[ CAS No. 105812-81-5 ] {[proInfo.proName]}

Name: 105812-81-5|(3S,4R)-4-(4-Fluorophenyl)-3-hydroxymethyl-1-methylpiperidine|95%
Brand: Ambeed
SKU: A632262
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Quality Control of [ 105812-81-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 105812-81-5 ]

SDS Specification

Alternatived Products of [ 105812-81-5 ]

Product Details of [ 105812-81-5 ]

CAS No. :	105812-81-5	MDL No. :	MFCD06658161
Formula :	C₁₃H₁₈FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CXRHUYYZISIIMT-AAEUAGOBSA-N
M.W :	223.29	Pubchem ID :	2734218
Synonyms :		Chemical Name :	(3S,4R)-4-(4-Fluorophenyl)-3-hydroxymethyl-1-methylpiperidine

Calculated chemistry of [ 105812-81-5 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.54
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	66.07
TPSA :	23.47 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.42
Log Po/w (XLOGP3) :	1.82
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	2.42
Log Po/w (SILICOS-IT) :	2.45
Consensus Log Po/w :	2.2

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.52
Solubility :	0.68 mg/ml ; 0.00304 mol/l
Class :	Soluble
Log S (Ali) :	-1.93
Solubility :	2.61 mg/ml ; 0.0117 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.16
Solubility :	0.153 mg/ml ; 0.000685 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.35

Safety of [ 105812-81-5 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P501-P273-P270-P264-P280-P391-P301+P312+P330-P305+P351+P338+P310	UN#:	3077
Hazard Statements:	H302-H318-H411	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 105812-81-5 ]

* 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.

Upstream synthesis route of [ 105812-81-5 ]
Downstream synthetic route of [ 105812-81-5 ]

[ 105812-81-5 ] Synthesis Path-Upstream 1~4

1
[ 335158-58-2 ]
[ 105812-81-5 ]

Yield	Reaction Conditions	Operation in experiment
78.4%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 10℃; Stage #2: for 0.5 h;	31.4g of trans-N-methyl-4'-fluorophenyl-3-carbomethoxypiperidine and 100mL of tetrahydrofuran were added into a 500mL round bottom flask with an agitator, a condenser and a thermometer, followed by an addition of 3. 31g of lithium aluminium hydride while maintaining the temperature at 10C and the mixture was agitated. After the reaction was completed, 50mL of distilled water and 30 mL of 10percent sodium hydroxide aqueous solution were slowly added, followed by agitation for 30 minutes. Then, 200mL of ethyl acetate was further added and then the mixture was agitated for another 30 minutes. The organic phase was separated from the aqueous phase and distilled off the solvent and low boiling organic materials. The remainder was recrystallized using a mixed solution of toluene and n-heptane to obtain trans-N-methyl-4'-fluorophenyl-3-hydroxymethylpiperidine (yield: 78.4percent, purity: 99.3percent). Rf= 0.3 (dichloromethane/methanol, 4/1) 'H NMR (CDCl3, (200MHz): 7.18 (t, 2H, J=8.7 Hz); 6.98 (t, 2H, J=8.7 Hz); 3.39 (dd, [1H,] J=10. 6 Hz, J=2.8 Hz); 3.25~3.14 (m, 2H); 2.93 (d, 1H, J=10.8 Hz); 2.70 (s, 1H) ; 2.31 (s, 3H); 2. 27~2. 21 (m, [1H)] ; 2.09~1.75 (m, 5H)

Reference： [1] Patent: WO2004/5254, 2004, A1, . Location in patent: Page 9
[2] Patent: WO2005/63707, 2005, A1, . Location in patent: Page 26
[3] Patent: WO2005/63707, 2005, A1, . Location in patent: Page 27

2
[ 188302-25-2 ]
[ 105812-81-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran; toluene at 15 - 65℃; Stage #2: With water; sodium hydroxide In tetrahydrofuran; toluene at 0 - 5℃; for 0.333333 h;	Lithium aluminum hydride (1.8 g, 47.49 mmol) was added to a mixture of tetrahydrofuron (15.0 mL) and toluene (5.0 mL) at 0-5 °C and stirred for 15 min at the same temperature. A solution of (3S,4R)-3-ethoxycarbonyl-4-(4'-fluorophenyl)-N-methyl piperidine-2,6-dione 6 (5.0 g, 17.05 mmol) in toluene (15.0 mL) was added slowly for 45-60 min at below 15 °C and the mixture was heated to 60-65 °C for 2 h. The mixture was cooled to 0-5 °C and basified with 10percent sodium hydroxide solution. Water (10.0 mL) was charged to the reaction mixture and then stirred for 20 min. The separated solid was filtered and washed with toluene (2 .x. 15 mL). The solvent was removed under reduced pressure and the crude compound was recrystalized from n-heptane to afford 7 (3.0 g, 80percent) as an white solid. inlMMLBox (c 1, ethanol); IR (cm^-1): 3153, 2943, 1602, 1509, 1222, 1379, 1069; ¹H NMR: (400 MHz, CDCl₃) δ, ppm: 7.14-7.17 (m, 2H), 6.96-7.0 (m, 2H), 3.38-3.42 (m, 1H), 3.13-3.25 (m, 2H), 2.92-2.95 (m, 1H), 2.29-2.34 (m, 4H), 1.97-2.03 (m, 5H); MS: m/z: 224.2 [M+H⁺].

Reference： [1] Tetrahedron Asymmetry, 2011, vol. 22, # 1, p. 1 - 3

3
[ 858938-15-5 ]
[ 105812-81-5 ]

Reference： [1] Patent: WO2005/63707, 2005, A1, . Location in patent: Page 30
[2] Patent: US2007/112031, 2007, A1, . Location in patent: Page/Page column 35
[3] Patent: US2007/112031, 2007, A1, . Location in patent: Page/Page column 35

4
[ 459-32-5 ]
[ 105812-81-5 ]

Reference： [1] Tetrahedron Asymmetry, 2011, vol. 22, # 1, p. 1 - 3

[ 105812-81-5 ] Synthesis Path-Downstream 1~88

1
[ 533-31-3 ]
[ 105812-81-5 ]
(-)-trans-4-(4-fluorophenyl)-1-methyl-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride [ No CAS ]

Reference： [1]Acta Chemica Scandinavica,1996,vol. 50,p. 164 - 169

2
[ 150-76-5 ]
[ 105812-81-5 ]
(-)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-1-methylpiperidine hydrochloride [ No CAS ]

Reference： [1]Acta Chemica Scandinavica,1996,vol. 50,p. 164 - 169

3
[ 98-59-9 ]
[ 105812-81-5 ]
[ 317323-77-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1:; Preparation of compound of formula IV; To a stirred solution of trans-(-)-paroxo (10Og), compound of formula IH, (wherein R' is methyl) in dichloromethane (500ml) was added triethylamine (75ml), and cooled to -5 to -15C. />-Toluenesulfonyl chloride (12Og) was slowly added and stirred for lhr at -5 to - 15 C. Methanesulfonic acid (44ml) was then added gradually and the mixture concentrated at about 50 C at atmospheric pressure. The residue was taken up in toluene, water was added, stirred for 30min. and the top toluene layer was separated. The pH of the aqueous layer was then adjusted to 9.0 to 9.5 with saturated NaHCO3 solution, the product was filtered, washed with water and dried to yield compound of formula IV (138.Og), as white to off-white solid, purity >99.0% by HPLC.

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258
[2]Patent: WO2007/15262,2007,A2 .Location in patent: Page/Page column 16

4
[ 105812-81-5 ]
[ 61869-08-7 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

5
[ 105812-81-5 ]
[ 110429-36-2 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

6
[ 105812-81-5 ]
Desmethylene-Paroxetine [ No CAS ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

7
[ 105812-81-5 ]
Brl 36610 [ No CAS ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

8
[ 105812-81-5 ]
[ 600135-90-8 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

9
[ 105812-81-5 ]
[ 600135-83-9 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

10
[ 105812-81-5 ]
[ 600135-89-5 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

11
[ 105812-81-5 ]
[ 600135-86-2 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

12
[ 105812-81-5 ]
[ 600135-88-4 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

13
[ 105812-81-5 ]
[ 600135-82-8 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

14
[ 105812-81-5 ]
[ 600135-84-0 ]

Reference： [1]Bioorganic Chemistry,2003,vol. 31,p. 248 - 258

15
[ 105812-81-5 ]
(-)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)piperidine acetic acid salt [ No CAS ]

Reference： [1]Acta Chemica Scandinavica,1996,vol. 50,p. 164 - 169

16
[ 105812-81-5 ]
[ 110429-35-1 ]

Reference： [1]Acta Chemica Scandinavica,1996,vol. 50,p. 164 - 169

17
[ 335158-58-2 ]
[ 105812-81-5 ]

Yield	Reaction Conditions	Operation in experiment
78.4%		31.4g of trans-N-methyl-4'-fluorophenyl-3-carbomethoxypiperidine and 100mL of tetrahydrofuran were added into a 500mL round bottom flask with an agitator, a condenser and a thermometer, followed by an addition of 3. 31g of lithium aluminium hydride while maintaining the temperature at 10C and the mixture was agitated. After the reaction was completed, 50mL of distilled water and 30 mL of 10% sodium hydroxide aqueous solution were slowly added, followed by agitation for 30 minutes. Then, 200mL of ethyl acetate was further added and then the mixture was agitated for another 30 minutes. The organic phase was separated from the aqueous phase and distilled off the solvent and low boiling organic materials. The remainder was recrystallized using a mixed solution of toluene and n-heptane to obtain trans-N-methyl-4'-fluorophenyl-3-hydroxymethylpiperidine (yield: 78.4%, purity: 99.3%). Rf= 0.3 (dichloromethane/methanol, 4/1) 'H NMR (CDCl3, (200MHz): 7.18 (t, 2H, J=8.7 Hz); 6.98 (t, 2H, J=8.7 Hz); 3.39 (dd, [1H,] J=10. 6 Hz, J=2.8 Hz); 3.25~3.14 (m, 2H); 2.93 (d, 1H, J=10.8 Hz); 2.70 (s, 1H) ; 2.31 (s, 3H); 2. 27~2. 21 (m, [1H)] ; 2.09~1.75 (m, 5H)
		Into a 1-L, three-necked, RB flask was charged 47 g of the crude compound obtained in step (iii) above and t-butanol (300 mL). Sodium borohydride (10 g) was added to the reaction mixture and heated to reflux temperature. Methanol (50 mL) was added in lots to the reaction mixture over a period of 6 hr. After the last lot addition reaction mixture was maintained at reflux for 2 hr and checked the TLC. Reaction mixture was quenched with 5 mL of acetic acid. Solvent was removed from the reaction mixture under vaccum and water (200 mL) added to the reaction mass. pH of the reaction mass was adjusted to 8-9 with sodium bicarbonate Compound was extracted into toluene (2 x 100 mL). Toluene layer was dried and distilled under vaccum to get 37 g of the crude product. Optical rotation is-35.4 (c = 1, MeOH). Chiral purity by HPLC is 97.5%. The crude compound was crystallized from hexane/toluene to get the pure compound of the formula-I as off- white solid (30 g). Purity by HPLC is 98.5%. Melting point is 98-99 C.
		Preparation of (3S, 4R)-trans-4- (4-fluorophenyl)-3-hydroxymethyl-1-methyl- piperidine Into a 2-L, three-necked RB flask were charged 500 mL of water, 200 mL of toluene, and 135 g of the compound obtained in step (i) above. Sodium bicarbonate (38 g) was slowly added to the reaction mass under stirring. Layers were separated and the aqueous layer extracted with 2 x 100 mL of toluene. Combined toluene layer was washed with water, dried and evaporated under vaccum to get 83 g of pure (3S, 4R)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N-methyl-piperidine. Optical rotation is-49.5 (c = 1, MeOH). Into a 1-L, three-necked RB flask was charged 300 mL of anhydrous THF under nitrogen atmosphere. Lithium aluminum hydride (7.5 g) was added to THF and cooled to-30 C. A solution of 50 g of above pure (3S, 4R)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N- methyl-piperidine in 100 mL of anhydrous THF was slowly added to the reaction mass over a period of 1 hr keeping the temperature below-25C. After stirring for 30 min reaction was found to be over by TLC. The reaction was quenched by adding 15 mL of water and stirred for Ihr at 25-30 C. The inorganic solids were removed by filtration and washed the salts with 200 mL of ethyl acetate. Solvents were distilled off from the filtrate and the residue dissolved in 200 mL of toluene and washed with 100 mL of water. Toluene was distilled off under vaccum to get 41 g of residue which was crystallized using hexane/toluene (9: 1) to get 37 g of pure (3S, 4R)-trans-4- (4-fluorophenyl)-3- hydroxymethyl-l-methyl-pipericline as white solid. Melting point is 99.5 C. Optical rotation is-38.1 (c = 1, Merl-1). Chiral purity by HPLC is 100%. Chemical purity by HPLC is 99.7%.

Reference： [1]Patent: WO2004/5254,2004,A1 .Location in patent: Page 9
[2]Patent: WO2005/63707,2005,A1 .Location in patent: Page 26
[3]Patent: WO2005/63707,2005,A1 .Location in patent: Page 27

18
[ 611-71-2 ]
[ 105812-81-5 ]
[ 859224-58-1 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 25 - 60℃; for 12 - 15h;	Into a I-L, three-necked, RB flask was charged 100 g of crude (3S, 4R)-trans-3- carbomethoxy-4- (4-fluorophenyl)-N-methyl-piperidine obtained according to the procedure given in Example 3 step (iii), 450 mL of isopropanol, and 60 g of (-)-mandelic acid. The reaction mass was heated to 55-60 C to get a clear solution. The reaction mass was slowly cooled to 25-30 C and kept under stirring for 12-15 hr. The reaction mass was further cooled-to 5-10 C and filtered the mass. The wet cake thus obtained was washed with 50 mL of isopropanol and dried to get 135 g of white solid. Melting point is 120 C. Optical rotation is-69.4 (c = 1, MeOH).

Reference： [1]Patent: WO2005/63707,2005,A1 .Location in patent: Page 26-27

19
[ 858938-15-5 ]
[ 105812-81-5 ]

Yield	Reaction Conditions	Operation in experiment
		Into a 1-L, three-necked, RB itask were charged 10 g of the above step (iii) compound and 70 mL oft-butanot. Sodium borohydride (2 g) was added to the reaction mixture and heated to reflux temperature. Methanol (20 mL) was added in lots to the reaction mixture over a period of 6 hr. After the last lot addition reaction mixture was maintained at reflux for 2 hr and checked the TLC. Reaction mixture was quenched with 2 mL of acetic acid. Solvent was removed from the reaction mixture under vaccum and added water (100 mL) to the residue. pH of the reaction mass was adjusted to 8-9 with sodium bicarbonate and the product extracted into toluene (2 x 75 mL). Toluene layer was dried and distilled under vaccum to get 7 g of the crude product. Optical rotation is-37.8 (c = 1, MeOH). Chiral purity by HPLC is 99.5%.
		To a cooled solution of LiAlH4 (2.7 mmol) in THF under argon was added (+/-)-trans-4-(4-fluorophenyl)-1-methyl-2,6-dioxo-piperidine-3-carboxylic acid ethyl ester (1 mmol, Chontech, Inc.) in THF. After addition was complete, the reaction was heated to 40-50 C. for 2 hours and then stirred overnight at ambient temperature. The reaction was cooled to 0 C. and quenched with water and aqueous NaOH. The mixture was then filtered and solids were washed with fresh THF. The solvent was removed under reduced pressure, the residue was taken up in EtOAc, washed with water, dried (MgSO4), and concentrated to afford the desired product, (+/-)-trans-[4-(4-fluorophenyl)-1-methyl-piperidin-3-yl]-methanol. 1H-NMR (CDCl3) delta ppm: 1.70-2.10 (m, 5H); 2.20-2.35 (m, 4H); 2.47 (s br, 1H); 2.90 (m, 1H); 3.16 (m, 2H); 3.36 (m, 1H); 6.94 (m, 2H); 7.12 (m, 2H).; A solution of (+/-)-trans-4-(4-fluorophenyl)-1-methyl-2,6-dioxo-piperidine-3-carboxylic acid ethyl ester (2.44 mmol) in tetrahydrofuran (10 mL) was treated with a solution of LiAlH4 (10 ml, 1.0 M in THF) at 0-5 C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature and stirred for 2.5 hours. The reaction was quenched with addition of water (6 ml), followed by 1.0 M aqueous sodium hydroxide (1 mL) and water (3 mL). The suspension was stirred for 30 minutes and filtered through celite. The celite was washed with EtOAc. The solvent was removed under reduced pressure, the residue was taken up in EtOAc, washed with water, dried (MgSO4), and concentrated to afford the desired product, (+/-)-trans-[4-(4-fluorophenyl)-1-methyl-piperidin-3-yl]-methanol.
		(+/-)-Trans-4-(4-fluorophenyl)-1-methyl-2,6-dioxo-piperidine-3-carboxylic acid ethyl ester (0.57 mmol) was dissolved in THF (2.1 mL) and added dropwise to a stirred solution of LiAlH4 (2.9 mL of a 1.0 M solution in THF, 2.9 mmol) at 0-5 C. under nitrogen. The reaction mixture was then warmed to ambient temperature and heated at reflux overnight. The mixture was cooled to ambient temperature, water (1.0 mL) was added dropwise and the mixture was stirred for 10 minutes. A 2.0 M aqueous solution of NaOH (3.0 mL) was then added and the reaction mixture was left to stir for a further 10 minutes. The mixture was then poured into saturated Rochelle's salt solution (30 mL) and extracted with EtOAc (4×20 mL). The organic extracts were combined, washed with brine (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the desired product, (+/-)-trans-[4-(4-fluorophenyl)-1-methyl-piperidin-3-yl]-methanol, which was used without further purification.

Reference： [1]Patent: WO2005/63707,2005,A1 .Location in patent: Page 30
[2]Patent: US2007/112031,2007,A1 .Location in patent: Page/Page column 35
[3]Patent: US2007/112031,2007,A1 .Location in patent: Page/Page column 35

20
[ 598-56-1 ]
[ 98-59-9 ]
[ 105812-81-5 ]
[ 318279-38-8 ]
[ 317323-77-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In dichloromethane;	EXAMPLE 3 Preparation of (3S,4R)-trans-4-(4-fluorophenyl)-1-methyl-3-p-toluenesulphonyloxymethyl-piperidine <strong>[105812-81-5](3S,4R)-trans-4-(4-fluorophenyl)-1-methyl-3-hydroxymethylpiperidine</strong> (10 kg) is dissolved in dichloromethane (50 L), treated with dimethylethylamine (6.5 L), and the resulting mixture cooled to 0 C. A solution of p-toluenesulphonyl chloride (9.8 kg) in dichloromethane (35 L) is cooled to 0 C., and added slowly (1 hour) to the stirred 4-(4-fluorophenyl)-1-methyl-3-hydroxymethylpiperidine solution, keeping the temperature below 5 C. After a further 1 hour stirring, the mixture is treated with cold aqueous sodium hydroxide (0.1 molar, 30 L) and stirred for 1 hour. The dichloromethane layer is then separated, dried with anhydrous magnesium sulphate (1 kg), filtered and evaporated to give a crystalline solid. Residual dichloromethane <1%.

Reference： [1]Patent: US2003/187269,2003,A1

21
[ 598-56-1 ]
[ 124-63-0 ]
[ 105812-81-5 ]
[ 608521-21-7 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; In dichloromethane;	EXAMPLE 2 Preparation of (3S,4R)-trans-4-(4-fluorophenyl)-1-methyl-3-methylsulphonyloxymethylpiperidine <strong>[105812-81-5](3S,4R)-trans-4-(4-fluorophenyl)-1-methyl-3-hydroxymethylpiperidine</strong> (20 kg) is dissolved in dichloromethane (150 L), treated with dimethylethylamine (13 L), and the resulting mixture cooled to 0 C. A solution of methanesulphonyl chloride (11 L) in dichloromethane (20 L) is cooled to between -10 and 0 C., and then added to the 4-(4-fluorophenyl)-1-methyl-3-hydroxymethylpiperidine solution over approximately two hours, with continuous stirring below 0 C. After the reaction is complete (30 minutes), the mixture is treated with a cold solution of aqueous ammonia (0.1 molar, 60 L) and stirred for 1 hour. The dichloromethane layer is then separated, dried with anhydrous magnesium sulphate (2 kg), filtered and evaporated to give a crystalline solid, substantially free of dichloromethane.

Reference： [1]Patent: US2003/187269,2003,A1

22
[ 598-56-1 ]
[ 98-09-9 ]
[ 105812-81-5 ]
4-(4'-fluorophenyl)-1-methyl-3-(3',4'-methylenedioxy-phenoxymethyl) piperidine [ No CAS ]
[ 153257-53-5 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; water;	EXAMPLE 1 Preparation of 4-(4'-fluorophenyl)-1-methyl-3-(3',4'-methylenedioxy-phenoxymethyl) piperidine Dichloromethane (1900 L) is charged to a dry vessel and further dried by azeotropic distillation. <strong>[105812-81-5](3S,4R)-trans-4-(4-fluorophenyl)-1-methyl-3-hydroxymethylpiperidine</strong> (250 kg) is added with stirring, followed by dimethylethylamine (168 L), and the resulting mixture is cooled to 0 C. A solution of benzenesulphonyl chloride (164 L) in dichloromethane (250 L) is cooled to between -10 and 0 C., and then added to the 4-(4-fluorophenyl)-1-methyl-3-hydroxymethylpiperidine solution over approximately one hour, with continuous stirring and maintaining the temperature below 0 C. 30 minutes after the completion of the addition, at a temperature of 0-5 C., water (750 L) is added and the mixture stirred for 1 hour. The dichloromethane layer is then separated from the aqueous layer and dried with anhydrous magnesium sulphate (25 kg). The clear dichloromethane solution is isolated by filtration and the solvent removed by distillation at reduced pressure to leave a crystalline solid product (3S,4R)-trans-4-(4-fluorophenyl)-1-methyl-3-phenylsulphonyloxymethylpiperidine. Residual dichloromethane level <0.7%.

Reference： [1]Patent: US2003/187269,2003,A1

23
[ 124-63-0 ]
[ 105812-81-5 ]
[ 608521-21-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;	To a solution of trans-(4R,3S)-[4-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-methanol (1.00 g, 4.48 mmol, 3B Medical Systems) in dry CH2Cl2 (7 mL) was added Et3N (1.5 mL). The mixture was cooled to 0 C. and treated with methanesulfonyl chloride (0.57 mL) and stirred in an ice bath for 0.5 hour and then for an additional 1.5 hours at ambient temperature. The reaction mixture was filtered through a cotton plug and washed through with additional dry CH2Cl2 (10 mL). The organic layer was diluted in a separatory funnel with ether (100 mL) and additional CH2Cl2 (20 mL) and washed three times with water (10 mL each time), dried (MgSO4), and concentrated to afford the desired product, methanesulfonic acid trans-(4R,3S)-4-(4-fluorophenyl)-1-methyl-piperidin-3-ylmethyl ester. Yield: 1.26 g (94%, 4.19 mmol). 1H-NMR (CDCl3) delta ppm: 1.79-1.90 (m, 2H); 1.91-2.37 (m, 4H); 2.38 (s, 3H); 2.87 (s, 3H); 2.95 (m, 1H); 3.12 (m, 1H); 3.81 (m, 1H); 3.93 (m, 1H); 7.01 (m, 2H); 7.16 (m, 2H).
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	General procedure: To a 0 C solution of (3S,4R)-tert-butyl 4-(4-fluoro-3-(methoxycarbonyl) phenyl)-3- (hydroxymethyl)piperidine-1-carboxylate (0.687 g, 1.87 mmol) in 25 mL DCM was added diisopropylethylamine (0.980 mL, 5.61 mmol) followed by methanesulfonylchloride (0.651 g, 3.74 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The resulting product was washed with water (1x), then brine (1x), dried over MgSO4, and concentrated in vacuo to give a clear oil (0.833 g crude). The product was used in subsequent reactions without further purification. To a 0 C solution of intermediate 7a (0.345g, 1.474 mmol) in 4 mL DMF was added 60% sodium hydride in mineral oil (0.062g, 1.54 mmol). The solution stirred for five min. To the reaction was added (3S,4R)-tert-butyl 4-(4-fluoro-3- (methoxycarbonyl)phenyl)-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (0.313 g, 0.702 mmol) in 4 mL DMF. The reaction was heated to 70 oC for 10 min then cooled to room temperature and treated with sat. NH4Cl solution. Extracted with ethyl acetate/ether (2x), washed with brine, dried with MgSO4, and concentrated in vacuo. Purified by flash chromatography using a gradient of 10% MeOH/DCM to give as a clear oil tert-butyl 5-(((3S,4R)-1-(tert- butoxycarbonyl)-4-(4-fluoro-3-(methoxycarbonyl)phenyl)piperidin-3-yl)methoxy)-1H-indazole- 1-carboxylate (9a) (0.135 g, 0.279 mmol, 40% yield over two steps).

Reference： [1]Patent: US2007/112031,2007,A1 .Location in patent: Page/Page column 33
[2]Molecular Pharmacology,2017,vol. 92,p. 707 - 717

24
[ 124-63-0 ]
[ 105812-81-5 ]
[ 1131450-87-7 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dichloro-ethane; at 20℃; for 6h;	((3S,4R)-4-(4-fluorophenyl)-l-methylpiperidin-3- yl)methanol (5) (2.00 g, 8.96 mmol) was dissolved in dichloroethane (20 mL) and methanesulfonyl chloride (0.73 mL) was added. The reaction was stirred for 6 h at rt. The reaction mixture was concentrated on a rotary evaporator to afford 6 as a white solid residue which was suitable for use in crude form. MS m/z: 302.1 (M+H).

Reference： [1]Journal of Pharmacology and Experimental Therapeutics,2015,vol. 354,p. 43 - 54
[2]Patent: WO2009/35652,2009,A1 .Location in patent: Page/Page column 57

25
[ 98-09-9 ]
[ 105812-81-5 ]
[ 153257-53-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N,N-dimethyl-ethanamine; In toluene; at 0 - 10℃; for 1.83333h;	A solution of 50 g of compound 5 (224 mmol) in toluene (230 mL) was cooled to < 5 C and then 48.8 <n="61"/>mL (450 mmol, 2.0 equiv) dimethylethylamine was added. To the reaction mixture was charged a solution of 48.23 g (0.273 mmol, 1.22 eq) benzenesulfonyl chloride in toluene (37.1 mL), keeping the temperature of the reaction mixture at less than or equal to 10 C. The mixture was stirred at 0-5 0C for 110 min. The reaction mixture was then quenched with a solution of 30.5% NaOH (7.5 mL, 37 mmol, 0.34 equiv) and water (140 mL). After stirring for 15 min, the aqueous layer was removed and discarded. The solution of compound 9 was stored at 0 C overnight.

Reference： [1]Patent: WO2009/35652,2009,A1 .Location in patent: Page/Page column 59-60

26
C₁₄H₁₅FO₃ [ No CAS ]
[ 105812-81-5 ]

Reference： [1]Tetrahedron Asymmetry,2011,vol. 22,p. 1 - 3

27
[ 188302-25-2 ]
[ 105812-81-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		Lithium aluminum hydride (1.8 g, 47.49 mmol) was added to a mixture of tetrahydrofuron (15.0 mL) and toluene (5.0 mL) at 0-5 C and stirred for 15 min at the same temperature. A solution of (3S,4R)-3-ethoxycarbonyl-4-(4'-fluorophenyl)-N-methyl piperidine-2,6-dione 6 (5.0 g, 17.05 mmol) in toluene (15.0 mL) was added slowly for 45-60 min at below 15 C and the mixture was heated to 60-65 C for 2 h. The mixture was cooled to 0-5 C and basified with 10% sodium hydroxide solution. Water (10.0 mL) was charged to the reaction mixture and then stirred for 20 min. The separated solid was filtered and washed with toluene (2 × 15 mL). The solvent was removed under reduced pressure and the crude compound was recrystalized from n-heptane to afford 7 (3.0 g, 80%) as an white solid. inlMMLBox (c 1, ethanol); IR (cm-1): 3153, 2943, 1602, 1509, 1222, 1379, 1069; 1H NMR: (400 MHz, CDCl3) delta, ppm: 7.14-7.17 (m, 2H), 6.96-7.0 (m, 2H), 3.38-3.42 (m, 1H), 3.13-3.25 (m, 2H), 2.92-2.95 (m, 1H), 2.29-2.34 (m, 4H), 1.97-2.03 (m, 5H); MS: m/z: 224.2 [M+H+].

Reference： [1]Tetrahedron Asymmetry,2011,vol. 22,p. 1 - 3

28
[ 459-32-5 ]
[ 105812-81-5 ]

Reference： [1]Tetrahedron Asymmetry,2011,vol. 22,p. 1 - 3

29
[ 105812-81-5 ]
[ 936838-88-9 ]

Reference： [1]Journal of Pharmacology and Experimental Therapeutics,2015,vol. 354,p. 43 - 54
[2]Patent: WO2009/35652,2009,A1
[3]Patent: WO2009/35652,2009,A1

30
[ 105812-81-5 ]
[ 1005412-34-9 ]

Reference： [1]Journal of Pharmacology and Experimental Therapeutics,2015,vol. 354,p. 43 - 54
[2]Patent: WO2009/35652,2009,A1
[3]Patent: WO2009/35652,2009,A1

31
[ 105812-81-5 ]
[ 923932-15-4 ]

Reference： [1]Journal of Pharmacology and Experimental Therapeutics,2015,vol. 354,p. 43 - 54
[2]Patent: WO2009/35652,2009,A1
[3]Patent: WO2009/35652,2009,A1
[4]Patent: WO2009/35652,2009,A1
[5]Patent: WO2009/35652,2009,A1

32
methyl (3S,4R)-4-(4-fluorophenyl)-6-hydroxy-1-methyl-2-oxopiperidine-3-carboxylate [ No CAS ]
[ 105812-81-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at -10 - 30℃; for 6h;Inert atmosphere;	Charged THF (30 mL) and (3S,4R)-methyl 4-(4-fluorophenyl)-6-hydroxy-l-methyl-2- oxopiperidine-3-carboxylate (IV) (5 g, 17.8 mmol) in a flask, followed by the addition of sodium borohydride (2.86 g, 74 mmol) and BF3-Etherate solution below -10 C under nitrogen atmosphere. The reaction mixture was gradually warmed to 25 - 30 C and continued stirring for 5-6 h. The reaction mixture was quenched with 3N HCl solution and the solvent was evaporated under reduced pressure. The reaction mass was diluted with demineralized (DM) water (15 mL), followed by addition of toluene (25 mL). The mixture was cooled to 5 C and the pH was adjusted to 12-14 using Lye solution at below 20 C. The mixture was filtered and the separated organic layer was evaporated completely under vacuum to obtain crude compound. The product was further purified by treatment with toluene (5 mL) and n-heptane (5 mL) to obtain the pure product (3.17 g, 80% yield), % ee : 97%, % HPLC purity: >98.5%.

Reference： [1]Patent: WO2017/37662,2017,A1 .Location in patent: Page/Page column 15

33
[ 105812-81-5 ]
(3S,4R)-tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-fluoro-3-(methoxycarbonyl)phenyl)piperidine-1-carboxylate [ No CAS ]