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CAS No. : | 594-61-6 | MDL No. : | MFCD00004459 |
Formula : | C4H8O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BWLBGMIXKSTLSX-UHFFFAOYSA-N |
M.W : | 104.10 | Pubchem ID : | 11671 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 24.31 |
TPSA : | 57.53 Ų |
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) : | -7.19 cm/s |
Log Po/w (iLOGP) : | 0.79 |
Log Po/w (XLOGP3) : | -0.36 |
Log Po/w (WLOGP) : | -0.16 |
Log Po/w (MLOGP) : | -0.39 |
Log Po/w (SILICOS-IT) : | -0.65 |
Consensus Log Po/w : | -0.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.19 |
Solubility : | 66.8 mg/ml ; 0.642 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.39 |
Solubility : | 42.8 mg/ml ; 0.411 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.57 |
Solubility : | 387.0 mg/ml ; 3.72 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine In acetonitrile | In steps 1-4, 2-hydroxy-isobutyric acid was protected with benzyl bromide, alkylated with ethyl iodide, deprotected, and esterified to afford 2-ethoxy-isobutyric acid chloromethyl ester. |
83% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 5 - 20℃; for 1 h; Stage #2: at 100℃; for 3 h; Microwave irradiation |
To a solution of 2-hydroxy-2-methylpropanoic acid (500 mg, 4.80 mmol) in dry THF (10 ml), NaH (60percent dispersion in mineral oil, 192 mg, 4.80 mmol) was added portionwise at 5° C. The resulting mixture was stirred 1 hour at RT. The solvent was removed, the residue was suspended in dry DMF (7 ml), and (bromomethyl)benzene (821 mg, 4.80 mmol) was added followed by a catalytic amount of KI. The reaction was heated under microwave irradiation at 100° C. for 3 hours. After cooling, the solvent was evaporated and the residue was partitioned between water and EtOAc; the organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc/petroleum ether=1/1) affording benzyl 2-hydroxy-2-methylpropanoate as a yellow liquid (773 mg, 3.98 mmol, 83percent yield). |
70% | With tetra-(n-butyl)ammonium iodide; sodium hydrogencarbonate In dichloromethane; water at 20℃; for 60 h; | A solution of 2-hydroxy-2-methylpropanoic acid (101, 9.27 g, 89.1 mmol), sodium bicarbonate (7.49 g, 89.1 mmol), benzyl bromide (16.8 g, 98.0 mmol) and tetrabutylammonium iodide (32.9 g, 89.1 mmol) in H2O/CH2C12 (1 : 1 , 300 mL) was stirred at room temperature for 2.5 d. The reaction mixture was diluted with CH2Cl2 (200 mL) and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2 x 50 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 7:3 hexanes/EtOAc) provided 102 (12.2 g, 70percent) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.37-7.32 (m, 5H), 5.20 (s, 2H), 3.05 (s, I H), 1.45 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 5 - 20℃; for 1 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide at 100℃; for 3 h; Microwave irradiation |
To a solution of 2-hydroxy-2-methylpropanoic acid (500 mg, 4.80 mmol) in dry THF (10 ml), NaH (60percent dispersion in mineral oil, 192 mg, 4.80 mmol) was added portionwise at 5°C. The resulting mixture was stirred lh at RT. The solvent was removed, the residue was suspended in dry DMF (7 ml) and (bromomethyl)benzene (821 mg, 4.80 mmol) was added followed by a catalytic amount of KI. The reaction was heated under microwave irradiation at 100°C for 3h. After cooling the solvent was evaporated and the residue was partitioned between water and EtOAc; the organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (EtO Ac/petroleum ether = 1/1) affording benzyl 2-hydroxy-2- methylpropanoate as a yellow liquid (773 mg, 3.98 mmol, 83percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine In acetonitrile at 20℃; for 0.666667 h; | Example 1 2-(Benzoyloxy)-2-methylpropanoic acid 2-Hydroxyisobutyric acid (50 g) was dissolved in acetonitrile (480 mL). To this solution, pyridine (78 mL) was added, and then, benzoyl chloride (56 mL) was added thereto. The resulting solution was stirred at room temperature for 40 minutes. To the reaction mixture, 2 N hydrochloric acid (300 mL) was added to acidify the solution, and then, extraction was performed with ethyl acetate (400 mL*2). The organic layers were combined and dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue was recrystallized from tert-butylmethyl ether/n-heptane, whereby the title compound (82 g, 82percent) having the following physical properties was obtained. TLC (Rf value): 0.37 (ethyl acetate) NMR (300 MHz, CDCl3): δ 8.20-9.40 (br, 1H), 8.01-8.06 (m, 2H), 7.53-7.59 (m, 1H), 7.40-7.46 (m, 2H), 1.73 (s, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.27% | at 182℃; under 300.03 Torr; for 10.0667h; | 1.2 kg (11.54 mol) of pure 2-hydroxyisobutyric acid (HIBA) were introduced into a still with column and condenser. The pressure was adjusted to 400 mbar and the reaction temperature was adjusted to approx. 180 C., the bottom temperatures being specified in Table 1. Water was removed from the reaction mixture continuously by distillation. The temperature at the top of the still was approx. 76 C. After the time intervals shown in Table 1, samples were taken from the bottoms and analysed by means of gas chromatography. TABLE 1 Temperature of Tetramethyl- Time the bottoms glycolide HIBA [min] [ C.] [% by wt.] [% by wt.] 79 178 40.19 58.07 139 180 56.04 42.95 199 184 74.48 23.72 259 185 80.84 18.25 334 188 95.20 2.63 414 187 95.45 2.70 504 188 97.60 0.23 594 182 98.19 0.24 604 182 98.27 0.23 It has been shown that, surprisingly, when 2-hydroxy-isobutyric acid is used as the reactant, essentially pure tetramethylglycolide is formed as the cyclic ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In ISOPROPYLAMIDE; at -10℃; for 0.5h; | 1.5 g of 2-hydroxy-2-methyl-propionic acid is mixed in 50 ml dimethylacetamide at -10 C. with 1.05 ml thionylchloride and stirred for 30 minutes at -10 C. A solution of 2 g 3-nitroaniline is dropped into 10 ml dimethylacetamide at -10 C. and stirred consecutively for one hour at -10 C., one hour at 0 C. and for 15 hours at ambient temperature. The solution is condensed off in the high vacuum, the residue is incorporated into a mixture of acetic acid ethylester and dichloromethane (1:3) and washed twice with semisaturated sodiumhydrogencarbonate solution. The organic phase is dried over sodium sulfate. After being purified by chromatography on silica gel, 2.42 g of title compound is obtained. 1H-nMR (CDCl3): delta=1.49 (s, 6H); 2.35 (s, 1H); 7.50 (t, 1H); 7.98 (d, 2H); 8.49 (s, 1H); 8.98 (s, b, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 7h; | Benzyl piperazine-1-carbamate (2.203 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); 2-hydroxy-2-methylpropionic acid (1.25 g, 12.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12.0 mmol), 1-hydroxy-1H-benzotriazole monohydrate (1.84 g, 12.0 mmol) and triethylamine (3.35 ml, 24.0 mmol) were added; and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and dried under reduced pressure to yield the title compound (2.823 g, 9.21 mmol, 92.1%) as a colorless oil. 1H-NMR Spectrum (CDCl3) delta (ppm): 1.50 (6H, s), 3.52-3.55 (4H, m), 3.60-3.70 (4H, m), 3.93 (1H, s), 5.16 (2H, s), 7.34-7.38 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Example 43 N-[1-(CYCLOHEXYLMETHYL)-2-(1-HYDROXY-1-METHYLETHYL)-LH-BENZIMIDAZOL-5-YLL- benzenesulfonamide; Diisopropylethylamine (291.4 mg, 2.25 mmol) was added into a solution OF N-{3- amino-4- [ (cyclohexylmethyl) amino] phenyl) benzene sulfonamide (540.1 mg, 1.50 mmol) (for preparation, see Steps B and C in Example 7) and 2-hydroxy isobutyric acid (171. 8 MG, 1. 65 MMOL) IN DMF (15 ML) AT 0 C. STIRRING FOR 20 MIN., HATU (684.4 mg, 1.80 mmol) was added. The reaction mixture was stirred for 24 h at room temperature, diluted with water (100 mL), and extracted with EtOAc (2X50 mL). The combined organic phases were washed with NACI (20 ML) and dried with anhydrous sodium sulphate. After filtration and concentration, the residue was dissolved in acetic acid (5 mL) in a sealed tube. The solutions were heated at 140C using a Personal Chemistry Smith Synthesizer microwave instrument for 30 min. Upon evaporation of the solvent, the residue was diluted with EtOAc (100 mL), washed with 2N NAOH (10 mL), sat. NACI (2x10 mL) and dried over anhydrous sodium sulphate. After filtration and evaporation, the residue was purified by MPLC (EtOAc on silica gel) to give 364.6 mg (57%) of a white solid as the title compound. Part of the product was converted to TFA SALT. H NMR (400 MHZ, CD30D) : OL. 17 (m, 5 H), 1.56 (m, 2 H), 1.70 (m, 3 H), 1.76 (s, 6 H), 2.09 (m, 1 H), 4.48 (d, J=7.62 Hz, 2 H), 7. 23 (M, 1 H), 7.47 (m, 2 H), 7.56 (m, 2 H), 7.72 (d, J=8.98 Hz, 1 H), 7.79 (m, 2 H); MS (ESI) (M+H) + = 428.0 ; Anal. Calcd for C23H29N303S+1. 2TFA: C, 54.05 ; H, 5.39 ; N, 7.45. Found: C, 54.09 ; H, 5.50 ; N, 7.42. | |
57% | Example 23; N [1- (CYCLOHEXYLMETHYL)-2- (1-HYDROXY-1-METHYLETHYL)-LH-BENZIMIDAZOL-5-YL]- benzenesulfonamide; Diisopropylethylamine (291.4 mg, 2.25 mmol) was added into a solution OF N-{3- AMINO-4-[(CYCLOHEXYLMETHYL) AMINOJPHENYL, TBENZENE SULFONAMIDE (540.1 mg, 1.50 mmol) (for preparation, see Steps B, C and D in Example 7) and 2-hydroxy isobutyric acid (171.8 mg, 1.65 mmol) in DMF (15 mL) at 0 C. Stirring for 20 min. , HATU (684.4 mg, 1.80 mmol) was added. The reaction mixture was stirred for 24 h at room temperature, diluted with water (100 mL), and extracted with EtOAc (2X50 mL). The combined organic phases were washed with NACL (20 mL) and dried with anhydrous sodium sulphate. After filtration and concentration, the residue was dissolved in acetic acid (5 ML) in a sealed tube. The solutions were heated at 140C using a Personal Chemistry Smith Synthesizer microwave instrument for 30 min. Upon evaporation of the solvent, the residue was diluted with EtOAc (100 mL), washed with 2N NAOH (10 ML), sat. NACI (2X10 mL) and dried over anhydrous sodium sulphate. After filtration and evaporation, the residue was purified by MPLC (EtOAc on silica gel) to give 364.6 mg (57%) of a white solid as the title compound. Part of the product was converted to TFA SALT. 1H NMR (400 MHZ, CD30D) : 51. 17 (m, 5 H), 1.56 (m, 2 H), 1.70 (m, 3 H), 1.76 (s, 6 H), 2.09 (m, 1 H), 4.48 (d, J=7.62 Hz, 2 H), 7.23 (m, 1 H), 7.47 (m, 2 H), 7.56 (m, 2 H), 7.72 (d, J=8. 98 HZ, 1 H), 7.79 (m, 2 H); MS (ESI) (M+H) + = 428.0 ; Anal. Calcd for C23H29N303S+1. 2TFA : C, 54.05 ; H, 5.39 ; N, 7.45. Found: C, 54.09 ; H, 5.50 ; N, 7.42. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 50℃; for 3h; | Compound 136 (150 mg, 0.555 mmol) was dissolved in DMF (2.5 mL), and <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (116 mg, 1.11 mmol), EDC hydrochloride (313 mg, 1.11 mmol) and 1-hydroxybenzotriazole monohydrate (170 mg, 1.11 mmol) were added thereto, followed by stirring at 50C for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate = 1:1) to afford the entitled Compound 137 (158 mg, 80 %). 1H NMR (CDCl3, delta ppm): 1.63 (s, 6H), 6.44 (dd, J = 1.8, 3.5 Hz, 1H), 7.21 (dd, J = 0.7, 3.5 Hz, 1H), 7.38 (dd, J = 0.7, 1.8 Hz, 1H), 7.39-7.53 (m, 3H), 7.78-7.82 (m, 2H), 10.6 (s, 1H). APCIMS m/z: [M+H]+ 357. m.p.: 153-154C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride; In diethyl ether; | alpha-Hydroxy Isobutyric Acid A one liter flask was charged with 193 milliliters (2.11 moles) of acetone cyanohydrin and 212 milliliters (2.12 moles) concentrated hydrochloric acid was placed in an addition funnel. The acid was slowly added dropwise to the stirred cyanohydrin. The temperature rose to approximately 100 C. before subsiding. A heating mantle was attached to maintain a temperature of 85-98 C. during the addition of the remaining acid. After addition the temperature was maintained at 85-98 C. for two hours. The mixture was cooled and the solid ammonium chloride by-product was filtered off, thoroughly washed with acetone and refiltered. The acetone extracts were combined with the initial filtrate and the solvent was extracted using reduced pressures. The residue was dissolved in ethyl ether and refiltered to remove any inorganic salt that remained. There was obtained 174 grams, 85% of theoretical yield of alpha-hydroxy isobutyric acid as a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With p-toluenesulfonic acid monohydrate; In toluene; | EXAMPLE 1 A mixture of 4-(4-chlorophenyl)benzaldehyde (15.0 g.), 2-hydroxy-2-methylpropionic acid (10.0 g.) and p-toluenesulphonic acid monohydrate (0.2 g.) was heated in toluene (200 ml.) under reflux for 6 hours with continuous removal of water by azeotropic distillation. The solution was then cooled, washed with 10% w/v sodium hydrogen carbonate solution (100 ml.) and then with water (2*100 ml.) before it was dried (Na2 SO4). The dried toluene solution was filtered and evaporated to give 2-[4-(4-chlorophenyl)phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (14.6 g.), m.p. 108-110 C. (after recrystallisation from cyclohexane and then from toluene). The 4-(4-chlorophenyl)benzaldehyde was obtained as follows: | |
With pyridine; In chlorobenzene; isopropyl alcohol; | EXAMPLE 14 A mixture of 4-(4-chlorophenyl)benzaldehyde (21.6 g.), 2-hydroxy-2-methylpropionic acid (10.2 g.) and cationic sulphonated polystyrene ion exchange resin (`AMBERLITE` *IR 120, free acid form; 2.0 g.) in chlorobenzene (125 ml.) was heated under reflux for 24 hours with continuous removal of water by azeotropic distillation. The mixture was cooled and the resin was separated by filtration. Pyridine (3 ml.) was added to the filtrate which was then evaporated. The residue was dissolved in hot 2-propanol (200 ml.). A small quantity of insoluble material was removed by filtration and the subsequent filtrate was allowed to cool to give 2-[4-(4-chlorophenyl)phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (11.8 g.), m.p. 108-110 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ISOPROPYLAMIDE; at 20℃; for 1h; | Example 266. Preparation of N-(3-[3-BROMO-4-[(2, 4-DIFLUOROBENZYL) oxy] -6- METHYL-2-OXOPYRIDIN-1 (2H)-YL] METHYL} BENZYL)-2-HYDROXY-2-METHYLPROPANAMIDE L- [3- (AMINOMETHYL) BENZYL]-3-BROMO-4- [ (2, 4-difluorobenzyl) oxy]-6-methylpyridin-2 (1H)- one (Example 161) (0.300 g, 0.668 mmol), 1-HYDROXYISOBUTYRIC acid (0.215 g, 2.064 mmol), 1-hydroxybenzotriazole (0.112 g, 0.826 mmol), and 1- (3-dimethylaminopropyl)-3- ETHYLCARBODIIMIDE hydrochloride (0.185 g, 0.963 mmol) were dissolved in N, N- dimethylacetamide (3 mL). N-methylmorpholine (0.209 g, 2.064 mmol) was added, and the reaction stirred for 1 hour at room temperature. The reaction was diluted with H20 (50 mL) and the aqueous layer extracted with ethyl acetate (3 x 25 mL). The combined organics were then washed with 1N HCl (25 mL), saturated Na2CO3 (25 mL), brine (25 mL), dried over NA2S04, and concentrated to yield an off-white solid (0.235 g, 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydride; In N,N-dimethyl-formamide; | Step A: Phenylmethyl 2-methyl-2-(phenylmethoxy)propanoate (28a) 1.56 g (15 mmol) of <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> was dissolved in 150 mL of anhydrous DMF. To the stirred solution was added sodium hydride (0.79 g, 33 mmol) and benzyl bromide (5.6 g, 3.9 mL, 33 mmol). The reaction was monitored by thin layer chromatography (TLC). After the starting material was completely consumed, the reaction was quenched by addition of a 1N HCl solution and then extracted with diethyl ether (twice). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered, and the solvents removed under reduced pressure using a rotary evaporator. The residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1:9) as eluent to provide 4.0 g (94% yield) of the title compound (28a). Rf=0.78 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CHCl3): delta=1.56 (s, 6H), 4.46 (s, 2H), 5.22 (s, 2H), 7.28-7.38 (m, 10H) ppm. |
47% | Step 1: NaH (2.64 g, 66 mmol, 60% in mineral oil, 2.20 eq) was added to 2-hydroxy-2- methyipropanoic acid (3.12 g, 30 mmol, 1 eq) in DMF (30 mL) at 000. The mixture was stirred a t 20C for 30 mins. (bromomethyl)benzene (10.26 g, 60 mmol, 7.13 mL, 2 eq) wasadded to the reaction mixture at 20C and stirred at 20C for 16 hours. The mixture was quenched by H20 (30 mL) and adjusted pH=7 by HCI (1 M, aq). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed by H20 (20 mL) and brine. The residue was dried over Na2504 and concentrated under vacuum. 1H NMR showed the compound was desired product. benzyl 2-(benzyloxy)-2-methylpropanoate (3.98g, 14 mmol, 47% yield) was obtained.1H NMR(CDCI3 400 MHz): 7.40-7.32 (m, 1OH), 5.24 (s, 2H), 4.48 (s, 2H), 1.58 (s, 6H). | |
47% | Step 1 : NaH (2.64 g, 66 mmol, 60% in mineral oil, 2.20 eq) was added to 2-hydroxy-2- methylpropanoic acid (3.12 g, 30 mmol, 1 eq) in DMF (30 mL) at 0C. The mixture was stirred a 1 20C for 30 mins. (bromomethyl)benzene (10.26 g, 60 mmol, 7.13 mL, 2 eq) was added to the reaction mixture at 20C and stirred at 20C for 16 hours. The mixture was quenched by H2O (30 mL) and adjusted pH=7 by HCl (1 M, aq). The mixture was extracted with ethyl acetate (30 mL chi 3). The combined organic layers were washed by H20 (20 mL) and brine. The residue was dried over Na2S04 and concentrated under vacuum. 1H NMR showed the compound was desired product, benzyl 2-(benzyloxy)-2-methylpropanoate (3.98 g, 14 mmol, 47% yield) was obtained. 1H NMR (CDCl3, 400 MHz): delta 7.40-7.32 (m, 10H), 5.24 (s, 2H), 4.48 (s, 2H), 1 .58 (s, 6H). |
47% | NaH (2.64 g, 66 mmol, 60% in mineral oil, 2.20 eq) was added to 2-hydroxy-2- methylpropanoic acid (3.12 g, 30 mmol, 1 eg) in DMF (30 mL) at 0C. The mixture was stirred a t 20C for 30 mins. (bromomethyl)benzene (10.26 g, 60 mmol, 7.13 mL, 2 eq) was added to the reaction mixture at 20C and stirred at 20C for 16 hours. The mixture was quenched by H20 (30 mL) and adjusted pH=7 by HCI (1 M, aq). The mixture was extracted with ethyl acetate (30 mL chi 3). The combined organic layers were washed by H20 (20 mL) and brine. The residue was dried over Na2S04 and concentrated under vacuum. 1H NMR showed the compound was desired product, benzyl 2-(benzyloxy)-2-methylpropanoate (3.98 g, 14 mmol, 47% yield) was obtained. (1254) 1H NMR (CDCI3 400 MHz): delta 7.40-7.32 (m, 10H), 5.24 (s, 2H), 4.48 (s, 2H), 1.58 (s, 6H). | |
42% | Synthesis of benzyl 2-(benzyloxy)-2-methylpropanoate: Sodium hydride (2.64 g, 60% in oil, 66 mmol) was added to 2-hydroxy-2-methyl- propionic acid (3.12 g, 30 mmol) in DMF (30 mL) at 0C. The reaction mixture was stirred for 30 min at room temperature. Benzyl bromide (10.03 g, 60 mmol) was added and the reaction mixture was stirred at room temperature over night. The reaction mixture was quenched with HCl (1 M) and extracted with Et20 (3x50 mL). The organic solution was washed with water, brine, and dried over MgS04. The solvent was evaporated and residue was purified by column to prepare benzyl 2-(benzyloxy)-2-methylpropanoate (3.6 g, 42% yield). 1H NMR (300 MHz, CDC13/TMS): delta 7.39-7.29 (m, 10H), 5.24 (s, 2H), 4.49 (s, 2H), 1.58 (s, 6H). | |
42% | [0555] Synthesis of benzyl 2-(benzyloxy)-2-methylpropanoate: [0556] Sodium hydride (2.64 g, 60% in oil, 66 mmol) was added to 2-hydroxy-2- methyl-propionic acid (3.12 g, 30 mmol) in DMF (30 mL) at 0C. The reaction mixture was stirred for 30 min at room temperature. Benzyl bromide (10.03 g, 60 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with HCl (1 M) and extracted with Et20 (3x50 mL). The organic solution was washed with water, brine, and dried over MgS04. The solvent was evaporated and residue was purified by column to prepare benzyl 2- (benzyloxy)-2-methylpropanoate (3.6 g, 42% yield). 1H NMR (300 MHz, CDC13/TMS): delta 7.39-7.29 (m, 10H), 5.24 (s, 2H), 4.49 (s, 2H), 1.58 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Example 162W-(3-Methoxybenzyl)-4-(2-((((rans)-4-(2-hydroxy-2-methylpropanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamideA mixture of 2-hydroxy isobutyric acid (10 mg, 0 10 mmol) and 1 -hydroxybenzatriotaazole (15 mg, 0 1 1 mmol) in 2- methyl tetrahydrofuran (2 mL) for was stirred for 5 minutes lambda/-(3-Methoxybenzyl)-4-(2-(((frans)-4-amiotanocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpiotacoliotanamiotade (prepared as described in Example 153) (0 050 g, 0 09 mmol), t?ethylamine (0 015 mL, 0 11 mmol), and polymer supported carbodiimide (0 1 1 g, 0 14 mmol) were added The mixture was stirred for 18 hours at room temperature and was then filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (21 mg, 45%) 1H NMR (400 MHz, DMSO-Cf6) delta ppm 9 19 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=8 1 Hz, 2 H), 6 90 (br s , 2 H), 6 80 (d, J=8 8 Hz, 1 H), 4 65 (d, J=6 6 Hz, 2 H), 4 49 (d, J=5 9 Hz, 2 H), 3 71 (s, 3 H), 3 21 - 3 35 (m, 1 H), 2 65 (s, 3 H), 1 91 - 2 05 (m, 1 H), 1 72 (d, J= 1 1 7 Hz, 2 H), 1 60 (d, J= 1 1 7 Hz, 2 H), 1 06 - 1 33 (m, 10 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Example 218/V-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2-hydroxy-2-methylpropanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamideA mixture of 2-hydroxy isobutyric acid (19 mg, 0 19 mmol) and 1 -hydroxybenzatriotaazole (25 mg, 0 19 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes lambda/-(3-Methoxybenzyl)-4- (2-(((c/s)-4-amiotanocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpiotacoliotanamiotade (prepared as described in Example 209) (0 085 g, 0 15 mmol), triethylamine (0 026 mL, 0 19 mmol), and polymer supported carbodiimide (0 18 g, 0 23 mmo.) were then added The mixture was allowed to stir for 18 hours at room temperature and then filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (20 mg, 25%) 1H NMR (400 MHz, DMSO-d5) delta ppm 9 19 (t, J=6 6 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 29 (d, J=8 05 Hz, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=8 1 Hz, 1 H), 5 35 (s, 1 H), 4 77 (d, J=I 3 Hz, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 17 - 2 30 (m, 1 H), 1 61 - 1 74 (m, 2 H), 1 42 - 1 55 (m, 4 H), 1 30 - 1 41 (m, 2 H), 1 22 (s, 6 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Example 220/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxy-2- methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamideA mixture of 2-hydroxy isobutyric acid (10 mg, 0 09 mmol) and 1 -hydroxybenzatriotaazole (1 1 mg, 0 08 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes lambda/-(4-Fluoro-3- methoxybenzy.)-4-(2-(((c/s)-4-amiotanocyc.ohexy.)methyl)-2H-tetrazol-5-yl)-6-methylpiotaco.iotanamiotade (prepared as described in Example 219) (0 040 g, 0 07 mmol), triethylamine (0 012 mL, 0 085 mmol), and polymer supported carbodiimide (0 082 g, 0 1 1 mmol) were added The mixture was stirred for 18 hours at room temperature and was then filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (10 mg, 29%) 1H NMR (400 MHz, DMSOd6) delta ppm 9 21 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 29 (d, J=7 3 Hz, 1 H), 7 05 - 7 20 (m, 2 H), 6 89 (d, J=3 7 Hz, 1 H), 5 35 (s, 1 H), 4 77 (d, J=Q 1 Hz, 2 H), 4 48 (d, J=5 9 Hz, 2 <n="297"/>H), 3 80 (s, 3 H), 3 71 (br s , 1 H), 2 61 - 2 70 (m, 3 H), 2 21 (d, J=3 7 Hz, 1 H), 1 61 - 1 74 (m, 2 H), 1 48 (dd, J=W 3, 3 7 Hz, 3 H), 1 27 - 1 40 (m, 2 H), 1 14 - 1 28 (m, 6 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine; In hexane; ethyl acetate; acetone; | 3,6,6-Trimethyl-1,4-dioxane-2,5-dione (2) (referred as dimethyl-substituted lactide) 5 g alpha-hydroxyisobutyric acid (48 mmol) and 5.15 mL 2-bromopropionyl chloride (50 mmol) were stirred at 75 C. under nitrogen for 12 h. 300 mL acetone and 14 mL anhydrous triethylamine (100 mmol) were added to the mixture and the solution was stirred for 3 h at 60 C. After filtration of the triethylammonium chloride salts, acetone was distilled off and the resulting mixture was dissolved in 450 mL ethyl acetate:hexane mixture (1:1). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from ethyl acetate:hexane mixture (1:10). 1H NMR (500 MHz, CDCl3): delta 5.1 (q, 1H), 1.705 (s, 6H), 1.69 (d, 3H). 13C NMR (500 MHz, CDCl3): delta 168.58, 166.64, 80.54, 72.90, 26.23, 25.27, 17.41. ELEM. ANAL. Calcd. for C7H10O4: C, 53.16; H, 6.33. Found: C, 52.86; H, 6.39. Yield: 46%. |
46% | 5 g alpha-hydroxyisobutyric acid (48 mmol) and 5.15 mL 2-bromopropionyl chloride (50 mmol) were stirred at 75 C. under nitrogen for 12 h. 300 mL acetone and 14 mL anhydrous triethylamine (100 mmol) were added to the mixture and the solution was stirred for 3 h at 60 C. After filtration of the triethylammonium chloride salts, acetone was distilled off and the resulting mixture was dissolved in 450 mL ethyl acetate:hexane mixture (1:1). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from ethyl acetate:hexane mixture (1:10). 1H NMR (500 MHz, CDCl3): delta 5.1 (q, 1H), 1.705 (s, 6H), 1.69 (d, 3H). 13C NMR (500 MHz, CDCl3): delta 168.58, 166.64, 80.54, 72.90, 26.23, 25.27, 17.41. E LEM . A NAL . Calcd. for C7H10O4: C, 53.16; H, 6.33. Found: C, 52.86; H, 6.39. Yield: 46%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In ethyl acetate; at 25 - 60℃; | Example 5: Synthesis of 2,5-dichloro-N-(2-( [( IR)-I -(4,4-dimethyl-5-oxo- 1, 3.2-dioxaborolan-2- yl)-3-methylbutyllamino)-2-oxoethyl)benzamide (1-5)[0331] To a solution of 2-hydroxyisobuty?c acid (0 0567 g, 0.545 mmol) in EtOAc (2.0 mL) with an internal temperature of about 60 C was added a solution of N,N',N"-{boroxin-2,4,6-t?ylt?s[[(lR)-3- methylbutane-l,l-diyl]imino(2-oxoethane-2,l-diyl)] }tris(2,5-dichlorobenzamide) (0.200 g, 0.195 mmol) in EtOAc (1 0 mL). The solution was cooled uncontrolled until the internal temperature was about 25 C and the solvent was removed by evaporation to yield 2,5-dichloro-N-(2-{ [(I R)-I -(4,4- dimethyl-5-oxo-l,3,2-dioxaborolan-2-yl)-3-methylbutyl]amino}-2-oxoethyl)benzamide as a white solid (0.225 g, 96%). MS (m/z) in CH3CN: [M+ Et3N+H] calculated for C24H39BCl2N3O5, 530.2; found, 530.0. MS (m/z) in CH3CN: [M-H] calculated for C18H22BCl2N2O5, 427.1; found, 427.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 18h; | Step 3 - Synthesis of (S)-2-hydroxy-2 -methyl- l-(4-(3-methylmorpholino)-2-(4- nitrophenyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)propan-l-one (jb): The product ja from Step 2 (212 mg, 0.54 mmol) was treated with 2-hydroxy isobutryic acid (112 mg, 1.08 mmol), HOBT (150 mg, 1.08 mmol), EDC (210 mg, 1.08 mmol), and DIPEA (0.47 mL, 2.7 mmol) in DMF (4.0 mL) for 18 h. The mixture was concentrated under reduced pressure and the residue diluted with ethyl acetate (30 mL) and washed with 1 N NaOH (3x10 mL). The combined aqueous phases were extracted with ethyl acetate (1 X 10 mL). The combined organic phases were washed with saturated NH4Cl (3 x 5 mL). The combined aqueous phases were extracted with ethyl acetate (1 X 5 mL). The combined organic phases were dried with Na2SO4, filtered and concentrated to afford 266 mg (94%) of the title compound jb as an oil: 1H NMR (400 MHz, CDCl3) delta 8.55 (d, J = 8.9 Hz, 2H), 8.29 (d, J = 8.9 Hz, 2H), 4.97 (d, J = 18.6 Hz, IH), 4.81 (d, J = 17.0 Hz, IH), 4.05 - 3.91 (m, 2H), 3.88 - 3.48 (m, 8H), 2.85 - 2.64 (m, 2H), 1.69 - 1.50 (m, HH), 1.37 (d, J = 9.2 Hz, 3H); LC-MS: m/z = +442. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | (^-N-fS-fl-fl^-difluorophenvDpyrrolidin-l-y?pyrazolorLS-alpyrimidin-S-vD-l- hydroxy-2-methylpropanamide; [00465] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidin-3 -amine (Preparation B; 25 mg, 0.079 mmol), <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (10 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was concentrated, re-dissolved in methanol, and purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as an off- white solid (21 mg, 66% yield). MS (apci) m/z = 402.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Example 57 N-[(3-[3-[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]-2-hydroxy-2-methylpropanamide; To a solution of <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (Aldrich) (20.84 mg, 0.200 mmol) in THF (2 mL) was added dropwise at room temperature 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.026 mL, 0.200 mmol). The resulting mixture was stirred at room temperature for 30 min. To this were successively added N-[1-[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (50 mg, 0.100 mmol) and DIPEA (0.052 mL, 0.300 mmol). After 1 hour of stirring at room temperature LCMS showed product as the major peak. The reaction mixture was concentrated under a stream of nitrogen in the Radleys blowdown apparatus, the residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (48.5 mg, 88%). LCMS (System A) RT=1.05 min, ES+ve m/z 549/551 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1.5h; | To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol- 1 -yl)-9- methyl-6-morpholin-4-yl-9H-purine (60 mg, 0.14 mmol), 2 -hydroxy obutyric acid (17 mg, 0.17 mmol) and DIPEA (29 muL, 0.17 mmol) in DCM (1 mL) was added EtaATU (63 mg, 0.17 mmol). The resulting yellow mixture was stirred for 1.5 h at r.t. then the reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/Me0H. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-6%) affording 721 as a foam (41 mg, 56%). LCMS (method I): Rx 3.00 min, [M+H]+ 519.2. 1U NMR (CDCl3, 400 MHz): delta 8.00-7.97 (1 H, m), 7.75-7.74 (1 H, m), 7.27-7.25 (2 H, m), 4.62 (1 H, s), 4.33 (5 H, s), 4.20 (1 H, s), 3.93 (1 H, s), 3.86 (4 H, t, J = 4.72 Hz), 3.76 (3 H, s), 3.64 (1 H, s), 3.34 (3 H, q, J = 7.44 Hz), 3.15-3.14 (2 H, m), 1.43-1.42 (9 H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 17h; | A mixture of 8-(2,2-dimethylpiperazin- 1 -ylmethyl)-2-(2-ethylbenzoimidazol- l-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.20 mmol), 2-hydroxyobutyric acid (24 mg, 0.23 mmol), EtaATU (85 mg, 0.22 mmol) and DIPEA (40 muL, 0.23 mmol) in DCM (2 mL) was allowed to stir at r.t. for 17 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NEta3/MeOEta. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-3%) affording 741 as a white solid (55 mg, 46%). LCMS (method I): Rx 2.89 min, [M+H]+ 576.3. 1H NMR (CDCl3, 400 MHz): delta 8.02-8.02 (1 H, m), 7.76-7.75 (1 H, m), 7.33-7.22 (2 H, m), 4.40-4.20 (5 H, m), 3.92 (3 H, s), 3.88-3.83 (5 H, m), 3.63 (2 H, s), 3.53 (2 H, s), 3.36 (2 H, q, J = 7.48 Hz), 2.59-2.53 (2 H, m), 1.50 (6 H, s), 1.45 (3 H, t, J = 7.48 Hz), 1.23 (6 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 4h; | A mixture of 2-(2-ethylbenzoimidazol- 1 -yl)-8-(3-methoxyazetidin-3-yl)-9- methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.33 mmol), 2-hydroxy-2-methylpropionic acid (52 mg, 0.50 mmol), EtaOBt (50 mg, 0.37 mmol), NMM (81 muL, 0.74 mmol) and EDCI (96 mg, 0.50 mmol) in TEtaF (3 mL) was allowed to stir at r.t. for 4 h. The resulting mixture was diluted with DCM and washed with sat. aq. NaHCO3 , dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si- PCC, THF:EtOAc, 0-50%) then triturated with Et2O/cyclohexane. The resulting solid was collected by filtration and dried in vacuo affording 811 (108 mg, 60%). LCMS (method I): RT 3.21 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): delta 8.06-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 5.23 (1 H, s), 5.05 (1 H, d, J = 10.74 Hz), 4.67 (1 H, d, J = 10.76 Hz), 4.55 (1 H, d, J = 10.69 Hz), 4.29 (4 H, brd s), 4.16 (1 H, d, J = 10.75 Hz), 3.79 (4 H, t, J = 4.62 Hz), 3.73 (3 H, s), 3.29-3.27 (2 H, m), 3.09 (3 H, s), 1.35 (3 H, t, J = 7.43 Hz), 1.30 (3 H, s), 1.25 (3 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 18h; | To a mixture of 4-[2-(2-ethylbenzoimidazol- 1 -yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ol (150 mg, 0.32 mmol), 2-hydroxyobutyric acid (41 mg, 0.39 mmol) and DIPEA (68 muL, 0.39 mmol) in DCM (2 mL) was added EtaATU (149 mg, 0.39 mmol). The resulting mixture was allowed to stir at r.t. for 18 h then diluted with DCM and washed with sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 790 (60 mg, 34%). LCMS (method I): Rx 3.09 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): delta 8.02-8.01 (1 H, m), 7.64-7.63 (1 H, m), 7.27- 7.23 (2 H, m), 5.84 (1 H, s), 5.42 (1 H, s), 4.25 (6 H, brd s), 3.98 (3 H, s), 3.77 (4 H, t, J = 4.55 Hz), 3.60 (1 H, brd s), 3.2-3.24 (3 H, m), 2.11-2.10 (2 H, m), 2.06-1.94 (2 H, m), 1.38- 1.30 (9 H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 4h; | To a solution of 2-hydroxyobutyric acid (49 mg, 0.47 mmol) in THF (3 mL) was added 2-(2-ethylbenzoimidazol- 1 -yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6- morpholin-4-yl-9H-purine (150 mg, 0.32 mmol), EtaOBt (47 mg, 0.35 mmol), NMM (77 muL, 0.69 mmol) and EDCI (91 mg, 0.47 mmol). The resulting mixture was allowed to stir at r.t. for 4 h then quenched with sat. aq. NH4Cl and extracted with DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) then triturated with MeOHZH2O. The resulting solid was collected by filtration and dried in vacuo affording 800 (111 mg, 63%). LCMS (method G): Rx 7.36 min, [M+H]+ 563.4. 1U NMR (DMSO, 400 MHz): delta 8.05-8.04 (1 H, m), 7.66-7.62 (1 H, m), 7.25-7.24 (2 H, m), 5.44 (1 H, s), 4.26 (6 H, brd s), 3.92 (3 H, s), 3.78 (4 H, t, J = 4.52 Hz), 3.30-3.23 (4 H, m), 3.09 (3 H, s), 2.26-2.16 (2 H, m), 2.19-2.02 (2 H, m), 1.35-1.33 (9 H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h; | A mixture of 2-azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-l-yl)-7- morpholin-4-ylthiazolo[5,4-<;i]pyrimidine (209 mg, 0.48 mmol), 2-hydroxyobutyric acid (56 mg, 0.54 mmol), HATU (200 mg, 0.53 mmol) and DIPEA (94 muL, 0.54 mmol) in DCM (5 mL) was allowed to stir at r.t. for 2 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0- 2%) followed by reverse phase HPLC (Phenomenex Gemini 5mum C 18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 814 as a white solid (89 mg, 35%). LCMS (method I): Rx 3.39 min, [M+H]+ 522.2. 1H NMR (CDCl3, 400 MHz): delta 8.00-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.28 (2 H, m), 4.62-4.12 (7 H, m), 4.05-3.92 (1 H, m), 3.88 (4 H, t, J = 4.76 Hz), 3.45 (1 H, s), 3.43-3.38 (2 H, m), 3.33 (2 H, q, J = 7.47 Hz), 3.27-3.21 (1 H, m), 1.43-1.42 (9 H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h; | To a solution of (i?)-l-[l-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-lH-benzoimidazol-2-yl]ethanol (57 mg, 0.13 mmol) in DCM (2 niL) was added 2-hydroxy-2-methyl-propionic acid (15 mg, 0.14 mmol), EtaOBt (19 mg, 0.14 mmol), NMM (31 muL, 0.28 mmol) and EDCI (27 mg, 0.14 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording 861 (14 mg, 21%). LCMS (method I): Rx 3.05 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): delta 7.97-7.94 (1 H, m), 7.71-7.68 (1 H, m), 7.30-7.26 (2 H, m), 5.58-5.57 (1 H, m), 5.39 (1 H, d, J = 6.33 Hz), 5.02 (1 H, s), 4.57-4.56 (1 H, m), 4.39-4.14 (4 H, brd s), 4.18 (1 H, dd, J = 10.39, 5.70 Hz), 4.04-4.02 (1 H, m), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.68 (1 H, dd, J = 9.67, 5.21 Hz), 3.23-3.20 (2 H, m), 1.60 (3 H, d, J = 6.48 Hz), 1.25 (6 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | D. N-{(R)-l-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyI-ethyl}-2- hydroxy-2-methyl-propionamide trifluoroacetate(R)-2-Amino-N-(6-arnino-pyridin-3-ylrnethyl)-3,3-dicyclohexyl-propionamide dihydrochloride (lOOmg, 0.23mmol) was dissolved in Cl-^C (20mls) and DMF (2mls). This solution was cooled to 0C. 2-Hydroxyisobutyric acid (27mg, 0.26mmol) was added followed by HOBt (38mg, 0.28mmol) and triethylamine (71mg, OJOmmol). Water soluble carbodiimide (49mg, 0.26mmol) was then added. After 18 hrs at 0C to room temperature reaction mixture was diluted with chloroform (50mls) and washed with NaHC03 (lx20mls), water (lx20mls), brine (lx20mls), dried (Na2S04) and evaporated in vacuo giving a yellow oil. The residue was purified by Prep HPLC (Sunfire prep CI 8 OBD column. 19x250mm, 10mu). 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H2O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.Yield = 55mg, 0.099mmol, 42%[M+H]+ = 445.60'H NMR: (400MHz) (CD30D) 1.04-1.35(12H,m), 1.42(6H,s), 1.52-1.77(12H,m), 4.26- 4.36(2H,m), 4.50-4.54(lH,m), 4.95(2H,s), 7.04(1 H,d,J=9.2Hz), 7.70(lH,d,J=8.9Hz), 7.82(lH,s), 7.93-7.96(lH,m), 8.65-8.78(lH,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 16h; | Example 1-1072-Hydroxy-2-methyl-N-{(S)-1-[6-propyl-4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-thieno[2,3-d]pyrimidin-2-yl]-pyrrolidin-3-yl}-propionamide 60 mg (0.115 mmol) of the compound obtained from Example 1-14, 18 mg (0.173 mmol) of 2-hydroxyisobutyric acid and 66 mg (0.173 mmol) of HATU were dissolved in 5.0 mL of N,N-dimethylformamide. To the solution was added 74 mg (0.575 mmol) of diisopropylethylamine and stirred for 16 hours. The reaction mixture was distilled in vacuo, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and distilled in vacuo. The residue was purified by column chromatography using a mixed solution of dichloromethane and methanol in the ratio of 92:8 to obtain the title compound 47 mg (76%).1H NMR (400 MHz, CDCl3); delta 7.05 (1H, d), 6.80 (1H, s), 5.19 (2H, s), 4.59 (1H, m), 4.35 (2H, t), 4.23 (2H, m), 3.90 (1H, dd), 3.71 (2H, m), 3.48 (1H, dd), 2.80 (2H, t), 2.32 (1H, m), 2.00 (1H, m), 1.75 (2H, m), 1.50 (6H, m), 1.03 (3H, t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: To 6-(1-hydroxy-4-methylpent-3-enyl)-5,8-dimethoxynaphthalene-1,4-dione 4 (0.1 mol) and carboxylic acid (0.15 mol) in anhydrous CH2Cl2 were added DCC (0.2 mol) and DMAP (0.05 mol). After stirring overnight at room temperature under nitrogen atmosphere, petroleum ether was added to the reaction mixture to facilitate precipitates, and then the solution was filtered, and concentrated in vacuo. The residual oil was purified by flash chromatography to give 5a-5v as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Compound 92: In a similar fashion, compound 70 (as the HC1 salt) (200 mg, 0.50 mmol) was treated with alpha-hydroxyisobutyric acid (52 mg, 0.5 mmol) in the presence of EDC(1 14 mg, 0.6 mmol), HOBt (81 mg, 0.6 mmol), and DIEA (0.1 mL, 0.5 mmol) in dry DCM. The reaction mixture was stirred for overnight at room temperature. After the work-up, the oily residue was purified by preparative TLC to give (S)-N-(6-(4-(4- fluorophenoxy)phenyl)pyridin-2-yl)-3-hydroxy-2-(2-hydroxy-2- methylpropanamido)propanamide (125mg, 56%). NMR (400 MHz, CD3OD): 8.05 (3H, d, J = 8.99 Hz), 8.02-8.07 (2H, m), 7.80 (1H, t, J - 8.10 Hz), 7.57 (6H, d, J = 7.9 Hz), 6.99- 7.16 (6H, m), 4.58-4.62 (1 H, br), 4.00 (1 H, dd, J - 4.6, 1 1.2 Hz), 3.87 (1 H, dd, J - 5.0, 1 1.2 Hz), 1.41 (6H, d, J = 5.3 Hz). LC/MS: m/z = 454.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Example 1351-((R)-3-(2-((S)-1-(9H-purin-6-ylamino)ethyl)-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-2-hydroxy-2-methylpropan-1-one 135A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-hydroxy-2-methylpropionic acid (47 mg, 0.455 mmol), HOAt (62 mg, 0.455 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (87 muL, 0.455 mmol) and 4-methylmorpholine (0.10 mL, 0.911 mmol) in anhydrous DCM (4 mL) was stirred at RT for 20 h. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-15% 2M NH3/MeOH in DCM) then triturated with diethyl ether affording 135 (65 mg, 35%). LCMS: RT 2.44 min [M+H]+ 449.1. 1H NMR (DMSO, 400 MHz): delta 8.24-7.90 (3H, m), 7.88-7.81 (1 H, m), 7.67-7.56 (1H, m), 7.23-7.07 (2H, m), 5.90 (1H, s), 5.51 (1H, s), 5.30-3.76 (4H, br), 2.45-2.28 (1H, m), 1.93-1.61 (5H, m), 1.48-1.27 (6H, m), 1.20-1.08 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example 121(S)-1-(4-(2-(1-(9H-purin-6-ylamino)ethyl)-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-2-hydroxy-2-methylpropan-1-one 121To a stirred solution of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (97 mg, 0.268 mmol) in DMF (5 mL) were added 2-hydroxy-2-methylpropionic acid (31 mg, 0.294 mmol), DIPEA (230 muL, 1.34 mmol) and HATU (153 mg, 0.401 mmol). Stirring at RT was continued for 18 h then the crude reaction mixture was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 121 as a pale beige solid (33 mg, 31%). LCMS: RT 2.28 min [M+H]+ 449.1. 1H NMR (CDCl3, 400 MHz): delta 8.51 (1H, s), 7.98 (1H, s), 7.79 (1H, d, J=7.80 Hz), 7.36-6.99 (4H, m), 5.32 (1H, bs), 5.02-4.88 (2H, m), 4.78 (1H, bs), 4.59-4.49 (1H, br), 2.64-2.44 (2 H, m), 2.37-2.22 (1H, m), 2.05 (1H, d, J=12.70 Hz), 2.95-1.49 (11H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.7% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 14h; | Step 3; 6-bromo-4-((lR,3S)-3-carbamoyl-2,2,3- trimethylcyclopentylamino)pyrrolo[ 1 ,2-b]pyridazine-3 -carboxamide[00333] To a solution of 6-bromo-4-(((3R,4R)-3-ethylpiperidin-4- yl)amino)pyrrolo[l,2-b]pyridazine-3 -carboxamide (275 mg, 0.75 mmol) and 2 -hydroxy - 2-methylpropanoic acid (156 mg, 1.501 mmol) in dichloromethane (3.8 ml) were added DIEA (1.3 ml, 7.5 mmol) and HATU (571 mg, 1.501 mmol). The reaction was stirred at room temperature for 14 hrs. The product mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to yield 6-bromo-4-(((3R,4R)-3-ethyl-l-(2-hydroxy-2- methylpropanoyl)piperidin-4-yl)amino)pyrrolo-[l,2-b]pyridazine-3 -carboxamide (240 mg, 0.531 mmol, 70.7 % yield) as a white solid. LCMS (Method K) m/z 454.4 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (0.04 g, 0.097 mmol, chiral intermediate from Example 212) and propanoic acid, 2-hydroxy-2-methyl-(0.012 g, 0.12 mmol) in N,N-dimethylformamide (0.54 mL) was treated with triethylamine (0.034 mL, 0.24 mmol) followed by 0-(benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (0.048 g, 0.13 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with methanol and acetonitrile and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of methanol/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 14%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) delta 8.11 (s, 1H), 7.54 (d, J=4.5 Hz, 1H), 6.25 (q, J=7.2 Hz, 1H), 5.08 (s, 1H), 4.88-4.77 (m, 1H), 4.73-4.60 (m, 1H), 4.50-4.35 (m, 1H), 4.29-4.09 (m, 2H), 3.85-3.73 (m, 2H), 2.55 (s, 3H), 1.73 (d, J=7.0 Hz, 3H), 1.37 (t, J=6.3 Hz, 3H), 1.26 (s, 3H), 1.22 (s, 3H). LCMS for C24H29ClN7O3 (M+H)+: m/z=498.2; Found: 498.2. |
14% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Example 247 4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]benzonitrile A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (0.04 g, 0.097 mmol, chiral intermediate from Example 212) and propanoic acid, 2-hydroxy-2-methyl- (0.012 g, 0.12 mmol) in N,N-dimethylformamide (0.54 mL) was treated with triethylamine (0.034 mL, 0.24 mmol) followed by 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.048 g, 0.13 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with methanol and acetonitrile and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of methanol/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 14%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) delta 8.11 (s, 1H), 7.54 (d, J=4.5 Hz, 1H), 6.25 (q, J=7.2 Hz, 1H), 5.08 (s, 1H), 4.88-4.77 (m, 1H), 4.73-4.60 (m, 1H), 4.50-4.35 (m, 1H), 4.29-4.09 (m, 2H), 3.85-3.73 (m, 2H), 2.55 (s, 3H), 1.73 (d, J=7.0 Hz, 3H), 1.37 (t, J=6.3 Hz, 3H), 1.26 (s, 3H), 1.22 (s, 3H). LCMS for C24H29ClN7O3 (M+H)+: m/z=498.2. Found: 498.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.7% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h; | To a mixture of 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acid (1.526 g, 3.96 mmol) and EDC (1.520 g, 7.93 mmol) in dry DCM (15 ml), benzyl 2-hydroxy-2-methylpropanoate (0.77 g, 3.96 mmol) and DMAP (0.484 g, 3.96 mmol) were added, and the resulting solution was stirred at RT for 24 hours. The solvent was evaporated and the residue was portioned between aqueous sat. NaHCO3 and EtOAc; the organic phase was washed with 1N HCl and brine, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (EtOAc/petroleum ether=1/9). The residue was triturated with diisopropylether and filtered to afford 1-(benzyloxy)-2-methyl-1-oxopropan-2-yl-4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate as a white powder (1.33 g, 2.368 mmol, 59.7% yield, MS/ESI+ 562.0 [MH]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | To a solution of <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (500 mg, 4.80 mmol) in dry THF (10 ml), NaH (60% dispersion in mineral oil, 192 mg, 4.80 mmol) was added portionwise at 5C. The resulting mixture was stirred lh at RT. The solvent was removed, the residue was suspended in dry DMF (7 ml) and (bromomethyl)benzene (821 mg, 4.80 mmol) was added followed by a catalytic amount of KI. The reaction was heated under microwave irradiation at 100C for 3h. After cooling the solvent was evaporated and the residue was partitioned between water and EtOAc; the organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (EtO Ac/petroleum ether = 1/1) affording benzyl 2-hydroxy-2- methylpropanoate as a yellow liquid (773 mg, 3.98 mmol, 83% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | A. solution of 1 -cyclopropyl- 1 ,2,3,4- tetrahydroquinoxaline (100 mg, 0.57 mmol, 1.0 equiv), <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (66 mg, 0.63 mmol, 1.10 equiv), HATU (262 nig, 0.69 mmol, 1 ,2 equiv) and DIEA (89 mg, 0.69 niniol, 1.2 equiv) in i^N-dimethylfomamide (2 mL) was stirred overnight at room temperature. The resulting solution was diluted with of Iota (5 mL) and extracted with of ethyl acetate (2x5 mL). The combined organic extract was washed with brine (1x10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetaterpetroleum ether 1 :5) to provide (30 mg, 20%) of If as yellow oil. MS (ES, m/z): 261 (M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With [m-(1,4-diazabicyclo[2.2.2]octanekN1:kN4)]hexamethyldialuminum; In toluene; for 1h;Inert atmosphere; Reflux; | General procedure: 4.2 General procedures: C. Reflux. Carried out under an inert atmosphere in the normal way. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With [2-[(2,2,6,6-tetramethylpiperidin-1-yl)methyl]phenyl]boronic acid; In toluene; for 14h;Reflux; Molecular sieve; | General procedure: [EXPERIMENTAL EXAMPLES 13 to 48]With use of the various catalysts shown in Table 2 and Table 3, the amide condensation between various alpha-hydroxycarboxylic acid compounds and various amine compounds was performed to obtain the corresponding carboxylic acid amide compounds. The synthesis procedures were similar to those in Experimental Examples 1 to 12, except that the reaction in Experimental Example 15 was performed under weakly acidic conditions by adding benzoic acid (1.0 equivalent) and that the reaction in Experimental Example 47 was performed in xylene (boiling point 144C) under weakly acidic conditions by adding benzoic acid (0.10 equivalent). The results are described in Table 2 and Table 3. Experimental Examples 14, 15, 19, 22, 26, 32, 37, 40, 43, 46 and 47 correspond to Inventive Examples, and the other Experimental Examples are Comparative Examples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dihydroxy-methyl-borane; In water; toluene; for 17h;Reflux; Molecular sieve; | General procedure: EXPERIMENTAL EXAMPLES 62 to 82] [0047] The amide condensation between various alpha-hydroxycarboxylic acids and various amines was performed with use of methylboronic acid catalyst. The synthesis procedures were similar to those in Experimental Example 59. The results are described in Table 7 and Table 8. The amide bond formation in (S)-3-phenyllactic acid took place without any racemization, and the corresponding amide was obtained in a high yield (Experimental Examples 62 to 68). The amide condensation of (R)-mandelic acid proceeded favorably but slight racemization occurred (Experimental Examples 69 to 75). This racemization was suppressed to some degree by using dichloroethane (boiling point 83C) as the reaction solvent. The condensation reactions involving high-reactive amines proceeded favorably even when the amount of the catalyst was decreased to 1 mol%. In the amide condensation reactions involving 2-hydroxyoctanoic acid, the corresponding amides were obtained in high yields (Experimental Examples 76 to 79). The amide condensation reactions between 2-hydroxyisobutyric acid having a quaternary carbon atom at the alpha position and a primary amine also afforded the corresponding amides in a high yield (Experimental Examples 80 to 82). Experimental Examples 62 to 82 correspond to Inventive Examples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine; In acetonitrile; at 20℃; for 0.666667h; | Example 1 2-(Benzoyloxy)-2-methylpropanoic acid 2-Hydroxyisobutyric acid (50 g) was dissolved in acetonitrile (480 mL). To this solution, pyridine (78 mL) was added, and then, benzoyl chloride (56 mL) was added thereto. The resulting solution was stirred at room temperature for 40 minutes. To the reaction mixture, 2 N hydrochloric acid (300 mL) was added to acidify the solution, and then, extraction was performed with ethyl acetate (400 mL*2). The organic layers were combined and dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue was recrystallized from tert-butylmethyl ether/n-heptane, whereby the title compound (82 g, 82%) having the following physical properties was obtained. TLC (Rf value): 0.37 (ethyl acetate) NMR (300 MHz, CDCl3): delta 8.20-9.40 (br, 1H), 8.01-8.06 (m, 2H), 7.53-7.59 (m, 1H), 7.40-7.46 (m, 2H), 1.73 (s, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Exam le 6 N-((2'S.4a,S.9a'igV2-amino-7,-(5-chloropyridin-3-yl)-l,.2',3'.4'.4a'.9a'-hexahvdro-5H- spiro[thiazole-4,9'-xanthenl-2'-yl)-2-hvdroxy-2-methylpropanamide [00115] DIEA (0.031 mL, 0.18 mmol) was added to a mixture of tert-butyl (43'5,93'Lambda)-2'- amino-7'-(5-chloropyridin-3-yl)-1^2 3 4^4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthene]-2- ylcarbamate (Example 5, Step A, 0.030 g, 0.060 mmol), <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (0.008 g, 0.072 mmol), and HATU (0.027 g, 0.072 mmol) in ACN (0.60 mL) at 0C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with brine, and the organic layer was dried (Na2S04) and concentrated. The residue was dissolved in DCM (1 mL) and treated with TFA (1 mL) for 1 h at room temperature. The mixture was concentrated, and the residue was purified by CI 8 semi-preparative HPLC with a gradient of 5- 95% ACN in water (+0.1% TFA) to afford N-((2 ,4a ,9a' ?)-2-amino-7,-(5-chloropyridin-3-yl)- l',2',3',4',4a',9a'-hexahydro-5H-spiro[thiazole-4,9'-xanthen]-2'-yl)-2-hydroxy-2- methylpropanamide trifluoroacetic acid salt (15 mg, 0.025 mmol, 36%; racemic, unknown configuration of single diastereomer). m/z (APCI-pos) M+l = 487.1 (100%), 489.1 (40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h; | In a 25 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate (0.1 g, 0.0002 mol), <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (0.052 g, 0.0005 mol) and DMF (10 mL) were added. To the flask, HATU (0.152 g, 0.0004 mol) and TEA (0.081 mL, 0.0006 mol) were added and then stirred at room temperature for 12 hours. To the reaction mixture was added water to provide a precipitate. The precipitate was collected by filtration to provide the crude product. The crude product was purified by flash column chromatography (2% methanol in chloroform) to obtain the title compound (0.06 g, 60%). LC-MS (ESI) Calculated mass. 585.2, Observed mass [M+H]+: 586.1 (RT=0.83 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.0% | With triethylamine; diethyl dicarbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;Sealed tube; | Compound 6 Synthesis of 1 ?-({5-chloro- 1- [3-(methylsulfonyl)propylj - 1H- benzimidazol-2-yl}methyl)- 1-(2-hydroxy-2-methylpropanoyl)spiro [azetidine-3,3indolj-2?(l?H)-one 1 ?-( {5 -chloro- 1- [3-(methylsulfonyl)propyl] - 1H-benzimidazo 1-2-yl} methyl)spiro [azetidine-3 ,3 ?-indo 1] -2?( 1 ?11)-one 5 (300 mg, 0.50 mmo ls), <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (117 mg, 1.12 mmols) and Et3N (0.482 ml, 2.80 mmols) werestirred vigorously at room temperature in dry DMF (4 ml), while DECP (0.188 ml, 1.12 mmols) was added dropwise. Stirring was continued for 1 hour at ambient temperature in a closed vessel. Some ice was added followed by a saturated sodium bicarbonate solution. The resulting suspension was stirred for 2 hours and the solid was filtered offand further purified by column chromatography eluting with a gradient of DCM andMeOH. All pure fractions were evaporated to give a yellowish foam which was furthertriturated in ether and filtered off to give the title product 6 (121 mg, Y = 42.0%). 1HNMR (400 MHz, DMSO-d6) 6 ppm 1.31 (s, 3 H) 1.33 (s, 3 H)2.11 -2.24 (m, 2 H) 3.00(s, 3 H) 3.18 - 3.27 (m, 2 H) 4.02 - 4.20 (m, 2 H) 4.47 (t, J7.37 Hz, 2 H) 4.55 - 4.75(m, 2 H) 5.23 (s, 2 H) 5.25 (s, 1 H) 7.11 -7.23 (m, 2 H) 7.27-7.35 (m, 2 H) 7.60-7.65(m, 1 H) 7.65 - 7.71 (m, 2 H); mlz = 545.41 (M+H)+Cl pattern. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.1% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | Preparation of Intermediate AG9 -(2,7-Dibromospiro[fluorene-9,4'-piperidine]- 1 '-yl)-2-hydroxy-2-methyl-propan- 1 -one To a stirred mixture of 2,7-dibromospiro[fluorene-9,4'-piperidine] (Hydrochloric Acid (1)), AG4, (60 mg, 0.1397 mmol) and HATU (64 mg, 0.1683 mmol) in DMF (1 mL) is added sequentially 2-hydroxy-2-methyl-propanoic acid (17.5 mg, 0.168 mmol) and Et3N (60 mu, 0.4305 mmol) at RT, stirred for 2 h, diluted with water (~3 mL), resultant precipitate is filtered, washed with water, heptane (1 mL), and dried under high vacuum to afford the title compound (52 mg, 68.1%) as white solid. XH NMR (400 MHz, CDC13) delta 7.71 (brs, J = 1.5 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 4.37 (s, 1H), 4.12 - 4.01 (m, 4H), 1.94 - 1.84 (m, 4H), 1.60 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Example 7 1-[4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-methyl-1,2,4-triazol-3-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added in one portion to <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (38.0 mg, 0.37 mmol), 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (100 mg, 0.26 mmol) and 2-hydroxy-pyridine N-oxide (57.9 mg, 0.52 mmol) dissolved in NMP (1.2 mL) under argon. The resulting solution was stirred at 25 C. for 3 hours. Pyridine (100 muL, 1.24 mmol) was added and the mixture was stirred for 18 hours. Additional 2-hydroxypyridine 1-oxide (57.9 mg, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added. The mixture was then heated up to 70 C. for 48 hours, more <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 2-hydroxypyridine 1-oxide (25.0 mg, 0.23 mmol) were added and the mixture was then kept to 70 C. for 8 hours. The solution was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound (71 mg, 58%) as a pale yellow solid. 1H NMR Spectrum: (CDCl3) 1.55 (15H, s br), 1.90 (2H, m), 2.15 (2H, m), 3.05-3.3 (4H, m), 4.32 (3H, s), 4.6 (1H, m), 9.03 (1H, s); Mass Spectrum [M+H]+=470. | |
58% | Example 7 1- [4- [5- [5-amino-6-( 5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)pyrazin-2-yll - l-methyl- 1 ,2,4- triazol-3-yll - 1-piperidyll -2-hydroxy-2-methyl-propan- 1-one l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added in one portion to <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (38.0 mg, 0.37 mmol), 3-(5- tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)-5-( 1 -methyl-3 -(piperidin-4-yl)- 1H- 1 ,2,4-triazol-5- yl)pyrazin-2-amine (100 mg, 0.26 mmol) and 2-hydroxy-pyridine N-oxide (57.9 mg, 0.52 mmol) dissolved in MP (1.2 mL) under argon. The resulting solution was stirred at 25 C for 3 hours. Pyridine (100 mu., 1.24 mmol) was added and the mixture was stirred for 18 hours. Additional 2-hydroxypyridine 1-oxide (57.9 mg, 0.52 mmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added. The mixture was then heated up to 70C for 48 hours, more 2-hydroxy-2- methylpropanoic acid (15 mg, 0.14 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 2-hydroxypyridine 1-oxide (25.0 mg, 0.23 mmol) were added and the mixture was then kept to 70C for 8 hours. The solution was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml / minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound (71 mg, 58 %) as a pale yellow solid. 1H MR Spectrum: (CDC13) 1.55 (15H, s br), 1.90 (2H, m), 2.15 (2H, m), 3.05-3.3 (4H, m), 4.32 (3H, s), 4.6 (1H, m), 9.03 (1H, s); Mass Spectrum [M+H]+ = 470. | |
58% | With pyridine; 2-hydroxy-pyridine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; at 25 - 70℃; for 77h;Inert atmosphere; | EDCI (100 mg, 0.52 mmol) was added in one portion to <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (38 mg, 0.37 mmol), 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1,2,4-triazol-5-yl)pyrazin-2-amine 39a (100 mg, 0.26 mmol) and 2-hydroxypyridine 1-oxide (57.9 mg, 0.52 mmol) dissolved in NMP (1.2 mL) under argon. The resulting solution was stirred at 25 C for 3 h. Pyridine (100 muL, 1.24 mmol) was added and the mixture was stirred for 18 h. Additional 2-hydroxypyridine 1-oxide (58 mg, 0.52 mmol) and EDCI (100 mg, 0.52 mmol) were added. The mixture was then heated up to 70 C for 48 h. More <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (15 mg, 0.14 mmol), EDCI (50 mg, 0.26 mmol) and 2-hydroxypyridine 1-oxide (25 mg, 0.23 mmol) were added and the mixture wasthen kept to 70 C for 8 h. The solution was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/min) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound (71 mg, 58%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example 322 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]-6-methylbenzonitrile The 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrile (0.075 g, 0.10 mmol, chiral intermediate from Example 320, Step 1) was dissolved in N,N-dimethylformamide (3.0 mL) and DIPEA (0.089 mL, 0.51 mmol) and the propanoic acid, 2-hydroxy-2-methyl- (0.013 g, 0.12 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.058 g, 0.15 mmol) were added. The reaction was stirred at room temperature for 18 hrs and was complete by LCMS. The product was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered to pH 10 to give the title compound as a white amorphous solid (0.025 g, 51%). The product was isolated as a single enantiomer. LCMS calculated for C25H32N7O3(M+H)+: m/z=478.2. found: 478.2. 1H NMR (300 MHz, DMSO-d6) delta 8.10 (s, 1H), 7.29 (s, 1H), 6.24 (q, J=6.8 Hz, 1H), 5.07 (s, 1H), 4.90-4.75 (m, 1H), 4.73-4.58 (m, 1H), 4.39 (p, J=8.5 Hz, 1H), 4.30-4.05 (m, 2H), 3.75 (d, J=7.1 Hz, 2H), 2.54 (s, 3H), 2.38 (s, 3H), 1.72 (d, J=6.9 Hz, 3H), 1.35 (t, J=6.1 Hz, 3H), 1.26 (s, 3H), 1.23 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | A mixture of 6-chloro-l -isopropyl-3-(piperazin-l -yl)-lH-pyrazolo[4,3-c]pyridine (200 mg, 0.710 mmol), <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (90.0 mg, 0.860 mmol), 0-(7-azabenzotriazol-l-yl)- N,N,NN-tetramethyluronium hexafluorophosphate (0.330 g, 0.860 mmol) NN- diisopropylethylamine (0.370 g, 2.86 mmol) in NN-dimethylformamide (4 mL) was stirred for 16 h at room temperature. The reaction was quenched with water, extracted twice with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (260 mg, 99%) as a brown solid. LCMS (ESI): [M+H]+ = 366. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5% Pd/C; ozone; In water; at 25℃; under 760.051 Torr;Darkness; | The ozonation reactions were performed in a 1.5 L glass reactor containing a 500 mL aqueous solution of CFA (100 or 25 mg/L) at ambient conditions (25 ± 2C) and atmospheric pressure. To the CFA solution, 250 mg catalyst was added and the ozone, maintaining a constant production of 1.2 g/h of O3, was continuously flowing through the reactor. Ozone was produced from pure O2(40 L/h), by an ozone generator (ANSEROS COM-AD-02). The samples were taken at regular time intervals for CFA conversion and mineralization degree by TOC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5% Pd/C; ozone; In water; at 25℃; under 760.051 Torr;Darkness; | The ozonation reactions were performed in a 1.5 L glass reactor containing a 500 mL aqueous solution of CFA (100 or 25 mg/L) at ambient conditions (25 ± 2C) and atmospheric pressure. To the CFA solution, 250 mg catalyst was added and the ozone, maintaining a constant production of 1.2 g/h of O3, was continuously flowing through the reactor. Ozone was produced from pure O2(40 L/h), by an ozone generator (ANSEROS COM-AD-02). The samples were taken at regular time intervals for CFA conversion and mineralization degree by TOC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tetrahydrofuran; diethyl ether; at 20℃; | General procedure: A solution of D,L-lactic acid (90%, 0.184 g, 2 mmol) in THF (3 ml) was added to a solution of compound 3 (0.264 g, 1 mmol) in Et2O (2 ml) at room temperature. The precipitate was filtered off, washed with Et2O (2×3 ml), and dried in vacuo for 2 h. Yield 0.310 g (100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | 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 16h; | (2,2-Dimethylpiperazin- 1 -yl)- [6-(4-fluorophenyl)-8-( 1-methylcyclopropyl)imidazo [1 ,2-b]pyridazin-2-yl]methanone (hydrochloride salt) (55 mg, 0.124 mmol) was dissolved in DMF (620 .iL) before HATU (66 mg, 0.17 mmol), 2- hydroxy-2-methyl-propanoic acid (17 mg, 0.16 mmol) and DIPEA (96 mg, 130 tL, 0.74 mmol) were added and the solution was stirred at r. t. for 16h. The product was purified by reverse phase chromatography to afford the title compound 1-[4-[6-(4-fluorophenyl)-8-(1- methylcyclopropyl)imidazo[ 1 ,2-b]pyridazine-2-carbonyl]-3 ,3 -dimethyl-piperazin- 1 -yl] -2- hydroxy-2-methyl-propan-1-one (32 mg, 51% yield). ?H NMR (400 MHz, DMSO-d6) oe 8.46 (s, 1H), 8.12 (dd, J = 8.8, 5.5 Hz, 2H), 7.54 (s, 1H), 7.37 (t, J = 8.8 Hz, 2H), 5.44 - 5.24 (m, 1H), 4.05 (d, J = 35.4 Hz, 5H), 3.64 - 3.38 (m, 2H), 1.69 (s, 2H), 1.59 (s, 3H), 1.55 - 1.40 (m, 7H), 1.32 (s, 6H), 0.95 - 0.91 (m, 2H). LC-MS: m/z = 494.39 (M+Hj, retention time: 4.58 minutes using Method D. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | 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℃; | General procedure: The product were prepared according to General Procedure 3 using (2,2- Dimethylpiperazin- 1 -yl)- [6-(4-fluorophenyl)-8-(trifluoromethyl)imidazo [1 ,2-b]pyridazin-2- yl]methanone (36 mg, 0.086 mmol), 2-hydroxy-2-methyl-propanoic acid (9.9 mg, 0.095 mmol), DIPEA (12 mg, 17 tL, 0.095 mmol), DMF (861 tL) and HATU (36 mg, 0.095 mmol) to afford 1 -[4-[6-(4-fluorophenyl)-8-(trifluoromethyl)imidazo [1 ,2-b]pyridazine-2- carbonyl]-3 ,3 -dimethyl-piperazin- 1 -yl] -2-hydroxy-2-methyl-propan- 1-one (16 mg, 35% yield). ?H NMR (400 MHz, DMSO-d6) oe 8.80 (s, 1H), 8.29 (s, 1H), 8.27 - 8.21 (m, 2H), 7.48 - 7.41 (m, 2H), 5.46 - 5.27 (m, 1H), 4.19 - 3.91 (m, 4H), 3.67 - 3.58 (m, 1H), 3.47 - 3.38 (m, 1H), 1.59 - 1.46 (m, 6H), 1.34 (s, 6H). LCMS: mlz = 508.49 (M+Hj, retention time: 1.5 minutes using Method C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | 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 2h; | To a solution of <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (9.4 mg, 0.09 mmol), (E)- (6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- chroman-2-yl)methanamine (50 mg, 0.09 mmol) in N,N-dimethylformamide (1.1 mL) was added HATU (50.6 mg, 0.13 mmol) and diisopropylethylamine (0.0722 mL, 0.40 mmol). The mixture was stirred for two hours at room temperature and concentrated. The resulting residue was purified by reverse phase eluting with a gradient of 52-69% acetonitrile in water with 0.05% TFA to afford (E)-N-((6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-chroman-2-yl)methyl)-2-hydroxy-2-methylpropanamide (29.9 mg, 53%) as a white solid. 1H-NMR (400 MHz, CDCl3) 1.51 (s, 3H), 1.51 (s, 3H), 2.05 (s, 3H), 2.11 (m, 1H), 2.60 (d, J = 15.2 Hz, 1H), 3.56 (m, 1H), 3.71 (m, 1H), 4.38 (d, J = 5.6 Hz, 1H), 4.74 (d, J = 9.6 Hz, 1H), 6.22 (s, 1H), 6.82 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 6.8 Hz, 1H), 7.18-7.25 (m, 3H), 7.34 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.76 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H). (ES, m/z): (M+H)+ 626. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With thionyl chloride; In tetrahydrofuran; toluene; at -15 - -5℃; for 6h; | <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (10.41 g, 100 mmol) and pyrrolidine (28.4 g, 400 mmol) was coupled in the presence of SOCI2 (14.3g 120 mmol) in 120 mL toluene and 120 mL THF at -15 C to -5C for 6 h, and 1 1 g of B-1 was obtained in 70% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | To a mixture of (2S, 4R) -1- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (3-(cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carbonyl) -4- ( (methoxycarbonyl) amino) pyrrolidine-2-carboxylic acid (350 mg, 0.55 mmol) in THF (10 mL) was added 1, 1'-carbonyldiimidazole (135 mg, 0.82 mmol) at rt. The mixture was stirred at 60 for 30 min, and <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (89 mg, 0.59 mmol) was added dropwise. After the addition, the mixture was stirred at 60 for 12 h and concentrated. The residue was diluted with water (10 mL) . The resulting mixture was extracted with EtOAc (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the title compound as a light yellow solid (253 mg, 63) .MS-ESI: m/z 725.70 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 2-hydroxy isobutyric acid (18 mg, 0.14x1.2 mmol) was dissolved in N.N-dimethylformamide (0.4 mL). 1-ethyl- 3 -(3-dimethylaminopropyl)-carbodiimide hydrochloride (33 mg, 0.14x1.2 mmol) and 1-hydroxybenzotriazol monohydrate (23 mg, 0.14x1.2 mmol) were added, and stirred at the room temperature for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added, and stirred at the room temperature overnight. The solvent was distilled off after the reaction. The mixture was dissolved in chloroform and washed with 1 mol/L hydrochloric acid, 1 mol/L sodium hydroxide aqueous solution, and the saturated sodium chloride solution, dried with anhydrous magnesium sulfate and distilled off the solvent. The residue was purified by Silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform/methanol) to obtain title compound (a yellow solid, 79 mg, quant.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.8% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | A mixture of 2-phenyl-2- [6- (6-methyl-piperazin-1 - yl) - thieno [3,2-d] pyrimidin-4-amino-yl] - ethanol ( 166.8mg, 0.3mmol) and 2-hydroxy-isobutyric acid (46.8mg, 0.45mmol) was dissolved in N, N- dimethylformamideamine (8ml) and then added O- BTA -N, N , N ', N'- tetramethyluronium tetrafluoroborate (144.5mg, 0.45mmol), andN, N- diisopropylethylamine (388.5mg, 3mmol), the reaction mixture was stirred at room temperature for 30 minutes, water was added (100ml ), ethyl acetate(100ml * 2) and extracted with saturated sodium chloride solution (100ml * 2) and washed, the resulting organic phase was dried over anhydrous sodium sulfate, and reducedpressure concentrated, the resulting residue was purified by silica gel column chromatography thereof, to give 2-hydroxy-1- (4- {5- [4- (2-hydroxy-1-phenyl - ethylamine) - thieno [3,2-d] pyrimidin -6-yl] - pyridin-2 - methyl} - piperazin -1-yl) -2- methyl - propan-1-one (70 mg of, off-whitesolid), yield: 43.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In acetonitrile; for 2h; | To 2-hydroxyisobutyric acid (0.046 g, 0.446 mmol), the product of Example 2I (0.10 g, 0.297 mmol) and triethylamine (0.050 ml, 0.357 mmol) in acetonitrile (2.0 ml) was added dimethylamino-N,N'-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 0.17 g, 0.45 mmol). The reaction was allowed to stir for 2 hours and then was diluted with ethyl acetate (10 ml) and transferred to sabarating funnel. The material was washed with water (5 ml) and brine (5 ml) dried over anhydrous MgSO4 filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 10% methanol in ethyl acetate) to afford the title compound (0.10 g, 0.237 mmol, 80% yield). H1 NMR (400 MHz, DMSO-d6) delta ppm 8.32(s, 1H), 7.69(td, J=7.8,1.7Hz, 1H), 7.65-7.55(m, 2H), 7.55-7.42 (m, 2H), 7.36-7.22(m, 2H), 5.94-5.10(m, 2H), 4.43-4.15(m, 1H), 3.74(d, J=9.7 Hz, 1H), 3.70-3.38(m, 1H), 3.11(d, J=79.8 Hz, 1H), 2.23(s, 1H), 1.97-1.66(m, 1H), 1.61-1.23(m, 6H); MS (ESI+) m/z 423 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In acetonitrile; for 2h; | To 2-hydroxyisobutyric acid (0.209 g, 2.01 mmol), the product of Example 1Q (0.45 g, 1.34 mmol) and triethylamine (0.224 ml, 1.61 mmol) in acetonitrile (10 ml) was added dimethylamino-N,N'-dimethyl(3-oxido-1H-[1,2,3] triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 0.763 g, 2.007 mmol). The reaction was allowed to stir for 2 hours and then was diluted with ethyl acetate (20 ml) and transferred to an sabarating funnel. The material was washed with water (20 ml) and brine (20 ml) dried over anhydrous MgSO4 filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 10% methanol in ethyl acetate) to afford the title compound (0.50 g, 1.18 mmol, 88% yield). H1 NMR (400 MHz, DMSO-d6) delta ppm 8.32(s, 1H), 7.69(td, J=7.8,1.7 Hz, 1H), 7.65-7.53(m, 2H), 7.53-7.42(m, 2H), 7.31(s, 2H), 5.97-5.09(m, 2H), 4.53-4.09(m, 1H), 3.84-3.56(m, 2H), 3.47(s, 1H), 3.24-2.91(m, 1H), 2.23(s, 1H), 1.97-1.57(m, 1H), 1.57-1.24(m, 6H). MS (ESI+) m/z 423 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With triethylamine; 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 40℃; for 1h; | dimethylamino-N,N'-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate (HATU, 119 mg, 0.31 mmol) was added to a mixture of the product of Example 1G (100 mg, 0.30 mmol), 2-hydroxyisobutyric acid (33 mg, 0.31 mmol) and triethylamine (0.124 ml, 0.89 mmol) in N,N'-dimethylformamide (2.0 ml) The reaction mixture was stirred at 40C for 60 minutes. The mixture was filtered through a glass microfiber frit and directly purified by preparative HPLC [Waters XBridgeTM C18 5mum OBD TM column, 50 x 100mm, flow rate 90 ml/minute, 5-95% gradient of acetonitrile in buffer (0.025M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (48 mg, 0.11 mmol, 38% yield). H1 NMR (400 MHz, DMSO-d6) delta ppm 8.32(s, 1H), 7.69(td, J=7.8, 1.5 Hz, 1H), 7.55-7.64(m, 2H), 7.43-7.54(m, 2H), 7.23-7.37(m, 2H), 5.48-5.59,5.85-5.91(two m, 1H, amide rotamers), 5.21-5.37(m, 1H),4.15-4.40(m, 1H), 3.59-3.78(m, 2H), 2.96-3.25(m, 1H), 2.15-2.34(m, 1H), 2.17-2.29(m, 1H), 1.72-1.97(m, 1H), 1.27-1.54(m, 6H); MS (ESI) m/z 421 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | A mixture of ((S)-(6-(2,5-difluorophenyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanamine (100 mg, 0.21 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol), 2-hydroxy-2-methyl- propanoic acid (30 mg, 0.31 mmol), and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (160 mg, 0.31 mmol) in DMF (1.0 mL) was stirred at room temperature for two hours. Then, the mixture was concentrated and purified via Prep-HPLC eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid to afford (S)-N-((6-(2,5- difluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2-yl)methyl)-2-hydroxy-2-methylpropanamide (55 mg, 47%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | 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 20℃; for 3h; | A solution of (S)-2-(6-(2,5-difluorophenyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethan-1-amine (100 mg, 0.20 mmol), 2- hydroxy-2-methylpropanoic acid (30 mg, 0.29 mmol), 1-[bis(dimethylamino) methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (150 mg, 0.39 mmol), diisopropylethylamine (50 mg, 0.39 mmol), and dichloromethane (15 mL) was stirred for three hours at room temperature. Then, the mixture was concentrated, and the residue was purified by Prep-HPLC eluting with a gradient of 50-80% acetonitrile in water with 0.1% trifluoroacetic acid to afford (S)-N-(2-(6-(2,5-difluorophenyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-2-hydroxy-2-methylpropanamide (56 mg, 48%) as a white solid. 1H-NMR (400 MHz, CD3OD) delta ^8.09 (dd, J = 7.8, 1.5 Hz, 1H), 8.04- 7.96 (m, 3H), 7.82 (t, J = 8.1 Hz, 1H), 7.34- 7.17 (m, 3H), 7.12 (m, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.48 (dd, J = 14.3, 2.5 Hz, 1H), 3.65 (tdd, J = 8.0, 4.3, 2.4 Hz, 1H), 3.41- 3.32 (m, 3H), 1.96- 1.73 (m, 2H), 1.37 (d, J = 4.9 Hz, 6H). (ES, m/z): (M+H)+ 585. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With hydrogenchloride; In water; at 110℃; for 3h;Sealed tube; | A stirred solution of Intermediate 93 (0.10 g, 0.18 mmol) and <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (0.19 g, 1.89 mmol) in 4M HC1 (5 mL) was heated in a sealed tube at 110C for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 solution (2 x 5 mL). The organic layer was separated, driedover anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the title compound (0.032 g, 40%, mixture of atropisomers)as a brown solid. LCMS (Method 3, ES+) 438.00 MH, 2.28 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Silver 2-hydroxyisobutyrate was prepared as follows. A solution of 50% sodium hydroxide solution (58.8 g; 0.735 moles) was added to 1.05 liter of chilled (15 C.) deionized (DI) water employing mechanical stirring and external cooling at 15 C. 2-Hydroxyisobutyric acid (78.1 g; 0.750 moles) was added in portions, maintaining the resulting reaction solution temperature near or below ambient temperature. After this addition, the homogenous reaction solution was stirred at 15 C. for 30 minutes to insure complete reaction. Silver nitrate (127.4 g; 0.75 mole) in deionized water (187.5 ml) was slowly added to the sodium 2-hydroxyisobutyrate solution over 10 minutes. During the addition, a precipitate formed. The reaction solution was stirred at 15 C. for 30 minutes, and the slurry was filtered (medium frit size 90) and washed with water (50 ml). The collected solid was further washed with two 200 ml portions of acetone and air dried to provide the desired product of silver 2-hydroxyisobutyrate at 60% yield. (0315) To a slurry of the formed silver 2-hydroxyisobutyrate (1 g, 4.76 mmol) in acetonitrile (5 ml), acetoxime (1.39 g, 19.05 mmol) was added and then stirred for an additional 10-15 minutes at 75 C. and upon cooling white crystals of the desired silver 2-hydroxyisobutyrate acetoxime were obtained. FIG. 1 shows the crystal structure of this silver alpha-oxy carboxylate-oxime complex. | |
60% | Silver 2-hydroxyisobutyrate was prepared as follows. A solution of 50% sodium hydroxide solution (58.8 g; 0.735 moles) was added to 1.05 liter of chilled (15 C.) deionized (DI) water employing mechanical stirring and external cooling at 150 C. 2-Hydroxyisobutyric acid (78.1 g; 0.750 moles) was added in portions, maintaining the resulting reaction solution temperature near or below ambient temperature. After this addition, the homogenous reaction solution was stirred at 15 C. for 30 minutes to insure complete reaction. Silver nitrate (127.4 g; 0.75 mole) in deionized water (187.5 ml) was slowly added to the sodium 2-hydroxyisobutyrate solution over 10 minutes. During the addition, a precipitate formed. The reaction solution was stirred at 15 C. for 30 minutes, and the slurry was filtered (medium frit size 90) and washed with water (50 ml). The collected solid was further washed with two 200 ml portions of acetone and air dried to provide the desired product of silver 2-hydroxyisobutyrate at 60% yield. | |
60% | Silver 2-hydroxyisobutyrate was prepared as follows. A solution of 50% sodium hydroxide solution (58.8 g; 0.735 moles) was added to 1.05 liter of chilled (15 C.) deionized (DI) water employing mechanical stirring and external cooling at 15 C. 2-Hydroxyisobutyric acid (78.1 g; 0.750 moles) was added in portions, maintaining the resulting reaction solution temperature near or below ambient temperature. After this addition, the homogeneous reaction solution was stirred at 15 C. for 30 minutes to ensure complete reaction. Silver nitrate (127.4 g; 0.75 mole) in deionized water (187.5 ml) was slowly added to the sodium 2-hydroxyisobutyrate solution over 10 minutes. During the addition, a precipitate formed. The reaction solution was stirred at 15 C. for 30 minutes, and the slurry was filtered (medium frit size 90) and washed with water (50 ml). The collected solid was further washed with two 200 ml portions of acetone and air dried to provide the desired product of silver 2-hydroxyisobutyrate at 60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Benzyl piperidin-4-ylcarbamate (512 mg, 2.18 mmol) was added to 2-hydroxy-2- methylpropanoic acid (227 mg, 2.18 mmol) in 1 ,4-dioxane (1 1 ml_) at room temperature. N,N-diisopropylethylamine (1 .14 ml_, 6.55 mmol) was added to the mixture and the stirring was continued for five minutes. 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (830 mg, 2.18 mmol) was added and the reaction mixture was stirred for sixteen hours. The reaction mixture was poured into saturated sodium bicarbonate, extracted with ethyl acetate (3X), dried over magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by silica gel chromatography, eluting with ethyl acetate:hexanes (1 :1 to 0:1) to give the title compound (315 mg, 43 % yield). NMR (400 MHz, CD3SOCD3) delta 1 .28 (s, 6 H), 1 .28-1 .36 (m, 2 H), 1 .74 (d, J = 12 Hz, 2 H), 2.60-3.24 (m, 2 H), 3.48-3.62 (m, 1 H), 4.10-4.70 (m, 2 H), 5.00 (s, 2 H), 5.33 (s, 1 H), 7.26-7.40 (m, 6 H); LC-MS (LC-ES) M+H = 321 | |
42.8% | Benzyl piperidin-4-ylcarbamate (0.512 g, 2.183 mmol) was added to 2-hydroxy-2- methylpropanoic acid (0.2273 g, 2.183 mmol) in 1 ,4-dioxane (10.9 mL) at room temperature. Then, N,N-diisopropylethylamine (1 .144 mL, 6.55 mmol) was added and the reaction mixture was stirred for five minutes. Then, 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (0.830 g, 2.183 mmol) was added and the reaction mixture was stirred for sixteen hours. The reaction mixture was poured into saturated sodium bicarbonate, extracted with ethyl acetate (3X), dried over magnesium sulfate, filtered, and concentrated. The reaction mixture was purified by silica gel chromatography, eluting with ethyl acetate:hexanes (1 :1 to 0:1 ) to give benzyl (1 -(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)carbamate (0.3151 g, 0.934 mmol, 42.8 % yield). 1H NMR (400 MHz, CD3SOCD3) delta 1 .28 (s, 6 H), 1 .28-1 .36 (m, 2 H), 1 .74 (d, J = 12 Hz, 2 H), 2.60-3.24 (m, 2 H), 3.48-3.62 (m, 1 H), 4.10- 4.70 (m, 2 H), 5.00 (s, 2 H), 5.33 (s, 1 H), 7.26-7.40 (m, 6 H); LC-MS (LC-ES) M+H = 321 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N,N-dimethyl-aniline; In chloroform; at 0℃; for 2h;Inert atmosphere; | 2-Hydroxy-2-methylpropanoic acid (2) (9.50?g, 91.3?mmol), N,N-dimethylaniline (34.6?mL, 274?mmol) and methyl chloroformate (21.2?mL, 274?mmol) were reacted on the basis of the procedure reported by Fischer et al. [35] . The title compound was obtained as a colorless solid. Yield: 12.0?g (74.0?mmol, 81% based on 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 4h; | To a suspension of the product from the previous step (9 mg, 0.013 mmol) in acetonitrile (130 mu) were added <strong>[594-61-6]2-hydroxy-2-methylpropanoic acid</strong> (2.0 mg, 0.02 mmol) EDC (5.0 mg, 0.026 mmol), and HOBt (4.0 mg, 0.026 mmol) and the resulting mixture was stirred at 20 C for 4 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 - 40%; 20 min; Column: XBridge C18, 5 muiotaeta, 19 mm x 150 mm) to afford the title compound (3.0 mg, 35 % yield) as an off-white solid.1H NMR (600 MHz, Methanol-) delta 8.96 (s, 1H), 8.01 (d, J= 7.2 Hz, 1H), 7.41 (d, J = 3.7 Hz, 1H), 7.06 (d, J= 3.7 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 5.31 - 5.22 (m, 2H), 5.08 (d, J= 16.5 Hz, 1H), 3.48 (dd, J= 17.2, 5.8 Hz, 1H), 3.36 - 3.32 (m, 2H), 3.02 (dd, J = 17.1, 1.8 Hz, 1H), 2.05 - 1.79 (m, 5H), 1.47 (d, J= 5.7 Hz, 8H), 1.31 (d, J= 6.7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 38% | With potassium hydroxide; In ethanol; water; at 4℃; for 504h;pH 5.0; | Method A: A quantity of Cd(NO3)2·4H2O (0.15g, 0.50mmol) was placed in a flask and dissolved in 10mL of 20 H2O. Subsequently, 0.10g (1.0mmol) of 21 alpha-hydroxy isobutyric acid (HIBAH2) was added under continuous stirring. An aqueous solution of 22 potassium hydroxide (0.1N KOH) was employed to adjust the pH of the reaction mixture to the final value of 5. The resulting reaction solution was allowed to stir for 30min and then placed at 4C, with addition of cold 23 ethanol to the reaction solution taking place occasionally (every 3days). After three weeks, colorless crystalline material appeared at the bottom of the vessel. The compound was isolated by filtration and air-dried at room temperature. The yield of the reaction was 0.060g (~38%). Anal. Calc. for 1, [Cd(C4H7O3)2]n (1) (24 C8H14CdO6, Mr: 318.60) (%) C: 30.10; Eta: 4.40. Found: C: 30.02; H: 4.41. |
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