Hydrochloric Acid → Caspofungin Acetate

HRID 1404677

반응식

HRID 1404677 반응식
C1(B(O)[OH:8])C=CC=CC=1.F[C:11](F)(F)[C:12](=N[Si](C)(C)C)[O:13][Si](C)(C)C.B.CSC.Cl.[CH3:30][CH2:31][CH:32]([CH2:34][CH:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([NH:47][C@@H:48]1[C:79](=[O:80])[NH:78][C@@H:77]([C@H:81]([OH:83])[CH3:82])[C:75](=[O:76])[N:74]2[C@@H:70]([CH2:71][C@@H:72]([OH:84])[CH2:73]2)[C:68](=[O:69])[NH:67][C@@H:66]([C@H:85]([OH:95])[C@@H:86]([OH:94])[C:87]2[CH:88]=[CH:89][C:90]([OH:93])=[CH:91][CH:92]=2)[C:64](=[O:65])[NH:63][C@@H:62]([C@H:96]([OH:100])[CH2:97][CH2:98][NH2:99])[C:60](=[O:61])[N:59]2[C@@H:55]([C@@H:56]([OH:101])[CH2:57][CH2:58]2)[C:53](=[O:54])[NH:52][C@H:51]([NH:102][CH2:103][CH2:104][NH2:105])[C@H:50]([OH:106])[CH2:49]1)=[O:46])[CH3:36])[CH3:33]>O.C(OCC)(=O)C.C(O)(=O)C.C(O)C.O1CCCC1>[CH3:30][CH2:31][CH:32]([CH2:34][CH:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([NH:47][C@@H:48]1[C:79](=[O:80])[NH:78][C@@H:77]([C@H:81]([OH:83])[CH3:82])[C:75](=[O:76])[N:74]2[C@@H:70]([CH2:71][C@@H:72]([OH:84])[CH2:73]2)[C:68](=[O:69])[NH:67][C@@H:66]([C@H:85]([OH:95])[C@@H:86]([OH:94])[C:87]2[CH:88]=[CH:89][C:90]([OH:93])=[CH:91][CH:92]=2)[C:64](=[O:65])[NH:63][C@@H:62]([C@H:96]([OH:100])[CH2:97][CH2:98][NH2:99])[C:60](=[O:61])[N:59]2[C@@H:55]([C@@H:56]([OH:101])[CH2:57][CH2:58]2)[C:53](=[O:54])[NH:52][C@H:51]([NH:102][CH2:103][CH2:104][NH2:105])[C@H:50]([OH:106])[CH2:49]1)=[O:46])[CH3:36])[CH3:33].[CH3:11][C:12]([OH:13])=[O:8].[CH3:11][C:12]([OH:13])=[O:8]

참가 물질

12

반응물 6

HCID 313Hydrochloric AcidHCID 1068Dimethyl SulfideHCID 6331BoraneHCID 66827Phenylboronic AcidHCID 94358Bis(trimethylsilyl)trifluoroacetamideHCID 2826718n-{(2r,6s,9s,11r,12s,14As,15s,20s,23s,25as)-12-[(2-aminoethyl)amino]-20-[(1r)-3-amino-1-hydroxypropyl]-23-[(1s,2s)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1r)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1h-dipyrrolo[2,1-c:2',1'-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl}-10,12-dimethyltetradecanamide

생성물 1

HCID 6850808Caspofungin Acetate수율 75%

시약·촉매·용매 5

HCID 176Acetic Acid용매HCID 702Ethanol용매HCID 962Water용매2회HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

실험 절차

Under N2, the compound of Formula 4 (1.0 g), phenyl boronic acid (0.14 g), tetrahydrofuran (40 ml) were refluxed for 30 min. The reaction mixture was cooled to the room temperature, and BSTFA (1.06 ml) was added and the solution was agitated for 1 h at the room temperature. The reaction mixture was cooled to −10 to −5° C., and the complex of borane and dimethyl sulfide (0.4 ml, 0.94%) was added dropwise. Upon addition, the reaction mixture was warmed to 10 to 15° C., and the reaction was conducted for 3.5 h. The conversion rate for the reaction was 82% monitored by HPLC. Afterwards, 2 N hydrochloric acid (2.4 ml) was added dropwise, and water (80 ml) was added. Upon addition, the reaction mixture was agitated for 24 h at the room temperature. The reaction was diluted with water, and loaded onto a preparative column. The column was eluted with 22% acetonitrile/water (0.15% acetic acid). The collections rich in the product were pooled, diluted with water for one time and loaded onto a preparative column. The column was eluted with 90% acetonitrile/water (0.15% acetic acid), and effluents were collected and lyophilized to obtain the crude caspofungin diacetate (0.80 g, yield 80%, the purity=98.0% by HPLC) in white solid. The crude caspofungin was dissolved into ethanol (6 ml) and 6% aqueous acetic acid (0.6 ml), and then ethyl acetate (10.5 ml) was added dropwise. The whole system was agitated for 1 h at 10° C. and then filtered, and the obtained solid was dried to obtain caspofungin diacetate (the compound of Formula 1) (0.75 g, yield 75%).

후처리

  1. additionwas added
  2. temperatureThe reaction mixture was cooled to −10 to −5° C.
  3. additionUpon addition
  4. temperaturethe reaction mixture was warmed to 10 to 15° C.
  5. waitthe reaction was conducted for 3.5 h
  6. additionUpon addition
  7. stirringthe reaction mixture was agitated for 24 h at the room temperature
  8. washThe column was eluted with 22% acetonitrile/water (0.15% acetic acid)
  9. additiondiluted with water for one time
  10. washThe column was eluted with 90% acetonitrile/water (0.15% acetic acid), and effluents
  11. customwere collected
  12. customto obtain the crude caspofungin diacetate (0.80 g, yield 80%
  13. stirringThe whole system was agitated for 1 h at 10° C.
  14. filtrationfiltered
  15. customthe obtained solid was dried

출처 및 근거

ORD 기록
ord-c20825f30ea84cd08c091a954a27cd81
출처 데이터셋
uspto-grants-2014_12
특허 번호
US08912309B2

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