Cyclosporin H → Cyclosporin A

HRID 2361620Notes

Reaction equation

C/C=C/CC1C2OC(C(C(C)C)N(C)CCCCNC(=O)C2NC1)=O.[CH3:26][CH2:27][C@@H:28]1[NH:71][C:69](=[O:70])[C@H:68]([C@H:72]([OH:79])[C@@H:73]([CH2:75]/[CH:76]=[CH:77]/[CH3:78])[CH3:74])[N:67]([CH3:80])[C:65](=[O:66])[C@@H:64]([CH:81]([CH3:83])[CH3:82])[N:63]([CH3:84])[C:61](=[O:62])[C@H:60]([CH2:85][CH:86]([CH3:88])[CH3:87])[N:59]([CH3:89])[C:57](=[O:58])[C@H:56]([CH2:90][CH:91]([CH3:93])[CH3:92])[N:55]([CH3:94])[C:53](=[O:54])[C@@H:52]([CH3:95])[NH:51][C:49](=[O:50])[C@H:48]([CH3:96])[NH:47][C:45](=[O:46])[C@H:44]([CH2:97][CH:98]([CH3:100])[CH3:99])[N:43]([CH3:101])[C:41](=[O:42])[C@H:40]([CH:102]([CH3:104])[CH3:103])[NH:39][C:37](=[O:38])[C@H:36]([CH2:105][CH:106]([CH3:108])[CH3:107])[N:35]([CH3:109])[C:33](=[O:34])[CH2:32][N:31]([CH3:110])[C:29]1=[O:30].CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@@H](C/C=C/C)C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O>>[CH3:26][CH2:27][C@@H:28]1[NH:71][C:69](=[O:70])[C@H:68]([C@H:72]([OH:79])[C@@H:73]([CH2:75]/[CH:76]=[CH:77]/[CH3:78])[CH3:74])[N:67]([CH3:80])[C:65](=[O:66])[C@H:64]([CH:81]([CH3:82])[CH3:83])[N:63]([CH3:84])[C:61](=[O:62])[C@H:60]([CH2:85][CH:86]([CH3:87])[CH3:88])[N:59]([CH3:89])[C:57](=[O:58])[C@H:56]([CH2:90][CH:91]([CH3:93])[CH3:92])[N:55]([CH3:94])[C:53](=[O:54])[C@@H:52]([CH3:95])[NH:51][C:49](=[O:50])[C@H:48]([CH3:96])[NH:47][C:45](=[O:46])[C@H:44]([CH2:97][CH:98]([CH3:100])[CH3:99])[N:43]([CH3:101])[C:41](=[O:42])[C@H:40]([CH:102]([CH3:104])[CH3:103])[NH:39][C:37](=[O:38])[C@H:36]([CH2:105][CH:106]([CH3:108])[CH3:107])[N:35]([CH3:109])[C:33](=[O:34])[CH2:32][N:31]([CH3:110])[C:29]1=[O:30]

Participants

Reactant 3

HCID 6476564Cyclosporin H

HCID 46877899HCID 46877899, compound

HCID 101607770HCID 101607770, compound

Product 1

HCID 5284373Cyclosporin A

Procedure

510 kg cyclosporin A-containing fermentation broth was extracted twice with 510 L methyl-tert.-butyl ether (MTBE) each, 2.6 kg of the Clariant MD07/049 polyacrylate being added. The ether phases were separated in a 300 L separator in throughfeed and combined. The cyclosporin A-containing ether phase was washed once with 700 L pure water having a pH of about 7, the phases were separated again in a separator and the ether phase was concentrated by azeotropic distillation in a 1000 L thin-layer evaporator at a temperature of about 53° C. so as to achieve a cyclosporin concentration of 100 g/kg. The temperature was then lowered to a value just below the boiling point and this temperature was kept for 2 hours, with MTBE escaping via the distillation head being replaced by fresh one. Thereafter, the solution was concentrated at normal pressure at 53° C. so as to achieve a cyclosporin concentration of 300 g/kg. The residual water content which had been about 1.4% by weight prior to the azeotropic distillation was then 0.1% by weight. Thereafter, the solution was carefully cooled from 53° C. to 45° C. in 120 minutes, to 40° C. in another 60 minutes, to 30° C. in another 60 minutes and to 0° C. in another 60 minutes. 8.55 kg white, crystalline cyclosporin A-MTBE solvate was obtained in a theoretical total yield of about 87%. The isocyclosporin A content was 0.008% by weight, the total content of cyclosporin H and cyclosporin T was 0.28% by weight, which was a highly significant reduction in the content of these contaminations as compared to an extraction method using butyl acetate.

Workup

extractionas compared to an extraction method

Sources & evidence

ORD record: ord-bef213c722874e1b8f98dcf52537af38
Source dataset: uspto-grants-2014_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08691770B2

Reaction notes

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