Triethylamine → Thiomorpholinecarboxylic acid ethyl ester

HRID 434255Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 434255
[C:1]([N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH:9]1C(O)=O)([O:3][C:4](C)(C)[CH3:5])=[O:2].Cl.C(OC(=O)[C@H](CS)N)C.C(N(CC)CC)C.BrC(Br)C>C1COCC1>[CH2:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1)=[O:2])[CH3:5]

Komponenten

6

Edukt 4

HCID 8471TriethylamineHCID 112011,1-DibromoethaneHCID 2723617Ethyl cysteinate hydrochlorideHCID 27568314-(tert-Butoxycarbonyl)thiomorpholine-3-carboxylic acid

Produkt 1

HCID 53680559Thiomorpholinecarboxylic acid ethyl esterAusbeute 87 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

4-Boc-thiomorpholine-3-carboxylic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: To THF was added cysteine ethyl ester hydrochloride (1.15 g, 6.18 mmol), triethylamine (4.17 mL, 30 mmol) and dibromoethane (2.51 mL, 6.2 mmol). After stirring for 1 hour and refluxing for 16 hours, the solids were removed by filtration. The solvent was removed in vacuo and the residue was chromatographed on silica to give thiomorpholinecarboxylic acid ethyl ester (0.94 g, 87%). The ester (15.3 g, 95 mmol) was dissolved in dioxane/water (1/1) and di-t-butyldicarbonate (24 g, 110 mmol) and LiOH were added. After stirring for 3 hours, the solvent was removed in vacuo and the pH was adjusted to 3 with KHSO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent was removed in vacuo to give 17.4 g (78%) 4-Boc-thiomorpholine-3-carboxylic acid: 1H NMR (CDCl3) δ 1.45 (m, 9), 2.45 (m, 1), 2.71 (m, 1). 2.93(m, 1), 3.10 (m. 1), 3.29 (m, 1), 4.11 (m, 1), 4.19 (m, 1), 5.20 (m, 1). 4-Boc-thiomorpholine-3-acetic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: To THF (50 mL) was added methyl bromocrotonate (1.0 mL, 8.6 mmol), Hünig's base (1.5 mL, 8.6 mmol), and N-Boc-2-aminoethanethiol (1.5 g, 8.6 mmol). After stirring for 3 hours, the reaction was poured into saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography (hexane/ethyl acetate, 6/1) gave N-Boc-2-aminoethanethiocrotonic acid methyl ester. The ester was dissolved in CH2Cl2 (80 mL) and TFA (20 mL) was added. After stirring for 1 hour, the solvent was removed in vacuo. The residue was added to a solution of toluene and TEA (2.5 ml). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed to give the thiomorpholine. The ester (18.0 g, 95 mmol) was dissolved in dioxane/water (1/1) and di-t-butyldicarbonate (19.6 g, 90 mmol) and LiOH were added. After stirring for 12 hours, the solvent was removed in vacuo and the pH was adjusted to 3 with KHSO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent was removed in vacuo to give 20.3 g (86%) 4-Boc-thiomorpholine-3-acetic acid: 1H NMR (CDCl3) δ 1.45 (m, 9), 2.45 (m, 1), 2.51 (m, 1), 2.68 (m, 1), 2.82 (m, 1), 3.05 (m. 4), 4.24 (s, 1), 4.93 (s, 1).

Aufarbeitung

  1. customcan be prepared in the following manner
  2. temperaturerefluxing for 16 hours
  3. customthe solids were removed by filtration
  4. customThe solvent was removed in vacuo
  5. customthe residue was chromatographed on silica

Quellen und Nachweise

ORD-Eintrag
ord-a5eee28b678740a5b60f36050e53b6b6
Quelldatensatz
uspto-grants-2003_12
Patentnummer
US06670473B2

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