МЭГЭНО Жевейер (US),МЭЛОНИ Марк Томас (US),МАРК Оливье Дж. (US),НЭДКАРНИ Дёргеш Вэсент (US),ПОЦЦО Марк Джон (US),ТЕЙШЕЙРА ДжейАр. Джон Джозеф (US)
申请号：
RU2014124989
公开号：
RU2014124989A
申请日:
2012.12.10
申请国别(地区):
RU
年份:
2016
代理人:
摘要：
1. A process for preparing a compound of formula 5avklyuchayuschy (i) reacting 9a and 11 in the presence of 1-propanephosphonic anhydride acid (T3R) to give compound 13a (ii) catalytic hydrogenation using Pd / C in THF 13a compound solution: HO with at least approximately 50% THF, to afford compound 14a formula (iii) the union 14a of a solution in THF to a compound of formula 15 in a reaction substantially without a base, to obtain a compound 6a (iv) reacting formula 6a with a compound of formula 19a in THF at the presence of DCC, to yield compound 2 0a (v) the union 20a with ε-amine peptide 2, dissolved in an aprotic polar fifteenth solvent, to afford a bioconjugate 3ai, optionally, further comprising the following step (vi) dissolving the compound 3a in DMSO (vii) adding a histidine buffer at a pH of about 5.5 to about 7.5 and a solution of DMSO During step (vi) (viii) adding an antibody comprising the variable light region including SEQ ID NO: 5 and a variable heavy portion comprising SEQ ID NO: 6, to a solution of step (vii), so that the molar ratio nen Id: antibody ranges from about 1.8: 1 to about 3: 1 (ix) agitation of the mixture formed in step (viii) at medium speed to avoid foaming of the reaction mixture for at least about 1 hour at a pH of about 5.5 to about 7.5 and at a temperature from about 5 ° C to 35 ° C, (x) filtering the solution of (ix) to extract the peptide-linker conjugate antibody 5a.gde q = 1, 2, 3, 4, or 5, X = F or Cl, m = 3, 4 or 5.2. A method according to Claim. 1 wherein the reaction between 9a and 11 is carried out in the presence of a first solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1-methyl-2-pyrrolidinone (NMP), N, N-dimetilforma
