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[ CAS No. 1221343-14-1 ] {[proInfo.proName]}

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Chemical Structure| 1221343-14-1
Chemical Structure| 1221343-14-1
Structure of 1221343-14-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1221343-14-1 ]

CAS No. :1221343-14-1 MDL No. :MFCD20527893
Formula : C8H7BO4 Boiling Point : -
Linear Structure Formula :- InChI Key :VXDGEAYKTHEYPI-UHFFFAOYSA-N
M.W : 177.95 Pubchem ID :58404071
Synonyms :

Calculated chemistry of [ 1221343-14-1 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 46.0
TPSA : 66.76 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.06 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.46
Log Po/w (WLOGP) : -0.55
Log Po/w (MLOGP) : -0.19
Log Po/w (SILICOS-IT) : -0.39
Consensus Log Po/w : -0.13

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -1.51
Solubility : 5.52 mg/ml ; 0.031 mol/l
Class : Very soluble
Log S (Ali) : -1.43
Solubility : 6.6 mg/ml ; 0.0371 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.25
Solubility : 10.1 mg/ml ; 0.0566 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.9

Safety of [ 1221343-14-1 ]

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

Application In Synthesis of [ 1221343-14-1 ]

* 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 [ 1221343-14-1 ]

[ 1221343-14-1 ] Synthesis Path-Downstream   1~57

  • 1
  • [ 1221343-14-1 ]
  • [ 121-57-3 ]
  • [ 1221343-15-2 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid; 4-aminobenzene sulfonic acid With 1-hydroxy-7-aza-benzotriazole; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; Stage #2: With potassium hydroxide In diethyl ether; water Inert atmosphere; Stage #3: With hydrogenchloride In water at 0℃; Inert atmosphere;
  • 2
  • [ 1221343-13-0 ]
  • [ 1221343-14-1 ]
YieldReaction ConditionsOperation in experiment
68% Stage #1: methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-methylbenzoate With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene at 100℃; for 4h; Inert atmosphere; Stage #2: With water; potassium hydroxide In diethyl ether at 20℃; for 1h; Inert atmosphere; Stage #3: With hydrogenchloride; water In diethyl ether at 0℃; Inert atmosphere;
  • 3
  • [ 947162-60-9 ]
  • [ 1221343-14-1 ]
YieldReaction ConditionsOperation in experiment
85% With hydrogenchloride In water Reflux;
85% With hydrogenchloride In water Inert atmosphere; Reflux; 1 A solution of compound C (100 mg, 0.63 mmol) in cone. HCl (10 mL) was refluxed for 3 h and cooled to RT. The mixture was filtrated. The solid was washed with water, dried to give the product D as a white solid (95 mg, 850Zo)-1H NMR (300 MHz, DMSO-J6): δ 12.92 (s, IH), 9.36 (s, IH), 8.10 (s, IH), 8.05 (d, IH), 7.54 (d, IH), 5.08 (s, 2H). LC-MS: 177 (M - I)+. Purity on HPLC: 50.5% (214 nm).
55% With hydrogenchloride; water for 24h; Reflux; 41 A suspension of 1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborole-6-carbonitrile (20.15 g, 127 mmol) in cone hydrochloric acid (1.50 L) was refluxed for 24 hours and cooled down to 10 °C. The suspension was filtered and filter cake washed with water (300 mL). Filter cake was suspended in water (500 mL) and freeze-dried. The residue was suspended in dichloromethane (500 mL) and filtered. Filter cake was wash with dichloromethane (200 mL) and dried in vacuo to give 1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborole-6-carboxylic acid as white powder. Yield: 12.30 g (55%). 1 H NMR spectrum (300 MHz, DMSO-d6, 5H): 12.92 (s, 1 H); 9.36 (s, 1 H); 8.37 (s, 1 H); 8.04 (dd, J=7.9 and 0.9 Hz, 1 H); 7.52 (d, J=8.1 Hz, 1 H); 5.05 (s, 2 H). LC-MS m/z: 178.2 (M+H).
With hydrogenchloride; water for 3h; Reflux; 1.63 A solution of Intermediate B81 (100 mg, 0.63 mmol) in cone. HCl (10 mL) was refluxed for 3 h and cooled to RT. The mixture was filtrated. The solid was washed with water, dried to give the desired product as a white solid (95 mg, 85%). 1H NMR (300 MHz, DMSO-J6): δ 12.92 (s, IH), 9.36 (s, IH), 8.10 (s, IH), 8.05 (d, IH), 7.54 (d, IH), 5.08 (s, 2H). LC-MS: 177 (M - I)+. Purity on HPLC: 50.5% (214 nm).

  • 7
  • [ 104-85-8 ]
  • [ 1221343-14-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide; sulfuric acid / water / 48 h / 10 °C / Darkness 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / Reflux 3.1: acetonitrile / 24 h / 70 °C 4.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 10 h / Inert atmosphere; Reflux 5.1: sodium hydroxide / methanol / 2 h / 30 °C 5.2: 1 h / 30 °C 6.1: hydrogenchloride; water / 3 h / Reflux
Multi-step reaction with 6 steps 1.1: sulfuric acid; N-Bromosuccinimide / 40 h / 10 °C / Darkness 2.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 3.1: acetonitrile / 24 h / 4 - 70 °C 4.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 18 h / Inert atmosphere; Reflux 5.1: sodium hydroxide / methanol / 2 h / 30 °C 5.2: 0.17 h 6.1: hydrogenchloride; water / 24 h / Reflux
  • 8
  • [ 42872-74-2 ]
  • [ 1221343-14-1 ]
  • 9
  • [ 89892-39-7 ]
  • [ 1221343-14-1 ]
  • 10
  • [ 89891-69-0 ]
  • [ 1221343-14-1 ]
  • 11
  • [ 90110-98-8 ]
  • [ 1221343-14-1 ]
  • 12
  • [ 1221343-14-1 ]
  • [ 1285533-33-6 ]
  • [ 1285533-12-1 ]
YieldReaction ConditionsOperation in experiment
41.2% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Synthesis of compound 5c To a solution of the hydrochloride salt of intermediate 4 (19.4 mg, 0.03 mmol) in DMF (2 mL) were added 2c (5.3 mg, 0.03 mmol), HATU (22.8 mg, 0.06 mmol) and diisopropylethylamine (0.5 mL). The resulting reaction mixture was stirred at room temperature overnight. Solvents were evaporated and residual was purified by reverse phase HPLC (CH3CN/H2O, 0.1% formic acid, 0-90%) to afford compound 5c as a pink solid (10 mg, 41.2%). LC-MS (ESI) m/z 809 [M+1]+, (calcd MS 808.1). 1H NMR (400 MHz, CD3OD) δ 8.14-8.24 (m, 1H), 8.04-8.12 (m, 1H), 7.92-8.02 (m, 1H), 7.81-7.88 (m, 1H), 7.52-7.66 (m, 2H), 7.48-7.53 (m, 1H), 7.26-7.33 (m, 1H), 5.67-5.86 (m, 2H), 5.22-5.35 (m, 1H), 5.03-5.15 (m, 3H), 4.43-4.61 (m, 2H), 4.03-4.13 (m, 1H), 3.98 (s, 3H), 2.89-3.00 (m, 1H), 2.54-2.65 (m, 1H), 2.16-2.35 (m, 2H), 1.8 -1.92 (m, 2H), 1.38-1.50 (m, 1H), 1.21-1.29 (m, 2H), 1.02-1.16 (m, 11H).
  • 14
  • methyl 4-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]
  • [ 1221343-14-1 ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: methyl 4-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate With potassium hydroxide In water at 20℃; Stage #2: With hydrogenchloride In water at 0℃; 1,3 Synthesis of 1-hydroxy-L,3-dihydrobenzo[cj[1,2]oxaborole-6-carboxylic acid To a solution of SKC-0l-138 (1.50 g, 5.43 mmol) in anhydrous CCI4 (30 ml)added N-bromosuccinimide (1.01 g, 5.70 mmol). To this stirred mixture,dicyclohexanecarbonitrile was added as a catalyst (0.07 g, 0.27 mmol) in four portions during I h. The mixture was stirred at 70°C overnight. LCMS showed a major peak atmm with the expected mass of the benzyl bromide. After cooling, the solvent was evaporated in vacuo. The crude product was dissolved in ether and filtered to removesuccinimide. The filtrate was extracted with KOH (15% w/v in H20, 3X7U ml).aqueous phase was stirred 1-2 h at room temperature (‘rt”). The solution was cooled at 0°C and HC1 (6N in 1-120, ‘-120 ml) was added slowly to reach pH <2. Theprecipitate was collected by filtration through a fritted glass lunnel and air driedafford the 5-carboxybenzoboroxole SKC-01-150 (0.800 g, 83% yield) as a whitepowder. ‘H NMR (400 MHz, DMSO-d6) 12.91 (s, IH), 9.35 (s, 1H), 8.38 (s,8.04 ‘dd,J= 8.0, 1.5 Hz, 1H), 7.52 d,J= 8.0 Hz, lH, 5.05 (s, 2H.
  • 15
  • [ 1221343-14-1 ]
  • [ 7400-27-3 ]
  • N’-(tert-butyl)-1-hydioxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohyrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% To a stirred solution of SKC-01-150 (150 mg,0.84 mmofl in anhydious DMF (1.5 ml) were added BOP (373 mg, 0.84 mmol), HOBt (129 mg, 0.84 mmol) and DIPEA (0.294 ml, 1.68 mmol) under argon at room temperature. The reaction mixture was stirred for 5 mm. To this was added <strong>[7400-27-3]tert-butyl hydrazine hydrochloride</strong> (105 mg, 0.84 mmol) and the reaction mixture was stirred at 40°C for I h. LCMS showed complete conversion of the boroxozole carboxylic acid. The reaction mixture was transferred to a scintillation vial, and tie DMF was removed using a Genevac. The sticky crude mixture was dissolved in 15percent aqueous KOH and ether. The reaction mixture was extracted with ether and washed three times with aqueous KOH. The aqueous fractions containing the product were cooled on an ice bath and 6N HC1 was added slowly to make it to pH 1-2. The mixture was extracted using ethyl acetate. The product stayed in aqueous fractions and was evaporated to dryness under vacuum. The solid KC1 was removed from the product by washing it with 5percent MeOH in DCM and collecting the filtrate to get 95percent pure product. This was further purified using an ISCO system after adsorbing the product on neutral alumina (24 g neutral alumina column, MeOH:DCM solvent mixture). The product eluted using -5percent MeOH in DCM. The fractions were collected and dried to give (0.187 g, 89percent yield) the pure boroxazole carbohydrazide SKC-02-0 11. The viscous product was dissolved in water and small amount of THF, frozen and lyophilized to get light yellow powder. ?H NMR (400 MHz, MeOD) 6 8.11 (s, 1H), 7.93 (dd, J 8.0, 1.7 Hz, 1H), 7.52 (dd, J 8.0, 0.7 Hz, 1H), 5.16 (s, 2H), 1.19 (s, 1OH).
  • 16
  • [ 1221343-14-1 ]
  • [ 162752-59-2 ]
  • N-(tert-butyl)-N’-(3,5-dimethylbenzoyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
9% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: N-(3,5-Dimethylbenzoyl)-N-tert-Butyl-Hydrazine In N,N-dimethyl-formamide at 75℃; Inert atmosphere; Cpd. No. 50 was also prepared using a one pot procedure with SKC-01-150 (100 mg, 0.56 mmol), BOP (249 mg, 0.56 mmol), HOBt (86 mg, 0.56 mmol), DIPEA (0.098 ml, 0.56 mmol). All the reagenis except the hydrazide were n.ixed in a 100 ml round bottom flask and dissolved in anhydrous DMF (2 ml) and stirred under argon formm at room temperature. To this, N-(tert-butyl)-3,5-dimethylhydrazide (124 mg,0.56 mmol) was added, and the reaction mixture was heated at 75°C overnight. LCMS showed two close peaks, one of the peaks showed the mass of the expected product (mwt. 380.24) in ES+ and ES-mode. The reaction mixture diluted with ether and extracted with 10% w/v aqueous KOH. LCMS of the aqueous fractions showed a single peak with the expected product mass. The aqueous layer was cooled to 0°C, treated with 6N HCL drop wise to make it acidic (pH 1-2), and extracted with ethyl acetate. The organic fractions were collected, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified using prep HPLC to get 20 mg (9%) of Cpd. No. 50.
  • 17
  • [ 170230-88-3 ]
  • [ 1221343-14-1 ]
  • 18
  • [ 876189-18-3 ]
  • [ 1221343-14-1 ]
  • 19
  • [ 1186377-08-1 ]
  • [ 1221343-14-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol / 12 h / 0 - 20 °C 2: sodium hydroxide / water / 12 h / 50 °C
  • 20
  • methyl 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate [ No CAS ]
  • [ 1221343-14-1 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hydroxide In water at 50℃; for 12h; 7 Example P7: Preparation of 1-hvdroxy-3H-2, 1-benzoxaborole-6-carboxylic acid: To a stirred solution of methyl 1-hydroxy-3H-2, 1-benzoxaborole-6-carboxylate (5 g, 26.04 mmol) in water (10 mL) was added sodium hydroxide (2.6 g, 65.1 mmol) dissolved in 10 ml water. Reaction mass was stirred at 50°C for 12 h. The reaction mixture was cooled to 10°C and diluted with 2N HCI to pH 2. Precipitation of fine white solid occurred, which was collected by filtration and washed with water and dried under vacuum to afford 1-hydroxy-3H-2, 1-benzoxaborole-6-carboxylic acid (4.2 g, 91 % of theoretical yield) as a white solid. H NMR (400 MHz, DMSO-d6) δ ppm 4.91 - 5.03 (m, 1 H) 5.05 (s, 2 H) 7.45 - 7.58 (m, 1 H) 7.98 - 8.10 (m, 1 H) 8.39 - 8.41 (m, 1 H) 8.63 - 10.03 (m, 1 H) 1 1.60 - 14.04 (m, 1 H) MS [M-H] ~ : 177 (rt 1.07-1.10 min)
  • 21
  • [ 64-17-5 ]
  • [ 1221343-14-1 ]
  • ethyl 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With sulfuric acid Reflux; 8 Example P8: Preparation of ethyl 1-hydroxy-3H-2, 1-benzoxaborole-6-carboxylate: To a stirred solution of 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid (0.1 g, 26.04 mmol) in ethanol (2 mL) was added cone. Sulphuric acid (0.2 ml). Reaction mass was refluxed overnight. The reaction mixture was the cooled to ambient temperature and solvent was evaporated under reduced pressure. The residual mass thus obtained was dissolved in ethyl acetate (10 mL). Organic layer was washed with water (3 x 200 mL) followed by brine wash (200 mL). Organic layer was then dried over sodium sulfate, filtered and evaporated completely to give crude compound. The crude obtained was purified by flash chromatography over silicagel with hexane / ethyl acetate 1 :0 to 80:20 as eluent to afford desired compound ethyl 1-hydroxy-3H-2, 1-benzoxaborole-6-carboxylate (0.101 g, 90% of theoretical yield). H NMR (400 MHz, DMSO-d6) δ ppm 1.18 - 1.37 (m, 3 H) 4.34 (q, J=7.03 Hz, 2 H) 5.07 (s, 2 H) 7.56 (d, J=7.91 Hz, 1 H) 8.07 (dd, J=7.91 , 1 .63 Hz, 1 H) 8.41 (dd, J=1.51 , 0.75 Hz, 1 H) 9.39 (s, 1 H) MS [M+H]+~ : 207.1 (rt 1.56-1.60 min)
  • 22
  • [ 71637-34-8 ]
  • [ 1221343-14-1 ]
  • 3-thienylmethyl 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; 9 Example P9: Preparation of 3-thienylmethyl 1-hydroxy-3H-2, 1-benzoxaborole-6-carboxylate: To a stirred solution of 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid (0.150 g, 0.843 mmol) in dichloromethane (10 mL/g, 23.4 mmol) were added 3-thienylmethanol (0.106 g, 0.927 mmol) , 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (0.178 g, 0.927 mmol) and DMAP (0.002g, 0.0169 mmol) and the RM was stirred at ambient temperature for 5 h. Reaction mixture was diluted 10 ml water and then acidified with dil.HCI till pH~3. The aqueous layer was then extracted with dichloromethane (2X50ml). The combined organic layer was washed with brine solution (2X10 ml) and then dried over anhydrous sodium sulfate, filtered and evaporated completely to give crude compound. The crude mass thus obtained was purified by flash chromatography over silica gel with hexane / ethyl acetate 1 :0 to 70:30 as eluent to afford desired compound 3-thienylmethyl 1- hydroxy-3H-2, 1-benzoxaborole-6-carboxylate (0.120 g, 52% of theoretical yield). H NMR (400 MHz, DMSO-c/6) δ ppm 1.17 (s, 1 H) 1.22 (s, 1 H) 2.50 (dt, J=3.70, 1.79 Hz, 3 H) 3.34 (s, 1 H) 5.06 (s, 2 H) 5.54 (s, 2 H) 7.06 (t, J=4.41 Hz, 1 H) 7.28 (d, J=3.64 Hz, 1 H) 7.54 - 7.62 (m, 2 H) 8.06 (d, J=7.83 Hz, 1 H) 8.40 (s, 1 H) 9.42 (s, 1 H)
  • 23
  • [ 1221343-14-1 ]
  • [ 104-86-9 ]
  • N-[(4-chlorophenyl)methyl]-1-hydroxy-3H-2,1-benzoxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With triethylamine; HATU In dichloromethane at 20℃; for 12h; 10 Example P10: Preparation of N-[(4-chlorophenyl)methyll-1-hydroxy-3H-2, 1-benzoxaborole-6- carboxamide: To a stirred solution of 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid (0.080 g, 0.4496 mmol) in dichloromethane (10 mL/g, 23.4 mmol) were added (4-chlorophenyl)methanamine (0.070 g 0.4945 mmol) , HATU (0.188 g, 0.4945 mmol) and triethylamine (0.136 g, 1.349 mmol) and the RM was stirred at ambient temperature for 12 h. Reaction mixture was diluted 10 ml water. The aqueous layer was then extracted with dichloromethane (2X50ml). The combined organic layer was washed with brine solution (2X10 ml) and then dried over anhydrous sodium sulfate, filtered and evaporated completely to give crude compound. The crude mass thus obtained was purified by flash chromatography over silica gel with hexane / ethyl acetate 1 :0 to 70:30 as eluent to afford desired compound N-[(4-chlorophenyl)methyl]-1-hydroxy-3H-2,1-benzoxaborole-6-carboxamide (0.055 g, 40% of theoretical yield). H NMR (400 MHz, DMSO-d6) δ ppm 4.47 (d, J=6.02 Hz, 2 H) 5.04 (s, 2 H) 7.33 - 7.41 (m, 4 H) 7.50 (d, J=7.78 Hz, 1 H) 7.97 (dd, J=8.03, 1.76 Hz, 1 H) 8.25 (s, 1 H) 9.09 (t, J=6.10 Hz, 1 H) 9.30 (s, 1 H) MS [M+H]+~ : 302.1/ 303.1 (rt 1.66-168 min)
  • 24
  • [ 1221343-14-1 ]
  • [ 1117-97-1 ]
  • 1-hydroxy-N-methoxy-N-methyl-3H-2,1-benzoxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 20℃; for 3h; 11 Example P11 : Preparation of 1-hvdroxy-N-methoxy-N-methyl-3H-2,1-benzoxaborole-6-carboxamide: To a stirred solution of 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid (0.1 g, 0.562 mmol) in dichloromethane (10 mL) were added Ν,Ο-dimethylhydroxylamine (0.043 g 0.6743 mmol), Propylphosphonic anhydride (0.282 g, 0.843 mmol) and triethylamine(0.17 g, 1.686 mmol).The reaction mixture was stirred at ambient temperature for 3 h. Reaction mixture was diluted 10 ml water and aqueous layer was then extracted with dichloromethane (2X50ml). The combined organic layer was washed with 2N HCI (1X 10 ml), water (2X 10 ml) finally with brine solution (2X10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated completely to afford desired compound 1-hydroxy-N-methoxy-N-methyl-3H-2, 1-benzoxaborole-6-carboxamide(0.050 g, 40% of theoretical yield). H NMR (400 MHz, DMSO-d6) δ ppm 3.23 - 3.31 (m, 3 H) 3.54 (s, 3 H) 5.04 (s, 2 H) 7.48 (d, J=8.03 Hz, 1 H) 7.69 (d, J=7.53 Hz, 1 H) 7.97 (s, 1 H) 9.34 (s, 1 H) MS [M+H]+~ : 220.7/ 221.7(rt 1.27-1.36 min)
  • 25
  • [ 1221343-14-1 ]
  • [ 1397-89-3 ]
  • C55H78BNO20 [ No CAS ]
YieldReaction ConditionsOperation in experiment
20.5% With triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; dimethyl sulfoxide; N,N-dimethyl-formamide; at 20℃; for 12h;pH 8; General procedure: 3?-N-acyl derivatives ofAmB (5-7) were prepared by the treatment of the unprotected AmB (1) withN-hydroxysuccinimide ester (-OSu) of the 3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-yl)propionic acid, 1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid or 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carboxylic acid which were obtained by the standard method using DCC.To a stirred solution of AmB (1) (150 mg, 0.162 mmol) in DMSO(100 mg ml- 1) were added the solution of N-hydroxysuccinimide ester ofthe corresponding acid (5 eq) in the mixture of DMF-CH2Cl2 (2:1)(150 mg ml- 1) and Et3N to pH 8. The reaction mixture was stirred for 12 hat room temperature, and then fivefold volume of Et2O was added. Theresulting mixture was shaken intensively to partially extract DMSO and DMF,and the layer of Et2O was separated. This procedure was repeated twice. To the obtained dark yellow oil, n-BuOH (20 ml) saturated with H2O was added andthe resultant solution was washed with H2O (10 ml). This procedure wasrepeated twice. The organic layer was evaporated in vacuum with 0.6 eq of H2Oto the volume~ 1 ml n-BuOH solution. The organic layer was poured into astirring mixture of Et2O to precipitate the crude reaction product. Theprecipitate was filtered, washed with Et2O and dried in vacuum to give ayellow powder. Crude products (5-7) were purified by the column chromatographymethod on silica gel in CHCl3MeOHH2OHCOOH(5:1:0.01:0.01, v/v) system. The yields of the pure N-acyl-derivatives (3-5)were: 40 mg (22%) for 3, 36 mg (20.5%) for 4 and 32 mg (18%) for 5.
  • 26
  • [ 1221343-14-1 ]
  • [ 5557-81-3 ]
  • benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-alaninate [ No CAS ]
  • 27
  • [ 937369-83-0 ]
  • [ 1221343-14-1 ]
  • (3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl carbamate With sodium t-butanolate In tetrahydrofuran at -5 - 0℃; for 1h; Inert atmosphere; Stage #2: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid In tetrahydrofuran Reflux; 1 A solution of (3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy -4,7,9, 12- tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl carbamate (1.6 g, 4.2 mmol) in dry THF (30 mL) under a nitrogen atmosphere was cooled to -5 to 0°C, to the solution was added sodium tert-butoxide (1.4 g, 12.6 mmol) over -10 min, maintaining the process temperature below 5°C. The reaction mixture was stirred at 0°C for 1 hr. At the same time, the mixture of l-hydroxy-1,3- dihydrobenzo[c][l,2]oxaborole-6-carboxylic acid (754 mg, 4.2 mmol) and CDI (1.4 g, 8.4 mmol) in THF (20 mL) was refiuxed for 1 hr, then added to the above solution dropwise and the mixture was stirred overnight. Water was added, the mixture was extracted with EtOAc, washed with brine, dried and concentrated. The crude product was purified by prep-HPLC to give (3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy- 4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl (l-hydroxy-l,3-dihydrobenzo[c] [l,2]oxaborole-6-carbonyl)carbamate l-hydroxy-1,3- dihydrobenzo[c][l,2]oxaborole-6-carboxylate (0.4 g, -65% purity). (0759)
  • 28
  • [ 1221343-14-1 ]
  • C11H15NO2 [ No CAS ]
  • 2,6-dimethylphenyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-alaninate [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 10℃; 1 Example 1. 2,6-Dimethylphenyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-alaninate(6-001) To a solution of Acid-01 (ACS Med. Chem. Lett., 2010, 1(4), 165-169, 178 mg, 1 .00 mmol), compound 4 (230 mg, 1 .00 mmol), EDC (384 mg, 2.00 mmol) and HOBt (270 mg, 2.00 mmol) in DMF (5 mL) was added DIPEA (387 mg , 3.00 mmol). The reaction mixture was stirred at 10 °C overnight, and then concentarted and purified by prep. HPLC to give 6-001 (270 mg, yield 76%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1 H), 9.02 (d , J = 6.62 Hz, 1 H), 8.30 (s, 1 H), 8.00 (dd, J = 7.94 Hz, 1 .32 Hz, 1 H), 7.51 (d, J = 8.38 Hz, 1 H), 7.13-6.99 (m, 3H), 5.04 (s, 2H), 4.74 (t, J = 6.84 Hz, 1 H), 2.10 (s, 6H), 1 .63 (d , J = 7.06 Hz, 3H);ESI-MS: m/z 354 [M+H]+; HPLC purity: 100% (220 nm), 100% (254 nm)
  • 29
  • [ 1221343-14-1 ]
  • C12H17NO2 [ No CAS ]
  • 2-phenylpropan-2-yl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-alaninate [ No CAS ]
YieldReaction ConditionsOperation in experiment
14% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 10℃; 15 Example 15. 2-Phenylpropan-2-yl (1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborole-6-carbonyl)-L-alaninate (6-015) To a solution of Acid-1 (178 mg, 1 mmol), compound 11 (207 mg, 1 mmol), EDCI (384 mg, 2 mmol) and HOBT (270 mg, 2 mmol) in DMF (5 mL) was added DIPEA (387 mg, 3 mmol). The mixture was stirred at 10 °C for overnight and then purified by prep. HPLC to give 6-015 (50 mg, yield 14%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1 H), 8.73 (d, J = 7.1 Hz, 1 H,), 8.24 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.48 (d, J = 7.9 Hz, 1 H), 7.39-7.34 (m, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.24-7.18 (m, 1 H), 5.03 (s, 2H), 4.46 (q, J = 7.3 Hz, 1 H,), 1.69 (d, J = 8.4 Hz, 6H), 1.42 (d, J - 7.50 Hz, 3H). ESI-MS m/z 390 [M + Na]+; HPLC purity: 98.55% (220 nm), 98.90%
  • 30
  • [ 1221343-14-1 ]
  • methyl (R)-2-amino-4-phenylbutanoate hydrochloride [ No CAS ]
  • methyl (R)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-4-phenylbutanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 10℃; 25 Example 25. Methyl (R)-2-(1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborole-6-carboxamido)-4- phenylbutanoate (6-025) General procedure: To a solution of Acid-01 (ACS Med. Chem. Lett., 2010, 1(4), 165-169, 178 mg, 1 .00 mmol), compound 4 (230 mg, 1 .00 mmol), EDC (384 mg, 2.00 mmol) and HOBt (270 mg, 2.00 mmol) in DMF (5 mL) was added DIPEA (387 mg , 3.00 mmol). The reaction mixture was stirred at 10 °C overnight, and then concentarted and purified by prep. HPLC to give 6-001 (270 mg, yield 76%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1 H), 9.02 (d , J = 6.62 Hz, 1 H), 8.30 (s, 1 H), 8.00 (dd, J = 7.94 Hz, 1 .32 Hz, 1 H), 7.51 (d, J = 8.38 Hz, 1 H), 7.13-6.99 (m, 3H), 5.04 (s, 2H), 4.74 (t, J = 6.84 Hz, 1 H), 2.10 (s, 6H), 1 .63 (d , J = 7.06 Hz, 3H);ESI-MS: m/z 354 [M+H]+; HPLC purity: 100% (220 nm), 100% (254 nm).Compound 6-025 was prepared from 13 and Acid-01 in a similar manner to the last step of Example 1 .1H NMR (400 MHz, DMSO-d6) 9.33 (br s, 1 H), 8.86 (d, 7.5 Hz, 1 H), 8.28 (s, 1 H), 7.99 (dd , 7.9, 1 .76 Hz, 1 H), 7.52 (d, 7.9 Hz, 1 H), 7.26-7.33 (m, 2H), 7.16-7.25 (m, 3H), 5.06 (s, 2H), 4.36-4.47 (m, 1 H), 3.64 (s, 3H), 2.62-2.83 (m, 2H), 2.03-2.18 (m, 2H); ESI-MS m/z 354 [M+H]; HPLC purity: 99.62% (220 nm), 100% (254 nm).
  • 31
  • [ 1221343-14-1 ]
  • C35H50N4O6 [ No CAS ]
  • C28H31BN4O3*3ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid; C35H50N4O6 With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 20℃; for 1h;
  • 32
  • [ 1221343-14-1 ]
  • C38H55N5O7 [ No CAS ]
  • C31H36BN5O4*3ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid; C38H55N5O7 With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 20℃; for 1h;
  • 33
  • [ 1221343-14-1 ]
  • C44H78N4O15 [ No CAS ]
  • C52H83BN4O18 [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 1h; Stage #2: C44H78N4O15 In tetrahydrofuran at 0 - 20℃; for 13h; General methods for compounds 13-18, 27, 28 General procedure: To a solution of the benzoxaborole 10, 11 or 12 and 1-hydroxy-benzo-triazole (HOBt, 1.65 mmol) in THF (15 ml)was added 1,3-dicyclohexylcarbodiimide (DCC, 1.65 mmol)at 0 °C and reaction was stirred for 1 h at the same temperature.The resulting precipitate was filtered off and thefiltrate was added to a solution of 4″-O-aminocarbamate (8or 9 or 25 or 26) (1.50 mmol) and 1-hydroxy-benzo-triazole(HOBt, 1.65 mmol) in THF (15ml) at 0 °C. The reactionmixture was stirred for 1 h at the same temperature and for12 h at room temperature. The reaction was concentrated invacuum and ethyl acetate (15 ml) was added. After stirred for1 h, the insoluble substance was leached. The filtrate wasquenched with 5% aqueous NaHCO3 (20ml) and the aqueouslayer was extracted with ethyl acetate (2 × 15ml). Thecombined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentratedin vacuum to afford the crude products 13-18, 27,28, which were further purified by flash column chromatography(dicholoromethane-ethanol, 5:1).
  • 34
  • [ 1221343-14-1 ]
  • C45H80N4O15 [ No CAS ]
  • C53H85BN4O18 [ No CAS ]
YieldReaction ConditionsOperation in experiment
10% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 1h; Stage #2: C45H80N4O15 In tetrahydrofuran at 0 - 20℃; for 13h; General methods for compounds 13-18, 27, 28 General procedure: To a solution of the benzoxaborole 10, 11 or 12 and 1-hydroxy-benzo-triazole (HOBt, 1.65 mmol) in THF (15 ml)was added 1,3-dicyclohexylcarbodiimide (DCC, 1.65 mmol)at 0 °C and reaction was stirred for 1 h at the same temperature.The resulting precipitate was filtered off and thefiltrate was added to a solution of 4″-O-aminocarbamate (8or 9 or 25 or 26) (1.50 mmol) and 1-hydroxy-benzo-triazole(HOBt, 1.65 mmol) in THF (15ml) at 0 °C. The reactionmixture was stirred for 1 h at the same temperature and for12 h at room temperature. The reaction was concentrated invacuum and ethyl acetate (15 ml) was added. After stirred for1 h, the insoluble substance was leached. The filtrate wasquenched with 5% aqueous NaHCO3 (20ml) and the aqueouslayer was extracted with ethyl acetate (2 × 15ml). Thecombined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentratedin vacuum to afford the crude products 13-18, 27,28, which were further purified by flash column chromatography(dicholoromethane-ethanol, 5:1).
  • 35
  • [ 1221343-14-1 ]
  • [ 1263095-23-3 ]
  • N-(1-benzyl-2-oxo-1,2-dihydropyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid; 3-amino-1-benzylpyridin-2(1H)-one With 4-methyl-morpholine; HATU In N,N-dimethyl-formamide for 16h; Stage #2: In N,N-dimethyl-formamide at 35℃; for 24h; PartC:N-(1-Benzyl-2-oxo-1,2-dihydropyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide To a solution of3-amino-1-benzylpyridin-2(1H)-one (750.1 mg, 3.75 mmol),1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (733 mg, 4.12mmol), and N-methylmorpholine (1.647 mL, 14.98 mmol) in N,N-dimethylformamide (18.7mL) was added HATU (1.567 g, 4.12 mmol), and the solution was stirred for 16h. LC/MS showed the reaction to beapproximatley 50% complete, so the solution was heated at 35 C and stirred for24 h. The solution was then cooled toroom temperature, and diluted with dichloromethane (200 mL). The solution was washed with 1 N aq. HCl (100mL), and the organic phase was dried over anhydrous Na2SO4,filtered, and concentrated in vacuo. Theresidue was azeotroped with MeOH (50 mL).The residue was then diluted with Et2O (200 mL) and washedwith water (50 mL). The aqueous phase wasextracted with Et2O (50 mL), and the combined organic phase wasdiluted with dichloromethane (50 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the solutionwas concentrated in vacuo. The residuewas purified by automated gradient reverse phase liquid chromatography (10% to100% MeCN-water). The desired fractionswere combined, and the MeCN was removed in vacuo. The resulting suspension was filtered and thesolid was dried in vacuo to afford 540.3 mg of N-(1-benzyl-2-oxo-1,2-dihydropyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide(40% yield) as a tan solid. LCMS: [M+H]+: 361.1.
  • 36
  • [ 1221343-14-1 ]
  • [ 39796-52-6 ]
  • N-(2-(benzylamino)-2-oxoethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
18% To a solution of1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (136.3 mg, 0.766mmol) in N,N-dimethylformamide (7.2 mL) was added N-methylmorpholine (421 µL,3.83 mmol) and HATU (320 mg, 0.843 mmol).The solution was stirred for 5 minutes, and then<strong>[39796-52-6]2-amino-N-benzylacetamide</strong> (126 mg, 0.766 mmol) was added. The solution was stirred for 4 h, and thenHOAc (1 mL) was added. The solution waspurified directly by automated gradient reverse phase liquid chromatography(10% to 100% MeCN-water). The desiredfractions were combined and concentrated in vacuo. The residue was triturated with MeCN (5 mL),and the solid was collected by vacuum filtration and dried under high vacuum toafford 43.7 mg of N-(2-(benzylamino)-2-oxoethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide (18% yield) as a yellow solid.LCMS: [M+H]+: 324.9.
  • 37
  • [ 1221343-14-1 ]
  • [ 1668-10-6 ]
  • N-(2-amino-2-oxoethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 16h; Compound 9:N-(2-amino-2-oxoethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide To a solution of1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (115.0 mg, 0.646mmol) in N,N-dimethylformamide (2.7 mL) was added N,N-diisopropylethylamine(564 µL, 3.23 mmol), 2-aminoacetamide hydrochloride (71.4 mg, 0.646 mmol), andHATU (270 mg, 0.711 mmol). The solutionwas stirred for 16 h, and to the suspension was added HOAc (1 mL) and water (1mL). The solution was then purifieddirectly by automated gradient reverse phase liquid chromatography (5% to 35%MeCN-water), and the desired fractions were combined and concentrated invacuo. The residue was triturated with75% EtOAc-hexanes, and the solid was collected by vacuum filtration and driedunder high vacuum to afford 42.8 mg of N-(2-amino-2-oxoethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide(28% yield) as a white solid. LCMS: [M+H]+: 234.5.
  • 38
  • [ 1221343-14-1 ]
  • [ 5680-79-5 ]
  • methyl 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido) acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: glycine ethyl ester hydrochloride In N,N-dimethyl-formamide for 4h; Part A:Methyl 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)acetate To a solution of1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (140.8 mg, 0.791mmol) in N,N-dimethylformamide (3.8 mL) was added N,N-diisopropylethylamine(138 µL, 0.791 mmol), and HATU (331 mg, 0.870 mmol). The mixture was stirred for 5 min, and thenmethyl 2-aminoacetate hydrochloride (99 mg, 0.791 mmol) was added, and thesolution was stirred for 4 h. Thesolution was poured into dichloromethane (50 mL), and the solution was washedwith 1 N aq. HCl (30 mL). The organicphase was dried over anhydrous Na2SO4, filtered, and concentrated invacuo. The residue was purified byautomated gradient reverse phase liquid chromatography (10% to 90% MeCN inwater), and the desired fractions were combined and concentrated in vacuo. The residue was azeotroped with MeOH (2 x 10mL) to afford 54.6 mg of methyl2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido) acetate (28 %yield) as a colorless oil. LCMS: [M+H]+: 249.7.
Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: glycine ethyl ester hydrochloride In N,N-dimethyl-formamide at 40℃;
  • 39
  • methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]
  • [ 1221343-14-1 ]
YieldReaction ConditionsOperation in experiment
94% Stage #1: methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate With sodium hydroxide In water at 20℃; for 5h; Stage #2: With hydrogenchloride In water at 4℃; 40 Methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (5, 21.8 g, 63.5 mmol) was added to a solution of sodium hydroxide (12.7 g, 318 mmol) in water (200 ml_) and the resulting mixture was stirred at room temperature for 5 hours. The mixture was filtered, washed with diethyl ether (200 ml_) and acidified with 35% hydrochloric acid (39.6 ml_, 444 mmol). The resulting white suspension was placed in the fridge over weekend. The precipitate was filtered, washed with water (3 x 50 ml_) and suspended in 20% aqueous solution of acetonitrile (100 ml_). The mixture was freeze-dried to afford l-hydroxy-l,3-dihydrobenzo[c] [ l,2]oxaborole-6-carboxylic acid (6) as white powder. Yield : 10.63 g (94%). JH NMR spectrum (300 MHz, DMSO-d6, δΗ) : 12.90 (s, 1 H); 9.35 (s, 1 H); 8.37 (s, 1 H); 8.04 (dd, J = 8.0 and 1.6 Hz, 1 H); 7.52 (d, J = 7.9 Hz, 1 H); 5.05 (s, 2 H). LC-MS purity: 100% (ELSD). LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile/water 5 :95 to 100 : 0 + 0.1% FA) : 3.90 min. LC-MS m/z: 179.2 (M + H)+.
  • 40
  • [ 771-61-9 ]
  • [ 1221343-14-1 ]
  • perfluorophenyl 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 4h;
64% With dicyclohexyl-carbodiimide In acetonitrile at 20℃; 40 Λ/,Λ/'-Dicyclohexylcarbodiimide (DCC, 2.50 g, 12.1 mmol) was added to a suspension of l-hydroxy-l,3-dihydrobenzo[c] [ l,2]oxaborole-6-carboxylic acid (6, 2.16 g, 12.1 mmol) and pentafluorophenol (PfpOH, 2.23 g, 12.1 mmol) in acetonitrile (150 mL) and the mixture was stirred at room temperature overnight. The solid was filtered off and washed with ethyl acetate (5 x 20 mL). The filtrates were combined and evaporated to dryness. Cyclohexane (100 mL) was added to the residue and the mixture was stirred at room temperature for 15 minutes. The mixture was decanted and the sediment was dried in vacuo to give perfluorophenyl l-hydroxy-l,3-dihydrobenzo[c][ l,2]oxaborole-6- carboxylate (7) as off-white solid. Yield : 2.67 g (64%). JH NMR spectrum (300 MHz, CDCI3, δΗ) : 8.62 (s, 1 H); 8.32 (dd, J = 8.1 and 1.7 Hz, 1 H); 7.55 (d, J = 8.3 Hz, 1 H); 5.22 (s, 2 H). LC-MS purity: 98% (ELSD). LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile/water 35: 65 to 100: 0 + 0.1% FA) : 4.08 min. LC-MS m/z: 345.3 (M + H)+.
  • 41
  • [ 3048-01-9 ]
  • [ 2769-64-4 ]
  • [ 1221343-14-1 ]
  • [ 1489-69-6 ]
  • N-(2-(butylamino)-1-cyclopropyl-2-oxoethyl)-1-hydroxy-N-(2-(trifluoromethyl)benzyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In methanol at 20℃; for 24h;
  • 42
  • [ 1221343-14-1 ]
  • C46H96N2O22 [ No CAS ]
  • C62H106B2N2O28 [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C46H96N2O22 In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
  • 43
  • [ 1221343-14-1 ]
  • [ 115416-38-1 ]
  • C23H33BN4O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: N-(5-aminopentyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)pentanamide In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
  • 44
  • [ 1221343-14-1 ]
  • [ 107-15-3 ]
  • N,N'-(ethylenediamine)bis-(6-(1-hydroxy-1,3-dihydro-2,1-benzoxaborole))amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: ethylenediamine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
  • 45
  • [ 929-59-9 ]
  • [ 1221343-14-1 ]
  • N,N'-(2,2-(ethylenedioxy)bis(ethylamine))bis(6-(1-hydroxy-1,3-dihydro-2,1-benzoxaborole))amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-diaminooctane In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
  • 46
  • [ 4246-51-9 ]
  • [ 1221343-14-1 ]
  • N,N'-(4,7,10-trioxa-1,13-tridecanediamine)bis(6-(1-hydroxy-1,3-dihydro-2,1-benzoxaborole))amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 4,7,10-trioxa-1,13-diaminotridecane In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
  • 47
  • [ 870-46-2 ]
  • [ 1221343-14-1 ]
  • tert-butyl 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)hydrazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% 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 45.1 Step 1: Preparation of tert-butyl 2- (1-hydroxy-1, 3-dihydrobenzo [c] [1, 2] oxaborole-6-carbonyl) hydrazine-1-carboxylate To a solution of 1-hydroxy-1, 3-dihydrobenzo [c] [1, 2] oxaborole-6-carboxylic acid (178 g) in DMF (10 mL) was added HATU (572 mg) , DIEA (259 mg) and tert-butyl hydrazinecarboxylate (158 mg) , the mixture was stirred at room temperature overnight. Monitored by LCMS until the reaction was completed. [0429] The reaction mixture was poured into water (50 mL) and extracted with EA (30 mL*3) , combined the organic layers, washed with brine, dried over Na 2SO 4. Concentrated in vacuo, the residue was purified by combi flash (PE: EA = 100%: 0%to 50%: 50%) to afford desired product tert-butyl 2- (1-hydroxy-1, 3-dihydrobenzo [c] [1, 2] oxaborole-6-carbonyl) hydrazine-1-carboxylate (120 mg, 41%) as a white solid
  • 48
  • [ 1221343-14-1 ]
  • methyl 2,3-diaminopropionate [ No CAS ]
  • methyl (S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃; 2 Example 2: Synthesis of mDA-Z4 (methyl (S)-2,3-bis(l-hydroxy-l,3- dihydrobenzo[c] [l,2]oxaborole-6-carboxamido)propanoate) N,N’-dimethylformamide (10 mL) was added along with 150 mg of methyl (S)-2, 3-diaminopropanoate (1.26 mmol) to a 100 mL round bottom flask containing a magnetic stir-bar. l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborole-6-carboxylic acid (1.36 g, 7.8 mmol) was added to the round bottom flask followed by l-ethy-3-(3- dimethylaminopropyl)carbodiimide (440 mg, 2.65 mmol) and 4- dimethylaminopyridine (324 mg, 2.65 mmol). (0129) This solution was stirred overnight, the solvent was removed in vacuo, and the solids obtained after the removal of the solvent were dissolved in ethyl acetate. The organic layer was extracted twice with water and, subsequently, the organic layer was removed to reveal a yellow oil (298 mg, 0.776 mmol, 54 % yield). The reaction scheme is shown below:
  • 49
  • [ 1221343-14-1 ]
  • C68H103N12O14Pol [ No CAS ]
  • C84H113B2N12O20Pol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With ethyl cyanoglyoxylate-2-oxime; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 3h; 4 Example 4: Synthesis of DA-Z4 KB28 PB29 A 25-mL peptide synthesis flask charged with 500 mg (0.275 mmol) of Fmoc- Thr(OtBu)-Wang resin was allowed to swell with dichloromethane (15 mL). The dichloromethane was removed and to this was added 25% piperidine in N’N- dimethylformamide. The flask containing the resin was allowed to agitate at room temperature for 25 minutes. The solution was drained, and the resin was subsequently washed with DMF, DCM, MeOH, DCM, and DMF (15 mL). The desired peptidic sequence was achieved using the appropriate amino acid (1.1 mmol) Oxyma Pure (ethyl cyano(hydroximino)acetate) (1.1 mmol) and N, N’-diisopropylcarbodiimide (DIC) (1.1 mmol) as coupling reagents dissolved in DMF (15 mL). The flask was agitated at room temperature for 45 minutes. After successful coupling of each amino acid, the resin was washed. Fmoc protecting groups were removed from each residue with 25% piperidine in DMF (15 mL). After the full sequence was obtained, the ivDde (4,4-dimethyl-2,6-dioxocyclohex-l-ylidene)-3-methylbutyl) protecting group was removed using 5% hydrazine hydrate (NH2NH2 · xFLO) in DMF (v/v, 15 mL). The resin was treated for 45 minutes with this solution a total of three times. After treatment, the resin was washed with DMF, DCM, MeOH, DCM, and DMF (15 mL). (S)-2,3-bis((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid was attached using Oxyma Pure (1.1 mmol) and DIC (1.1 mmol) dissolved in DMF (15 mL). The flask was agitated at room temperature for 60 minutes. The resin was washed with DMF, DCM, MeOH, DCM, and DMF (15 mL). The Fmoc protecting groups were removed with 25% piperidine in DMF (25 mins, 15 mL). The resin was washed with DMF, DCM, MeOH, DCM, and DMF (15 mL). Next l-hydroxy-l,3-dihydro-2,l- benzoxaborole-6-carboxylic acid (1.65 mmol) was conjugated to the free amines using Oxyma Pure (1.65 mmol) and DIC (1.65 mmol). This was allowed to react at room temperature for 180 minutes. The solution was drained, and the resin was washed with DMF, DCM, MeOH, DCM, and DMF (15 mL). The resin was treated with a trifluoroacetic acid (TFA) solution (95% TFA, 2.5% triisopropylsilane, and 2.5% water) for 120 mins. The solution was drained into a round bottom flask. The reaction solution was concentrated by removing TFA in vacuo. The residue was then transferred to a 50-mL conical tube and triturated with cold diethyl ether. The solid were collected via centrifugation. The solids were washed once more with cold diethyl ether. Residual diethyl ether was removed under vacuum to obtain a solid. This solid was dissolved in water and purified to homogeneity by reverse phase HPLC with an eluent of solvent A (water/0.1% TFA) and solvent B (ACN/0.1% TFA). The purified DA-Z4 KB28 PB29 was characterized by LC/MS. Obtained: 1366.92 [M + H] The scheme is illustrated in FIG. 4.
  • 50
  • [ 1221343-14-1 ]
  • heptadecan-9-yl 8-((3-aminopropyl)(8-oxo-8-(undecan-3-yloxy)octyl)amino)octanoate [ No CAS ]
  • heptadecan-9-yl 8-((3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propyl)(8-oxo-8-(undecan-3-yloxy)octyl)amino)octanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 48h; 1.BA BA. Compound 62. Heptadecan-9-yl 8-((3-(1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propyl)(8-oxo-8-(undecan-3- yloxy)octyl)amino)octanoate To a solution of heptadecan-9-yl 8-((3-aminopropyl)(8-oxo-8-(undecan-3- yloxy)octyl)amino)octanoate (180 mg, 0.24 mmol) and 1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (54 mg, 0.29 mmol) in 5 mL DCM was added DMAP (3 mg, 0.02 mmol) and EDC-HCl (70 mg, 0.36 mmol) followed by DIEA (175 uL, 0.97 mmol). The resulting mixture was stirred at room temp for 48 hours after which no starting material remained by LC/MS. The solution was diluted with DCM, washed once with a saturated aqueous sodium bicarbonate solution, dried (Na2SO4), filtered and the filtrate conc. to a colorless oil/white solid mixture. This was chromatographed on silica gel with 100% DCM going to 100% 80:20:1 DCM/MeOH/ammonium hydroxide, then 50:50:1 DCM/MeOH/ammonium hydroxide to give a white solid/colorless syrup mixture. This material was again chromatographed on silica gel with 100% DCM going to 100% 50:50:1 DCM/MeOH/ammonium hydroxide. The product-containing fractions were combined, conc. and the residue triturated with diethyl ether. The precipitated solids were removed via filtration and the filtrate conc. to give heptadecan-9-yl 8-((3-(1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propyl)(8-oxo-8-(undecan-3- yloxy)octyl)amino)octanoate (66 mg, 0.07 mmol, 28%) as a colorless syrup. UPLC/ELSD: RT = 3.02 min. MS (ES): m/z (MH+) 911.53 for C55H99BN2O7. 1H NMR (300 MHz, CDCl3) d: ppm 8.76 (br s, 1H); 8.59 (br s, 1H); 8.01 (d, 1H, J = 7.9 Hz); 7.36 (d, 1H, J = 7.9 Hz); 5.07 (s, 2H); 4.81 (m, 2H); 4.71 (s, 1H); 3.60 (m, 2H); 2.96 (br s, 2H); 2.81 (br s, 4H); 2.24 (dt, 4H, J = 5.6 Hz, 1.8 Hz); 2.05 (br s, 2H); 1.75-1.39 (m, 16H); 1.38-1.12 (m, 49H); 0.94- 0.78 (m, 12H).
  • 51
  • [ 1221343-14-1 ]
  • [ 49755-94-4 ]
  • 1-hydroxy-N-[2-(methylamino)-2-oxoethyl]-3H-2,1-benzoxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: glycine-N-methylamide hydrochloride In N,N-dimethyl-formamide at 40℃;
  • 52
  • [ 1221343-14-1 ]
  • [ 71666-94-9 ]
  • N-[(1R)-2-amino-1-benzyl-2-oxoethyl]-1-hydroxy-3H-2,1-benzoxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% Stage #1: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (R)-2-amino-3-phenylpropanamide hydrochloride In N,N-dimethyl-formamide at 40℃;
  • 53
  • [ 1221343-14-1 ]
  • [ 29022-11-5 ]
  • (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidine-2-carboxylic acid [ No CAS ]
  • ((2S,4S)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidine-2-carbonyl)glycine [ No CAS ]
YieldReaction ConditionsOperation in experiment
27 mg Stage #1: N-(fluoren-9-ylmethoxycarbonyl)glycine With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.0833333h; Stage #3: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid; (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidine-2-carboxylic acid Further stages; 2 Synthesis of Example 2: Chlorotrityl resin (1.5 mmol/eq, 300mg) was swelled in dry DCM (5mL) for 30 minutes.The solvent was removed under a stream of nitrogen and a solution of Fmoc-glycine (0.5M) in DCM with DIPEA (1M) was added immediately and gently mixed for 1 hr. The mixture was washed with DCM, and unreacted sites were capped with a solution of 20% MeOH in a solution of DCM and DIEA (1M) and mixed for 1hr. The resin was washed with DCM (2x5mL) and then DMF (2x5mL). The solution was removed under a stream of nitrogen, and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL). A solution of (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidine-2-carboxylic acid (280 mg, 0.5 mmol) with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 190 mg, 0.5 mmol), and DIPEA (200 μl) in DMF (5mL) was added to the resin and mixed at 50 C for 20 minutes. The resin was washed with DMF (3x5mL), and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL), and a solution of 1- hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (177 mg, 1 mmol) with HATU (380 mg, 1mmol) and DIPEA (200 μL ) in DMF (5mL) was added to the resin and mixed at 50 C for 30 minutes. The resin was washed with DMF (3x 5mL) and then DCM (3x 5mL). A solution of trifluoroacetic acid with triisopropyl silane and water (95:2.5:2.5, 5 mL) was added to the resin and mixed for 90 minutes. The solution was collected and dried under vacuum, dissolved in DMSO (100μL) and fractionated by reverse-phase (RP) flash chromatography on a C18 column with a gradient of 20% ACN in water with 0.1% TFA to 60% ACN in water with 0.1% TFA over 10 minutes. Pure fractions were isolated, combined, frozen, and lyophilized to yield Example 2 as a white powder (27 mg). Expected mass [M+H]: 508.16; Observed [M+H]: 508.13 FIG.2 is a mass spectrum plot confirming the synthesis of Example 2.
  • 54
  • (3-carboxy-4-nitro phenyl)dihydroxy borane [ No CAS ]
  • [ 1221343-14-1 ]
  • [ 29022-11-5 ]
  • (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)pyrrolidine-2-carboxylic acid [ No CAS ]
  • ((2S,4S)-1-(5-borono-2-nitrobenzoyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidine-2-carbonyl)glycine [ No CAS ]
YieldReaction ConditionsOperation in experiment
15 mg Stage #1: N-(fluoren-9-ylmethoxycarbonyl)glycine With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.0833333h; Stage #3: (3-carboxy-4-nitro phenyl)dihydroxy borane; 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid; (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)pyrrolidine-2-carboxylic acid Further stages; 3 Synthesis of Example 3. Chlorotrityl resin (1.5 mmol/eq, 300mg) was swelled in dry DCM (5mL) for 30 mins. The solvent was removed under a stream of nitrogen and a solution of Fmoc-glycine (0.5M) in DCM with DIPEA (1M) was added immediately and gently mixed for 1 hr. The mixture was washed with DCM, and unreacted sites were capped with a solution of 20% MeOH in a solution of DCM and DIEA (1M) and mixed for 1hr. The resin was washed with DCM (2x5mL) and then DMF (2x5mL). The solution was removed under a stream of nitrogen, and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL). A solution of (2R,4R)-1-(((9H-fluoren-9- yl)methoxy)carbonyl)-4-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)pyrrolidine- 2-carboxylic acid (258 mg, 0.5 mmol) with 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 190 mg, 0.5 mmol), and DIPEA (200 μL) in DMF (5mL) was added to the resin and mixed at 50 C for 20 minutes. The resin was washed with DMF (3x5mL) and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL) and a solution of 5-borono-2-nitrobenzoic acid (105 mg, 0.5 mmol) with HATU (190 mg, 0.5 mmol) and DIPEA (200 μL) in DMF (5mL) was added to the resin and mixed at 50 C for 30 minutes. The resin was washed with DMF (3x5mL) and a solution of 4% hydrazine in DMF was added to the resin (3x5mL) and mixed for 5 minutes. The resin was washed with DMF (3x5mL) and a solution of 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (89 mg, 0.5 mmol) with HATU (190 mg, 0.5 mmol) and DIPEA (200 μL) in DMF (5mL) was added to the resin and mixed at 50 C for 30 minutes. The resin was washed with DMF (3x 5mL) and then DCM (3x 5mL). A solution of trifluoroacetic acid with triisopropyl silane and water (95:2.5:2.5, 5 mL) was added to the resin and mixed for 90 minutes. The solution was collected and dried under vacuum, dissolved in DMSO (100μL) and fractionated by reverse-phase (RP) flash chromatography on a C18 column with a gradient of 20% ACN in water with 0.1% TFA to 60% ACN in water with 0.1% TFA over 10 minutes. Pure fractions were isolated, combined, frozen, and lyophilized to yield Example 3 as a white powder (15 mg). Expected mass [M+H]: 541.15; Observed [M+H]: 541.13 FIG.3 is a mass spectrum plot confirming the synthesis of Example 3.
  • 55
  • [ 1221343-14-1 ]
  • [ 1436-59-5 ]
  • [ 79-08-3 ]
  • N-(2-amino-2-oxoethyl)-1-hydroxy-N-((1R,2R)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)cyclohexyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
5 mg Stage #1: bromoacetic acid With diisopropyl-carbodiimide In N,N-dimethyl-formamide at 50℃; for 0.166667h; Stage #2: cis-cyclohexane-1,2-diamine In N,N-dimethyl-formamide at 50℃; for 0.166667h; Stage #3: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid Further stages; 14 Synthesis of Example 14: Rink-amide resin (1.2 mmol/eq, 150 mg) was swelled in DMF (5mL) for 20 minutes. The solution was removed under a stream of nitrogen and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL). Bromoacetic acid in DMF (1 M, 5mL) with 1 M N,N’- diisopropylcarbodiimide (DIC, 1M, 1mL) in DMF was added to the resin and heated at 50 C for 10 min. The reaction mixture was washed with DMF (2 x 5mL). A solution of (1R,2S)-cyclohexane-1,2-diamine (2 M, 5mL) in DMF was added to the reaction mixture and heated at 50 C for 10 min. The resin was washed with DMF (3x5mL), and a solution of 1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (0.2 M, 5mL) in DMF with 1 M N,N’- diisopropylcarbodiimide (DIC, 1M, 1mL), Oxyma (0.5 M, 2mL) in DMF was added and heated at 50 C for 30 min. The resin was washed with DMF (3x 5mL) and then DCM (3x 5mL). A solution of trifluoroacetic acid with triisopropyl silane and water (95:2.5:2.5, 5 mL) was added to the resin and mixed for 90 minutes. The solution was collected and dried under vacuum, dissolved in DMSO (100μL) and fractionated by reverse-phase (RP) flash chromatography on a C18 column with a gradient of 20% ACN in water with 0.1% TFA to 60% ACN in water with 0.1% TFA over 10 minutes. Pure fractions were isolated, combined, frozen, and lyophilized to yield Example 14 as a white powder (5 mg). Expected mass [M+H]: 492.19; Observed [M+H]: 492.14 [M+H-H2O]: 475.27; [M+Na]:513.07 FIG.14 is a mass spectrum plot confirming the synthesis of Example 14.
  • 56
  • [ 1221343-14-1 ]
  • [ 101084-81-5 ]
  • fmoc-Nβ-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-2,3-diaminopropionic acid [ No CAS ]
  • (S)-(3-((1-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-1-oxopropan-2-yl)carbamoyl)-5-nitrophenyl)boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
11 mg Stage #1: fmoc-Nβ-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-2,3-diaminopropionic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 50℃; for 0.333333h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.0833333h; Stage #3: 1-(hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carboxylic acid; (3-carboxy-5-nitrophenyl)boronic acid Further stages; 4 Synthesis of Example 4: Rink-amide resin (1.2 mmol/eq, 150 mg) was swelled in DMF (5mL) for 20 minutes. The solution was removed under a stream of nitrogen and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL). A solution of Fmoc-Nβ-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-2,3-diaminopropionic acid (266 mg, 0.5 mmol) with 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 190 mg, 0.5 mmol), and DIPEA (200 μL) in DMF (5mL) was added to the resin and mixed at 50 C for 20 minutes. The resin was washed with DMF (3x5mL) and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL) and a solution of 20% piperidine in DMF (5mL) was added to the resin and mixed for 5 minutes. The resin was washed with DMF (3x5mL) and a solution of 3-borono-5-nitrobenzoic acid (105 mg, 0.5 mmol) with HATU (190 mg, 0.5 mmol) and DIPEA (200 μL) in DMF (5mL) was added to the resin and mixed at 50 C for 30 minutes. The resin was washed with DMF (3x5mL) and a solution of 4% hydrazine in DMF was added to the resin (3x5mL) and mixed for 5 minutes. The resin was washed with DMF (3x5mL) and a solution of 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (89 mg, 0.5 mmol) with HATU (190 mg, 0.5 mmol) and DIPEA (200 μL) in DMF (5mL) was added to the resin and mixed at 50 C for 30 minutes. The resin was washed with DMF (3x 5mL) and then DCM (3x 5mL). A solution of trifluoroacetic acid with triisopropyl silane and water (95:2.5:2.5, 5 mL) was added to the resin and mixed for 90 minutes. The solution was collected and dried under vacuum, dissolved in DMSO (100μL) and fractionated by reverse- phase (RP) flash chromatography on a C18 column with a gradient of 20% ACN in water with 0.1% TFA to 60% ACN in water with 0.1% TFA over 10 minutes. Pure fractions were isolated, combined, frozen, and lyophilized to yield Example 4 as a white powder (11 mg). Expected mass [M+H]: 457.13; Observed [M+H]: 457.00 [M+H-H2O]: 440.13 FIG.4 is a mass spectrum plot confirming the synthesis of Example 4.
  • 57
  • [ 1606-67-3 ]
  • [ 1221343-14-1 ]
  • C24H16BNO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride In methanol at 20℃; for 72h;
Same Skeleton Products
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