Processes for preparing phosphorodiamidate morpholino oligomers
A technology of oligomeric compounds and compounds, applied in the field of compounds, can solve the problems of limited pharmacological options for DMD
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
preparation example Construction
[0269] Preparation process of Golodirsen
[0270] Provided herein are methods of preparing Golodirsen.
[0271] In one aspect, provided herein are methods of preparing oligomeric compounds of formula (G):
[0272]
[0273] The method described therein comprises the following sequential steps:
[0274] (a) contacting a compound of formula (I) with a deblocking agent:
[0275]
[0276] where R 1 as the carrier medium,
[0277] To form a compound of formula (II):
[0278]
[0279] where R 1 is the carrier medium;
[0280] (b) contacting a compound of formula (II) with compound (B):
[0281]
[0282] to form a compound of formula (III):
[0283]
[0284] where R 1 as the carrier medium;
[0285] (c) exposing a compound of formula (III) to a deblocking agent to form a compound of formula (IV):
[0286]
[0287] where R 1 as the carrier medium;
[0288] (d) contacting a compound of formula (IV) with a compound of formula (DPG):
[0289]
[0290] to...
Embodiment 1
[0544] Example 1: NCP2 anchor synthesis
[0545] Preparation of 1.4-fluoro-3-nitrobenzoic acid methyl ester (1)
[0546]
[0547] 12.7kg of 4-fluoro-3-nitrobenzoic acid was added to a 100L flask, 40kg of methanol and 2.82kg of concentrated sulfuric acid were added. The mixture was stirred at reflux (65°C) for 36 hours. The reaction mixture was cooled to 0 °C. Crystals formed at 38°C. The mixture was kept at 0 °C for 4 hours, then filtered under nitrogen. The 100 L flask was washed with 10 kg of methanol which had been cooled to 0° C., and the filter cake was washed. The solid cake was dried on the funnel for 1 hour, transferred to a tray, and dried in a vacuum oven at room temperature to constant weight 13.695 kg methyl 4-fluoro-3-nitrobenzoate (100% yield; HPLC 99% ).
[0548] 2. Preparation of 3-nitro-4-(2-oxopropyl)benzoic acid
[0549] A. (Z)-4-(3-Hydroxy-1-methoxy-1-oxobut-2-en-2-yl)-3-nitrobenzoic acid methyl ester (2)
[0550]
[0551] To a 100 L flask was...
Embodiment 2
[0570] Example 2: Anchor resin synthesis
[0571] About 52 L of NMP and 2600 g of aminoethyl polystyrene resin were added to a 75 L solid phase synthesis reactor. The resin was stirred in NMP to swell for about 2 hours, then drained. The resin was washed twice with about 39 L of DCM per wash, then twice with 39 L of neutralizing solution per wash, then twice with 39 L of DCM per wash. The NCP2 anchoring solution was slowly added to the stirred resin solution, stirred at room temperature for 24 hr, and drained. The resin was washed four times with 39L NMP per wash and six times with 39L DCM per wash. The resin was treated and stirred with 1 / 2 DEDC capping solution for 30 minutes, drained, and treated with a second 1 / 2 DEDC capping solution and stirred for 30 minutes and drained. The resin was washed six times with 39L DCM each time, and then dried in an oven to a constant weight of 3573.71g to obtain an anchored resin.
PUM
Login to View More Abstract
Description
Claims
Application Information
Login to View More