mol) is added, and the mixture is
hydrogenated at 45-50 psi and 48°C until the reaction is judged to be
complete by HPLC (<2% lactol). The reaction is usually done after 10 h, but
can be run overnight. The reaction mixture is cooled and removed from the
hydrogenator using a methanol (150 ml) rinse. The combined reaction mixture
and rinse is filtered through a bed of solka floc (10 g). The solka floc is
washed thoroughly with methanol (100 ml) and the filtrate is concentrated to
remove methanol while ethyl acetate is being added back. The volume of this
solution of the (2-diisopropylamino)ethyl)benzyl)-p-cresol is adjusted to 700
ml using ethyl acetate and the mixture is heated to 55°C.
To form the hydrochloride salt of the (2-diisopropylamino)ethyl)benzyl)-p_x0002_cresol (Tolterodine), concentrated hydrochloric acid (52.5 ml, 630 mmol) is
added over 15 min. The resulting slurry is gradually cooled to -15°-20°C and
held at this temperature for 1 h. Tolterodine hydrochloride is collected by
filtration, washed 3 times with ethyl acetate, and dried overnight under
reduced pressure at 600 to give the tolterodine hydrochloride, melting point
199°-201°C.
Tolterodine hydrochloride (130.0 g, 359 mmol), methylene chloride (1.3 L)
and water (650 ml) are mixed. The mixture is stirred rapidly while adding
sodium hydroxide (50%, 13.0 ml) and sodium carbonate (13.0 g, 123 mmol).
The pH as determined by pH paper is 10-11. After stirring thoroughly for
approximately 15 min two clear homogeneous phases form. Stirring is
continued for another 45 min, the layers are separated and the organic phase
is washed with water (2 times 650 ml). The methylene chloride mixture is
concentrated under reduced pressure. The concentrate is dissolved in ethanol
(325 ml) and warmed to 60°-70°C. L-tartaric acid (80.84 g, 539 mmol)
slurried in hot ethanol (810 ml) is added via add funnel at 60°-70°C over
approximately 30 min. When the addition is done the slurry is refluxed for 1
h, gradually cooled to 0°C and held at this temperature for 1 h. The slurry is
filtered, washed with ethanol (2 times 260 ml) previously cooled to 0°C, and
dried overnight under reduced pressure at 60°C to give the crude title
compound. The crude product (136.0 g) and ethanol (5.44 L) are mixed and
heated to 80°C for 30 min. The mixture is concentrated to half the initial
volume by distilling 2.72 L of ethanol. The mixture is gradually cooled to 20°-
25°C over 1 h, placed in an ice bath, and held at 0°C for 1 h. The tolterodine
L-tartrate is collected by filtration, washed with ethanol (2 times 272 ml )
previously cooled to 0°C, and dried overnight under reduced pressure at 60°C to give product. This procedure was repeated a second time on 81.0 g of once
recrystallized tolterodine L-tartrate to give the optically active (+)-(R)-2-(α-
(2-(diisopropylamino)ethyl)benzyl)-p-cresol L-tartrate, melting point
(uncorrected)=210°-211°C.
Therapeutic Function
Anticholinergic
General Description
Tolterodine (Detrol), 2-[3-[bis(1-methylethyl)amino]-1-phenyl-propyl]-4-methyl-phenol, is an antimuscarinicagent that acts on M2 and M3 muscarinic subtypereceptors. By competitively blocking of the muscarinicreceptors results in a reduction of the smooth muscle tone,allowing for greater volume of urine to be stored in the bladder.This results in less urinary incontinence, urgency, andfrequency.
Check Digit Verification of cas no
The CAS Registry Mumber 124937-51-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,4,9,3 and 7 respectively; the second part has 2 digits, 5 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 124937-51:
(8*1)+(7*2)+(6*4)+(5*9)+(4*3)+(3*7)+(2*5)+(1*1)=135
135 % 10 = 5
So 124937-51-5 is a valid CAS Registry Number.
InChI:InChI=1/C22H31NO.ClH/c1-16(2)23(17(3)4)14-13-20(19-9-7-6-8-10-19)21-15-18(5)11-12-22(21)24;/h6-12,15-17,20,24H,13-14H2,1-5H3;1H
124937-51-5Relevant articles and documents
Palladium-catalyzed diastereoselective synthesis of β,β-diarylpropionic acid derivatives and its application to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718
Zhi, Wubin,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
, p. 537 - 540 (2018)
Palladium-catalyzed diastereoselective synthesis of optically active β,β-diarylpropionic acid derivatives employing 4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary under an air atmosphere in excellent yields with high diastereoselectivity is reported. The catalytic system is applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718.
Enantioselective synthesis of (S)- and (R)-tolterodine by asymmetric hydrogenation of a coumarin derivative obtained by a Heck reaction
Ulgheri, Fausta,Marchetti, Mauro,Piccolo, Oreste
, p. 6056 - 6059 (2007)
(Chemical Equation Presented) An efficient and short enantioselective synthesis of (S)- and (R)-tolterodine was performed by asymmetric hydrogenation of a coumarin intermediate, easily obtained by a Heck reaction from inexpensive and commercially available starting materials.
Chiral Fe(ii) complex catalyzed enantioselective [1,3] O-to-C rearrangement of alkyl vinyl ethers and synthesis of chromanols and beyond
Dong, Shunxi,Feng, Xiaoming,Lin, Qianchi,Liu, Xiaohua,Wang, Lifeng,Zhou, Pengfei
, p. 10101 - 10106 (2020/10/19)
A highly efficient enantioselective [1,3] O-to-C rearrangement of racemic vinyl ethers that operates under mild conditions was developed. This method with chiral ferrous complex catalyst provided an efficient access to a wide range of chromanols with high yields and excellent enantioselectivities. In addition, an important urological drug (R)-tolterodine and others were easily obtained after simple transformations.
Catalytic asymmetric synthesis of chiral phenols in ethanol with recyclable rhodium catalyst
Yao, Jian,Liu, Na,Yin, Long,Xing, Junhao,Lu, Tao,Dou, Xiaowei
supporting information, p. 4946 - 4950 (2019/09/30)
A general method to access diverse chiral phenols by rhodium-catalyzed asymmetric conjugate arylation using hydroxylated arylboronic acids in ethanol was developed. Recycling of the rhodium catalyst by flash chromatography on silica gel was feasible in this system. The synthetic utility of the strategy was demonstrated by efficient synthesis of chiral drug tolterodine.
