Formate → (R)-propyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate

HRID 475488

반응식

HRID 475488 반응식
P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH:9]([O-:11])=[O:10].[Na+].[NH2:13][C@@H:14]([C:16](O)=O)[CH3:15].C1C=[N+:23]([C@@H:25]2O[C@H:28]([CH2:30]OP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H:27](O)[C@H:26]2O)[CH:22]=[C:21]([C:60](N)=O)[CH:20]=1.[CH3:63][C:64]1[C:69](O)=C(C=O)C(COP(O)(O)=O)=CN=1.[C:79]([O-])(=O)C(C)O.C([O-])=O.Cl>O>[NH2:13][C@H:14]1[CH2:16][N:23]2[C:25]3[C:60]([C:21]([CH2:20][C:9]([O:11][CH2:63][CH2:64][CH3:69])=[O:10])=[C:22]2[CH2:79][CH2:15]1)=[CH:30][CH:28]=[CH:27][CH:26]=3

참가 물질

10

반응물 8

HCID 283FormateHCID 313Hydrochloric AcidHCID 1051Pyridoxal 5'-phosphateHCID 5892NadideHCID 24243Trisodium PhosphateHCID 71080D-AlanineHCID 91435LactateHCID 2723810Sodium Formate

생성물 1

HCID 58349691(R)-propyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate수율 80%

시약·촉매·용매 1

HCID 962Water용매

실험 절차

Sodium phosphate, dibasic (3.8 equiv.) and sodium formate (266 equiv.) were added to a solution of D-Alanine (38 equiv.) in water. The pH was measured as 7.6. Nicotinamide Adenine Dinucleotide (0.04 equiv.), Pyridoxal-5-phosphate (0.11 equiv.), Lactate dehydrogenase (1 equiv.), Formate dehydrogenase (1 equiv.), and Amine-Transaminase-117 (1 equiv.) were added under stirring and slowly dissolved. The measured pH was 7.3. The mixture was aged at 22° C. for 1 h. The flask was flushed with nitrogen and propyl (7-oxo-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate from Step 5 was added as a DMSO (0.06 M) solution. The reaction was adjusted to pH 7.2 and aged at 30° C. overnight under nitrogen atmosphere. Upon completion of the reaction as determined by HPLC, the pH of the reaction was adjusted to pH 4.0 with 6 N HCl and Celite (20 g per L) was added. After stirring for 1 hr the reaction was filtered through a Celite bed and the filter cake was washed twice with 0.1 N HCl. The combined aqueous filtrate was extracted with 1 volume of MTBE. The organic layer did not contain amine and was discarded. The aqueous layer was diluted with an equal volume of MTBE and the pH of the mixture was adjusted to pH 9.5 using 5N NaOH. The two phases were separated and the aqueous layer was extracted with MTBE. The spent aqueous layer had no detectable amine and was discarded. The combined organic layers were washed with dilute sodium carbonate and dried over Na2SO4. Evaporation of the volatiles afforded the crude title compound (80%). The ee was determined as 99% by SFC assay. The SFC conditions are ADH column (250×4.6 mm, 5 um), isocratic 20% MeOH, 25 mM iso-proply amine/CO2, 2 ml/min, 35° C., 200 bar, 215 nm, 15 min. Under these conditions the desired R-amine has an 8.99 min retention time (S-amine; 5.82 min)

후처리

  1. dissolutionslowly dissolved
  2. customThe flask was flushed with nitrogen and propyl (7-oxo-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate from Step 5
  3. additionwas added as a DMSO (0.06 M) solution
  4. waitaged at 30° C. overnight under nitrogen atmosphere
  5. customUpon completion of the reaction
  6. additionwas added
  7. stirringAfter stirring for 1 hr the reaction
  8. filtrationwas filtered through a Celite bed
  9. washthe filter cake was washed twice with 0.1 N HCl
  10. extractionThe combined aqueous filtrate was extracted with 1 volume of MTBE
  11. additionThe aqueous layer was diluted with an equal volume of MTBE
  12. customThe two phases were separated
  13. extractionthe aqueous layer was extracted with MTBE
  14. washThe combined organic layers were washed with dilute sodium carbonate
  15. dry with materialdried over Na2SO4
  16. customEvaporation of the volatiles

출처 및 근거

ORD 기록
ord-97054c43b03f45369be7288ca0117c46
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08637541B2

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