Reaktion #1702107

Reaktionsgleichung

3-[(1,4-Dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-[4-(ethoxy-methyl-phosphinoylmethyl)-phenyl]-thiophene-2-carboxylic acid methyl ester

Sodium borohydride

HCl

lithium hydroxide monohydrate

HCl

→

5-[4-(Ethoxy-methyl-phosphinoylmethyl)-phenyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid

Ausbeute 6.0%

Lösungsmittel

THF

water

methanol

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturThe reaction was then cooled to room temperature
2. 2
   ExtraktionThe solution was then extracted twice with ethyl acetate
3. 3
   WaschenThe combined ethyl acetate layers were then washed twice with saturated NaHCO3, twice with water
4. 4
   Trocknenonce with brine, dried over sodium sulfate
5. 5
   Filtrationfiltered
6. 6
   Einengenconcentrated
7. 7
   Sonstigeto afford the crude ketone (176 mg)
8. 8
   Temperaturcooled to −25° C.
9. 9
   workup.STIRRINGThe reaction was stirred 1.5 hours at −25° C.
10. 10
    Sonstigewas quenched with 3 mL 2 N HCl
11. 11
    Temperaturwarmed to room temperature
12. 12
    ExtraktionThe solution was then extracted twice with ethyl acetate
13. 13
    WaschenThe combined ethyl acetate layers were washed once with brine
14. 14
    Trocknendried over sodium sulfate
15. 15
    Filtrationfiltered
16. 16
    Einengenconcentrated
17. 17
    workup.DISSOLUTIONThis crude product (173 mg) was dissolved in 2 mL THF
18. 18
    workup.STIRRINGStirring
19. 19
    workup.STIRRINGThe reaction was stirred at 40° C. for 45 minutes whereupon the reaction
20. 20
    EinengenThe reaction was concentrated
21. 21
    workup.DISSOLUTIONredissolved in methanol
22. 22
    Sonstigepurified by reverse phase preparative HPLC

Vorschrift

3-[(1,4-Dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-[4-(ethoxy-methyl-phosphinoylmethyl)-phenyl]-thiophene-2-carboxylic acid methyl ester (204 mg, 0.331 mmol, 1 eq.) was weighed into a small flask and dissolved in 3 mL THF. Next, 2 mL of 3.6 N HCl was added and the reaction was stirred at 40° C. for 1.5 hours. The reaction was then cooled to room temperature and diluted with 40 mL water. The solution was then extracted twice with ethyl acetate. The combined ethyl acetate layers were then washed twice with saturated NaHCO3, twice with water, and once with brine, dried over sodium sulfate, filtered and concentrated to afford the crude ketone (176 mg). This material (176 mg, ˜0.307 mmol) was dissolved in 5 mL anhydrous THF and cooled to −25° C. using an acetonitrile/dry ice bath. Sodium borohydride (9 mg, 0.230 mmol, 0.75 eq.) was added as a solid in two portions. The reaction was stirred 1.5 hours at −25° C., then was quenched with 3 mL 2 N HCl and warmed to room temperature. The solution was then extracted twice with ethyl acetate. The combined ethyl acetate layers were washed once with brine, and then dried over sodium sulfate, filtered and concentrated. This crude product (173 mg) was dissolved in 2 mL THF. Stirring was begun and 0.5 mL methanol and a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol, 2 eq. in 0.5 mL water) were added. The reaction was stirred at 40° C. for 45 minutes whereupon the reaction was stopped by the addition of 0.35 mL 2 N HCl. The reaction was concentrated, then redissolved in methanol and purified by reverse phase preparative HPLC to afford 5-[4-(Ethoxy-methyl-phosphinoylmethyl)-phenyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (11 mg, 6%). MS (m/z) 562.1 [M+H]+ HPLC retention time: 3.152 min (5-95% acetonitrile with 0.05% TFA: water with 0.05% TFA).

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