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Chemical Structure| 6850-38-0 Chemical Structure| 6850-38-0

Structure of 6850-38-0

Chemical Structure| 6850-38-0

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Product Details of [ 6850-38-0 ]

CAS No. :6850-38-0
Formula : C6H13NO
M.W : 115.17
SMILES Code : OC1C(N)CCCC1
English Name :2-Aminocyclohexanol
MDL No. :MFCD00191368
InChI Key :PQMCFTMVQORYJC-UHFFFAOYSA-N
Pubchem ID :23286

Safety of [ 6850-38-0 ]

Computational Chemistry of [ 6850-38-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 32.71
TPSA ?

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

46.25 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.17
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

-0.06
Log Po/w (WLOGP)?

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

0.25
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.

0.21
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

0.39
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.39

Water Solubility

Log S (ESOL):?

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

-0.52
Solubility 35.1 mg/ml ; 0.305 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.

-0.46
Solubility 39.9 mg/ml ; 0.347 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

-0.1
Solubility 92.3 mg/ml ; 0.802 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

No
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.

-7.05 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

1.0
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)

1.85

Application In Synthesis of [ 6850-38-0 ]

* 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 [ 6850-38-0 ]

[ 6850-38-0 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 493-72-1 ]
  • [ 6850-38-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Stage #1: 5-phenyl-cyclohexane-1,3-dione; 2-aminocyclohexanol In tetrahydrofuran for 12h; Heating / reflux; Stage #2: With 2,4,6-trimethylphenyl bromide; potassium carbonate In DMF (N,N-dimethyl-formamide) at 150℃; for 4h; 5 Reference Example 5 A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 2-aminocyclohexanol (3.2 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (100 ml). To the solution were added 2-bromomesitylene (4.2 g), tetrakistriphenylphosphine palladium (0.6 g) and potassium carbonate (5.9 g), and the mixture was stirred at 150° C. for 4 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazol-4-one (3.4 g). mp. 257-259° C. 1H-NMR(CDCl3) δ: 1.60-1.90 (4H, m), 2.26-2.82 (6H, m), 2.84-3.06 (2H, m), 3.40-3.60 (1H, m), 7.16-7.48 (5H, m), 8.07 (1H, br).
  • 2
  • [ 421561-65-1 ]
  • [ 6850-38-0 ]
  • [ 651292-57-8 ]
YieldReaction ConditionsOperation in experiment
60% With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 18h; 3.I General Procedure for Step I. A [1- [5-ARYL-6-ALKYL-THIENO] [2,3-d] pyrimidin-4-yl]-piperidin-4-one 10 (0.134 mmol) and [1-AMINO-2-ALKYL] (aryl) alcohol (0.134 mmol) were mixed in dry dichloromethane [(2ML)] and then treated with sodiumtriacetoxyborohydride (0.2 mmol) and acetic acid (0.134 [MMOL).] The mixture was stirred at room temperature under N2 atmosphere for 18h until the reactants were consumed as determined by TLC analysis. The reaction mixture was quenched by addition of IN [NAOH] and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to afford crude product. The crude product was subjected to column chromatography (2% [MEOH/DCM)] to yield the product [11.] Typical yields were from 60-80%. The specific compounds listed below were made by this procedure, e. g. 2-[1-(5-Phenyl-thieno [2,3-d] [PYRIMIDIN-4-YL)-PIPERIDIN-4-YLAMINO]-CYCLOHEXANOL] 2-[1-(6-Methyl-5-phenyl-thieno [2,3-d] pyrimidin-4-yl)-piperidin-4-ylamino]- cyclohexanol 1-[1-(6-Methyl-5-phenyl-thieno [2,3-d] [PYRIMIDIN-4-YL)-PIPERIDIN-4-YLAMINO]-] indan-2-ol 5-Methoxy-2- [{ [I- (5-PHENYL-THIENO [2,] 3-d] [PYRIMIDIN-4-YL)-PIPERIDIN-4-YLAMINO]-] [ METHYL}-PHENOL] [BIS- (2-FLUORO-BENZYL)- [1- (5-PHENYL-THIENO [2,] 3-d] [PYRIMIDIN-4-YL)-PIPERIDIN-4-YL]-] amine 1- [{1- [5- (4-BROMO-PHENYL)-THIENO] [2,3-d] [PYRIMIDIN-4-YL]-PIPERIDIN-4-YLAMINO}-] indan-2-ol [ 1- [1- (5-P-TOLYL-THIENO [2, 3-D] PYRIMIDIN-4-YL)-PIPERIDIN-4-YLAMINO]-INDAN-2-OL] [2-FLUORO-6-[1-(6-METHYL-5-PHENYL-THIENO] [2,3-d] pyrimidin-4-yl) -piperidin-4- [ YLAMINO]-METHYL}-PHENOL] [2-] ({1-[5-(4-Bromo-phenyl)-thieno [2, 3-d]pyrimidin-4-yl]-piperidin-4-ylamino}- methyl)-6-fluoro-phenol 2-Fluoro-6-[1-(5-p-tolyl-thieno [2,3-d] pyrimidin-4-yl)-piperidin-4-ylamino]- methyl}-phenol [1- [I- (5-PHENYL-THIENO] [2, [3-D] PYRIMIDIN-4-YL)-PIPERIDIN-4-YLAMINO]-INDAN-2-OL] [1- (4-FLUORO-PHENOXY)-3- [1- (5-PHENYL-THIENO] [2,3-d] [PYRIMIDIN-4-YL)-PIPERIDIN-4-] ylamino]-propan-2-ol [1-JL- (5-PHENYL-THIENO] [2, 3-d]pyrimidin-4-yl)-piperidin-4-ylamino]-3-(4- trifluoromethoxy-phenoxy)-propan-2-ol [No. 1-(3, ]4-Difluoro-phenoxy) -3- {1-[5-(4-fluoro-phenyl)-thieno [2,3-d] pyrimidin-4- [ YL]-PIPERIDIN-4-YLAMINO}-PROPAN-2-OL]
  • 3
  • [ 1146615-53-3 ]
  • [ 6850-38-0 ]
  • [ 1146614-58-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 6-chloro-3-(2-methoxy-pyridin-4-yl)-imidazo[1,2-a]pyridine With sodium t-butanolate In 1,2-dimethoxyethane at 20℃; Stage #2: 2-aminocyclohexanol In 1,2-dimethoxyethane at 100℃; for 2h; Microwave radiation; 2.8 6-Chloro-3-(2-methoxy-pyridin-4-yl)-imidazo[1,2-a]pyridine (Intermediate G) (1 eq, 200 mg, 0.769 mmol), sodium tert-butoxide (2.4 eq, 1.8 mmol, 177 mg), palladium acetate (17 mg, 0.1 eq), (R)-1-[(lS)-2-(diphenylphosphinojferrocenyljethyldicyclohexylphosphine (43 mg, 0.1 eq) are stirred at RT under an inert atmosphere of argon in DME (3 ml) and degassed thoroughly before adding 2-aminocyclohexanol (2eq, 1.53 mmol, 176 mg) The reaction is heated using microwave radiation at 100 °C for 2 hours. The majority of the solvent is removed in vacuo and the resulting residue is loaded onto a SCX-2 cartridge (resin loading 0.67 mmol/g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and further purified by flash chromatography (10%MeOH/EtOAc) to afford the title compound; [M+H]+ = 339
  • 4
  • [ 6850-38-0 ]
  • [ 31877-31-3 ]
  • [ 917566-93-9 ]
YieldReaction ConditionsOperation in experiment
94% Stage #1: ethyl 4-(2-furyl)thiazol-2-carboxylate With water In methanol at 50℃; for 1h; Stage #2: With hydrogenchloride In methanol; water Stage #3: 2-aminocyclohexanol With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; for 3h;
94% Stage #1: ethyl 4-(2-furyl)thiazol-2-carboxylate With sodium hydroxide In methanol at 50℃; for 1h; Stage #2: 2-aminocyclohexanol With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h; 568.1 Step 1: Ethyl 4-(2-furyl)thiazol-2-carboxylate (335 mg, 1.50 mmol) obtained in Reference Example 567 was dissolvedin methanol. To the solution was added 4 mol/L of sodium hydroxide aqueous solution (2.5 mL), and the mixturewas stirred at 50°C for 1 hour. After neutralization with hydrochloric acid, the solvent was evaporated under reducedpressure. The resulting residue was dissolved in DMF (5 mL), and 2-aminocyclohexanol (518 mg, 4.50 mmol), EDChydrochloride (864 mg, 4.50 mmol), and 1-hydroxybenzotriazole monohydrate (689 mg, 4.50 mmol) were addedthereto, then the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to thereaction mixture, and the mixture was extracted. The organic layer was washed with brine and dried over anhydrousmagnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane:ethyl acetate = 1:1) to give 4-(2-furyl)-N-(2-hydroxycyclohexyl)thiazole-2-carboxamide (413 mg, 94 %). 1H NMR (CDCl3, δ ppm): 1.26-1.49 (m, 4H), 1.74-1.81 (m, 2H), 2.04-2.16 (m, 2H),3.48-3.55 (m, 1H), 3.78-4.00 (m, 1H), 6.51 (dd, J = 1.8, 3.3 Hz, 1H), 6.81 (dd, J = 0.7, 3.3 Hz, 1H), 7.48 (dd, J =0.7, 1.8 Hz, 1H), 7.61 (s, 1H).
  • 5
  • [ 383132-27-2 ]
  • [ 6850-38-0 ]
  • [ 1473450-26-8 ]
YieldReaction ConditionsOperation in experiment
50% Stage #1: 4,6-dimethyl-1H-indole-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 2-aminocyclohexanol In N,N-dimethyl-formamide at 20℃; for 16h;
  • 6
  • [ 6850-38-0 ]
  • [ 20439-47-8 ]
  • [ 1436-59-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-aminocyclohexanol In ethanol for 1h; Stage #2: With ammonia; hydrogen In ethanol at 160℃; for 16h; Overall yield = 98 %; 1 Example 1 in a 200 ml reaction kettle, 1 g of the reaction substrate, 2-aminocyclohexanol, was added to 99 g of an ethanol solvent,The concentration of 2-aminocyclohexanol was 1 wt%, and 0.5 g of a supported catalyst Rh / SiO2 (Rh content2% by weight) and stirred for about 1 hour. The atmosphere in the reaction kettle was then replaced with hydrogen, under constant stirringAmmonia gas of 0.4 MPa was charged and dissolved for 1 hour while stirring. Then, 1.5 MPa of hydrogen was charged and reacted at 160 ° C for 15 hours.After completion of the reaction, the resulting product was isolated by distillation to obtain pure, confirmed by gas chromatographyPurity greater than 99%,70% of the trans-isomer was obtained, and the yield was 98%.
  • 7
  • [ 6850-38-0 ]
  • [ 921602-83-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / -30 - 20 °C 2: pyridinium chlorochromate / dichloromethane / 20 °C 3: diethylamino-sulfur trifluoride / dichloromethane / 24 h / -70 - 20 °C / Inert atmosphere 4: hydrogenchloride / water; methanol / 35 °C
  • 8
  • [ 6850-38-0 ]
  • [ 4342-43-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-heptane / 4 h / Reflux 2.1: 15-crown-5; sodium hydroxide / tetrahydrofuran / 9 h / -5 - 20 °C 3.1: hydrogenchloride / toluene / 12 h / -10 - 0 °C 3.2: 12 h / -5 - 0 °C
  • 9
  • [ 6850-38-0 ]
  • [ 1182996-38-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In dichloromethane at 20℃; for 16h; 10 N-(cyclopropylmethyl)-N'-(2-hydroxycyclohexyl)oxamide Preparation 10 N-(cyclopropylmethyl)-N'-(2-hydroxycyclohexyl)oxamide Scheme 2, step B: Add TEA (115 mL, 0.8 mol) to a solution of ethyl 2-(cyclopropylmethylamino)-2-oxo-acetate (128.5 g, 0.75 mol) in DCM (1.6 L) at ambient temperature. Add 2-aminocyclohexanol (91 g, 0.8 mol) to the mixture and stir for 16 hr at ambient temperature. Filter the resulting precipitate and air dry to give the title compound (147 g, 80%) as a white solid mixture of cis and trans isomers. LC-ES/MS (m/z) 241.1 (M+H).
  • 10
  • [ 52781-10-9 ]
  • [ 6850-38-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
19% With triethylamine In ethyl acetate at 20 - 80℃; for 4h; 1 N-allyl-N'-(2-hydroxycyclohexyl)oxamide Preparation 1 N-allyl-N'-(2-hydroxycyclohexyl)oxamide Scheme 1, step A: Combine 2-aminocyclohexanol (7.7 g, 66.8 mmol), ethyl-2-(allylamino)-2-oxo-acetate (10.0 g, 63.6 mmol) and triethylamine (9.8 mL, 70.0 mmol) in EtOAc (127.3 mL) and heat the mixture at 80° C. for 4 hr. Cool the mixture to ambient temperature and stir overnight. Isolate the resulting precipitate by vacuum filtration, wash the filter cake with EtOAc, and dry for 4 hr to give the title compound (7.2 g, 50%) as a white, crystalline solid. Concentrate the filtrate under reduced pressure and sonicate the resulting solid in Et2O. Isolate the solid by vacuum filtration, wash the filter cake with Et2O, and dry for 1.5 hr to give an additional lot of the title compound (2.8 g, 19%) as a white, crystalline solid. The product is a mixture of cis and trans isomers. LC-ES/MS (m/z): 227.0 (M+H).
10 g With triethylamine In ethanol at 80℃; for 4h; 1.A Scheme 1, step A Combine 2-aminocyclohexanol (7.7 g, 66.8 mmol), ethyl-2-(allylamino)-2-oxo-acetate (10.0 g, 63.6 mmol, Matrix Scientific, CAS 52781-10-9) andTEA (9.8 mL, 70.0 mmol) in EtOH (127.3 mL) and heat the mixture at 80 °C for 4 hr. Cool the mixture to ambient temperature and stir overnight. Isolate the resulting precipitate by vacuum filtration, wash the filter cake with EtOAc, and dry for 4 hr to obtain the title compound (7.2 g, 50% yield) as a white, crystalline solid. Evaporate thefiltrate under reduced pressure and sonicate the resulting solid in Et20. Collect the solid by vacuum filtration, wash the filter cake with Et20, and dry for 1.5 hr to give an additional lot of the title compound (2.8 g, 19% additional yield) as a white, crystalline solid. The product is a mixture of cis and trans isomers. ES/MS (m/z): 227.0 (M+H).
  • 11
  • [ 6850-38-0 ]
  • [ 2416311-96-9 ]
  • [ 2416311-54-9 ]
YieldReaction ConditionsOperation in experiment
56% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; 39.4 Step-4: To a solution of 4-[4-(2-chloropyridin-4-yl)-benzyl]-pyrrolo[l,2-h]pyridazine-2- carboxylic acid(4l.O mg, 0.11 mmol) in DCM (5.0 mL) at 0 to 5 °C under N2, DIPEA (0.04 mL, 0.23mmol),TBTU (40.0 mg, O.l2mmol) and l-amino-2-hydroxy-cyclohexane( 13.0 mg, O. l lmmol) were added sequentially. The reaction mass was gradually warmed to r.t, and was stirred for 4 h. The reaction mixture was quenched with ice water (5.0 mL) and was extracted with DCM (10 mL x 2). Organic layer was washed with brine solution (50 mL), dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure to obtain the crude compound which was purified by flash chromatography using to afford the title compoundN- [( 1 S ,2S )-2-Hydroxycyclohexyl] -4- [4-(2-chloropyridin-4-yl)-benzyl] -pyrrolo [ 1 ,2b]pyridazine- 2- carboxamide(29.0 mg) in 56% yield.1H - NMR (400 MHz, CDCl3): 58.43 (d, J = 5.2 Hz, 1H), 7.75 (s, 1H), 7.56 (d, J =7.9 Hz, 2H), 7.51 (s, 1H), 7.40 (d, J =7.9 Hz, 2H), 7.40 (d, J = 5.2 Hz, 1H), 7.19 (s, 1H), 6.95 (dd, J = 1.9, 4.0 Hz, 1H), 6.60 (d, J = 4.0 Hz, 1H), 4.22 (s, (0279) 2H), 3.88-3.78 (m, 1H), 3.55-3.46 (m, 1H), 3.02 (d, J = 4.4 Hz, 1H), 2.18-2.07 (m, 2H), 1.85-1.75 (m, 2H), 1.45-1.25 (m, 4H); Mass (m/z); 461.1 (M+H)+.
  • 12
  • [ 6850-38-0 ]
  • [ 2734205-91-3 ]
  • [ 2734201-16-0 ]
YieldReaction ConditionsOperation in experiment
48.08% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 4℃; for 4h; 1.61 Into a 100-mL round-bottom flask, was placed N-(2-(4-methoxypyridin-2-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine (150.00 mg, 0.477 mmol, 1.00 equiv), 2-aminocyclohexan-1-ol (82.44 mg, 0.716 mmol, 1.50 equiv), HATU (272.16 mg, 0.716 mmol, 1.5 equiv), DIEA (185.02 mg, 1.432 mmol, 3 equiv), and DCM (20.00 mL). The resulting solution was stirred for 4 hr at 4°C. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers were combined, dried in an oven under reduced pressure, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2SHIMADZU (HPLC-01)): Column, Atlantis HILIC OBD Column, 19*150mm*5um; mobile phase, Water (0.05%NH3H2O) and ACN (5% PhaseB up to 18% in 8 min). This resulted in 95.2 mg (48.48%) of N-((1R,2R)-2-hydroxycyclohexyl)-2-((2-(4-methoxypyridin-2-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as a white solid.1H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.04 (dd, J = 5.7, 2.6 Hz, 1H), 4.54 (d, J = 4.8 Hz, 1H), 4.25 (d, J = 16.4 Hz, 1H), 4.15 (d, J = 16.3 Hz, 1H)3.89 (s, 3H), 3.48-3.36 (m, 1H), 3.31-3.22 (m, 4H), 3.14 (t, J = 4.7 Hz, 2H), 2.82 (t, J = 7.9 Hz, 2H), 2.03-1.93 (m, 2H), 1.86-1.49 (m, 4H), 1.32-1.05 (m, 4H). LCMS (ES) [M+1] + m/z: 412.3.
  • 13
  • [ 3660-90-0 ]
  • [ 6850-38-0 ]
  • [ 3009013-37-7 ]
YieldReaction ConditionsOperation in experiment
44.7 % In ethanol at 100℃; 10.1 Step 1: Synthesis of 2-((4-bromophthalazin-1-yl)amino)cyclohexanol A solution of 1,4-dibromophthalazine (100 mg, 347 mmol) and 2-aminocyclohexanol (40.0 mg, 347 mmol) in EtOH (3.00 mL) was stirred at 100°C for 24 hours.The reaction solution is cooled to room temperature, solid precipitates, filter, and the filter cake is dried under reduced pressure.The target compound (50.0 mg, yield 44.7%, white solid) was obtained and used directly in the next step.
  • 14
  • [ 6850-38-0 ]
  • [ 3054118-35-0 ]
  • [ 3054118-40-7 ]
YieldReaction ConditionsOperation in experiment
55 % With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; 4.11.13. 2-(4-Ethoxyphenyl)-N-(7-((2-hydroxycyclohexyl)amino)-7-oxoheptyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide (11) The coupling reaction of acid 3 (107 mg, 0.2 mmol) with 2-aminocyclohexanol(as a mixture of cis and trans isomers, 23 mg, 0.2 mmol) wasperformed in THF (2 mL) in the presence of HOBt hydrate (46 mg, 0.3mmol), EDCI hydrochloride (58 mg, 0.3 mmol) and Et3N (0.11 mL, 0.8mmol) at room temperature for 12 h to give compound 11 as solids (70mg, 55% yield). The purity of compound 11 was 95.3%, as shown byHPLC on an HC-C18 column (Merck, 4.6 × 100 mm, 2 μm particle size),tR = 8.0 min [MeOH/(0.1% TFA aqueous solution) = 6.5:3.5] at a flowrate of 1.0 mL/min. C34H42N6O6; white solid; mp = 199-200 C; TLC(CH2Cl2/MeOH = 98:2) Rf = 0.15; IR νmax (KBr) 3290, 2932, 2862,1735, 1654, 1598, 1509, 1474, 1400, 1248, 1164, 1052 cm 1; 1H NMR(400 MHz, CDCl3) δ 9.90 (1 H, s), 8.19 (2 H, d, J = 8.9 Hz), 8.04 (1 H, t, J= 6.2 Hz), 7.47 (1 H, td, J = 8.4, 1.6 Hz), 7.40 (1 H, d, J = 7.5 Hz),7.12-7.08 (2 H, m), 6.96 (2 H, d, J = 8.9 Hz), 5.93 (1 H, d, J = 7.1 Hz),4.04 (2 H, q, J = 7.0 Hz), 3.76 (3 H, s), 3.65-3.50 (3 H, m), 3.34-3.27 (1H, m), 2.21-2.16 (2 H, m), 2.06-1.90 (3 H, m), 1.70-1.63 (6 H, m),1.41-1.07 (11 H, m); 13C NMR (100 MHz, CDCl3) δ 174.9, 164.3, 160.9,156.7, 155.5, 153.6, 152.9, 132.5, 130.8, 129.8, 129.6, 129.3 (2×),120.9, 120.5, 119.1, 114.2 (2×), 112.5, 75.1, 63.5, 55.9, 55.7, 38.9,36.4, 34.5, 31.5, 29.4, 28.3, 26.1, 25.4, 24.6, 24.1, 14.7; ESI-HRMS calculated for C34H43N6O6: 631.3239 found: m/z 631.3237 [M + H]+.
55 % With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; 4.11.13. 2-(4-Ethoxyphenyl)-N-(7-((2-hydroxycyclohexyl)amino)-7-oxoheptyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide (11) The coupling reaction of acid 3 (107 mg, 0.2 mmol) with 2-aminocyclohexanol(as a mixture of cis and trans isomers, 23 mg, 0.2 mmol) wasperformed in THF (2 mL) in the presence of HOBt hydrate (46 mg, 0.3mmol), EDCI hydrochloride (58 mg, 0.3 mmol) and Et3N (0.11 mL, 0.8mmol) at room temperature for 12 h to give compound 11 as solids (70mg, 55% yield). The purity of compound 11 was 95.3%, as shown byHPLC on an HC-C18 column (Merck, 4.6 × 100 mm, 2 μm particle size),tR = 8.0 min [MeOH/(0.1% TFA aqueous solution) = 6.5:3.5] at a flowrate of 1.0 mL/min. C34H42N6O6; white solid; mp = 199-200 C; TLC(CH2Cl2/MeOH = 98:2) Rf = 0.15; IR νmax (KBr) 3290, 2932, 2862,1735, 1654, 1598, 1509, 1474, 1400, 1248, 1164, 1052 cm 1; 1H NMR(400 MHz, CDCl3) δ 9.90 (1 H, s), 8.19 (2 H, d, J = 8.9 Hz), 8.04 (1 H, t, J= 6.2 Hz), 7.47 (1 H, td, J = 8.4, 1.6 Hz), 7.40 (1 H, d, J = 7.5 Hz),7.12-7.08 (2 H, m), 6.96 (2 H, d, J = 8.9 Hz), 5.93 (1 H, d, J = 7.1 Hz),4.04 (2 H, q, J = 7.0 Hz), 3.76 (3 H, s), 3.65-3.50 (3 H, m), 3.34-3.27 (1H, m), 2.21-2.16 (2 H, m), 2.06-1.90 (3 H, m), 1.70-1.63 (6 H, m),1.41-1.07 (11 H, m); 13C NMR (100 MHz, CDCl3) δ 174.9, 164.3, 160.9,156.7, 155.5, 153.6, 152.9, 132.5, 130.8, 129.8, 129.6, 129.3 (2×),120.9, 120.5, 119.1, 114.2 (2×), 112.5, 75.1, 63.5, 55.9, 55.7, 38.9,36.4, 34.5, 31.5, 29.4, 28.3, 26.1, 25.4, 24.6, 24.1, 14.7; ESI-HRMS calculated for C34H43N6O6: 631.3239 found: m/z 631.3237 [M + H]+.
 

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