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Chemical Structure| 180975-66-0 Chemical Structure| 180975-66-0

Structure of 180975-66-0

Chemical Structure| 180975-66-0

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Product Details of [ 180975-66-0 ]

CAS No. :180975-66-0
Formula : C11H22N2O2
M.W : 214.30
SMILES Code : C[C@H]1CNC[C@@H](C)N1C(=O)OC(C)(C)C
English Name :tert-Butyl cis-2,6-dimethylpiperazine-1-carboxylate
MDL No. :MFCD09265026
InChI Key :RBOGBIZGALIITO-DTORHVGOSA-N
Pubchem ID :21021901

Safety of [ 180975-66-0 ]

Computational Chemistry of [ 180975-66-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 0
Fraction Csp3 0.91
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 68.12
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

41.57 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.67
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.32
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.84
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.15
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.69
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.34

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.8
Solubility 3.38 mg/ml ; 0.0158 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.79
Solubility 3.44 mg/ml ; 0.0161 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.6
Solubility 5.42 mg/ml ; 0.0253 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.67 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.01

Application In Synthesis of [ 180975-66-0 ]

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

  • Downstream synthetic route of [ 180975-66-0 ]

[ 180975-66-0 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 1122-91-4 ]
  • [ 180975-66-0 ]
  • [ 923565-85-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-bromo-benzaldehyde; (2R,6S)-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 72h; Stage #2: With sodium hydrogencarbonate In water; 1,2-dichloro-ethane for 0.5h; Stage #3: In dichloromethane for 2h; Description 43: 1,1 -Dimethylethyl (2/?,6S)-4-[(4-bromophenyl)methyl]-2,6-dimethyl-1- piperazinecarboxylate (D43). A mixture of 4-bromobenzaldehyde (1.85g, lOmmol), 1,1 -dimethylethyl (2f?,6S)-2,6- dimethyl-1 -piperazinecarboxylate (2.15g, 10mmol) and sodium triacetoxyborohydride (3.18g) in 1,2-DCE (35ml) was stirred at room temperature for 3 days. Saturated aq. NaHCO3 solution was added and the mixture stirred for 30mins. The product was extracted into EtOAc and the extracts dried (Na2SO4) and concentrated. The residue was dissolved in DCM and treated with PS-hydrazine resin with stirring for 2h. The resin was removed by filtration and the solvent removed in vacuo. Chromatography (0-40%EtOAc/hexane) gave the title compound (3.52g). MS (ES): MH+ 383/385.
With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;
  • 2
  • [ 923565-67-7 ]
  • [ 180975-66-0 ]
  • [ 923565-92-8 ]
YieldReaction ConditionsOperation in experiment
61% With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 3h;
Stage #1: 4-(2-(4-((4-fluorophenyl)amino)-1-piperidinyl)-2-oxoethyl)-benzaldehyde; (2R,6S)-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester In 1,2-dichloro-ethane at 20℃; for 0.0833333h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane for 3h; Stage #3: With sodium hydrogencarbonate In water; 1,2-dichloro-ethane for 0.25h; 1 Example 1: 1-[(4-[(3R,5S)-3,5-Dimethyl-1-piperazinyl]methyl}phenyl)acetyl]-W-(4- fluorophenyl)-4-piperidinamine (E1). A mixture of D4 (149mg, 0.438mmol) and 1 ,1-dimethylethyl (2R,6S)-2,6-dimethyl-1- piperazinecarboxylate (94mg, 0.438mmol) in 1 ,2-DCE (3ml) was stirred for 5mins at room temperature. Sodium tri(acetoxy)borohydride (139mg, 0.66mmol) was added and the mixture was stirred for 3h then saturated aq. NaHCO3 solution was added. The mixture was stirred for 15mins then extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product which was purified by chromatography. Elution with 20-90% EtOAc/pentane gave 1,1-dimethylethyl (2R,6S)-4-[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-2- oxoethyl) phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate (143mg). δH (CDCI3, 400MHz) 1.06 (1 H, m), 1.27 (6H, d), 1.30 (1H, m), 1.46 (9H1 s), 1.93 (1H, m), 2.05 (1 H, m), 2.12 (2H, dd), 2.59 (2H1 d), 2.88 (1 H1 m), 3.13 (1 H, m), 3.29 (1 H1 m), 3.38 (1 H, m), 3.45 (2H, s), 3.74 (2H1 s), 3.86 (1 H, m), 4.07 (2H1 m), 4.50 (1H1 m), 6.50 (2H, m), 6.87 (2H1 1), 7.20 (2H, m), 7.31 (2H, d). MS (ES): MH+ 539 This whole was dissolved in 2:1 DCM/TFA and stirred for 1h. The mixture was concentrated and the free base title compound was isolated using an lsolute SCX cartridge. δH (CDCI3, 400MHz) 1.01 (6H1 d), 1.06 (1H, m), 1.29 (1 H, m), 1.62 (2H, t), 1.93 (1 H, m), 2.04 (1 H, m), 2.74 (2H, d), 2.83-2.94 (3H1 m), 3.12 (1H, m), 3.36 (2H, m), 3.46 (2H, s), 3.73 (2H, s), 3.86 (1H, m), 4.51 (1 H, m), 6.55 (2H, m), 6.86 (2H, t), 7.20 (2H1 m), 7.26 (2H, d). MS (ES): MH+ 439This whole was converted to the dihydrochloride salt of the title compound (104mg).
  • 3
  • [ 923565-82-6 ]
  • [ 180975-66-0 ]
  • [ 923565-94-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-(3-(4-((4-fluorophenyl)amino)-1-piperidinyl)-3-oxopropyl)-benzaldehyde; (2R,6S)-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Stage #2: With sodium hydrogencarbonate In water; 1,2-dichloro-ethane for 0.25h; 23 Example 23: 1-[3-(4-[(3R,5S)-3,5-Dimethyl-1-piperazinyl]methyl}phenyl)propanoyl]-Λ/-(4- fluorophenyl)-4-piperidinamine (E23). To a mixture of D41 (100mg, 0.282mmol) and 1 ,1-dimethylethyl (2/?,6S)-2,6- dimethyl-1-piperazinecarboxylate (61 mg, 0.283mmol) in 1 ,2-DCE (5ml) was added sodium tri(acetoxy)borohydride (90mg, 0.423mmol) and the mixture stirred at room temperature overnight. Saturated aq. NaHCO3 solution was added, the mixture was stirred for 15mins and then extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product which was purified by chromatography eluting with 0-100% EtOAc/pentane to give 1 ,1-dimethylethyl (2f?,6S)-4-[4-(3-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-3-oxopropyl)phenyl]methyl}- 2,6-dimethyl-1-piperazinecarboxylate. MS (ES): MH+ 553This whole was dissolved in 2:1 DCM/TFA (3ml) and stirred for 1.5h. The mixture was concentrated and the title compound (100mg) was isolated using an lsolute SCX cartridge. δH (CDCI3, 400MHz) 7.23 (2H, d), 7.17 (2H, d), 6.88 (2H, t), 6.53 (2H, m), 4.52 (1 H, m), 3.79 (1H1 m), 3.42 (4H1 m), 3.09 (1 H, m), 2.94 (4H, m), 2.83 (1 H1 m), 2.75 (2H, m), 2.63 (2H, m), 2.03 (2H1 m), 1.59 (2H, t), 1.29 (1 H, m), 1.17 (1 H, m), 1.02 (6H, d). MS (ES): MH+ 453.This whole was dissolved in DCM and treated with 1 M HCI in Et2O (243ul) to give hydrochloride salt of the title compound (98mg). MS (ES): MH+ 453.
With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;
  • 4
  • [ 1211442-78-2 ]
  • [ 180975-66-0 ]
  • [ 1211443-36-5 ]
YieldReaction ConditionsOperation in experiment
74% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 16h; 75 7-Cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (1 mol. eq.), amine (1.1 mol eq.) are dissolved in dichloromethane (~ 30 vols.) and stirred until the solution is clear (in cases where the amine is sourced as a hydrochloride salt, 1 mol. eq. Et3N is added). Where necessary, MeOH and/or 1 drop acetic acid is added to aid dissolution and imine formation. Na(OAc)3BH (1.5 - 2 mol. eq.) is then added to the mixture and stirring continued at rt for further 16h. The reaction is quenched with aqueous NaHCO3 solution and the product extracted with dichloromethane, ethyl acetate or CHCl3/i-PrOH (2: 1). The combined organic fractions are dried (Na2SO4 or MgSθ4) filtered and the solvent evaporated. The crude product is purified by SiO2 chromatography
  • 5
  • [ 1421503-00-5 ]
  • [ 180975-66-0 ]
  • [ 1421503-32-3 ]
YieldReaction ConditionsOperation in experiment
40% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 18h; 62 To a stirring solution of (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1 H- indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (150mg, 0.154mmol) in DMSO (1.5mL) were added DIPEA (0.143mL, 0.87mmol) and (2R,6S)-2,6-Dimethyl-piperazine- 1 -carboxylic acid tert-butyl ester (124mg, 0.58mmol) and the mixture stirred at room temperature for 18 hours. The crude reaction mass was purified by prep-HPLC Method F to afford (3R,5S)-5'-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro- imidazo[4,5-c]pyridine-5-carbonyl}-3,5-dimethyl-2,3,5,6-tetrahydro-[1 ,2']bipyrazinyl-4-carboxylic acid tert-butyl ester as an off white solid (80 mg, 40 %).
  • 6
  • [ 2022976-11-8 ]
  • [ 180975-66-0 ]
  • [ 2022976-30-1 ]
YieldReaction ConditionsOperation in experiment
91% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 90℃; for 0.5h; 27 (2S,6R)-tert-Butyl 4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4- yl)-2,6-dimethylpiperazine-1-carboxylate To a solution of 4,6-dichloro-8-fluoro-7-(2-fluoro-6- methoxyphenyl)quinazoline (250 mg, 0.733 mmol) in dioxane (30 mL) at RT, DIEA (303 mg, 2.35 mmol) and (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (251 mg, 1.17 mmol) were added. The resulting mixture was stirred at 90 °C for 30 min. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/ petroleum ether = 1:3) to afford the desired product (346 mg, 91% yield). ESI-MS m/z : 519.3 [M + H]+
  • 7
  • [ 1698027-26-7 ]
  • [ 180975-66-0 ]
  • [ 2022976-20-9 ]
YieldReaction ConditionsOperation in experiment
94.7% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 90℃; for 2h; Inert atmosphere; 25 Ethyl 7-bromo-4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-6- chloro-8-fluoroquinoline-3-carboxylate A mixture of ethyl 7-bromo-4,6-dichloro-8-fluoroquinoline-3- carboxylate (552 mg, 1.50 mmol), (2R,6S)-tert-butyl 2,6-dimethylpiperazine-1- carboxylate (644 mg, 3.0 mmol), DIPEA (774 mg, 6.0 mmol) in dioxane (40 mL) was stirred at 90oC under argon for 2 h. The mixture was cooled to RT and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to afford the desired product as a yellow solid (794 mg, 94.7% yield). ESI-MS m/z: 546.3 [M + H]+.
  • 8
  • [ 180975-66-0 ]
  • [ 489471-57-0 ]
  • [ 2070905-14-3 ]
YieldReaction ConditionsOperation in experiment
73.6% In acetonitrile at 20℃; for 16h; 41.1 Example 41. Step 1. tert-butyl (2S,6R)-4-((1H-imidazol-1-yl)sulfonyl)-2,6-dimethylpiperazine-1-carboxylate A solution of 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (4.000 g, 11.041 mmol) and tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (2.603 g, 12.145 mmol) in acetonitrile (100 mL) was stirred at the room temperature for 16 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (SiO2, 80 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give tert-butyl (2S,6R)-4-((1H-imidazol-1-yl)sulfonyl)-2,6-dimethylpiperazine-1-carboxylate as yellow solid (2.800 g, 73.6 %).
  • 9
  • [ 2080367-38-8 ]
  • [ 180975-66-0 ]
YieldReaction ConditionsOperation in experiment
97.8% With 10% Pd/C; hydrogen In ethanol at 20℃; for 17h; 372.3 [Step 3] Tert-butyl (2R.6S)-2,6-dimethylpiperazine- l-carboxylate [5019] A stirred solution of 4-benzyl 1 -(tert-butyl) ( 2R,6S)-2,6-dimethylpiperazine- l ,4-dicarboxylate (6.350 g. 18.224 nimol) in ethanol ( 150 mL) was slowly added dropwise at the room temperature with 10%-Pd/C ( 1 g). The reaction mixture was stirred at the same temperature under the hygdrogen atmosphere (H2 balloon) for additional 17 hr, filtered through a celite pad to remove solids, and concentrated under the reduced pressure. Tert-butyl (2R,6S)-2,6-dimethylpiperazine- l -carboxylate was used without further purification (3.820 g, 97.8 %, yellow oil).
226 mg With Pd/C; hydrogen In isopropyl alcohol at 25℃;
  • 10
  • [ 2080362-70-3 ]
  • [ 180975-66-0 ]
  • [ 2080367-39-9 ]
YieldReaction ConditionsOperation in experiment
99.6% With potassium carbonate In acetonitrile at 20℃; for 17h; 372.4 [Step 4] Tert-butyl (2S,6R)-4-(4-(1,1-dioxidothiomorpholine-4-carboxamido)benzyl)-2,6-dimethylpiperazine-1-carboxylate [5022] N-(4-(chloromethyl)phenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide ( 1.000 g, 3.303 mmol), tert-butyl (2S.6R)-2,6-dimethylpiperazine- l-carboxylate ( 1.062 g, 4.954 mmol) and potassium carbonate ( 1.369 g, 9.909 mmol) were mixed at the room temperature in acetonitrile (20 mL) and then stirred at the same temperature for 17 hr, concentrated under the reduced pressure. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (SiO;, 24 g cartridge; ethyl acetate / hexane - 10 % to 60 %) to give tert- butyl (2S,6R)-4-(4-( l , l -dioxidothiomorpholine-4-carboxamido)benzyl)-2,6-dimethylpiperaz ine- l-carboxylate as white solid ( 1.950 g, 99.6 %).
  • 11
  • [ CAS Unavailable ]
  • [ 180975-66-0 ]
  • [ 2098512-00-4 ]
YieldReaction ConditionsOperation in experiment
95% With triethylamine In tetrahydrofuran at 20℃; for 0.5h; 1 (2R,6S)-tert-Butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6- dimethylpiperazine- 1-carboxylate To a stirred solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1.7g, 5.19 mmol) in THF (25 mL) and Et3N (1.6 g, 15.57 mmoL) at RT, (2R,6S)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (1.12 g, 5.19 mmol) was added and the resulting mixture was stirred at RT for 30 mm. The mixture was partitioned between water and dichloromethane. The organic layer was washed with NaHCO3 aqueous solution and iN HC1 aqueous solution, dried over Na2SO4 and, filtered and concentrated in vacuo. The residue was purified by recrystallization with 10% (ethyl acetate/Petroleum ether) to afford the product (2.5 g, 95% yield)
  • 12
  • [ 1370411-44-1 ]
  • [ 180975-66-0 ]
  • [ 2158301-56-3 ]
YieldReaction ConditionsOperation in experiment
58% With N-ethyl-N,N-diisopropylamine at 20℃; 191.A Step A: Benzyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate: A suspension of benzyl 2,4-dichloro- 5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (500 mg, 1.48 mmol), tert-butyl cis-2,6- dimethylpiperazine-l-carboxylate (349 mg, 1.63 mmol) and DIEA (0.26 mL) π Ν,Ν- dimethylacetamide (1 mL) was stirred at r.t. overnight. The reaction mixture was divided between EtOAc (15 mL) and 1M NaHCCb (5 mL) and the layers separated. The organic layer was washed with 2M Na2CCb and brine (2 mL each), dried over Na2S04 and evaporated in vacuo. The residue was chromatographed on silica gel Redisep 24g column using 20 to 50% EtOAc in hexane as eluent to give a colorless solid (0.440 g, 58%). ES+APCI MS m/z 516.2 [M+H]+.
58% With N-ethyl-N,N-diisopropylamine at 20℃; 191.A Example 191 1-((2S,6R)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8- -tetrahydropyrido [3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one Step A: Benzyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5- ,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate A suspension of benzyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (500 mg, 1.48 mmol), tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate (349 mg, 1.63 mmol) and DIEA (0.26 mL) in N,N-dimethylacetamide (1 mL) was stirred at r.t. overnight. The reaction mixture was divided between EtOAc (15 mL) and 1M NaHCO 3 (5 mL) and the layers separated. The organic layer was washed with 2M Na 2CO 3 and brine (2 mL each), dried over Na 2SO 4 and evaporated in vacuo. The residue was chromatographed on silica gel Redisep 24 g column using 20 to 50% EtOAc in hexane as eluent to give a colorless solid (0.440 g, 58%). ES+APCI MS m/z 516.2 [M+H] +.
  • 13
  • [ 1698028-11-3 ]
  • [ 180975-66-0 ]
  • [ 2098512-00-4 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h; 3 (2S,6R)-tert-Butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (2S,6R)-tert-Butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (0336) 7-Bromo-2,4,6-trichloro-8-fluoroquinazoline (500 mg, 1.52 mmol) was added to the mixture of DIEA (588 mg, 4.56 mmol) in THF (15 mL). The mixture was stirred for 5 min and then (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (385 mg, 1.82 mmol) was added. The resulting mixture was stirred at RT for 1 h, poured into water and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-10% ethyl acetate/petroleum ether) to afford the desired product (800 mg, 100% yield) as a solid.
  • 14
  • [ CAS Unavailable ]
  • [ 180975-66-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: (M)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione With N-ethyl-N,N-diisopropylamine; trichlorophosphate In acetonitrile at 80℃; for 1h; Stage #2: (2R,6S)-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester In acetonitrile at 0 - 20℃; for 1h; 16.1 Step 1:
tert-Butyl (M)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-cis-2,6-dimethylpiperazine-1-carboxylate
Phosphorous oxychloride (0.34 mL, 3.63 mmol) was added dropwise to a solution of (M)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (Intermediate G, 1.03 g, 2.96 mmol) and Hunig's base (0.69 mL, 3.93 mmol) in acetonitrile (3.02 mL). The mixture was heated to 80° C. for 1 h, then was cooled to 0° C. DIPEA (1.58 mL, 9.07 mmol) and t-butyl cis-2,6-dimethylpiperazine-1-carboxylate (0.64 g, 3.62 mmol, Enamine, San Diego, Calif.) were added. This mixture was warmed to rt, stirred for 1 h, then poured into a cold solution of saturated NaHCO3 and stirred vigorously for 10 min. The mixture was partitioned between EtOAc and brine, the layers were separated, the aqueous layer was back-extracted with EtOAc and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: 0-40% EtOAc-EtOH (3:1)/heptanes) to provide tert-butyl (M)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-cis-2,6-dimethylpiperazine-1-carboxylate (1.38 g, 84% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, J=4.8 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 4.32-4.16 (m, 4H), 3.66-3.55 (m, 2H), 2.65-2.56 (m, 1H), 1.94 (s, 3H), 1.44 (s, 9H), 1.29 (dd, J=3.1, 6.6 Hz, 6H), 1.14-0.95 (m, 6H). 19F NMR (376 MHz, DMSO-d6) δ ppm -128.10 (s, 1F); m/z (ESI, +ve ion): 545.2 (M+H)+.
 

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