[ CAS No. 124937-52-6 ] {[proInfo.proName]}

Name: 124937-52-6|(R)-2-(3-(Diisopropylamino)-1-phenylpropyl)-4-methylphenol (2R,3R)-2,3-dihydroxysuccinate|98%
Brand: Ambeed
SKU: A299510
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Quality Control of [ 124937-52-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 124937-52-6 ]

SDS Specification

Alternatived Products of [ 124937-52-6 ]

Product Details of [ 124937-52-6 ]

CAS No. :	124937-52-6	MDL No. :	MFCD07771985
Formula :	C₂₆H₃₇NO₇	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TWHNMSJGYKMTRB-KXYUELECSA-N
M.W :	475.57	Pubchem ID :	443878
Synonyms :	PNU-200583E;Kabi-2234;Tolterodine (tartrate)

Calculated chemistry of [ 124937-52-6 ]

Physicochemical Properties

Num. heavy atoms :	34
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.46
Num. rotatable bonds :	10
Num. H-bond acceptors :	8.0
Num. H-bond donors :	5.0
Molar Refractivity :	131.45
TPSA :	138.53 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-8.15 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.2
Log Po/w (XLOGP3) :	1.48
Log Po/w (WLOGP) :	3.22
Log Po/w (MLOGP) :	1.91
Log Po/w (SILICOS-IT) :	5.2
Consensus Log Po/w :	3.0

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	1.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.32
Solubility :	0.227 mg/ml ; 0.000476 mol/l
Class :	Soluble
Log S (Ali) :	-4.0
Solubility :	0.048 mg/ml ; 0.000101 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.54
Solubility :	0.000136 mg/ml ; 0.000000286 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.31

Safety of [ 124937-52-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 124937-52-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 124937-52-6 ]

[ 124937-52-6 ] Synthesis Path-Downstream 1~52

1
[ 87-69-4 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4: Preparation of Tolterodine tartrate; Tolterodine hydrobromide (100 g, 0.246 mol), ethyl acetate (2 L) and water (500 ml) were mixed at room temperature in a glass reactor, forming a mixture. The mixture was stirred rapidly while adding potassium hydroxide (50%, 300 ml). After stirring thoroughly for approximately 15-30 minutes, two clear homogeneous layers formed. The layers were separated, and an organic phase was obtained. The organic phase was washed with water (2x with 500ml).L-tartaric acid (38.33 g) dissolved in ethanol (800 ml) was added rapidly in one portion to the organic phase, at room temperature, forming a slurry. The slurry was cooled to 00C +/-5C over 2 hours and maintained at this temperature for about 15 hours. The slurry was filtered using a suction filter, washed with cold ethanol (2x with 100 ml), and dried at about 60C under vacuum for about 10 hours, yielding Tolterodine tartarate (62.6 g). The Tolterodine tartrate was recrystallized from dry ethanol twice, yielding Tolterodine tartrate (41.2 g) of 99.84% purity as determined by HPLC. Level of impurities as determined by HPLC: RRT 0.18, 0.22, 0.50: 0% area, RRT 0.33: 0.01% area.; Example 5: Preparation of Tolterodine tartrate; Tolterodine hydrobromide (100 g, 0.246 mol), ethyl acetate (2 L) and water (500 ml) were mixed at room temperature in a glass reactor, forming a mixture. The mixture was stirred rapidly while adding potassium hydroxide (50%, 300 ml). After stirring thoroughly for approximately 30 minutes, two clear homogeneous layers formed. The layers were separated, and an organic phase was obtained. The organic phase was washed with water (2x with 500 ml). L-tartaric acid (38.4 g) dissolved in ethanol (800 ml) was added to the organic phase rapidly in one portion, at room temperature, forming a slurry. The slurry was cooled to 0C+/-5C over about 1 hour and maintained at this temperature for about 4 hours. The slurry was filtered using a suction filter, washed with cold ethanol (2x with 100 ml), and dried at about 60C under vacuum for about 10 hours to yield Tolterodine tartrate (65.2 g). The Tolterodine tartrate was recrystallized from dry ethanol, yielding Tolterodine tartrate (41.8 g) of 99.97% purity as determined by HPLC. Level of impurities, as determined by HPLC: RRT 0.18, 0.22, 0.33, 0.50: 0% area. EPO <DP n="18"/>; Example 6: Preparation of Tolterodine tartrate; Tolterodine hydrobromide (583 g, 1.434 mol), ethyl acetate (20 L) and water (5 L) were mixed at room temperature in a glass reactor, forming a mixture. The mixture was stirred rapidly while adding potassium hydroxide (50%, 1.5 L). After stirring thoroughly for approximately 30 minutes, two clear homogeneous layers formed. The layers were separated and an organic phase was obtained. The organic phase was washed with water (2x with 5 L).L-tartaric acid (385 g) dissolved in ethanol (8 L) was added rapidly in one portion to the organic phase, at room temperature, forming a slurry. The slurry was cooled to 0C +50C over about 1 hour and maintained at this temperature for about 12 hours. The slurry was filtered using a suction filter, washed with cold ethanol (2x with IL), and dried at about 6O0C under vacuum for 3 hours to yield Tolterodine tartrate (310 g). The Tolterodine tartrate was recrystallized twice from dry ethanol, yielding Tolterodine tartrate (219 g) of 99.98% purity as determined by HPLC. Level of impurities as determined by HPLC: RRT 0.18, 0.22, 0.33, 0.50: 0% area.; Example 7: Preparation of Tolterodine tartrate; Tolterodine hydrobromide (20 g, 0.049 mol), ethyl acetate (400 ml) and water (100 ml) were mixed at room temperature in a glass reactor, forming a mixture. The mixture was stirred rapidly while adding potassium hydroxide (50%, 35 ml). After stirring thoroughly for approximately 30 minutes, two clear homogeneous layers formed. The layers were separated and an organic phase was obtained. The organic phase was washed with water (2x with 100 ml).The organic phase was added to L-tartaric acid (7.7 g) dissolved in ethanol (160 ml) over about 30 minutes at room temperature, creating a slurry. The slurry was cooled to 00C +/-5C over about 2 hours and maintained at this temperature for about 4 hours. The slurry was filtered using a suction filter, washed with cold ethanol (2x with 20 ml), and dried at about 600C under vacuum for about 14 hours to yield Tolterodine tartrate (12.5 g).The Tolterodine tartrate (8.5 g) was recrystallized twice from dry ethanol, yielding Tolterodine tartrate (6.0 g) of 99.98% purity as determined by HPLC. Level of impurities as determined by HPLC: RRT 0.18, 0.22, 0.33, 0.50: 0% area. EPO <DP n="19"/>; Example 8: Preparation of Tolterodine tartrate; Tolterodine hydrobromide (20 g, 0.049 mol), ethyl acetate (400ml) and water (100 ml) were mixed at room temperature in a glass reactor, forming a mixture. The mixture was stirred rapidly while adding potassium hydroxide (50%, 35 ml). After stirring thoroughly for approx...

Reference： [1]Patent: WO2006/74478,2006,A1 .Location in patent: Page/Page column 16-18

2
[ 124936-74-9 ]
[ 87-69-4 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
18%	In ethanol; at 60 - 85℃;	A solution of 0.069 kg L-(+) Tartaric acid in 0.35 L ethanol was prepared and stirred. This solution was heated up to 60-650C for 1 hr. To this solution, a solution of 0.1 kg N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine in 0.5 L ethanol was added slowly at 60-650C. After completion of addition, the reaction mixture was stirred at 80-85 C for 1 hr and cooled gradually to RT and then to 00C to obtain a solid. The solid was filtered and washed with chilled ethanol (0.1 L x 2) to obtain wet cake. The wet cake was dried at 60-650C for 10-12 hrs to get white solid of Crude (+)-(R)-Tolterodine-L- tartrate (Yield: 0.058 kg).[207][208] Crystallization: 1[209] 0.058 kg Crude (+)-(R)-Tolterodine-L-tartrate was dissolved in 2.32 L ethanol and refluxed at 80-850C for 2-3 hrs to obtain a solution. The solution was concentrated to half the initial volume by distilling 1.16 lit of ethanol and gradually cooled to RT and then at 00C for 1 hr to obtain product. The product was filtered, washed with cooled ethanol (0.05 L x 2) & dried under reduced pressure (2-5 mm Hg) at 60 C for 12-14 hrs to obtain Tolterodine-L-(+)-tartrate -I (Yield: 0.044 kg, 28%).[210][211] Crystallization: 2[212] 0.044 kg (+)-(R)-Tolterodine-L-tartrate -I (First Crystallize Product) was dissolved in 1.76 L ethanol & refluxed at 80-850C for 2-3 hrs to obtain a solution. The solution was concentrated to half the initial volume by distilling 0.88 L of ethanol. The solution was cooled to RT and then at 00C for 1 hr to obtain product. The product was filtered, washed with cooled ethanol (0.04 L x 2) & dried under reduced pressure at 600C for 12-14 hrs to obtain Tolterodine-L-(+) -tartrate (Yield: 0.025 kg, 18%).[213] HPLC Purity > 98.5 %.
	In ethanol; at 0 - 80℃; for 5h;Resolution of racemate;	5.2 ml of NaOH (50%) were added to a suspension of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl-propylamine hydrobromide (53 g, 0.131. mol) in 750 ml of CH2Cl2 and 375 ml of water, adjusting the pH to 9.5 with acetic acid if necessary. Once this pH was reached, it was maintained under stirring for 45 minutes and extracted with CH2Cl2, giving 42.55 g of the free amine. Then, a solution of 29.43 g of L-tartaric acid dissolved in 280 ml of ethanol at 60C was added to the amine dissolved in 140 ml of ethanol at 60C. The reaction was maintained at a temperature comprised between 60C and 70C for 1 hour and cooled slowly to 0C, maintaining it at said temperature for another hour. The resulting white precipitate was filtered and dried under vacuum for 14 hours, giving 31.08 g of the product. Then, 1,200 ml of ethanol were mixed with the 31.08 g of product obtained and heated at 80C for 30 minutes; the ethanol volume was concentrated to half by distillation and was gradually cooled at room temperature and subsequently for 1 hour at 0C. Tolterodine L-tartrate was obtained by filtration and it was dried under vacuum at 60C for 14 hours, giving 27.51 g of product. This process was repeated a second time with the 27.51 g of recrystallized tolterodine L-tartrate to give 22.23 g with a purity of 99.80% of the optically active compound.
	In methanol; acetone; toluene; at 20 - 60℃; for 12.5h;Resolution of racemate;	Tolterodine L-Tartrate The toluene solution comprising crude 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2- ol from Example 1 (theoretical = 333.3g in l.5L of toluene) was diluted with methanol (750ml, 5ml/g), then diisopropylamine (583ml, 421g, 4.161 mol, 3eq) was added. The <n="13"/>black solution was then hydrogenated over 20wt% Pd(OH)2/C moist (10wt%, 33g) at 62IxIO3 Nm'2 (90 psi) and 1100C for 48 hours. A sample was removed for analysis.The reaction mixture was filtered through Arbocel (filter aid) to remove catalyst residues and then heated to reflux and all diisopropylamine and methanol removed by distillation and replaced with toluene resulting in a final volume of 10ml/g. The black solution was then cooled to 25C, acetone (750L, 5ml/g) was added, and then the solution heated to 55-6O0C. A solution of L-Tartaric acid (312g, 2.081mol, 1.5eq) in methanol (1.05L, 7ml/g) was added over 30 minutes maintaining the temperature at 55-6O0C. The resulting suspension was then allowed to cool to room temperature and stirred for 12 hours. The suspension was filtered, washed with acetone (2 X 600ml, 4ml/g), then dried in a vacuum oven at 5O0C for 12 hours to give the title compound as an off white solid [159.2g, 48% (24% from p-Cresol)]. Achiral purity was 100% (no impurities detected) and chiral purity was 91.4% e.e.

In ethanol;Product distribution / selectivity;

Example 6. Testing of crystallization; R-tolterodine tartarate was prepared according to the scheme:Apparatus: glass separator 80 1 equipped with a stirrerProcedure: Tolterodine hydrogenbromide 7 was stirred in a mixture of 5% Na2CO3 and dichloromethane until the product dissolved, about 1 hour. The organic phase was separated and filtered. The aqueous phase was extracted twice more with dichloromethane. The combined organic phases were extracted with water and concentrated in a rotary vacuum evaporator. The obtained tolterodine base was dissolved in ethanol and a solution of L(+)tartaric acid in ethanol was added. After adding a seed, the solution was left without stirring at room temperature until the next day. After filtration, the crude product was crystallized from ethanol, Batch I three times, Batches II and III twice, about 50 liters of the solvent for 1 kg of R(+)tolterodine tartarate. The fourth crystallization of Batch I and the third crystallization of Batches II and Batch III were performed from water, about 10 liters of water for 1 kg of R(+)tolterodine tartarate.Theoretical yield: 12.11 II 4.21 III 4.45 kgActual yield:Batch I: 1.0 kg, i.e. 47.4 % HPLC quality 99.63 % S(-)tolterodine Batch II: 2.4 kg, i.e. 57.0 % 99.70 % Batch III: 2.1 kg, i.e. 47.2 % 99.84 % 13.4 %1st crystallization:Yield:Batch I: 0.87 kg, i.e. 80.0 % HPLC quality 99.77 % SQtolterodine 3.3 % <n="20"/>Batch II: 1.74 kg, i.e. 72.5 % 99.70 % 3.7 % Batch III: 1.60 kg, i.e. 76.2 % 99.27 % 3.2 %IInd crystallization:Yield:Batch I: 0.62 kg, i.e. 77.5 % HPLC quality 99.85 % S(-)tolterodine 0.70%Batch II: 1.50 kg, i.e. 86.2 % not analyzed0.76%Batch III: 1.33 kg, i.e. 83.1 % 99.89 % 0.85%After two crystallizations from ethanol, the content of S-Tolterodine was still unsatisfactory.IIIrd crystallization:Yield:Batch I: 0.53 kg, i.e. 85.5 % HPLC quality 99.73 % S(-)tolterodine 0.19%Batch II: 1.26 kg, i.e. 84.0 % 99.95 % <0.07%Batch III: 1.13 kg, i.e. 85.0 % 100.0 % <0.07 %After crystallization from water, the content of S-tolterodine decreased to an immeasurable value (< 0.07 %) for both batches. In the case of crystallization from ethanol, it oscillated on the borderline of acceptability 0.2 %. After three crystallizations from ethanol, the content of sulfate ash was still not satisfactory in Batch I, it was 0.34 %. Therefore, one more crystallization was performed.Batch I: 0.40 kg, i.e. 76.0 % HPLC quality 99.81 % S(-)tolterodine <0.07 %After the crystallization, the content of sulfate ash was 0.03 %. The content of S-tolterodine also dropped to the expected value. <n="21"/>For all the batches, measurement of particle size was performed without any treatment using the microscopic method.Results:Batch I (Fig. 1): 91.95 % of all particles smaller than 30 mum; 40.9 % of weight of the material would pass through the 250 mum sieve and the maximal crystal size is 623 mum.Batch II (Fig. 2): 94.73 % of particles smaller than 30 mum; 47.2 % of weight of the material would pass through the 250 mum sieve and the maximal crystal size is 439 mum.Batch III (Fig. 3): 89.29 % of particles smaller than 30 mum; 41.3 % of weight of the material would pass through the 250 mum sieve and the maximal crystal size is 702 mum.Example 7The most advantageous method of preparation of APITolterodine hydrobromide 7 in the amount 3.4 kg (8.4 mol) of was stirred in a mixture of 5% Na2CO3, which was prepared by dissolving 0.9 kg of sodium carbonate in water and adjusting the volume to 18 liters of the solution and 27 liters of dichloromethane for ca. 60 minutes. The organic phase was separated, the aqueous layer was extracted two more times with 5 liters of dichloromethane. The solvent was distilled out from the combined organic phases. The obtained tolterodine base was dissolved in 30 liters of ethanol and a solution of 1.26 kg (8.4 mol) of L(+)tartaric acid in 65 1 of ethanol was added. The solution was stirred for about 2 hours and then placed in a refrigerator at the temperature of about 5-8 C. The next day the precipitated product was filtered. The crystals were washed with cold ethanol and dried. The crude product was first crystallized from ethanol. R-Tolterodine tartarate in the amount of 2.2 kg was dissolved in 110 liters of ethanol under reflux. The solution was left to cool down spontaneously without stirring until the next day. The precipitated crystals were filtered and dried. The final crystallization was performed from water. The product crystallized from ethanol in the amount 1.76 kg was dissolved in 18 liters of water under reflux. The solution was left to cool down spontaneously without stirring until the next day. The precipitated crystals were filtered and dried. 1.5 kg of R-tolterodine tartarate of declared quality were obtained.

Reference： [1]Patent: WO2010/46801,2010,A2 .Location in patent: Page/Page column 19-20; 10
[2]Patent: EP1698615,2006,A1 .Location in patent: Page/Page column 10
[3]Patent: WO2007/138440,2007,A1 .Location in patent: Page/Page column 11-12; 13-14
[4]Patent: WO2008/17278,2008,A2 .Location in patent: Page/Page column 18-20

3
[ 837376-36-0 ]
[ 87-69-4 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
39%		Example 7 [214] Preparation of (+)-(R)-Tolterodine-L-tartrate; [215][217] [218] Hydrobromic salt of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl amine was stirred with 2N NaOH (0.030 L), DM water (0.675 L) and dichloromethane (1.5 L). The organic layer was separated out and washed with DM water (1 L) and brine (1 L). The solvent was distilled out completely under reduced pressure to obtain oily free base (0.12 Kg). The oily free base (0.12 Kg) was stirred in ethanol (0.375 L) at 60- 650C followed by addition of solution of 0.083 kg L-(+) Tartaric acid in 0.83 L ethanol. After completion of addition, the reaction mixture was stirred at 80-85 C for 1-2 hrs and cooled gradually to RT and then to 00C to obtain a solid. The solid was filtered and washed with chilled ethanol (0.1 L x 2) to obtain wet cake. The wet cake was dried at 50-550C for 10-12 hrs to get white solid of Crude (+)-(R)-Tolterodine-L-tartrate (Yield: 0.080 kg)[219][220] 0.080 kg Crude (+)-(R)-Tolterodine-L-tartrate was dissolved in 3.2 L ethanol and refluxed at 80-850C for 2-3 hrs to obtain a solution. The solution was concentrated to half the initial volume by distilling 1.6 lit of ethanol and gradually cooled to RT and then at 00C for 1-2 hrs to obtain product. The product was filtered, washed with cooled ethanol (0.05 L x 2) &; dried under reduced pressure (2-5 mm Hg) at 50-550C for 12-14 hrs to obtain Tolterodine-L-(+)-tartrate -I[221] (Yield: 0.07 kg, 39%)[222] HPLC Purity >; 99.5 %.

Reference： [1]Patent: WO2010/92500,2010,A2 .Location in patent: Paragraph 213-222

4
[ 124936-70-5 ]
[ 87-69-4 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 25 - 30℃; for 0.5h;Resolution of racemate;Product distribution / selectivity;	Example 4: Alternative Process for the Preparation of crude (R)-2-(3-(diisopropylamino) - l-phenylpropyl)-4-methylphenol Z,-tartrate (I)N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropan- 1 -amie hydrochloride (VI, 10Og) is dissolved in dichloromethane (1100 ml) resulting in a clear solution. Under argon atmosphere, boron tribromide (28 ml, 99%) is added drop wise. The solution is stirred for an additional 1 h. Aqueous solution of NaOH (680 ml, 10%) is added drop wise at temperature from about 300C to about 35C and the mixture is stirred vigorously for 30 min. Two phases are obtained and the aqueous phase is extracted with dichloromethane (550 ml). The organic layers are combined and the solvent is evaporated. The corresponding hydroxyl amine is obtained as brown viscous oil.Ethanol (1000 ml) is added to the brown viscous oil and the mixture is stirred at 25~30C until a clear solution is obtained. To this solution, a solution of Z-tartaric acid (46 g) in ethanol (1000ml) is added. The mixture is stirred for 30 min at 25~30C. Cool the mixture to 0~5C and stir at this temperature for additional 3 h. The solid is filtered and dried under vacuum for about 1 h (dry under vacuum at 6O0C for 6 h). Then the solid is mixed with ethanol (ca. 1300-1400 ml). The mixture is heated to 75~80C with stirring until a clear solution is obtained. Filter this solution while hot to remove any non-soluble particles. Gradually cool down the filtrate to 0~5C and stir at this temperature for 1 h. Filter the suspension and dry the solid to yield 45-50 g of title compound as white powder.

Reference： [1]Patent: WO2010/94292,2010,A1 .Location in patent: Page/Page column 8

Yield	Reaction Conditions	Operation in experiment
80%	In ethanol; at 75 - 80℃;Purification / work up;	Example 6: Alternative Process for the Purification of (/?)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-methyIphenol /.-tartrate (I)Crude (J?)-2-(3-(diisopropylamino) -l-phenylpropyl)-4-methylphenol Z-tartrate (I, 35 g) is mixed with ethanol (1400 ml) and heated to 75-8O0C and stir until a clear solution is obtained. The solution is cooled gradually to 0~5C and stir this mixture for 1 h. Filter the suspension under vacuum and dry the resulted solid to yield 28 g (80% w/w) of title compound as white powder.

6
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine hydrochloride [ No CAS ]
[ 87-69-4 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
		49.2 g of sodium hydroxide flakes (NaOH) were charged into a round bottom flask containing 4920 ml of water with stirring. Cooled the solution to 25-35 C. and charged 4100 ml of dichloromethane (DCM). 410 g of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine hydrochloride from Example 3 was added and stirred for 5-10 minutes. Separated the aqueous layer and extracted with 410 ml of DCM. Combined organic layers were washed with 4100 ml of water. Separated the organic layer and distilled the solvent completely under vacuum (about 600 mm Hg) below 45 C. Charged a mixture of methanol (1950 ml) and acetonitrile (1950 ml) to the residue and stirred for 5-10 minutes. Charged 195 g of L-(+)-tartaric acid to the solution and heated to reflux. Stirred at reflux for 1-2 hours and then cooled to 0-5 C. Stirred for 1-2 hours, filtered the solid and washed with 390 ml of acetonitrile. The wet solid thus obtained was dissolved in a mixture of NaOH (42 g) in water (2665 ml) and DCM (2460 ml) under stirring for 10-15 minutes. Separated the aqueous layer and extracted with 246 ml of DCM. Combined organic layers were washed with 2255 ml of water. Separated the organic layer and distilled the solvent completely under vacuum (about 600 mm Hg) below 45 C. Charged a mixture of methanol (740 ml) and acetonitrile (740 ml), to the residue and stirred for 5-10 minutes. Charged 74 g of L-(+)-tartaric acid to the solution and heated to reflux. Stirred at reflux for 1-2 hours and then cooled to 0-5 C. Stirred for 1-2 hours, filtered the solid and washed with 74 ml of acetonitrile. The wet solid thus obtained was dissolved again in a mixture of NaOH (36 g), in water (2050 ml) and DCM (1845 ml) under stirring for 10-15 minutes. Separated the aqueous layer and extracted with 184 ml of DCM. Combined organic layers were washed twice with a total of 2520 ml of water. Separated the organic layer and distilled the solvent completely under vacuum (about 600 mm Hg) below 45 C. Charged acetonitrile (500 ml) to the residue and stirred for 5-10 minutes. Filtered to remove undissolved solids and washed the solids with 100 ml of acetonitrile. Filtrate was charged to a flask and a solution of 60 g of L-(+)-tartaric acid dissolved in 600 ml of methanol was added. Heated the contents to reflux and stirred at reflux for 1-2 hours. Cooled to 25-35 C. and stirred for 1-2 hours. Filtered the solid and washed with 60 ml of acetonitrile. Dried the solid at 45-50 C. under a vacuum of about 600 mm Hg for 4-5 hours to get 129 g of the title compound. (Purity: 99.98% by HPLC)
		Comparative Example 43 (crystallization according to EP 325571)Fractional crystallization of Tolterodine hydrochloride ((R)/(S) = 50/50)(solvent ethanol 95%)45 g of tolterodine Hydrochloride as racemate (0.124 mol), 400 ml of methylene chloride, 220 ml of water, 8.7 ml of NaOH 30% and 4.5 g of Na2CO3 are mixed and stirred. Two phases separate, water is removed and the organic phase is concentrated under vacuum obtaining crude tolterodine base (46 g). The residue is dissolved in 112 ml of ethanol 95% and the solution is heated to 60-70C and added with 27.9 g of L-tartaric acid dissolved in 280 ml of ethanol 95%. The mixture is heated at 60-70C for 1 hour, cooled to 0-5C, and stirred for 10 hours before filtration. The isolated product is washed with cold ethanol 95% and dried under vacuum to obtain 46.9 g of (R)/(S)-tolterodine tartrate ratio 60/40.This product is dissolved 1.90 L of ethanol 95% v/v; after distilling off940 ml of solvent the mixture is cooled to room temperature and then to 0-5C to obtain, after filtration, washing and drying, 25.5 g of (R)/(S)-tolterodine tartrate ratio 95/5.After a new recrystallization in about 560 ml of ethanol 95%, using a procedure as above, 22 g of (R)/(S)-tolterodine tartrate ratio 99.6/0.4 are recovered.The product was characterized by means of IR, DSC and XRDP, showing that the crystalline form is equivalent to the originator one [main XRDP 2Th peaks: 11.9, 14.2, 15.9 16.9, 18.4, 18.8, 20.3, 21.0, 22.0, 23.9, 24.8, 25.4, 26.3, 29.8].

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 918 - 921
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029
[3]Patent: US2006/94904,2006,A1 .Location in patent: Page/Page column 7
[4]Patent: WO2012/98044,2012,A1 .Location in patent: Page/Page column 25-26

7
[ 897314-72-6 ]
[ 87-69-4 ]
[ 873551-03-2 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 38 Preparation of N,N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3-phenyl propylamine (R,S)-(I) as hydrochloride salt A well dried 3 L round bottomed flask, fitted with a mechanical stirrer, is purged with nitrogen and loaded with compound (R,S)-(V) (50 g, 0.147 mol) and toluene (500 mL). The suspension is cooled with an ice bath and a first portion of Vitride (27g, ?65% w/w in toluene) is added, dropwise, over 30 min., at 5-10C (exothermic reaction and H2 evolution occur). Then the second portion of Vitride (157 g, ?65% w/w in toluene) is added, over 30 min, warming gently to 20-25C. Then, the temperature is allowed to rise up to 30C. This temperature is maintained for 3 hrs before warming the reaction to 40C for 2h. Acetone (60 mL) is slowly dropped letting the temperature rise to 60-70C, After 5 min 10%NaOH (150 mL) is added and the mixture is stirred for 15 min at 40-60C, before cooling it to RT. Then, the aqueous phase is separated and the organic phase washed, in order, with dil. NaOH (5 mL 30% NaOH + 100 mL H2O), 7% aqueous NaHCO3 (75 mL, until the pH of the discarded aqueous phase was 8-9) and finally with water (2 x 75 mL). The final organic solution is evaporated under reduced pressure using a water bath (Tmax 50-60C). The residue (about 54g) is dissolved in methyl-isobutyl-ketone (350 mL) and warmed to 50-60C. 30% HCl is dropped (18 mL) and 100 mL of methyl-isobutyl-ketone are distilled, under reduced pressure. Then the mixture was cooled to 20C in 1hr, stirred for 2 hrs at this temperature and filtered to afford (R,S)-(I) hydrochloride [49 g (c.y. 92%)].; Example 39 Preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propylamine (I) as L-tartrate salt The reduction of 20 g compound (V) with Vitride is carried out as in the previous example but the mixture, at the end of reaction, is worked as follows. The residue, obtained after work-up and evaporation of the solvent, is dissolved in 95% ethanol (50 mL) and warmed to 60-70C. Tartaric acid (12 g) was dissolved in ethanol (125 mL) at 60-70 mL and the solution was added to the tolterodine solution, over 15 min, keeping the temperature in the 60-70C range. The suspension was warmed to reflux, maintained for 1hr, cooled to RT in 1 hr and stirred overnight. Than, the mixture was cooled to 0-5C and stirred for 10 hrs. The product is collected by filtration, washed with cold 95% ethanol (2 x 25 mL) and dried under vacuum to afford high pure compound (I) as L-tartrate [19.8 g (c.y.78%), assay: 99.4%.,(R)-(I)/(S)-(I) ratio=60/40. This product may be then crystallized in EtOH 95% according to a known procedure to afford highly pure (R)-(I) [c.y 37%, e.e.99.4%].
		Example 40Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3-phenyl propylamine (I) as L-tartrate saltThe reduction of 50 g of compound (V) with Vitride is carried out and worked up as in the previous example to obtain crude (I) after the evaporation of solvent. The viscous residue (about 54 g) is dissolved in isopropanol (500 mL) and the solution warmed 70-75C. At this point, L-Tartaric acid (25 g) is added and the temperature is maintained for 30 min under stirring. The suspension is cooled to RT in lhr and stirred for 2h. The product is filtered and washed with isopropanol to afford (I) as L-tartrate salt. Yield: 90%. (R)-(I)/(S)-(I) ratio=51/49.

Reference： [1]Patent: EP2476665,2012,A1 .Location in patent: Page/Page column 11
[2]Patent: WO2012/98044,2012,A1 .Location in patent: Page/Page column 24

8
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine hydrochloride [ No CAS ]
[ 87-69-4 ]
[ 873551-03-2 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 0 - 70℃;	Example 42Comparative examples of partial enriched N,N-diisopropyl-3-(2- Hydroxy-5-methylphenyl)- 3-phenyl propylamine (I) as L-tartrate salt.A) starting from (R)-(I)/(S)-(I) (ratio=50/50) as HC1 salt40.4 g of racemic (I), obtained starting from the corresponding hydrochloride (45 g, 0.124 mol), are diluted in 112 mL of EtOH 95%, heated at 60C and added with a hot solution of 27.9 g (1.5 eq) of L-Tartaric acid in 280 mL of EtOH 95%. The mixture is maintained at 60-70c for 30', cooled in 1 h at RT, maintained overnight at RT, and then for lOh a 0-5C, filtered and washed with 2x 90 mL of cold EtOH to afford 46.9 g of L-tartrate salt [(R)-(I)/(S)- (I) ratio=60/40].B) starting from (R)-(I)/(S)-(I) (ratio=51/49) as L-tartrate salt59 g (0.124 mol) of this L-tartrate salt are diluted in 252 mL of EtOH 95%, heated at 60C and added with a hot solution of 9.3 g (0.5 eq) of L-Tartaric acid in 140 mL of EtOH 95%. The mixture is maintained at 60-70C for 30', cooled in 1 h at RT, maintained overnight at RT, and then for lOh a 0-5 C, filtered and washed with 2x 90 mL of cold EtOH to afford 35.6 g of L-tartrate salt [(R)-(I)/(S)- (I) ratio=82/18].

Reference： [1]Patent: WO2012/98044,2012,A1 .Location in patent: Page/Page column 25

9
[ 897314-72-6 ]
[ 87-69-4 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
37%		Example 39Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3-phenyl propylamine (I) as L-tartrate saltThe reduction of 20 g compound (V) with Vitride is carried out as in the previous example but the mixture, at the end of reaction, is worked as follows. The residue, obtained after work-up and evaporation of the solvent, is dissolved in 95% ethanol (50 mL) and warmed to 60-70C. Tartaric acid (12 g) was dissolved in ethanol (125 mL) at 60-70 mL and the solution was added to the tolterodine solution, over 15 min, keeping the temperature in the 60-70 C range. The suspension was warmed to reflux, maintained for lhr, cooled to RT in 1 hr and stirred overnight. Than, the mixture was cooled to 0-5C and stirred for 10 hrs. The product is collected by filtration, washed with cold 95% ethanol (2 x 25 mL) and dried under vacuum to afford high pure compound (I) as L-tartrate [19.8 g (c.y. 78%), assay: 99.4%, (R)-(I)/(S)- (I) ratio=60/40. This product may be then crystallized in EtOH 95% according to a known procedure to afford highly pure (R)-(I) [c.y 37%, e.e. 99.4%].

Reference： [1]Patent: WO2012/98044,2012,A1 .Location in patent: Page/Page column 24

10
[ 1043911-42-7 ]
[ 87-69-4 ]
[ 124937-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol; at 20 - 65℃;Resolution of racemate; Reflux;Purification / work up;	Example 46Fractional crystallization of racemic (I)-L-tartrate obtained from the treatment of the mother liquors70 g of (I)-L-tartrate (0.15 mol) obtained in Example 45, having a (R)/(S) ratio of 50/50, and 6.7 g (0.04 mol) of L-Tartaric Acid are charged in isopropanol / water (409 ml, 70/30). The suspension is heated to reflux for about 15-30 minutes, then maintained at 60-65C and finally cooled to room temperature and maintained under stirring till the product is isolated by filtration and dried under vacuum (36.7 g, 52%, (R)/(S) ratio 88/12).35 g of (I)-L-tartrate (73 mmol), having a (R)/(S) ratio of 88/12, obtained as described above, and 0.9 g (6 mmol) of L-Tartaric Acid are suspended in 140 ml of isopropanol/water (70/30) and the mixture is heated to reflux to obtain complete dissolution. The solution is then slowly cooled under stirring till a temperature of about 60-65 C and maintained for about lh to crystallize.Afterwards, the suspension is cooled to room temperature and maintained under stirring till the product is filtered and washed to obtain 33 g of wet (I)-L-tartrate ((R)/(S) ratio 98.9/1.1).This wet product is crystallized again, following the procedure described above, in order to obtain the final (I)-L-tartrate as a dried product (22.2 g, ((R)/(S) ratio 99.9/0.1).Example 47

Reference： [1]Patent: WO2012/98044,2012,A1 .Location in patent: Page/Page column 28-29

11
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl-2-propenamide [ No CAS ]
[ 873551-03-2 ]
[ 124937-52-6 ]

Reference： [1]Patent: WO2012/98044,2012,A1
[2]Patent: WO2012/98044,2012,A1

12
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl-2-propenamide [ No CAS ]
[ 124937-52-6 ]

Reference： [1]Patent: WO2012/98044,2012,A1
[2]Patent: WO2012/98044,2012,A1

13
[ 897314-72-6 ]
[ 873551-03-2 ]
[ 124937-52-6 ]

Reference： [1]Patent: WO2012/98044,2012,A1

14
C₂₃H₂₄O₄S [ No CAS ]
[ 124937-52-6 ]

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 918 - 921

15
[ 4850-49-1 ]
[ 124937-52-6 ]

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 918 - 921

16
[ 851789-43-0 ]
[ 124937-52-6 ]

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 918 - 921

17
2-(3-(4-nitrobenzenesulfonyloxy)-1-phenylpropyl)-4-methylphenyl p-toluenesulfonate [ No CAS ]
[ 124937-52-6 ]

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 918 - 921

18
[ 94-02-0 ]
[ 124937-52-6 ]

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 918 - 921

19
[ 87-88-7 ]
[ 124937-52-6 ]
C₂₂H₃₁NO*C₄H₆O₆*C₆H₂Cl₂O₄ [ No CAS ]

Reference： [1]Journal of the Chemical Society of Pakistan,2013,vol. 35,p. 333 - 337

20
[ 84-58-2 ]
[ 124937-52-6 ]
tolterodine tartarate [ No CAS ]

Reference： [1]Journal of the Chemical Society of Pakistan,2013,vol. 35,p. 333 - 337

21
[ 124937-52-6 ]
[ 848768-06-9 ]

Reference： [1]Patent: JP2016/160255,2016,A

22
[ 124937-52-6 ]
(R)-2-(4-(benzyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)acetonitrile [ No CAS ]

Reference： [1]Patent: JP2016/160255,2016,A
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029

23
[ 124937-52-6 ]
(R)-benzyl-7-((4-(benzyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenethyl)amino)-7-oxoheptanoate [ No CAS ]

Reference： [1]Patent: JP2016/160255,2016,A
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029

24
[ 124937-52-6 ]
(R)-7-((3-(3-(diisopropylamino)-1-phenylpropyl)-4-hydroxyphenethyl)amino)-7-oxoheptanoic acid [ No CAS ]

Reference： [1]Patent: JP2016/160255,2016,A
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029

25
[ 124937-52-6 ]
C₇₃H₁₂₈N₃O₁₂P [ No CAS ]

Reference： [1]Patent: JP2016/160255,2016,A

26
[ 124937-52-6 ]
[ 124937-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 0.583333h;	To a solution of 1.50 g (3.15 mmol) of tolterodine L-tartrate in 20 ml of dichloromethane was added 20 ml of water,171 mg (4.28 mmol) NaOH and 229 mg (2.16 mmol) Na 2 CO 3 were added at 0 C.After standing at 0 C. for 5 minutes,Warm up to room temperature,And the mixture was stirred for 30 minutes.The reaction mixture was diluted with dichloromethane (DCM)Washed with water,Drying over Na 2 SO 4 and removing the solvent under reduced pressure gave the corresponding amine as a colorless viscous oil.The oil was dissolved in 4 ml of DMF,1.74 g (12.6 mmol) of K 2 CO 3 and 450 muL (3.79 mmol) of BnBr were added,Reaction was carried out at room temperature for 13 hours,The solvent was removed under reduced pressure.The reaction was diluted with DCM,Washed with water,It was dried over Na 2 SO 4,The solvent was removed under reduced pressure,The crude product was purified by silica gel chromatography (n-hexane / AcOEt 4: 1) to give Compound 7 ((R) -3- (2- (benzyloxy) -5-methylphenyl) -N, N- diisopropyl- -phenylpropan-1-amine) as a pale yellow oil (1.35 g, 3.24 mmol).
6.9 g	With sodium hydrogencarbonate; In ethyl acetate;	Suspended <strong>[124937-52-6]tolterodine tartrate</strong> (1) (10 g) in EtOAc (100 mL) and added saturated solution of sodium bicarbonate (100 mL). Separated the organic layer and washed it with water (100 mL) and distil out solvent under vacuum to get an oily (R)-tolterodine free base (3) (6.9 g).MF: C22H31N0; MW: 325.49; MS (mlz): 326.31 (M+H).IR (KBr) vcm1: 1217.8, 1250.6 and 1492.6.1H NMR (400 MHz, CDC13) oe 1.06 (d, 6H), 1.11 (d, 6H), 2.05 (m, 1H), 2.06 (s, 3H),2.35 (m, 2H), 2.73 (m, 1H), 3.23 (q, 2H), 4.46-4.49 (q, 1H), 6.53 (d, 1H), 6.78-6.85(m, 2H), 7.19-7.22 (m, 1H), 7.28-7.35 (m, 4H)

Reference： [1]Patent: JP2016/160255,2016,A .Location in patent: Paragraph 0056
[2]Patent: WO2017/137955,2017,A1 .Location in patent: Page/Page column 22; 23

27
[ 124937-52-6 ]
[ 214601-54-4 ]

Reference： [1]Patent: JP2016/160255,2016,A
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029

28
[ 124937-52-6 ]
[ 156755-37-2 ]

Reference： [1]Patent: JP2016/160255,2016,A
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029

29
[ 124937-52-6 ]
C₂₉H₃₆ClNO [ No CAS ]

Reference： [1]Patent: JP2016/160255,2016,A
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029

30
[ 124937-52-6 ]
C₃₀H₄₀N₂O [ No CAS ]

Reference： [1]Patent: JP2016/160255,2016,A
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4020 - 4029

31
[ 124937-52-6 ]
(R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol [ No CAS ]

Reference： [1]Patent: WO2017/137955,2017,A1

32
[ 124937-52-6 ]
[ 207679-81-0 ]

Reference： [1]Patent: WO2017/137955,2017,A1

33
[ 124937-52-6 ]
[ 380636-50-0 ]

Reference： [1]Patent: WO2017/137955,2017,A1

34
[ 124937-52-6 ]
(R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde [ No CAS ]

Reference： [1]Patent: WO2017/137955,2017,A1

35
[ 124937-52-6 ]
(R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine [ No CAS ]

Reference： [1]Patent: WO2017/137955,2017,A1

36
[ 124937-52-6 ]
(R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid [ No CAS ]

Reference： [1]Patent: WO2017/137955,2017,A1

37
[ 92-48-8 ]
[ 124937-52-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2018,vol. 360,p. 322 - 333

38
[ 98-80-6 ]
[ 124937-52-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2018,vol. 360,p. 322 - 333

39
[ 827007-19-2 ]
[ 124937-52-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2018,vol. 360,p. 322 - 333

40
[ 828933-86-4 ]
[ 87-69-4 ]
[ 108-18-9 ]
[ 124937-52-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2018,vol. 360,p. 322 - 333

41
[ 124937-52-6 ]
[ 74-98-6 ]

Reference： [1]Journal of Thermal Analysis and Calorimetry,2018,vol. 131,p. 1345 - 1360

42
[ 854306-68-6 ]
[ 124937-52-6 ]