ChemicalBook CAS DataBase List Butanedioic acid, 2,3-bis[(4-methylbenzoyl)oxy]-, (2S,3S)-, compd. with methyl (4S)-8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4-quinazolineacetate (1:1)

Butanedioic acid, 2,3-bis[(4-methylbenzoyl)oxy]-, (2S,3S)-, compd. with methyl (4S)-8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4-quinazolineacetate (1:1) synthesis

9synthesis methods

Product Name:Butanedioic acid, 2,3-bis[(4-methylbenzoyl)oxy]-, (2S,3S)-, compd. with methyl (4S)-8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4-quinazolineacetate (1:1)
CAS Number:917389-30-1
Molecular formula:C50H48F4N4O12
Molecular Weight:972.9293

4-Quinazolineacetic acid, 8-fluoro-3,4-dihydro-2-[4-(3-Methoxyphenyl)-1-piperazinyl]-3-[2-Methoxy-5-(trifluoroMethyl)phenyl]-, Methyl ester

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32634-68-7 Synthesis

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Butanedioic acid, 2,3-bis[(4-methylbenzoyl)oxy]-, (2S,3S)-, compd. with methyl (4S)-8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4-quinazolineacetate (1:1)

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Yield:917389-30-1 141 kg

Reaction Conditions:

in ethyl acetate at 0 - 20; for 76 h;Large scale;

Steps:

4A Example 4A(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5- -(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate (1:1 salt) chlorination/amination/crystallization

A solution of {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazoline-4-yl}methyl acetate (Example 3A, 129.2 kg) in chlorobenzene (800 l) is heated to reflux and azeotropically dried.
Phosphorous oxychloride (144 kg) is added, and the reaction mixture is agitated for 3 h at reflux.
Then, DBU (95 kg) and chlorobenzene (45 l) are added and agitated for additional 9 h at reflux.
The reaction mixture is cooled to room temperature, hydrolyzed by adding water, diluted with chlorobenzene (80 l), and neutralized with an aqueous solution of ammonia (25%).
The phases are separated, the organic phase is washed with water and the solvent is distilled off.
The remaining residue is dissolved in dioxane (170 l).
3-methoxyphenylpiperazine (66 kg), DBU (52 kg), and an additional 90 l of dioxane are added and the reaction mixture is heated for 4 h at reflux.
The reaction mixture is cooled to room temperature, added to ethyl acetate (1300 l), washed once with water, 3 times with 0.2 N HCl, and once with an aqueous solution of NaCl, and the solvent is distilled off.
The resulting residue is dissolved in ethyl acetate (800 l) and added to a solution of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (121 kg) in ethyl acetate (600 l).
The resulting mixture is agitated for approx.
60 min. at room temperature and then inoculated with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate and agitated for 3 days at room temperature.
It is then cooled to 0-5° C. and agitated for an additional 3 h.
The suspension is filtered and the remaining solid is rewashed in batches with ethyl acetate.
A total of about 141 kg (calculated as dry weight) of the salt is thus obtained as a solid, corresponding to around 46.2% of theory, in three stages (chlorination, amination and crystallization) compared to the racemate).
¹H NMR (300 MHz, d₆-DMSO): δ=7.90 (d, ²J=7.8, 4H), 7.56 (d, ²J=8.3, 1H), 7.40 (d, ²J=7.8, 4H), 7.28-7.05 (m, 4H), 6.91-6.86 (m, 2H), 6.45 (d, ²J=8.3, 1H), 6.39-6.36 (m, 2H), 5.82 (s, 2H), 4.94 (m, 1H), 4.03 (q, ²J=7.1, 2H), 3.83 (brs, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.47-3.36 (m, 8H and water, 2H), 2.98-2.81 (m, 5H), 2.58-2.52 (m, 1H), 2.41 (s, 6H), 1.99 (s, 3H), 1.18 (t, ²J=7.2, 3H) ppm; HPLC (Method 1): RT=16.6 and 18.5 min