Water → HCID 178439820, compound

HRID 556224Notes

Reaction equation

HRID 556224 reaction equation
O.[NH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:14][NH:15][C:16]3[CH:66]=[CH:65][C:19]([C:20]([NH:22][C@@H:23]([CH2:27][CH2:28][C:29]([NH:31][C@@H:32]([CH2:61][C:62]([OH:64])=[O:63])[C:33]([NH:35][C@@H:36]([CH2:54][CH2:55][CH2:56][NH:57][C:58]([NH2:60])=[NH:59])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]([OH:53])=[O:52])[C:41]([NH:43][C@@H:44]([C:47]([OH:49])=[O:48])[CH2:45][SH:46])=[O:42])=[O:38])=[O:34])=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[CH:18][CH:17]=3)[N:9]=2)[N:4]=1.[C:67](=[O:116])([O:105][CH2:106][CH2:107][S:108]SC1C=CC=CN=1)[O:68][CH2:69][CH2:70][N:71]1[C@@H:87]2[C@H:72]1[CH2:73][CH2:74][CH2:75][C@H:76]([CH3:104])[C@H:77]([OH:103])[C@@H:78]([CH3:102])[C:79](=[O:101])[C:80]([CH3:100])([CH3:99])[C@@H:81]([OH:98])[CH2:82][C:83](=[O:97])[O:84][C@H:85](/[C:88](/[CH3:96])=[CH:89]/[C:90]1[N:91]=[C:92]([CH3:95])[S:93][CH:94]=1)[CH2:86]2>C1COCC1.P([O-])([O-])([O-])=O>[NH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:14][NH:15][C:16]3[CH:66]=[CH:65][C:19]([C:20]([NH:22][C@@H:23]([CH2:27][CH2:28][C:29]([NH:31][C@@H:32]([CH2:61][C:62]([OH:64])=[O:63])[C:33]([NH:35][C@@H:36]([CH2:54][CH2:55][CH2:56][NH:57][C:58]([NH2:60])=[NH:59])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]([OH:53])=[O:52])[C:41]([NH:43][C@H:44]([C:47]([OH:49])=[O:48])[CH2:45][S:46][S:108][CH2:107][CH2:106][O:105][C:67]([O:68][CH2:69][CH2:70][N:71]4[C@@H:87]5[C@H:72]4[CH2:73][CH2:74][CH2:75][C@H:76]([CH3:104])[C@H:77]([OH:103])[C@@H:78]([CH3:102])[C:79](=[O:101])[C:80]([CH3:99])([CH3:100])[C@@H:81]([OH:98])[CH2:82][C:83](=[O:97])[O:84][C@H:85](/[C:88](/[CH3:96])=[CH:89]/[C:90]4[N:91]=[C:92]([CH3:95])[S:93][CH:94]=4)[CH2:86]5)=[O:116])=[O:42])=[O:38])=[O:34])=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[CH:18][CH:17]=3)[N:9]=2)[N:4]=1

Participants

6

Reactant 3

HCID 962WaterHCID 86616576HCID 86616576, compoundHCID 178512886HCID 178512886, compound

Product 1

HCID 178439820HCID 178439820, compoundYield 83.5%

Reagents, catalysts & solvents 2

HCID 1061PhosphateSolventHCID 8028TetrahydrofuranSolvent

Procedure

To 15 mL of H2O (bubbled with argon for 10 min before use) was added to (S)-2-(4-((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methylamino)benzamido)-5-((S)-3-carboxy-1-((S)-1-((S)-3-carboxy-1-((S)-1-carboxy-2-mercaptoethylamino)-1-oxopropan-2-ylamino)-5-guanidino-1-oxopentan-2-ylamino)-1-oxopropan-2-ylamino)-5-oxopentanoic acid (498 mg, 0.534 mmol) in a 50 mL size centrifuge tube. To this suspension, while bubbling with argon, was added dropwise saturated NaHCO3 solution (bubbled with argon for 10 min before use) until the pH of the resulting solution reached 6.9. 2-((1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-5,9-dioxo-4-oxa-17-aza-bicyclo[14.1.0]heptadecan-17-yl)ethyl 2-(2-(pyridin-2-yl)disulfanyl)ethyl carbonate (400 mg, 0.534 mmol) in THF was added quickly and the resulting homogenous solution was stirred under argon for 30 min. The reaction progress was checked by analytical HPLC at 15 min. The product peak came out at ˜6.4 min under analytical HPLC conditions. The mixture was diluted with ˜15 mL of phosphate buffer and the THF was removed under vacuum. The cloudy solution was centrifuged and filtered. The yellow filtrate was divided into two portions and purified by preparative HPLC. Pure fractions (>98% pure) were pooled and freeze-dried. Tail fractions (<98% pure) were collected and re-purified for every 3-6 chromatography runs to provide 700 mg of the title compound as a white powder (contains 11.8% by weight of water and 8.7% by weight sodium and sodium phosphate salts, as determined by Karl Fischer and elemental analyses).

Workup

  1. customTo this suspension, while bubbling with argon
  2. additionwas added dropwise saturated NaHCO3 solution (bubbled with argon for 10 min before use) until the pH of the resulting solution
  3. waitThe reaction progress was checked by analytical HPLC at 15 min
  4. waitThe product peak came out at ˜6.4 min under analytical HPLC conditions
  5. customthe THF was removed under vacuum
  6. filtrationfiltered
  7. custompurified by preparative HPLC
  8. customfreeze-dried
  9. customTail fractions (<98% pure) were collected
  10. customre-purified for every 3-6 chromatography

Sources & evidence

ORD record
ord-046824a8838a4738a9c44dee711dd8c8
Source dataset
uspto-grants-2011_11
Patent number
USRE042930E1

Reaction notes

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