Diisopropylethylamine → 3-(4-{[2-(4-Chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

HRID 554842Notes

Reaction equation

HRID 554842 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:19]([OH:21])=O)=[C:11]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[N:12]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][C:35]=2[O:41][CH3:42])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:19]([C:10]3[S:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH2:13][CH:14]([O:15][CH3:16])[O:17][CH3:18])=[O:21])=[CH:36][C:35]=2[O:41][CH3:42])[CH2:32]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 46835556Tert-butyl 3-(4-amino-2-methoxyphenoxy)azetidine-1-carboxylateHCID 674605292-(4-Chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carboxylic acid

Product 1

HCID 674612343-(4-{[2-(4-Chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterYield 90.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

Dissolve 2-(4-chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carboxylic acid (147 g, 448 mmol), 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (120 g, 402 mmol), and 1-hydroxybenzotriazole hydrate (75 g, 490 mmol) in THF (1.2 L) and cool to about 10° C. under a nitrogen atmosphere Treat the above solution with diisopropylethylamine (117 mL, 673 mmol) dropwise over 2 min while keeping the temperature between 10-15° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93 g, 489 mmol) to the solution and stir at room temperature for 19 h. Cool the solution to 0° C. and dilute with water (1.2 L). Collect the precipitate by filtration and triturate with water (5×700 mL). Dry the tan solid for 3 days at 50° C. under vacuum to obtain 219 g (90%) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 10.03 (s, 1H), 7.90 (m, 2H), 7.66 (d, 1H, J=2.4), 7.42 (m, 2H), 6.88 (dd, 1H, J=2.4, 8.6), 6.57 (d, 1H, J=8.6), 4.86 (m, 1H), 4.84 (t, 1H, J=5.7), 4.26 (dd, 2H, J=6.7, 10.6), 4.08 (dd, 2H, J=4.3, 10.6), 3.90 (s, 3H), 3.53 (s, 6H), 3.37 (d, 2H, J=5.5), 1.43 (s, 9H).

Workup

  1. custombetween 10-15° C
  2. temperatureCool the solution to 0° C.
  3. customCollect the precipitate
  4. filtrationby filtration
  5. customtriturate with water (5×700 mL)
  6. customDry the tan solid for 3 days at 50° C. under vacuum

Sources & evidence

ORD record
ord-266892c84e5f4b45aa36324a51c05a27
Source dataset
uspto-grants-2011_11
Patent number
US08049013B2

Reaction notes

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