1,4-Dioxane → 4-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochloride

HRID 533342Notes

Reaction equation

HRID 533342 reaction equation
C(OC(=O)[N:7]([C:10]1[S:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][C:11]=1[Cl:21])[CH2:8][CH3:9])(C)(C)C.O1CCOCC1.Cl.O1CCOCC1>CCOCC>[ClH:21].[Cl:21][C:11]1[N:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:14][C:10]=1[NH:7][CH2:8][CH3:9]

Participants

5

Reactant 3

HCID 312751,4-DioxaneHCID 204431481,4-Dioxane hydrochloride2×HCID 59580483(4-Chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-carbamic acid tert-butyl ester

Product 1

HCID 666452174-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochlorideYield 209%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
25 °C

Procedure

Into a 1 L three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-carbamic acid tert-butyl ester (63.5 g, 187 mmol) and 1,4-dioxane (125 mL). To the solution was added 4 M HCl/dioxane (100 mL, 400 mmol). The mixture exothermed from 31° C. to 49° C. over 10 seconds and slowly turned from an auburn solution to a green-black solution. After 10 minutes the reaction had cooled back to 25° C. After 30 min a green-yellow precipitate began to form in the reaction mixture. The reaction conversion was 31% after 10 min, 32% after 1.5 hours and 67% after 16 hours. Additional 4M HCl/dioxane (75 mL, 300 mmol) was added (note: no exotherm this time) and the reaction stirred at 23° C. for 1.5 hours (no change in reaction progress by HPLC analysis). The reaction was heated to 40° C. for 4 hours which led to complete conversion. The reaction was allowed to cool to 25° C. and ether (200 mL) was added. The green-yellow suspension was stirred for 30 min and the solid collected by vacuum filtration and washed with ether (2×50 mL). This gave a green-yellow filter cake which was allowed to stand in the air for 16 hours. This gave 67.99 g (131%) of a green-yellow wet cake that assayed to >99% purity by HPLC at 254 nm. The sample was placed into a vacuum oven (55° C., 74 mmHg vacuum, 4 hours). This gave 53.96 g (quantitative yield) of a green solid:

Workup

  1. customInto a 1 L three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, and nitrogen inlet
  2. waitAfter 30 min a green-yellow precipitate began
  3. customto form in the reaction mixture
  4. customafter 10 min
  5. wait32% after 1.5 hours
  6. wait67% after 16 hours
  7. customin reaction progress by HPLC analysis)
  8. temperatureThe reaction was heated to 40° C. for 4 hours which
  9. temperatureto cool to 25° C.
  10. stirringThe green-yellow suspension was stirred for 30 min
  11. filtrationthe solid collected by vacuum filtration
  12. washwashed with ether (2×50 mL)
  13. customThis gave a green-yellow filter cake which
  14. waitto stand in the air for 16 hours
  15. customwas placed into a vacuum oven (55° C., 74 mmHg vacuum, 4 hours)

Sources & evidence

ORD record
ord-4e5003b53fc14f1280b52dd741f26bd6
Source dataset
uspto-grants-2014_10
Patent number
US08853246B2

Reaction notes

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