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Product Details of [ 123855-51-6 ]

CAS No. :123855-51-6 MDL No. :MFCD02094488
Formula : C11H21NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :CTEDVGRUGMPBHE-UHFFFAOYSA-N
M.W : 215.29 Pubchem ID :2764081
Synonyms :
Chemical Name :tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate

Calculated chemistry of [ 123855-51-6 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 62.56
TPSA : 49.77 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.78 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.66
Log Po/w (XLOGP3) : 1.17
Log Po/w (WLOGP) : 1.24
Log Po/w (MLOGP) : 1.15
Log Po/w (SILICOS-IT) : 0.93
Consensus Log Po/w : 1.43

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.65
Solubility : 4.84 mg/ml ; 0.0225 mol/l
Class : Very soluble
Log S (Ali) : -1.81
Solubility : 3.33 mg/ml ; 0.0155 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.11
Solubility : 16.7 mg/ml ; 0.0774 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.12

Safety of [ 123855-51-6 ]

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

Application In Synthesis of [ 123855-51-6 ]

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

  • Upstream synthesis route of [ 123855-51-6 ]

[ 123855-51-6 ] Synthesis Path-Upstream   1~20

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Reference: [1] Patent: WO2018/13867, 2018, A1, . Location in patent: Paragraph 525
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YieldReaction ConditionsOperation in experiment
88%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; Inert atmosphere
Stage #2: With water; sodium hydroxide In tetrahydrofuran at 0 - 20℃;
A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.94 g, 9.0 mmol) in THF (15.0 mL) was added drop-wise to a 1M solution of LiAlH4 in THF (13.5 mL, 13.5 mmol) under argon.
The reaction mixture was stirred at room temperature for 17 hours and then cooled to 0° C. A mixture of THF and water (1:1 ratio, 1.5 mL) was added drop-wise.
A gelatinous white solid formed. 4M aq NaOH solution (0.6 mL) was added drop-wise.
Water (2 mL) was added and the resulting mixture stirred at room temperature for 2 hours.
The white solid was removed by filtration.
The filtrate was loaded onto an Isolute HM-N liquid-liquid extraction column and then eluted with EtOAc (200 mL).
The resulting organic phase concentrated in vacuo yielding (1-methylpiperidin-4-yl)methanol as a yellow oil (1.02 g, 88percent).
Analytical LCMS: purity ~90percent (System B, RT=1.88 min), ES+: 129.8 [MH]+.
(
88%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 17 h; Inert atmosphere
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃;
A solution of tert-bvXy\\ 4-(hydroxymethyl)piperidine-l-carboxylate (1.94 g, 9.0 mmol) in THF (15 mL) was added drop-wise to IM solution Of LiAlH4 in THF (13.5 mL, 13.5 mmol) under argon. The reaction mixture was stirred at room temperature for 17 hours, cooled to 0 0C and quenched by the dropwise addition of a mixture of THF and water (1 :1 ratio, 1.5 mL). 4M aq NaOH solution (0.6 mL), and water (2.0 mL) were added and the mixture stirred at room temperature for 2 hours. A white solid was removed by filtration. The filtrate was purified by using an Isolute HM-N cartridge, eluting with EtOAc (200 mL). The eluent was concentrated in vacuo yielding (l-methylpiperidin-4-yl)methanol (1.02 g, 88percent) as a yellow oil. Analytical LCMS: (System A, Rτ = 0.32 min), ES+: 130.3 [MH]+.
Reference: [1] Patent: US2009/281087, 2009, A1, . Location in patent: Page/Page column 9-10
[2] Patent: WO2009/147219, 2009, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2009/71677, 2009, A1, . Location in patent: Page/Page column 22
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2305 - 2308
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  • [ 91419-52-2 ]
Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 7, p. 1157 - 1163
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  • [ 581060-27-7 ]
Reference: [1] Patent: US2016/243100, 2016, A1,
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  • [ 145508-94-7 ]
YieldReaction ConditionsOperation in experiment
92% With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 14 h; To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate 22 (2.25 g, 10.5 mmol, 1.0 eq.), imidazole (858 mg, 12.6 mmol, 1.2 eq.) and triphenylphosphine (3.30 g, 12.6 mmol, 1.2 eq.) in dry THF (30 mL) was added drop-wise a solution of iodine (3.20 g, 12.6 mmol, 1.2 eq.) in dry THF (30 mL) at 0°C. The reaction mixture was stirred at room temperature for 14h. The mixture was quenched with a saturated Na2S2O3 solution. The aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The crude was several times diluted with cold diethyl ether, and white crystals was filtered. After concentration of filtrate in vacuo, the compound 23 was obtained as a colorless oil (92percent yield); 1H NMR (CDCl3, 400 MHz) δ 4.11 (m, 2H), 3.10 (d, 3J = 5.8 Hz, 2H), 2.68 (m, 2H), 1.83 (m, 2H), 1.64-1.61 (m, 1H), 1.46 (s, 9H), 1.19-1.09 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 154.6 (CO), 79.5 (Cq), 43.4 (2*CH2), 38.6 (CH), 32.5 (2*CH2), 28.4 (3*CH3), 13.5 (CH2); IR (neat, cm-1) ν 2975, 2932, 2850, 1692, 1422, 1243, 1157, 965. Spectral and analytical data matched with literature.[5]
84% With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 3.16667 h; To a solution 1 ,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (10 g, 46.4 mmol), triphenylphosphine (15 g, 55.7 mmol) and imidazole (4 g, 55.7 mmol) in tetrahydrofuran (25 ml_) at 0 0C was added via an addition funnel iodine (14 g, 55.7 mmol) in tetrahydrofuran (25 ml_) over 10 min. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was diluted with 20percent ethyl acetate:hexane and filtered through a pad of silica with copious 20percent ethyl acetate:hexane washings. Silica was added and the volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 25percent ethyl acetate:hexane) to afford 13 g (84percent) of the title compound. 1H NMR (400 MHz, CDCI3): 54.19- EPO <DP n="233"/>3.96 (m, 2H), 3.05 (d, 2H, J= 6.4 Hz), 2.71-2.56 (m, 2H), 1.78 (d, 2H, J= 13.4 Hz), 1.64-1.50 (m, 1 H), 1.40 (s, 9H), 1.16-1.01 (m, 2H).
30%
Stage #1: With 1H-imidazole; triphenylphosphine In dichloromethane at 0 - 20℃; for 1.08333 h;
Stage #2: at 0 - 20℃; for 1.08333 h;
A 250 mL round bottom flask was charged with 5.8 g (27 mmol) of 22, 8.5 g (32.37 mmol) of triphenylphosphine, and 2.2 g (32.37 mmol) of imidazole. One hundred milliliters of methylene chloride were added, and the resulting solution was stirred at 0° C. for about 5 minutes. Finally, 8.2 g (32.37 mmol) of iodine were added and the solution was stirred at 0° C. for 5 minutes and at room temp for about 1 hour. The reaction mixture was diluted with 200 mL of hexane, and the triphenylphosphine oxide precipitate was filtered off (this was repeated until all precipitate was removed). The crude mixture was purified by flash chromatography using a 5percent-10percent ethyl acetate/hexane solvent system. A Phosphomolybdic acid stain (PMA), was used to see the product on the TLC plate. The resulting yield of pure 23 as an oil was 2.6 g (30percent). 1H NMR in CDCl3: 2H quartet at 1.1 ppm (J=12 Hz), a 9H singlet at 1.4 ppm, a 1H broad signal at 1.55 ppm, a 2H doublet at 1.75 (J=12 Hz), a 2H broad signal at 2.65 ppm, a 2H doublet at 3.05 ppm (J=6 Hz), and a 2H broad signal at 4.1 ppm. The Rf=0.13 using a 5percent ethyl acetate/hexane solvent system
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 17, p. 2721 - 2734
[2] European Journal of Medicinal Chemistry, 2019, p. 234 - 248
[3] Organic and Biomolecular Chemistry, 2014, vol. 12, # 5, p. 783 - 794
[4] Patent: WO2007/30366, 2007, A1, . Location in patent: Page/Page column 231-232
[5] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 9, p. 2233 - 2239
[6] Patent: US2003/229092, 2003, A1, . Location in patent: Page 11; 13
[7] Patent: WO2004/35556, 2004, A1, . Location in patent: Page 89
[8] Patent: WO2009/76140, 2009, A1, . Location in patent: Page/Page column 151
[9] Patent: US2007/21405, 2007, A1, . Location in patent: Page/Page column 11
[10] Patent: WO2015/8230, 2015, A1,
[11] Patent: WO2015/154039, 2015, A2, . Location in patent: Paragraph 633; 634
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Reference: [1] Patent: US6265434, 2001, B1,
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  • [ 118811-07-7 ]
Reference: [1] Patent: CN106883217, 2017, A, . Location in patent: Paragraph 0308; 0309; 0310; 0311
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  • [ 158407-04-6 ]
YieldReaction ConditionsOperation in experiment
94% With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 22 h; Compound 14; EPO <DP n="122"/> N-BOC piperidine-4-methanol (1 g; 46.5 mmol) and carbon tetrabromide (1.7 g; 51.3 mmol) were dissolved in dichloromethane (20 ml) and cooled to 0 0C. Triphenyl phosphine (0.98 g; 37.3 mmol) was added and the reaction stirred at room temperature for 16 hours. Further triphenyl phosphine (0.4 g; 15.7 mmol) and carbon tetrabromide (0.24 g; 7.2 mmol) were added and stirring continued for 6 hours. The solvent was evaporated and the residue chromatograplied on silica. N-BOC piperidine-4 methyl bromide was eluted with 20percent ethyl acetate in heptane (1.22 g, 94percent).
61.9% With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.0 g,9.29 mmol) in DCM (30 mL) was added CBr4 (5.1 g, 15.51 mmol) in one portion. The resultingcolorless solution was cooled to 0°C and PPh3 (4.1 g, 15.51 mmol) was added in one portion. The resulting dark orange solution was first stirred at 0°C for 1 h and then warmed to rt and stirred overnight. The mixture was washed by H20 (20 mL x 2) and the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel columnchromatography (petroleum ether: EtOAc = 20: 1) to give tert-butyl 4- (bromomethyl)piperidine-1-carboxylate (1.6 g, 61.9percent yield) as a yellow oil. LC-MS m/z: 263 [M+H- 15j.
55 mg With carbon tetrabromide; triphenylphosphine In diethyl ether at 20℃; for 18 h; 4-N-Boc-piperidine-methanol (200 mg, 0.93 mmol) was dissolved in diethyl ether (9 mL) and carbon tetrabromide (370 mg, 1.1 mmol) and PPh3(292 mg, 1.1 mmol) were added at rt. The reaction was allowed to stir for 18 h at rt and filtered over a pad of celite. The filtrate was concentrated and purified by flash chromatography (hexane/EtOAc, 1 :0→ 4:1 ) to give 55 mg of the title compound. H-NMR (400 MHz, DMSO-c/6) δ ppm 4.02-3.98 (m, 2 H), 3.47 (d, 2 H), 2.78-2.65 (m, 2 H), 1.89-1.74 (m, 3 H), 1.45 (s, 9 H), 1.12-0.98 (m, 2 H).
960 mg With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 0 - 20℃; A solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled to 0°C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added. The reaction mixture is stirred at room temperature over the weekend. The solution is taken up in ethyl ether, the insoluble matter is filtered off and the organic phase is evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 80/20 EtOAc/heptane) to give 960 mg of tert-butyl 4- bromomethylpiperidine-1-carboxylate, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 279. tr (min) = 2.13. 1H NMR (300 MHz, δ in ppm, CDCl3): 1 .09-1.29 (m, 2H), 1.47 (s, 9H), 1 .71-1.88 (m, 3H), 2.62-2.78 (m, 2H), 3.31 (d, 2H), 4.07-4.25 (m, 2H).
960 mg With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 20℃; A solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled to 0° C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added.
The reaction mixture is stirred at room temperature over the weekend.
The solution is taken up in ethyl ether, the insoluble matter is filtered off and the organic phase is evaporated to dryness.
The residue is purified by chromatography on silica gel (eluent: 80/20 EtOAc/heptane) to give 960 mg of tert-butyl 4-bromomethylpiperidine-1-carboxylate, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 279 tr (min)=2.13
1H NMR (300 MHz, δ in ppm, CDCl3): 1.09-1.29 (m, 2H), 1.47 (s, 9H), 1.71-1.88 (m, 3H), 2.62-2.78 (m, 2H), 3.31 (d, 2H), 4.07-4.25 (m, 2H).

Reference: [1] Patent: WO2016/75661, 2016, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2006/50506, 2006, A1, . Location in patent: Page/Page column 120-121
[3] RSC Advances, 2016, vol. 6, # 52, p. 46170 - 46185
[4] Patent: WO2017/27684, 2017, A1, . Location in patent: Paragraph 00266
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2615 - 2620
[6] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 82
[7] Patent: US2008/76758, 2008, A1, . Location in patent: Page/Page column 95-96
[8] Patent: US2004/77646, 2004, A1, . Location in patent: Page 130
[9] Patent: WO2013/80141, 2013, A1, . Location in patent: Page/Page column 139
[10] Patent: WO2013/190123, 2013, A1, . Location in patent: Page/Page column 129; 130
[11] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1318 - 1323
[12] Patent: US2015/183804, 2015, A1, . Location in patent: Paragraph 1080; 1081; 1082; 1083; 1084
[13] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 96 - 112
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YieldReaction ConditionsOperation 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 (3*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).
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, Rf (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 SiO2 chromatography, 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 Rf=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, Rf=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.

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YieldReaction ConditionsOperation in experiment
76.6% at 20 - 80℃; for 24 h; NaCN (4.00 g, 80.0 mmol) and H2O (20 ml) at room temperature were added to a stirred solution of tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (15.3 g) in EtOH (80 ml). The reaction mixture was stirred at 80 °C for 24 h. After completing the reaction, the solvents were concentrated in vacuo. The residue was dissolved in AcOEt (300 ml) and H2O (100 ml). The aqueous layer was extracted with AcOEt (300 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane-AcOEt) to give 7 (6.87 g, 76.6percent from 7) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.21-1.31 (2H, m), 1.46 (9H, s), 1.78-1.86 (3H, m), 2.31 (2H, d, J = 6.4 Hz), 2.64-2.78 (2H, m), 4.07-4.21 (2H, m).
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