(WO2014145035) Provided herein are methods of making the compound of Formula I (I) and certain intermediates involved in such process.
(WO2014145035) WHAT IS CLAIMED IS: 1. A method for making the compound of Formula 1 : which comprises: (a) reacting the compound of Formula 2 Thapsigargin (Tg) C34H50O12 Mol. Wt.: 650.75 to produce the compound of Formula 3 8-O-Debutanoyl-thapsigargin (DBTg) C30H44O11 Mol. Wt.: 580.66 and (b) reacting the compound of Formula 3 to obtain the compound of Formula 5 C47H75N014 Mol. Wt.: 878.1 and (c) dissolving the compound of Formula 5 and mixing with trifluoroacetic acid (TFA) to obtain the compound of Formula 6 (TFA salt MW = 892.00) and (d) reacting the compound of Formula 6 with the compound of Formula 7 Boc-Asp-Glu(OtBu)-Glu(OtBu)-Glu(OtBu)-OtBu C49H83N5O.18 Mol. Wt.: 1030.21 in a mixture of dimethylformamide (DMF), hydroxybenzotriazole hydrate (HOBt), and 12-ADT-TFA and (e) adding diisopropylethylamine (DIPEA) and (3- Dimethylaminopropyl)ethylcarbodiimide hydrochloride (EDC-HCl) to produce the compound of Formula 8 and (e) reacting the compound of Formula 8 to produce the compound of Formula 9 and (f) purifying the compound of Formula 9 to produce the compound of Formula 1. 2. The method of claim I, wherein step (a) is performed using sodium ethoxide in ethanol. 3. The method of claims 1 or 2, wherein step (b) is performed using 4- dimethylaminopyridine (4-DMAP), the compound of Formula 4, dichloromethane and diisopropylcarbodiimide (DIC). 4. The method of claims 1 , 2, or 3, wherein the dissolution in step (c) is performed using dichloromethane (CH2CI2). 5. The method of claims I, 2, 3 or 4, wherein step (e) is performed using dichloromethane, triethylsilane (EtsSiH) and trifluoroacetic acid. 6. The method of any of claims 1 through 5, wherein step (f) is performed using CI 8 reverse-phase chromatography. 7. The method of claim 6, wherein step (f) further comprises using a concentration column. 8. A method of making the compound of Formula 4, comprising the scheme Mol. Wt: 215.33 Boc20 DMAP R3N NHBoc Boc-12-AD MeOH C18H35N04 C17H33N04Exact Mass: 329.26 Exact Mass: 315.24Mol. Wt.: 329.47 Mol. Wt.: 315.45 9. A method for making a compound having the formula Boc-(CH2)n-NH2, wherein n is an integer greater than 2, using the method of Claim 8, wherein the starting material for such method is a compound having the formula (CH2)n-NH2, wherein n is an integer greater than 2. 10. A compound having any of the formulas of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11 or Formula 12. 11. A compound having the formula of any of the compounds shown in Claims 8 or 9. 12. A compound having the formula Boc-(CH2)n-NH2, wherein n is an integer greater than 2. 13. A compound produced by the method of claims 1 or 9. 14. A method for making the compound of Formula 6: (TFA salt MW = 892.00) which comprises: (a) reacting the compound of Formula 2 Thapsigargin (Tg) C34H50O12 Mol. Wt.: 650.75 to produce the compound of Formula 3 8-O-Debutanoyl-thapsigargin (DBTg) C30H44O11 Mol. Wt.: 580.66 and (b) reacting the compound of Formula 3 to obtain the compound of Formula 5 and (c) dissolving the compound of Formula 5 and mixing with trifluoroacetic acid (TFA) to obtain the compound of Formula 6. 15. The method of claim 14, wherein step (a) is performed using sodium ethoxide in ethanol. 16. The method of claims 14 or 15, wherein step (b) is performed using 4- dimethylaminopyridine (4-DMAP), the compound of Formula 4, dichloromethane and diisopropylcarbodiimide (DIC). 17. The method of claims 14, 15, or 16, wherein the dissolution in step (c) is performed using dichloromethane (CH2CI2). 18. A compound produced by the method of claim 14.
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