[ CAS No. 166815-96-9 ] {[proInfo.proName]}

Name: 166815-96-9|tert-Butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate|97%
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SKU: A336184
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Quality Control of [ 166815-96-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 166815-96-9 ]

SDS Specification

Alternatived Products of [ 166815-96-9 ]

Product Details of [ 166815-96-9 ]

CAS No. :	166815-96-9	MDL No. :	MFCD05864740
Formula :	C₁₈H₂₇NO₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DARTVAOOTJKHQW-UHFFFAOYSA-N
M.W :	369.48	Pubchem ID :	10642851
Synonyms :

Calculated chemistry of [ 166815-96-9 ]

Physicochemical Properties

Num. heavy atoms :	25
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.61
Num. rotatable bonds :	7
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	100.07
TPSA :	81.29 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.82
Log Po/w (XLOGP3) :	3.2
Log Po/w (WLOGP) :	4.05
Log Po/w (MLOGP) :	2.74
Log Po/w (SILICOS-IT) :	2.09
Consensus Log Po/w :	3.18

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.86
Solubility :	0.0507 mg/ml ; 0.000137 mol/l
Class :	Soluble
Log S (Ali) :	-4.58
Solubility :	0.00974 mg/ml ; 0.0000264 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.2
Solubility :	0.0236 mg/ml ; 0.0000638 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.24

Safety of [ 166815-96-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 166815-96-9 ]

* 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 [ 166815-96-9 ]
Downstream synthetic route of [ 166815-96-9 ]

[ 166815-96-9 ] Synthesis Path-Upstream 1~9

1
[ 166815-96-9 ]
[ 581060-27-7 ]

Reference： [1] Patent: US2016/243100, 2016, A1,
[2] Patent: WO2004/56773, 2004, A1,

2
[ 98-59-9 ]
[ 123855-51-6 ]
[ 166815-96-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With dmap; triethylamine In dichloromethane at 0 - 17℃; for 2 h; Inert atmosphere	Example 1A tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol), Et₃N (5.64 g, 55.8 mmol) and DMAP (1.13 g, 9.3 mmol) in DCM (100 mL) was added in protions TosCl (9.73 g, 51.2 mmol) at 0° C. under N₂ atmosphere. After stirring at 17° C. for 2 h, water (100 mL) was added to quench. The aqueous layer was extracted with DCM (100 mL*2). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to give the residue which was purified by column chromatography to give the title compound (17 g, 99percent yield) as a white solid. LCMS (ESI) m/z: 370 (M+1).
92.1%	With triethylamine In dichloromethane at 10 - 20℃; for 12 h;	(1) N-Boc-4- piperidinemethanol (0.1mol) was dissolved in 300ml of dichloromethane. Ice bath cooling to 10 deg.C. 20ml of triethylamine was added. Then, portionwise add p-toluenesulfonyl chloride (0.11 mmol ). After addition was complete, react at room temperature for 12h. Completion of the reaction, the reaction solution was washed with water, saturated sodium bicarbonate solution, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was passed through the column (eluent PE: EA = 1: 1) as a colorless oil was 34g, 92.1percent yield,
91%	at 0 - 20℃; for 16 h;	EXAMPLE 12; Synthesis l,l-dimethylethyI 4-[(2-[(4-[(2,4-dimethylphenyI)amino]carbonyl}- lH-imidazol-S-y^carbonyljaminoj-lH-benzimidazol-S-yOoxylmethyljpiperidine-1-carboxylate; Synthesis of tert-Butyl 4-(tosyloxymethyl)piperidine-l-carboxylate; [00183] 4-Hydroxylmethyl-N-(tert-butylcarboxylate)piperidine (10.76 g, 50 mmoles, 1 equivalent, commercially available from Aldrich) was dissolved in anhydrous pyridine (40ml) and cooled to 0 ⁰C in an ice-water-salt bath, p- Toluenesulfonyl chloride (10.48 g, 55 mmoles, 1.1 equivalent) was added in one lot to the stirred reaction mixture. The reaction mixture was then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water <n="109"/>(200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined ethyl acetate solution was washed with 5percent aqueous hydrochloric acid (200 ml), water (200 ml) and saturated sodium chloride solution (200 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate solution filtered and evaporated under reduced pressure to give 16.86 g of tert-butyl 4-(tosyloxymethyl) piperidine-1-carboxylate (yield, 91percent). ¹H-NMR (400 MHz, OMSO-d6) δ 7.88 (d, 2H), 7.45 (d, 2H), 3.84 (m, 4H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, IH), 1.54 (m, 2H)1.38 (s, 9H), 0.95 (m, 2H). MS (EI) 370 (MH+).; EXAMPLE 84; Synthesis of 1,1-dimethylethyl 4-[(2-[(4-[(5-chloro-2- methylphenytyaminolcarbonylJ-lH-imidazol-S-yOcarbonyllaminoJ-lH- benzimidazol-5-yl)oxy]methyl}piperidine-l-carboxylate; Synthesis of tert-Buty\\ 4-(tosyloxymethyl)piperidine-l-carboxylate; [00307] 4-Hydroxylmethyl-N-(rerr-butylcarboxylate)piperidine (10.76 g, 50 mmoles, 1 equivalent, commercially available from Aldrich) was dissolved in anhydrous pyridine (40ml) and cooled to 0 ⁰C in an ice-water-salt bath, p- Toluenesulfonyl chloride (10.48 g, 55 mmoles, 1.1 equivalent) was added in one lot to the stirred reaction mixture. The reaction mixture was then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined ethyl acetate solution was washed with 5percent aqueous hydrochloric acid (200 ml), water (200 ml) and saturated sodium chloride solution (200 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 16.86 g of ter/-butyl 4-(tosyloxymethyl) piperidine-1-carboxylate (yield, 91percent). ¹H- NMR (400 MHz, DMSO-ctoe) δ 7.88 (d, 2H), 7.45 (d, 2H), 3.84 (m, 4H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, IH), 1.54 (m, 2H)1.38 (s, 9H), 0.95 (m, 2H). MS (EI): 370 (MH+).; EXAMPLE 141; Synthesis of N⁵-(2-chloro-6-fluoropheny-)-N⁴-{2-methyl-4-[(piperidin-4- ylmethyl)oxy]phenyl}-lH-imidazole-4,5-dicarboxamide hydrochloride; Synthesis of tett-buty\\ 4-(tosyloxymethyl)piperidine-l-carboxylate; [00397] 4-Hydroxylmethyl-N-(tert-butylcarboxylate)piperidine (10.76 g, 50 mmoles, 1 equivalent, commercially available from Astatech) was dissolved in anhydrous pyridine ( 40ml) and cooled to 0 ⁰C in an ice-water-salt bath, p-Toluenesulfonyl chloride (10.48 g, 55 mmoles, 1.1 equivalent) was added in one lot to <n="212"/>the stirred reaction mixture. The reaction mixture was then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (3x with 200 ml). The combined ethyl acetate solution was washed with 5percent aqueous hydrochloric acid (200 ml), water (200 ml) and saturated sodium chloride solution (200 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 16.86 g of tert-buXy\\ 4-(tosyloxymethyl)piperidine-l-carboxylate (yield, 91percent). ¹H-NMR (400 MHz, OMSO-d6) δ 7.88 (d, 2H), 7.45 (d, 2H), 3.84 (m, 4H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, IH), 1.54 (m, 2H) 1.38 (s, 9H), 0.95 (m, 2H). MS (EI): 370 (MH+).

91%	With pyridine In 1,4-dioxane at 0 - 20℃; for 19.67 h; Inert atmosphere	Preparation intermediate 11tert-Butyl 4-(tosyloxymethyl)piperidine-l-carboxylateTo a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine- l- carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mL) at 0°C under nitrogen, /?-toluenesulfonyl chloride (4.87 g, 25.55 mmol) was added in one portion. The reaction was stirred at 0°C for 100 minutes before warming to RT. After 18 hours the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with aqueous hydrochloric acid (2 100 mL, 1.0 M solution), saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo to yield the title compound (7.87 g, 91percent). NMR (400 MHz, CDCl₃-d): δ 7.77-7.70 (m, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 3.80 (d, J = 6.5 Hz, 2 H), 2.61 (d, J = 13.1 Hz, 2 H), 2.41 (s, 3 H), 1.84-1.72 (m, 1 H), 1.60 (d, J = 13.1 Hz, 2 H), 1.46- 1.36 (m, 9 H), 1.05 (ddd, J = 24.9, 12.5, 4.4 Hz, 2 H), -0.05 (t, J = 3.3 Hz, 2 H).
91%	at 0 - 20℃; for 19.6667 h; Inert atmosphere	To a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mL) at 0° C. under nitrogen, p-toluenesulfonyl chloride (4.87 g, 25.55 mmol) was added in one portion. The reaction was stirred at 0° C. for 100 minutes before warming to RT. After 18 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (350 mL). The combined organic extracts were washed with aqueous hydrochloric acid (2100 mL, 1.0 M solution), saturated sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to yield the title compound (7.87 g, 91percent). ¹H NMR (400 MHz, CDCl₃): δ 7.77-7.70 (m, 2H), 7.31 (d, J=8.0 Hz, 2H), 3.80 (d, J=6.5 Hz, 2H), 2.61 (d, J=13.1 Hz, 2H), 2.41 (s, 3H), 1.84-1.72 (m, 1H), 1.60 (d, J=13.1 Hz, 2H), 1.46-1.36 (m, 9H), 1.05 (ddd, J=24.9, 12.5, 4.4 Hz, 2H), -0.05 (t, J=3.3 Hz, 2H).
91%	at 0 - 20℃; for 19.67 h; Inert atmosphere	A stirred solution of tert-butyl 4-(hydroxymethyl) piperidine-1-carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mE) at 0° C. under nitrogen was added with p-toluenesulfonyl chloride (4.87 g, 25.55 mmol) in one portion. The reaction was stirred at 0° C. for 100 minutes before warming to room temperature. Afier 18 hours the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic extracts were washed with aqueous 1M hydrochloric acid (x2), brine, dried (magnesium sulfate), filtered and evaporated under reduced pressure to yield the title compound as a yellow solid (7.87 g, 9 1percent). 1H NMR (400 MHz, CDC13): ö 7.78 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.15-4.07 (m, 2H), 3.85 (d, J=6.5 Hz, 2H), 2.68-2.60 (m, 2H), 2.46 (s, 3H), 1.88-1.78 (m, 1H), 1.66-1.59 (m, 2H), 1.44 (s, 9H), 1.16-1.04 (m, 2H).
91%	With dmap; triethylamine In dichloromethane at 20℃; Inert atmosphere	A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (50 g, 232.25 mmol, 1.00 equiv), triethylamine (35.2 g, 347.86 mmol, 1.50 equiv), 4-dimethylaminopyridine (2.8 g, 22.92 mmol, 0.10 equiv) and 4-methylbenzene-1-sulfonyl chloride (53 g, 278.00 mmol, 1.20 equiv) in CH₂Cl₂(500 mL) was stirred under argon overnight at room temperature. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column (Ethyl Acetate/Petroleum ether=1/3 9v/v)) to provide 78 g (91percent) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6): δ 7.78 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 3.87 (m, 4H), 2.49 (m, 2H), 2.42 (s, 3H), 1.76 (m, 1H), 1.53 (m, 2H), 1.36 (s, 9H), 0.96 (m, 2H) ppm.
87%	at 20℃; for 5.25 h;	To a mixture of 5 (5.7 g, 26.4 mmol), DMAP (0.16 g, 1.3 mmol) in pyridine (15 mL, 186 mmol) cooled to 0-5 °C (ice-bath), tosyl chloride (5.3 g, 27.8 mmol) was added in portion over a period of 15 min. After addition the reaction mixture was stirred at room temperature for 5 h and then poured into ice water (150 mL). The resulting mixture was extracted with EA (2 × 120 mL), the combined organic extracts was washed with dilute hydrochloric acid (1 N, 3 × 100 mL), saturated NaHCO₃ (80 mL) and dried over anhydrous Na₂SO₄,filtered, and evaporated. 20 mL PE was added and solid formed, the mixture was stirred vigorously for 20 min, the forming precipitation was filtrated under reduced pressure to give 6 (8.5 g, 87percent) as a white powder, R_f(PE /EA, 4:1) = 0.24. ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 7.76(d, J = 8.1 Hz, 2H), 7.34(d, J = 8.1 Hz, 2H), 4.07(d, J = 13.4 Hz, 2H), 3.83 (d, J = 6.5 Hz, 2H), 2.72-2.56 (m, 2H), 2.44 (s, 3H), 1.89-1.74 (m, 1H), 1.61 (t, J = 12.7 Hz, 2H), 1.50-1.38 (m, 9H), 1.08 (ddd, J = 25.0, 12.5, 4.4 Hz, 2H).
87%	at 0 - 20℃; for 5 h;	To a mixture of 4 (5.7 g, 26.4 mmol), DMAP (0.16 g, 1.3 mmol) in pyridine (15 mL, 186 mmol) cooled to 0-5 °C (ice-bath), tosyl chloride (5.3 g, 27.8 mmol) was added in portion over a period of 15 min. After addition the reaction mixture was stirred at room temperature for 5 h and then poured into ice water (150 mL). The resulting mixture was extracted with EA (2 × 120 mL), the combined organic extracts was washed with dilute hydrochloric acid (1 N, 3 × 100 mL), saturated NaHCO₃ (80 mL) and dried over anhydrous Na₂SO₄,filtered, and evaporated. 20 mL PE was added and solid formed, the mixture was stirred vigorously for 20 min, the forming precipitation was filtrated under reduced pressure to give 6 (8.5 g, 87percent) as a white powder. ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 7.76(d, J = 8.1 Hz, 2H), 7.34(d, J = 8.1 Hz, 2H), 4.07(d, J = 13.4 Hz, 2H), 3.83 (d, J = 6.5 Hz, 2H), 2.72-2.56 (m, 2H), 2.44 (s, 3H), 1.89-1.74 (m, 1H), 1.61 (t, J = 12.7 Hz, 2H), 1.50-1.38 (m, 9H), 1.08 (ddd, J = 25.0, 12.5, 4.4 Hz, 2H).
85%	Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane In tert-butyl methyl ether at 20℃; for 0.25 h; Stage #2: at 0 - 20℃; for 3 h;	1,4-Diazabicyclo [2.2. 2] octane (42.4 g, 0.378 mol) was added to a solution OF 4- HYDROXYMETHYL-1-TERT-BUTYLOXYCARBONYLPIPERIDINE (52.5 g, 0.244 mol) in tert-butyl methyl ether (525ML) and the reaction stirred at ambient temperature for 15 minutes. The reaction was cooled to 5 °C and a solution of 4-toluenesulphonyl chloride (62.8 g, 0.33 mmol) in tert-butyl methyl ether (525 ml) was added dropwise over 2 hours while maintaining the temperature at 0 °C. The reaction was stirred at ambient temperature for 1 hour, isohexane was added and the resultant precipitate was collected by suction filtration. Solvent evaporation in vacuo afforded a solid which was dissolved in diethyl ether (250 ml) and washed successively with 0.5 N aqueous hydrochloric acid (2 x 500 ml), water, saturated sodium hydrogen carbonate and brine. Solvent evaporation and drying in vacuo yielded 4- (4-METHYLPHENYLSULPHONYLOXY- METHYL)-L-TERT-BUTYLOXY-CARBONYLPIPERIDINE (76.7g, 85 percent yield) as a white solid: 'H NMR (CDC13) : 7.80 (d, 2H), 7.35 (d, 2H), 4.00-4. 20 (s, 2H), 3.85 (d, 1H), 2.55-2. 75 (m, 2H), 2.45 (s, 3H), 1.75-1. 90 (M, 2H), 1.65 (d, 2H), 1.45 (s, 9H), 1.00-1. 20 (m, 2H) : MS (+ve ESI): 392 (M+Na) +
85%	Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane In tert-butyl methyl ether at 20℃; for 0.25 h; Stage #2: at 0 - 20℃; for 3 h;	1,4-Diazabicyclo[2.2.2]octane (42.4g, 0.378mol) was added to a solution of 4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (52.5g, 0.244mol) in tert-butyl methyl ether (525ml). After stirring for 15 minutes at ambient temperature, the mixture was cooled to 5°C and a solution of toluene sulphonyl chloride (62.8g, 0.33mmol) in tert-butyl methyl ether (525ml) was added in portions over 2 hours while maintaining the temperature at 0°C. After stirring for 1 hour at ambient temperature, petroleum ether (11) was added. The precipitate was removed by filtration. The volatiles were removed by evaporation to give a solid. The solid was dissolved in ether and washed successively with 0.5M aqueous hydrochloric acid (2x500ml), water, saturated sodium hydrogen carbonate and brine, dried (MgSO₄) and the volatiles were removed by evaporation to give 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (76.7g, 85percent). ¹H NMR Spectrum: (CDCl₃) 1.0-1.2(m, 2H); 1.45(s. 9H); 1.65(d, 2H); 1.75-1.9(m, 2H); 2.45(s, 3H); 2.55-2.75(m, 2H); 3.85(d, 1H); 4.0-4.2(br s, 2H); 7.35(d, 2H); 7.8(d, 2H) MS (ESI): 392 [MNa]⁺
85%	With 1,4-diaza-bicyclo[2.2.2]octane In tert-butyl methyl ether at 0℃; for 3 h;	1,4-Diazabicyclo[2.2.2]octane (42.4g, 0.378mol) was added to a solution of 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (52.5g, 0.244mol) in tert-butyl methyl ether (525ml). After stirring for 15 minutes at ambient temperature, the mixture was cooled to 5°C and a solution of toluene sulphonyl chloride (62.8g, 0.33mmol) in tert-butyl methyl ether (525ml) was added in portions over 2 hours while maintaining the temperature at 0°C. After stirring for 1 hour at ambient temperature, petroleum ether (11) was added. The precipitate was removed by filtration. The filtrate was evaporated to give a solid. The solid was dissolved in ether and washed successively with 0.5N aqueous hydrochloric acid (2*500ml), water, saturated sodium hydrogen carbonate and brine, dried (MgSO₄) and evaporated to give 1-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (76.7g, 85percent). MS (ESI): 392 [MNa]⁺ ¹H NMR Spectrum: (CDCl₃) 1.0-1.2(m, 2H); 1.45(s, 9H); 1.65(d, 2H); 1.75-1.9(m, 2H); 2.45(s, 3H); 2.55-2.75(m, 2H); 3.85(d, 1H); 4.0-4.2(br s, 2H); 7.35(d, 2H); 7.8(d, 2H)
78%	With triethylamine In dichloromethane at 0 - 15℃; for 12 h;	To a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1 -carboxylate (I-47) (60 g, 46 mmol) and TEA (42.3 g, 418 mmol) in CH2CI2 (300 mL) was added TsCI (55.8 g, 293 mmol) in portions at 0~5 °C. The resulting mixture was stirred at 15 °C for 12 h. TLC (petroleum ether/EtOAc=3:1 , Rf ~0.7) showed that the reaction was completed. The reaction mixture was washed with saturated NaHC03 (3 x 300 mL) and brine (3 x 300 mL).The organic phase was dried over Na2S04, filtered and concentrated in vacuo to give the crude product, which was stirred in petroleum ether (50 mL) for 10 min and then filtered, dried in vacuo to obtain tert-butyl 4-([(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1 -carboxylate (I-85) (80 g, 78percent) as a white solid. 1H NMR (400 MHz, CDCI3) δ ppm 7.77 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 4.08 (br. s., 2 H), 3.84 (d, J = 6.4 Hz, 2 H), 2.45 (s, 3 H), 1 .81 - 1 .83 (m, 1 H), 1 .61 - 1 .69 (m, 2 H), 1 .43 (s, 9 H), 1 .06 - 1 .14 (m, 2 H).
76%	With dmap; triethylamine In tetrahydrofuran; dichloromethane at 40℃;	A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (4.0 g, 18.6 mmol), tosyl chloride (4.25 g, 22.3 mmol), TEA (5.4 mL, 37.2 mmol), DMAP (568 mg, 4.65 mmol) in DCM (64 mL) and THF (16 mL) was stirred at 40° C. overnight. The reaction mixture was then concentrated, diluted with EtOAc (100 mL), and washed with an aqueous HCl solution (0.5 M, 40 mL) and then brine (2×50 mL). The organic layer was dried (MgSO₄), filtered, and concentrated. The residue was purified by SiO₂chromatography, eluting with a PE/EtOAc gradient (100percent to 50percent in 50 min) to afford the target compound (5.2 g, 76percent) as a white solid. LCMS (ESI): m/z=314.2 [M−55]⁺.
70.5%	With dmap; triethylamine In dichloromethane for 16 h;	Tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate 5a (2.15 g, 10 mmol) (Shaoyuan Chemical,SY005902), triethylamine (2.77 mL, 20 mmol),4-dimethylaminopyridine (122 mg, 1 mmol)Dissolved in 30 mL of methylene chloride,P-Toluenesulfonyl chloride (2.86 g, 15 mmo 1) was added and reacted for 16 hours. To the reaction mixture was added 50mL water, liquid separation, aqueous useThe organic layer was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system C The title product 4_ (tolueneSulfonate) piperidine-1-carboxylate 5b (2.6 g, pale yellow solid), yield: 70.5percent.
65%	at 20℃; for 13 h; Inert atmosphere; Cooling with ice	General procedure: Boc-piperidinemethanol (27) or Boc-piperidineethanol (28) (23 mmol) dissolved in pyridine (50 mL) and cooled down under nitrogen. Then a tosyl chloride (27,87 mmol) was added portionwise. The was carried out for 3 h on bath-ice, then warm to room temperature and stirred for additional 10 h. The reaction mixture was extracted with CH₂Cl₂ (150 mL) and the organic phase was washed with 1 M KHSO₄ (4 .x. 50 mL), water, brine and dried over Na₂SO₄. The tosyl derivatives (29, 30) were separated by column chromatography using SiO₂ and CH₂Cl₂ followed by CH₂Cl₂/MeOH = 9/0.1. Next tosyl derivatives (2.44 mmol) were reacted with 4-chlorophenylpiperazine (2 mmol) by heating them in the presence of TEA (21.5 mmol) the boiling mixture of THF/toluene (5 mL/10 mL) for 20 h. After solvent evaporation the crude product was purified on silica gel column chromatography (CH₂Cl₂/MeOH 9/0.5, v/v) to yield Boc-protected piperidine 31 and 32. For the next stage the products were converted into their TFA salts and were isolated as white foams.
57%	at 0 - 20℃; Inert atmosphere	tert-Butyl-4-(hydroxymethyl)piperidine-1-carboxylate (1 g, 4.64 mmol) was stirred in pyridine (3.7 mL) at 0 °C. p-Toluene sulfonyl chloride (0.974 mg, 5.11 mmol) was added in one batch under nitrogen and the mixture stirred for 100 minutes at 0 °C. The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was poured onto water (25 mL) and extracted with ethyl acetate (3 15 mL). The organic layer was washed with 1M HCl (15 mL) and brine (15 mL), dried over MgSO₄ and concentrated under reduced pressure. Purification by column chromatography (1:20 to 1:1 EtOAc: hexane) afforded tert-butyl-4-(tosyloxy)methyl)piperidine-1-carboxylate as a colourless oil which solidified on standing (0.981 g, 57percent). ¹H NMR (500 MHz, CDCl₃) δ: 1.11 (dtd, 2H, CH₂, J = 4.9, 10.0, 13.2 Hz), 1.42-1.52 (m, 9H, CH₃), 1.61-1.69 (m, 2H, CH₂), 1.83 (dddd, 1H, CH, J = 2.4, 5.0, 10.0, 11.8 Hz), 2.47 (s, 3H, CH₃), 2.61-2.73 (m, 2H, CH₂), 3.86 (d, 2H, CH₂, J = 6.5 Hz), 7.36 (d, 2H, ArH, J = 8.0 Hz), 7.79 (d, 2H, ArH, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 14.20, 21.66, 28.42, 35.78, 43.16, 73.99, 79.55, 127.88, 129.89, 132.91, 144.86, 154.67. HRMS (ESI): calc’d for C₁₈H₂₇NO₅SNa [M+Na]⁺392.1502; found 392.1479
45%	With triethylamine In dichloromethane at 20℃; for 16 h;	4-Methylbenzene-1-sulfonyl chloride (13 g, 67.5 mmol, 1.10 equiv) and triethylamine (12 g, 118 mmol, 2.00 equiv) were added to a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (13 g, 54.3 mmol, 1.00 equiv) in dichloromethane (200 mL). The resulting mixture was stirred at ambient temperature for about 16 hours, washed with water, dried over anhydrous sodium sulfate, and purified by silica gel chromatography (ethyl acetate/petroleum ether 1:10) to give the title product as a brown oil (10 g, yield 45percent).
21 g	With triethylamine In dichloromethane at 0 - 20℃; for 16 h;	Synthesis of tert-butyl 4-(tosyloxymethyl) piperidine-1-carboxylate To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (13.0 g, 60.4 mmol, 1.0 eq) and triethylamine (25.3 mL, 181 mmol, 3.0 eq) in dichloromethane (130 mL) was added TsCl (17.2 g, 90.0 mmol, 1.5 eq) slowly at 0° C. The mixture was allowed to stir at room temperature for 16 hr. After completion of the reaction (monitored by thin layer chromatography, 30percent ethyl acetate in hexanes R_f=0.4), the mixture was poured into cold water and extracted with dichloromethane. The organic extract was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh), eluting with a 15-20percent gradient of ethyl acetate in hexanes to afford tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (21 g) as a white solid. LCMS purity: 97.53percent; (ES⁺): m/z 314 (M-56+H⁺); tr=2.35 min.
40 g	With triethylamine In dichloromethane at 0 - 20℃;	Reaction Step 1 Synthesis of tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (30.0 g, 139 mmol, 1.0 eq) and triethylamine (58.0 mL, 147 mmol, 3.0 eq) in dichloromethane (300 mL) was added TsCl (39.8 g, 209 mmol, 1.5 eq) slowly at 0° C. The mixture was allowed to stir at room temperature for 16 h. After completion of the reaction (monitored by TLC, 50percent ethyl acetate-hexane, R_f=0.5), the mixture was poured into cold water and extracted with dichloromethane. The organic extract was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral alumina, eluting with a 0-12percent gradient of ethyl acetate in hexanes to afford tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (40.0 g, 78percent) as a white solid. LCMS purity: 89.04percent; (ES⁺): m/z 370.17 (M+H⁺); tr=2.35 min.

Reference： [1] Patent: US2017/29430, 2017, A1, . Location in patent: Paragraph 0255
[2] Patent: CN105315267, 2016, A, . Location in patent: Paragraph 0033; 0049
[3] Patent: WO2008/42282, 2008, A2, . Location in patent: Page/Page column 107-108; 168-169; 210-211
[4] Patent: WO2012/168349, 2012, A1, . Location in patent: Page/Page column 37
[5] Patent: US2013/34504, 2013, A1, . Location in patent: Paragraph 0147; 0148; 0149
[6] Patent: US2016/235734, 2016, A1, . Location in patent: Paragraph 0370; 0384; 0385; 0386
[7] Patent: US2016/243100, 2016, A1, . Location in patent: Paragraph 0075-0076
[8] Organic Process Research and Development, 2016, vol. 20, # 2, p. 233 - 241
[9] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4497 - 4505
[10] Bioorganic Chemistry, 2018, vol. 81, p. 681 - 688
[11] Patent: WO2004/58752, 2004, A1, . Location in patent: Page 140
[12] Patent: EP1119567, 2005, B1, . Location in patent: Page/Page column 35
[13] Patent: EP1244647, 2006, B1, . Location in patent: Page/Page column 19
[14] Patent: WO2016/97918, 2016, A1, . Location in patent: Page/Page column 78
[15] Patent: US2015/31674, 2015, A1, . Location in patent: Paragraph 0271; 0272
[16] Angewandte Chemie - International Edition, 2018, vol. 57, # 10, p. 2712 - 2715[17] Angew. Chem., 2018, vol. 130, p. 2742 - 2745,4
[18] Patent: CN103382206, 2016, B, . Location in patent: Paragraph 0277-0281
[19] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 4, p. 1545 - 1556
[20] Tetrahedron Letters, 2017, vol. 58, # 15, p. 1467 - 1469
[21] Patent: US2010/75916, 2010, A1, . Location in patent: Page/Page column 19
[22] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # 13, p. 1289 - 1300
[23] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3116 - 3135
[24] Patent: US2006/40889, 2006, A1, . Location in patent: Page/Page column 26
[25] Patent: WO2006/15357, 2006, A2, . Location in patent: Page/Page column 72
[26] Patent: WO2007/36713, 2007, A2, . Location in patent: Page/Page column 48; 49
[27] Patent: US2003/225111, 2003, A1, . Location in patent: Page 26, 27
[28] Patent: US6806274, 2004, B1, . Location in patent: Page/Page column 44;45
[29] Patent: WO2011/101774, 2011, A1, . Location in patent: Page/Page column 27-28
[30] Patent: US2012/71489, 2012, A1, . Location in patent: Page/Page column 55
[31] MedChemComm, 2015, vol. 6, # 5, p. 831 - 838
[32] Patent: US2015/252022, 2015, A1, . Location in patent: Paragraph 0211
[33] Molecules, 2016, vol. 21, # 12,
[34] ChemBioChem, 2017, vol. 18, # 21, p. 2156 - 2164
[35] Patent: US2017/298060, 2017, A1, . Location in patent: Paragraph 0085; 0086
[36] Patent: US2016/24056, 2016, A1, . Location in patent: Paragraph 0260
[37] Patent: WO2009/47161, 2009, A1, . Location in patent: Page/Page column 72

3
[ 280-57-9 ]
[ 107-83-5 ]
[ 98-59-9 ]
[ 123855-51-6 ]
[ 166815-96-9 ]

Reference： [1] Patent: US7235559, 2007, B1,

4
[ 6457-49-4 ]
[ 166815-96-9 ]

Reference： [1] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # 13, p. 1289 - 1300
[2] Molecules, 2016, vol. 21, # 12,
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4497 - 4505
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 10, p. 2712 - 2715[5] Angew. Chem., 2018, vol. 130, p. 2742 - 2745,4
[6] Bioorganic Chemistry, 2018, vol. 81, p. 681 - 688

5
[ 24424-99-5 ]
[ 166815-96-9 ]

Reference： [1] Molecules, 2016, vol. 21, # 12,
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4497 - 4505
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 10, p. 2712 - 2715[4] Angew. Chem., 2018, vol. 130, p. 2742 - 2745,4
[5] Bioorganic Chemistry, 2018, vol. 81, p. 681 - 688

6
[ 6457-49-4 ]
[ 24424-99-5 ]
[ 98-59-9 ]
[ 166815-96-9 ]

Reference： [1] Patent: US5763458, 1998, A,

7
[ 280-57-9 ]
[ 98-59-9 ]
[ 123855-51-6 ]
[ 166815-96-9 ]

Reference： [1] Patent: US2004/48881, 2004, A1,

8
[ 773837-37-9 ]
[ 166815-96-9 ]
[ 256411-39-9 ]

Reference： [1] Patent: US2017/29430, 2017, A1, . Location in patent: Paragraph 0257

9
[ 166815-96-9 ]
[ 597563-39-8 ]

Reference： [1] Patent: WO2009/47161, 2009, A1,

[ 166815-96-9 ] Synthesis Path-Downstream 1~21

1
[ 166815-96-9 ]
[ 259143-03-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With tetraethylammonium fluoride In acetonitrile at 70℃; for 6h;

Reference： [1]Gilissen; Bormans; De Groot; Verbruggen [Journal of labelled compounds and radiopharmaceuticals, 1999, vol. 42, # 13, p. 1289 - 1300]

2
[ 166815-96-9 ]
[ 196603-96-0 ]
[ 338992-20-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium carbonate; In N,N-dimethyl-formamide; at 18 - 95℃; for 2h;	Potassium carbonate (414mg, 3mmol) was added to a suspension of <strong>[196603-96-0]4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline</strong> (546mg, 1.5mmol) in DMF (5ml). After stirring for 10 minutes at ambient temperature, 1-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (636mg, 1.72mmol) was added and the mixture was heated at 95C for 2 hours. After cooling, the mixture was poured onto cooled water (20ml). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (665mg, 79%). MS - ESI: 561-563 [MH]+ 1H NMR Spectrum: (DMSOd6) 1-15-1.3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, 1H), 2.65-2.9 (m, 2H), 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, 1H), 7.48 (d, 1H), 7.55 (t, 1H), 7.65 (d, 1H), 7.8 (s, 1H), 8.35 (s, 1H), 9.55 (br s, 1H)
77%	With sodium hydroxide; In water; toluene; at 70℃; for 18h;Product distribution / selectivity;	7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (9.7 g), sodium hydroxide (47% w/w, 5.0ml) and Adogen 464 (1.5 g) were added to water (50 ml) with stirring. l-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine (10.0 g) as a solution in toluene (35 ml) was then added to the reaction mixture and heated to 700C for 18 hours. The reaction mixture was then cooled to 2O0C and the product was isolated by filtration. The product was then washed with toluene (20 ml) and dried at 500C. Yield: 8.72 g, 77%; NMR Spectrum (DMSOd6) 1.15-1.3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H), 2.0- 2.1 (m, IH), 2.65-2.9 (m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, IH), 7.48 (d, IH), 7.55 (t, IH), 7.65 (d, IH), 7.8 (d, IH), 8.35 (s, IH), 9.55 (br s, IH); Mass Spectrum [ESI] (M+H)+ - 561-563
40%		Potassium carbonate (1.5 g, 10.8 mmol, 2.00 equiv) was added to a solution of 4-(4-bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol (2.0 g, 5.22 mmol, 1.00 equiv) and N,N-dimethylformamide (20 mL). After stirring at ambient temperature for about 10 minutes, tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (2.3 g, 5.91 mmol, 1.15 equiv) was then added. The resulting solution was stirred at about 95 C. for about 2 hours, and then diluted with ice-cold water (40 mL). The resulting solids were collected by filtration, and purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether 1:5) to give the title product as a white solid (1.3 g, yield 40%). LC-MS: m/z=561/563 (MH)+.

With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 6h;

Add 7.3 (20 mmol) of 4-((4-bromo-2-fluorophenyl)amino)-6-methoxy-7-ol (Compound 6) to 200 mL of DMF and heat to 75 C, add 8.9 dropwise g (24 mmol) 4-((toluenesulfonyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (Compound 7),The dropping time is about 1 h; during the dropping process,Add 1.4g (10mmol) potassium carbonate in batches (in 6 batches,Added within 1h),The reaction was continued for 6 h after the addition was completed.After the reaction is over,Filter, filter cake with a little DMF rinse,The filtrate was concentrated under reduced pressure.The concentrate is added to 100g of ice water and stirred.Filtration gave the target product.

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 1300 - 1312
[2]Patent: EP1244647,2006,B1 .Location in patent: Page/Page column 19
[3]Patent: WO2007/36713,2007,A2 .Location in patent: Page/Page column 57
[4]Patent: US2010/75916,2010,A1 .Location in patent: Page/Page column 19-20
[5]Patent: CN108558828,2018,A .Location in patent: Paragraph 0076; 0101-0102

3
[ 3943-74-6 ]
[ 166815-96-9 ]
[ 906565-52-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine In N,N-dimethyl-formamide at 120℃; for 5h;
86%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0025h; Stage #2: N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine In N,N-dimethyl-formamide for 3h; Reflux;	1 Synthesis of methyl 4-(N-Boc-4-piperidinylmethoxy)-3-methoxybenzoate Methyl trioxalate (1g, 5.49mmol) was weighted into a 100 mL eggplant-shaped bottle, and anhydrous potassium carbonate (1.52g, 10.98mmol) and about 50 mL of DMF were added, and stirred for about 15 min at room temperature. Tert-butyl tert-butyl-4-((tosyloxy)methyl)piperidine-1-carboxylate (2.75g, 7.41mmol) was added, heated to 95°C and refluxed for 3h. The reaction was confirmed as being completed by TLC. The reaction mixture was extracted with saturated sodium chloride/ethyl acetate and dried over anhydrous sodium sulfate. Most of the solvent was removed in vacuo, and the residual DMF was removed by a diaphragm pump at 70°C for about 20 minutes. The crude product was separated by silica gel-column chromatography (petroleum ether / ethyl acetate = 8: 1) to obtain 2 g of methyl 4-(N-Boc-4-piperidinylmethoxy)-3-methoxybenzoate with a yield of 86%. 1H NMR(400MHz, DMSO): δ 7.57 (d, J = 8.4Hz, 1H), 7.45 (s, 1H), 7.07 (d, J = 8.4Hz, 1H), 3.97 (d, J = 12Hz, 2H), 3.9 (d, J= 6.4Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 2.74 (s, 2H), 1.95-1.85 (m, 1H), 1.75 (d, J = 8.4Hz, 2H), 1.4 (s, 9H), 1.15 (m, 2H).
	With potassium carbonate In N,N-dimethyl-formamide

Reference： [1]Li, Qiannan; Zhang, Tao; Li, Shiliang; Tong, Linjiang; Li, Junyu; Su, Zhicheng; Feng, Fang; Sun, Deheng; Tong, Yi; Wang, Xia; Zhao, Zhenjiang; Zhu, Lili; Ding, Jian; Li, Honglin; Xie, Hua; Xu, Yufang [ACS Medicinal Chemistry Letters, 2019, vol. 10, # 6, p. 869 - 873]
[2]Current Patent Assignee: EAST CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY; CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - EP3778586, 2021, A1 Location in patent: Paragraph 0060-0061
[3]Boschelli, Diane H.; Ye, Fei; Wu, Biqi; Wang, Yanong D.; Barrios Sosa, Ana Carolina; Yaczko, Deanna; Powell, Dennis; Golas, Jennifer M.; Lucas, Judy; Boschelli, Frank [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3797 - 3800]

4
[ 612501-52-7 ]
[ 166815-96-9 ]
6-[(1-tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 4h;	Reference Example 4; 6-{ [(1-tert-Butoxycarbonyl) piperidin-4-yl] methoxy}-4- (3-chloro-2-fluoroanilino)-7- methoxyquinazoline; 4- (3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2,700 mg, 2.19 mmol) was dissolved in DMA (35 ml). Potassium carbonate (1209 mg, 8.76 mmol) and tert-butyl 4- (toluene-4-sulfonyloxymethyl) piperidine-l-carboxylate (prepared as described in Example 1 in WO 9427965; 808 mg, 2.19 mmol) were added, and the mixture was stirred at 80C for 4 hours. The solvent was evaporated, and the residue was partitioned between water (100 ml) and DCM (100 ml). The aqueous layer was extracted with DCM (3x 100 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper, and evaporated, giving the product as a brown solid (1290 mg, 98%) ; 1H NMR : 1.20 (m, 2H), 1.39 (s, 9H), 1.82 (m, 2H), 2.03 (br. m, 1H), 2.70-2. 85 (br. m, 2H), 3.93 (s, 3H), 3.95-4. 05 (br. m, 2H), 3.98 (d, 2H), 7.19 (s, 1H), 7.26 (dd, 1H), 7.46 (dd, 1H), 7.50 (dd, 1H), 7.76 (s, 1H), 8.35 (s, 1H), 9.57 (s, 1H); Mass Spectrum : 517. 3, 519.3

Reference： [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 163
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4908 - 4912

5
[ 166815-96-9 ]
[ 635678-09-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: K₂CO₃ / dimethylformamide 2: aq. HCO₂H
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.25 h / 20 °C 1.2: 5 h / 120 °C 2.1: formic acid / 0.5 h / 20 °C 2.2: 8 h / 120 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0 h / 20 °C 1.2: 3 h / Reflux 2.1: formic acid / 0.01 h / 20 °C 2.2: 0.6 h / 95 °C / Inert atmosphere

Reference： [1]Boschelli, Diane H.; Ye, Fei; Wu, Biqi; Wang, Yanong D.; Barrios Sosa, Ana Carolina; Yaczko, Deanna; Powell, Dennis; Golas, Jennifer M.; Lucas, Judy; Boschelli, Frank [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3797 - 3800]
[2]Li, Qiannan; Zhang, Tao; Li, Shiliang; Tong, Linjiang; Li, Junyu; Su, Zhicheng; Feng, Fang; Sun, Deheng; Tong, Yi; Wang, Xia; Zhao, Zhenjiang; Zhu, Lili; Ding, Jian; Li, Honglin; Xie, Hua; Xu, Yufang [ACS Medicinal Chemistry Letters, 2019, vol. 10, # 6, p. 869 - 873]
[3]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS); EAST CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY - EP3778586, 2021, A1

6
[ 617-05-0 ]
[ 166815-96-9 ]
[ 264208-58-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N-methyl-acetamide;	d) 4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (40 g, 0.11 mol) was added to a suspension of ethyl 3-methoxy-4-hydroxybenzoate (19.6 g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) in dry dimethylformamide (200 ml) and the reaction was heated at 95 C. for 2.5 hours. The reaction was cooled to ambient temperature, partitioned between water and ethyl acetate/diethyl ether, before the organic layer was washed with water and brine. Solvent evaporation in vacuo afforded a clear oil which crystallized on standing. Washing with isohexane and drying in vacuo yielded ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35 g, 89%) as a white solid: m.p. 81-83 C.: 1H NMR (CDCl3): 7.65 (d, 1H), 7.55 (s, 1H), 6.85 (d, 1H), 4.35 (q, 2H), 4.05-4.25 (s, 2H), 3.95 (s, 3H), 3.9 (d, 2H), 2.75 (t, 2H), 2.00-2.15 (m, 2H), 1.80-1.90 (d, 2H), 1.48 (s, 9H), 1.40 (t, 3H), 1.20-1.35 (m, 2H): MS (+ve ESI): 416 (M+Na)30 :
89%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 95℃; for 2.5h;	4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (40g, 0.11mol) was added to a suspension of ethyl 3-methoxy-4-hydroxybenzoate (19.6g, 0.1mol) and potassium carbonate (28g, 0.2mol) in dry DMF (200ml). After stirring at 95C for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The resulting oil was crystallized from petroleum ether and the suspension was stored overnight (at 5C). The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35g, 89%). m.p. 81-83C 1H NMR Spectrum: (CDCl3) 1.2-1.35(m, 2H); 1.4(t, 3H); 1.48(s, 9H); 1.8-1.9(d, 2H); 2.0-2.15(m, 2H); 2.75(t, 2H); 3.9(d, 2H); 3.95(s, 3H); 4.05-4.25(br s, 2H); 4.35(q, 2H); 6.85(d, 1H); 7.55(s, 1H); 7.65(d, 1H) MS (ESI): 416 [MNa]+ Elemental analysis Found C 63.4 H 8.0 N 3.5 C21H31NO6 0.3H2O Requires C 63.2 H 8.0 N 3.5%
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; for 2.5h;	The starting material was prepared as follows: 1-(tert-Butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (40g, 0.11mol), (prepared as described for the starting material in Example 1), was added to a suspension of <strong>[617-05-0]ethyl 4-hydroxy-3-methoxybenzoate</strong> (19.6g, 0.1mol) and potassium carbonate (28g, 0.2mol) in dry DMF (200ml). After stirring at 95C for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The resulting oil was crystallized from petroleum ether and the suspension was stored overnight at 5C. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-3-methoxybenzoate (35g, 89%). m.p. 81-83C MS (ESI): 416 [MNa]+ 1H NMR Spectrum: (CDCl3) 1.2-1.35(m, 2H); 1.4(t, 3H); 1.48(s, 9H); 1.8-1.9(d, 2H); 2.0-2.15(m, 2H); 2.75(t, 2H); 3.9(d, 2H); 3.95(s, 3H); 4.05-4.25(br s, 2H); 4.35(q, 2H); 6.85(d, 1H); 7.55(s, 1H); 7.65(d, 1H)

	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 95℃; for 2.5h;	The 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline used as a starting material was prepared as follows: A solution of di-tert-butyl dicarbonate (41.7 g) in ethyl acetate (75 ml) was added dropwise to a stirred solution of ethyl piperidine-4-carboxylate (30 g) in ethyl acetate (150 ml) which had been cooled to 0 to 5 C. in an ice-bath. The resultant mixture was stirred at ambient temperature for 48 hours. The mixture was poured into water (300 ml). The organic layer was separated, washed in turn with water (200 ml), 0.1N aqueous hydrochloric acid solution (200 ml), a saturated aqueous sodium bicarbonate solution (200 ml) and brine (200 ml), dried over magnesium sulphate and evaporated. There was thus obtained ethyl N-tert-butoxycarbonylpiperidine-4-carboxylate (48 g); NMR Spectrum: (CDCl3) 1.25 (t, 3H), 1.45 (s, 9H), 1.55-1.7 (m, 2H), 1.8-2.0 (d, 2H), 2.35-2.5 (m, 1H), 2.7-2.95 (t, 2H), 3.9-4.1 (br s, 2H), 4.15 (q, 2H). A solution of the material so obtained in THF (180 ml) was cooled at 0 C. and lithium aluminium hydride (1M solution in TBF; 133 ml) was added dropwise. The mixture was stirred at 0 C. for 2 hours. Water (30 ml) and 2N aqueous sodium hydroxide solution (10 ml) were added in turn and the mixture was stirred for 15 minutes. The resultant mixture was filtered through diatomaceous earth and the solids were washed with ethyl acetate. The filtrate was washed in turn with water and with brine, dried over magnesium sulphate and evaporated. There was thus obtained N-tert-butoxycarbonyl-4-hydroxymethylpiperidine (36.3 g); NMR Spectrum: (CDCl3) 1.05-1.2 (m, 2H), 1.35-1.55 (m, 10H), 1.6-1.8 (m, 2H), 2.6-2.8 (t, 2H), 3.4-3.6 (t, 2H), 4.0-4.2 (br s, 2H). 1,4-Diazabicyclo[2.2.2]octane (42.4 g) was added to a solution of N-tert-butoxycarbonyl-4-hydroxymethylpiperidine (52.5 g) in tert-butyl methyl ether (525 ml) and the mixture was stirred at ambient temperature for 15 minutes. The mixture was then cooled in an ice-bath to 5 C. and a solution of 4-toluenesulphonyl chloride (62.8 g) in tert-butyl methyl ether (525 ml) was added dropwise over 2 hours while maintaining the reaction temperature at approximately 0 C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 1 hour. Petroleum ether (b.p. 60-80 C., 1L) was added and the precipitate was removed by filtration. The filtrate was evaporated to give a solid residue which was dissolved in diethyl ether. The organic solution was washed in turn with 0.5N aqueous hydrochloric acid solution, water, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated. There was thus obtained N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine (76.7 g), NMR Spectrum: (CDCl3) 1.0-1.2 (m, 2H), 1.45 (s, 9H), 1.65 (d, 2H), 1.75-1.9 (m, 2H), 2.45 (s, 3H), 2.55-2.75 (m, 2H), 3.85 (d, 1H), 4.0-4.2 (br s, 2H), 7.35 (d, 2H), 7.8 (d, 2H). A portion (40 g) of the material so obtained was added to a suspension of <strong>[617-05-0]ethyl 4-hydroxy-3-methoxybenzoate</strong> (19.6 g) and potassium carbonate (28 g) in DMF (200 ml) and the resultant mixture was stirred and heated to 95 C. for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between water and a mixture of ethyl acetate and diethyl ether. The organic layer was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The resulting oil was crystallised from petroleum ether (b.p. 60-80 C.) and the suspension was stored overnight at 5 C. The resultant solid was collected by filtration, washed with petroleum ether and dried under vacuum. There was thus obtained ethyl 4-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-3-methoxybenzoate (35 g), m.p. 81-83 C.; NMR Spectrum: (CDCl3) 1.2-1.35 (m, 2H), 1.4 (t, 3H), 1.48 (s, 9H), 1.8-1.9 (d, 2H), 2.0-2.15 (m, 2H), 2.75 (t, 2H), 3.9 (d, 2H), 3.95 (s, 3H), 4.05-4.25 (br s, 2H), 4.35 (q, 2H), 6.85 (d, 1H), 7.55 (s, 1H), 7.65 (d, 1H). The material so obtained was dissolved in formic acid (35 ml), formaldehyde (12M, 37% in water, 35. ml) was added and the mixture was stirred and heated to 95 C. for 3 hours. The resultant mixture was evaporated. The residue was dissolved in methylene chloride and hydrogen chloride (3M solution in diethyl ether; 40 ml) was added. The mixture was diluted with diethyl ether and the mixture was triturated until a solid was formed. The solid was collected, washed with diethyl ether and dried under vacuum overnight at 50 C. There was thus obtained ethyl 3-methoxy4(N-methylpiperidin-4-ylmethoxy)benzoate (30.6 g), NMR Spectrum: (DMSOd6) 1.29 (t, 3H), 1.5-1.7 (m, 2H), 1.95 (d, 2H), 2.0-2.15 (br s, 1H), 2.72 (s, 3H), 2.9-3.1 (m, 2H), 3.35-3.5 (br s, 2H), 3.85 (s, 3H), 3.9-4.05 (br s, 2H), 4.3 (q, 2H), 7.1 (d, 1H), 7.48 (s, 1H), 7.6 (d, 1H). The material so obtained was dissolved in methylene chloride (75 ml) and the solution was cooled in an ice-bath to 0-5 C. Trifluoroacetic acid (37.5 ml) was added followed by the dropwise addition over 15 minutes...
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 95℃; for 2.5h;	A portion (40 g) of the material so obtained was added to a suspension of <strong>[617-05-0]ethyl 4-hydroxy-3-methoxybenzoate</strong> (19.6 g) and potassium carbonate (28 g) in DMF (200 ml) and the resultant mixture was stirred and heated to 95 C. for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between water and a mixture of ethyl acetate and diethyl ether. The organic layer was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The resulting oil was crystallised from petroleum ether (b.p. 60-80 C.) and the suspension was stored overnight at 5 C. The resultant solid was collected by filtration, washed with petroleum ether and dried under vacuum. There was thus obtained ethyl 4(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-3-methoxybenzoate (35 g), m.p. 81-83 C.; NMR Spectrum: (CDCl3) 1.2-1.35 (m, 2H), 1.4 (t, 3H), 1.48 (s, 9H), 1.8-1.9 (d, 2H), 2.0-2.15 (m, 2H), 2.75 (t, 2H), 3.9 (d, 2H), 3.95 (s, 3H), 4.05-4.25 (br s, 2H), 4.35 (q, 2H), 6.85 (d, 1H), 7.55 (s, 1H), 7.65 (d, 1H).

Reference： [1]Patent: US7235559,2007,B1
[2]Patent: EP1119567,2005,B1 .Location in patent: Page/Page column 35
[3]Patent: EP1244647,2006,B1 .Location in patent: Page/Page column 21
[4]Patent: US2003/225111,2003,A1 .Location in patent: Page 26, 27
[5]Patent: US6806274,2004,B1 .Location in patent: Page/Page column 45

7
[ 4939-28-0 ]
[ 166815-96-9 ]
[ 674348-05-1 ]

Yield	Reaction Conditions	Operation in experiment
		I)] To a stirred solution of <strong>[4939-28-0]2-methyl-4-hydroxymethylquinoline</strong> (2.22g) in DMF (40ml) was added a 60% suspension of sodium hydride in mineral oil (620mg). After 15 min, tert-butyl 4-([(4- methylphenyl) [SULPHONYL] OXY} METHYL) PIPERIDIN-L-YLCARBOXYLATE] (4.7g) (Preparation of quinazolinyl ureas, thioureas and guanidines for use in the prevention or treatment of T cell mediated diseases or medical conditions; Crawley, [MCKERRECHER,] Poyser, Hennequin and Lambert (Astrazeneca UK Limited, [UK] ; Zeneca Pharma S. A. ) WO 0104102 169 pp) was added and the mixture stirred at [20C] for 18 h. The mixture was quenched carefully with water (100ml) and extracted repeatedly with EtOAc. The combined EtOAc extracts were washed with water, brine, dried and evaporated to an oil. This was chromatographed on silica in EtOAc-isohexane mixtures affording [TERT-BUTYL] [4- { [ (2-METHYLQUINOLIN-4-YL) METHOXY] METHYL}] piperidin-1-ylcarboxylate (1.2g) as an oil; NMR 1.1-1. 3 (m, 2H), 1.35 (s, 9H), 1.7-1. 9 [(M,] 3H), 2.6-2. 8 (s, m, 5H), 3.45 (d, 2H), 4.0-4. 2 (m, 2H), 4.9 (s, 2H), 7.3 (s, 1H), 7.45 (t, 1H), 7.65 (t, 1H), 7.8 (d, 1H), 8.05 (d, 1H) ; MS 371.2 (MH+).

Reference： [1]Patent: WO2004/24698,2004,A1 .Location in patent: Page 53-54

8
[ 636-93-1 ]
[ 166815-96-9 ]
[ 1208902-77-5 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; In acetonitrile; at 90℃; for 16h;Inert atmosphere;	To a stirred solution of tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (Compound 111-02) (3.2 g, 8.67 mmol, 1.2 eq) in acetonitrile (32 mL) at RT, was added 2-methoxy-5-nitrophenol (1.22 g, 7.23 mmol, 1.0 eq) and K2CO3 (1.99 g, 14.4 mmol, 2.0 eq) under N2 atmosphere. The reaction mixture was stirred at 90 C. for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water and extracted with (2*100 mL) DCM. The combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated to provide crude product. The crude was purified by trituration with diethyl ether to afford tert-butyl 4-((2-methoxy-5-nitrophenoxy)methyl)piperidine-1-carboxylate (Compound 111-03) (2.1 g, yield: 66%). TLC system: EtOAc:Hexane (50:50), Rf value: ?0.5; 1H NMR (400 MHz, CDCl3) delta 7.91 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 11H), 4.16 (brs, 2H), 3.96 (s, 3H), 3.91 (d, J=7.2 Hz, 2H), 2.80-2.74 (m, 2H), 2.09-2.05 (m, 1H), 1.89-1.85 (m, 2H), 1.46 (s, 9H), 1.34-1.30 (m, 2H).

Reference： [1]Tetrahedron,2010,vol. 66,p. 962 - 968
[2]Patent: US2020/39979,2020,A1 .Location in patent: Paragraph 0382-0383

9
[ 178747-83-6 ]
[ 166815-96-9 ]
[ 1331782-33-2 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium carbonate In ISOPROPYLAMIDE at 50℃; for 20h; Industry scale;	1 Tert-butyl 4-((4-fluorobenzo[d]isoxazol-3-yloxy)methyl)piperidine-1- carboxylate (6): To a 20L jacketed reactor were charged dimethylacetamide (4.28 L), tert-butyl 4-(tosyloxymethyl)piperidine-1 -carboxylate (5) (1.68 Kg, 4.56 mol), 4-fluorobenzo[d]isoxazol-3-ol (4) (540 g, 3.51 mol), and potassium carbonate (960 g, 6.98 mol) resulting in a thick beige slurry. The reaction mixture was heated to 50°C and stirred for 20 h and then cooled to 20°C, followed by the addition of water (7.5 L) and ethyl acetate (5.37 L). After mixing for 15 min, the phases were settled and split. The organic layer was washed with water (5.37 L), sending the aqueous wash to waste. The organic mixture was distilled under vacuum with a maximum jacket temperature of 40°C until approximately 5 L remained in the reactor. Methanol (2.68 L) was added and the resulting solution concentrated under vacuum to about 3 L of a yellow oil. Methanol (2.68 L) was charged to the reactor and the resulting solution was stirred at 25°C for 15 min. Water (0.54 L) was added over 15 min resulting in a white slurry. The mixture was cooled to 15°C, stirred for 1 h and then filtered. The filter cake was washed with a solution of water (0.54 L) in methanol (2.14 L), then air dried for 30 min, transferred to a vacuum oven and dried at 40°C for 12 h. The desired product, (6) (746 g, 2.13 mol), was isolated in 61 % yield. 1 H NMR (400 MHz, CDCI3) δ ppm 1.23-1 .37 (m, 2H), 1 .45 (s, 9H), 1 .78-1 .88 (m, 2H), 2.04-2.17 (m, 1 H), 2.67-2.83 (m, 2H), 4.02- 4.26 (m, 2H), 4.28 (d, 6.6, 2H), 6.89 (dd, J=8.6, 7.5, 1 H), 7.21 (d, J=9, 1 H), (td, 8.6, 4.9); LRMS 351.171 (m+1 ).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/101774, 2011, A1 Location in patent: Page/Page column 25; 28

10
[ 166815-96-9 ]
[ 1331782-27-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl acetamide / 24 h / 50 °C / Industrial scale 2.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl acetamide / 0.5 h / 25 °C / Industrial scale 2.2: 6 h / 24 - 50 °C / Industrial scale 3.1: ethyl acetate / 9.25 h / 20 - 65 °C / Industrial scale 4.1: sodium carbonate / water; ethyl acetate / 0.5 h / 20 °C / Industrial scale 4.2: 16 h / 25 - 50 °C / Industrial scale
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl acetamide / 24 h / 50 °C / Industrial scale 2.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl acetamide / 0.5 h / 25 °C / Industrial scale 2.2: 6 h / 24 - 50 °C / Industrial scale 3.1: hydrogenchloride / diethyl ether / 16 h / 0 - 20 °C / Inert atmosphere 4.1: triethylamine / methanol / 18 h / Inert atmosphere; Reflux

Reference： [1]Widlicka, Daniel W.; Murray, John C.; Coffman, Karen J.; Xiao, Chunguang; Brodney, Michael A.; Rainville, Joseph P.; Samas, Brian [Organic Process Research and Development, 2016, vol. 20, # 2, p. 233 - 241]
[2]Widlicka, Daniel W.; Murray, John C.; Coffman, Karen J.; Xiao, Chunguang; Brodney, Michael A.; Rainville, Joseph P.; Samas, Brian [Organic Process Research and Development, 2016, vol. 20, # 2, p. 233 - 241]

11
[ 850363-67-6 ]
[ 166815-96-9 ]
tert-butyl 4-[(5-bromo-4-methoxy-2H-indazol-2-yl)methyl]piperidin-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.57 g	With caesium carbonate In N,N-dimethyl-formamide at 20 - 60℃;	261a Tert-butyl 4-[(5-bromo-4-methoxy-2H-indazol-2-yl)methyl]piperidin-1-carboxylate General procedure: 5 g of 5-bromo-4-methyl-1H-indazole was dissolved in 110 ml DMF and treated with 11.5 g of caesium carbonate and 7.9 g of N-Boc-4-(bromomethyl)piperidine. The mixture was stirred for 3 hrs at 60° C. and overnight at RT. The reaction mixture was next diluted with ethyl acetate, and the organic phase was washed twice with water, dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4 via a 65 i-Si colunm. Gradient: hexaneethyl acetate 0-100%.Yield: 3.53 g of the title compound. Analogously to Example 1c, 5.57 g of the title compound was obtained from 9.65 g of 5-bromo-4-methoxy-1H-indazole and 23.55 g of tert-butyl-4-[(tosyloxy)methyl]piperidin-1-carboxylate. 1H-NMR (400 MHz, chloroform-d): δ [ppm], 1.16-1.31 (2H), 1.39-1.49 (9H), 1.52-1.64 (2H), 2.16-2.36 (1H), 2.56-2.80 (2H), 4.11 (5H), 4.26 (2H), 7.28-7.33 (1H), 7.34-7.39 (1H), 7.99 (1H).

Reference： [1]Current Patent Assignee: BAYER AG - US2016/89364, 2016, A1 Location in patent: Page/Page column 24; 135

12
[ 850363-67-6 ]
[ 166815-96-9 ]
tert-butyl 4-({4-methoxy-5-[N-(2-methoxyethyl)carbamoyl]-2H-indazol-2-yl}methyl)piperidin-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 20 - 60 °C 2: tri tert-butylphosphoniumtetrafluoroborate; sodium carbonate; palladium diacetate / 1,4-dioxane; water / 0.42 h / 140 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: BAYER AG - US2016/89364, 2016, A1

13
[ 166815-96-9 ]
[ 581060-27-7 ]

Reference： [1]Patent: US2016/243100,2016,A1
[2]Patent: WO2004/56773,2004,A1

14
[ 166815-96-9 ]
[ 52601-89-5 ]
tert-butyl 4-[(4-aminopyrimidin-5-yl)oxy]methyl}piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36 g	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 12h;Inert atmosphere;	To a mixture of tert-butyl 4-([(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1 -carboxylate (I-85) (66.5 g, 180.01 mmol) and <strong>[52601-89-5]4-amino-5-hydroxypyrimidine</strong> (1-91) (20 g, 180.01 mol) in anhydrous DMF (1000 mL) was added Cs2C03 (1 17 g, 360 mmol) at room temperature under a N2 atmosphere. The resulting mixture was heated at 60 C for 12 hr. TLC (CH2CI2/MeOH = 10:1) showed the reaction was complete. The mixture was cooled to 0 C, and H20 (350 mL) and CH2CI2 (300 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2CI2 (3 x 250 mL). The organic layers were combined, washed with H20 (4 x 150 mL), brine (2 x 100 mL), dried over Na2S04 and concentrated in vacuo to give the crude product, which was stirred in a mixed solvent of petroleum ether/EtOAc (1 :1 , 150 mL) for 10 min and then filtered, dried in vacuo to give tert-butyl 4-[(4-aminopyrimidin-5-yl)oxy]methyl}piperidine-1 -carboxylate (I-92) (36 g, 65%) as a white solid.

Reference： [1]Patent: WO2016/97918,2016,A1 .Location in patent: Page/Page column 80-81

15
[ 773837-37-9 ]
[ 166815-96-9 ]
[ 256411-39-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 100℃; for 16h;	Example 1B tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate A mixture of EXAMPLE 1A (19 g, 55.7 mmol), sodium cyanide (8.19 g, 167 mmol) in dimethylsulfoxide (100 mL) was reacted at 100 C. for 16 h. After being cooled to room temperature, the mixture was diluted with water (200 ml). The aqueous layer was extracted with EtOAc (100 mL*3). The combined organic layers were washed with water (50 mL), and brine (50 mL), then dried over Na2SO4, filtered and evaporated to provide the title compound (11 g) which could be used directly in the next step without further purification. LCMS (ESI) m/z: 225 (M+1)

Reference： [1]Patent: US2017/29430,2017,A1 .Location in patent: Paragraph 0257

16
[ 166815-96-9 ]
[ 443913-73-3 ]

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1467 - 1469

17
[ 1215387-58-8 ]
[ 166815-96-9 ]
tert-butyl 4-((5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Sodium hydride (60% suspension in mineral oil, 1.53 g, 38 mmol, 1.5 eq) was added to a stirred solution of <strong>[1215387-58-8]5-bromo-1H-pyrrolo[2,3-c]pyridine</strong> (5.0 g, 25.0 mmol, 1.0 eq) in DMF (50 mL) at 0 C. and stirring was continued at room temperature for 30 min. The mixture was again cooled to 0 C. and a solution of tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (10.4 g, 28 mmol, 1.1 eq) in DMF (50 mL) was slowly added at 0 C. and stirring was continued at 65-70 C. for 16 hr. After completion of the reaction (monitored by thin layer chromatography, 30% ethyl acetate in hexanes, Rf=0.5), the reaction was quenched by adding ice cubes and the mixture was extracted with tert-butyl methyl ether (2*200 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel 100-200 mesh, eluting with a 25-40% gradient of ethyl acetate in hexanes to afford tert-butyl 4-((5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)piperidine-1-carboxylate (9.0 g, 90%) as an off white solid. LCMS purity: 80%; (ES+): m/z 394.26 (M+H+).

Reference： [1]Patent: US2017/298060,2017,A1 .Location in patent: Paragraph 0090; 0091

18
[ 1216963-74-4 ]
[ 166815-96-9 ]
[ 301185-41-1 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide

Reference： [1]Lowe, Phillip T.; Dall'Angelo, Sergio; Mulder-Krieger, Thea; IJzerman, Adriaan P.; Zanda, Matteo; O'Hagan, David [ChemBioChem, 2017, vol. 18, # 21, p. 2156 - 2164]

19
[ 93755-77-2 ]
[ 76-05-1 ]
[ 166815-96-9 ]
(E)-2-(3-(3-methoxy-4-(piperidin-4-ylmethoxy)phenyl)acrylamido)benzoic acid trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.6%	Stage #1: (E)-2-[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid; N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine With potassium hydroxide In acetone at 80℃; for 16h; Stage #2: trifluoroacetic acid In water; acetonitrile	50 (E)-2-(3-(3-methoxy-4-(piperidin-4-ylmethoxy)phenyl)acrylamido)benzoic acid (50) A mixture of 2-[[(E)-3-(4-hydroxy-3-methoxy-phenyl)prop-2-enoyl]amino]benzoic acid (150 mg, 0.479 mmol, 1.0 equiv. Bioorg. Med. Chem. Lett. 2009, 19, 7003-7006), tert- butyl 4-(p-tolylsulfonyloxymethyl)piperidine-l-carboxylate (265 mg, 0.718 mmol, 1.5 equiv.) and potassium hydroxide (0.5 M, 3.8 mL, 4.0 equiv.) in acetone (3 mL) was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure and the residue stirred in 4M hydrogen chloride in dioxane (10 mL). The solvent was removed in vacuo and the residue purified by preparative HPLC to give the desired product as a yellow solid as the trifluoroacetic acid salt (60.5 mg, 26.6%); 1H NMR (DMSO-d6, 400 MHz) δ 11.32 (s, IH), 8.65-8.60 (m, 2H), 8.32 (br. s, IH), 8.02 (dd, = 8.0 Hz, = 1.2 Hz, IH), 7.62 (t, = 8.0 Hz, IH), 7.57(d, = 15.6 Hz, IH), 7.40 (d, = 1.6 Hz, IH), 7.25 (d, = 8.0 Hz, IH), 7.18 (t, = 8.0 Hz, IH), 7.03 (d, = 8.4 Hz, IH), 6.81 (d, = 15.6 Hz, IH), 3.92 (d, = 6.4 Hz, 2H), 3.88 (s, 3H), 3.20 - 3.35 (m, 2H), 2.85 - 3.00 (m, 2H), 2.00 - 2.20 (m, IH), 1.80 - 2.00 (m, 2H), 1.40 - 1.55 (m, 2H); MS (ESI+) m/z 411.2 (M+H)+; 90.3% purity, RT 2.16 min (Method 11).

Reference： [1]Current Patent Assignee: CERTA THERAPEUTICS; SHISEIDO COMPANY LIMITED - WO2018/144620, 2018, A1 Location in patent: Paragraph 00345

20
[ 166815-96-9 ]
[ 597563-39-8 ]

Reference： [1]Patent: WO2009/47161,2009,A1

21
[ 166815-96-9 ]
[ 25979-85-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate / 3 h / 25 °C 2: potassium carbonate; sodium iodide / acetonitrile / 16 h / 25 - 80 °C

Reference： [1]Current Patent Assignee: NANCHANG UNIVERSITY - CN111732558, 2020, A

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[ CAS No. 166815-96-9 ] {[proInfo.proName]}

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[ 166815-96-9 ] Synthesis Path-Upstream 1~9

[ 166815-96-9 ] Synthesis Path-Downstream 1~21

Pharmaceutical Intermediates of [ 166815-96-9 ]

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Amides

Sulfonates

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Aliphatic Heterocycles

Piperidines

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