Formaldehyde → HCID 68115573, compound

HRID 1503942Notes

Reaction equation

HRID 1503942 reaction equation
Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.C=O.[BH3-][C:32]#N.[Na+]>CO.O>[CH3:2][N:3]([CH3:32])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 86695115HCID 86695115, compound

Product 1

HCID 68115573HCID 68115573, compoundYield 36.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

A solution of tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (115 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL) cooled down to 0° C. was added hydrochloric acid (12 M, 0.5 mL). The resulting solution was stirred for 1 h at 0° C. and concentrated in vacuo to give 2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride (100 mg, crude) as a light yellow solid. The crude hydrochloride (100 mg) dissolved in methanol (3 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at 0° C. Then NaBH3CN (44.35 mg, 0.71 mmol) was added and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with water, extracted with 3×20 mL of chloroform/i-PrOH. The combined organic layers were concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide (35 mg) as a white solid. MS (ES): m/z 405 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (1H, s), 5.28-5.21 (1H, m), 3.94-3.88 (3H, m), 3.61-3.56 (2H, m), 3.14-2.97 (2H, m), 2.67-2.54 (2H, m), 2.42-2.31 (10H, m), 2.02 (2H, d), 1.62-1.43 (4H, m).

Workup

  1. stirringthe resulting solution was stirred for 2 h at room temperature
  2. extractionextracted with 3×20 mL of chloroform/i-PrOH
  3. concentrationThe combined organic layers were concentrated under vacuum
  4. customThe crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU)
  5. waitmobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min)
  6. customThe product-containing fractions were collected
  7. custompartially evaporated
  8. customto remove water and CH3CN under reduced pressure
  9. waitThe residue was lyophilized overnight

Sources & evidence

ORD record
ord-02915c24487b48ff83d58ddb393a375d
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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