Reacción #1702107

Ecuación de reacción

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

Rendimiento 6.0%

Disolventes

THF

water

methanol

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaThe reaction was then cooled to room temperature
2. 2
   ExtracciónThe solution was then extracted twice with ethyl acetate
3. 3
   LavadoThe combined ethyl acetate layers were then washed twice with saturated NaHCO3, twice with water
4. 4
   Secadoonce with brine, dried over sodium sulfate
5. 5
   Filtraciónfiltered
6. 6
   Concentraciónconcentrated
7. 7
   Otroto afford the crude ketone (176 mg)
8. 8
   Temperaturacooled to −25° C.
9. 9
   workup.STIRRINGThe reaction was stirred 1.5 hours at −25° C.
10. 10
    Otrowas quenched with 3 mL 2 N HCl
11. 11
    Temperaturawarmed to room temperature
12. 12
    ExtracciónThe solution was then extracted twice with ethyl acetate
13. 13
    LavadoThe combined ethyl acetate layers were washed once with brine
14. 14
    Secadodried over sodium sulfate
15. 15
    Filtraciónfiltered
16. 16
    Concentraciónconcentrated
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
    ConcentraciónThe reaction was concentrated
21. 21
    workup.DISSOLUTIONredissolved in methanol
22. 22
    Otropurified by reverse phase preparative HPLC

Procedimiento

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).

Fuente