ICOTINIB
4-((3-ethynylphenyl)amino)-6,7-benzo-12-crown-4-quinazoline
N-(3-Ethynylphenyl)-7,8,10,11,13,14-hexahydro[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine
[1,4,7,10]Tetraoxacyclododecino[2,3-g]quinazolin-4-amine, N-(3-ethynylphenyl)-7,8,10,11,13,14-hexahydro-
BPI 2009H, UNII-JTD32I0J83
610798-31-7 CAS BASE
Icotinib Hydrochloride, 1204313-51-8, CS-0918, HY-15164, Conmana Zhejiang Beta Pharma Ltd.
NEW PATENT
General synthetic route
Compound A, the present invention is provided for availability, but are not limited to, the following synthetic route to achieve:
The present invention is to provide beta available but are not limited to, the following synthetic route is now:
A BETA
The present invention is to provide a compound C, can be used, but are not limited to, the following synthetic route to achieve:
Wherein
And are independently selected from the group consisting of methyl, ethyl, propyl or isopropyl, or
, And they are connected in common to the N atom form a 3-7 membered ring.R 3 and R4 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, iso-butyl or benzyl group, or,
R 3 and R4 to form a 3-7 membered ring.
The present C can be used for the direct preparation of Icotinib:
Wherein
And are independently selected from the group consisting of methyl, ethyl, propyl or isopropyl, or
, And they are connected in common to the N atom form a 3-7 membered ring.
Icotinib
Icotinib Hydrochloride
Example Synthesis of compound 1 A
1 Synthesis of Compound 2
2
79.5g 3,4 – dihydroxybenzene nitrile, 272g of potassium carbonate, acetonitrile (6L) was added to a 10L three-necked reaction flask, and dissolved with stirring, heated to reflux and reflux was added dropwise an acetonitrile solution of the compound 1 (compound 1, 200 g; acetonitrile , 2L), and completion of the dropping, the HPLC monitoring of the completion of the reaction, the mixture was cooled to room temperature, filtered, and the solvent was removed, and the resulting solid was washed with ethyl acetate was dissolved, filtered, and the filtrate was concentrated, the resulting residue was dissolved in petroleum ether by rotary evaporation, the resulting solid was purified to give 18.9g of the compound 2.
1 LAI MR (CDC1 3-Sppm): 7.30 ~ 7.33 (m, 1H); 7.25 (s, 1H); 6.97-6.99 (d, 1H); 4.19 – 4.23 (m, 4H); 3.83 ~ 3.91 (m, 4H); 3.77 (s, 4H). MS: (M + H) +250 2 Synthesis of compound A
2 A
41.6g of compound 2 was dissolved in 580ml of acetic acid, dropwise addition of 83ml of fuming nitric acid at 30 ° C under completion of the dropping, the dropwise addition of 42ml of concentrated sulfuric acid at 30 ° C under the reaction at room temperature overnight, TLC monitoring completion of the reaction, the reaction solution was poured into ice water 4L , the precipitated solid was filtered, washed with cold water (500 mL X 2), vacuum 35 ° C and dried crude A compound 46g, isopropanol recrystallization was purified to give 33g of compound A.
1 LAI MR (CDC1 3-Sppm): 7.90 (s, 1H); 7.36 (s, 1H); 4.33 ~ 4.36 (m, 4H); 3.87 ~ 3.89 (m, 4H); 3.737 (s, 4H). Embodiment of Example 2 Synthesis of Compound B
AB
32g of compound A, 30.5g of iron powder, 5% acetic acid solution in methanol 1070ml 2L reaction flask was heated to reflux
TLC monitoring of the end of the reaction cooled and concentrated, dissolved in ethyl acetate, filtered, dried over anhydrous NaS0 4 23g of compound B. The solvent was removed.
1HNMR (d 6-DMSO-Sppm): 7.07 (s, 1H); 6.36 (s, 1H); 5.73 (s, 2H); 3.95 ~ 4.22 (m, 4H); 3.77-3.78 (m, 2H); 3.34 3.62 (m, 6H). Embodiment of Example 3 Synthesis of Compound CI
B CI
500mL three-necked flask, the Add 5g compound B, 5g v, v-dimethyl formamide dimethyl acetal and 160ml of dioxane was heated to reflux the TLC monitoring progress of the reaction, the reaction time is about 12 hours, after the end of the reaction The reaction solution was cooled to room temperature, spin-dry to give 5.8g of compound Cl.
1 LAI MR (CDCl 3-Sppm): 7.56 (s, 1H); 7.15 (s, 1H); 6.51 (s, 1H); 4.12-4.18 (m, 4H); 3.89-3.91 (m, 2H); 3.78 -3.80 (m, 6H); 3.07 (s, 6H); Example 4 Icotinib Synthesis
5 g of the compound Cl, 2.2 g inter-aminophenyl acetylene, 230ml of acetic acid was added to a 500 ml reaction flask was heated to 100 ° c,
TLC monitoring of the reaction. The end of the reaction, the reaction system spin dry methanol was added, and shock dispersion, filtration, wash with methanol, 5g Icotinib.
^ M (d 6-DMSO-5ppm): 11.98 (s, IH); 9.50 (s, IH); 8.53 (s 1H); 8.14 (s, IH); 8.04-8.05 (m, IH); 7.90-7.92 (m, IH); 7.38-7.42 (m, IH); 7.31 (s IH); 7.20-7.22 (m, IH); 4.29-4.30 (m, 4H); 4.21 (s, IH); 3.74-3.81 ( m, 4H); 3.64 (s, 4H); 1.91 (s, 3H);
Synthesis Example 5 Exe hydrochloride erlotinib
Exeter for Nick for; s
700mg Icotinib Add to a 100 ml reaction flask, add 40 ml of methanol, stirred pass into the hydrogen chloride gas or concentrated hydrochloric acid, and filtered to give crude hydrochloric acid Icotinib after, and purified by recrystallization from isopropanol to give 760mg hydrochloride Icotinib.
1HNMR (d 6-DMSO-Sppm): 11.37 (s, IH); 8.87 (s, IH); 8.63 (s, IH); 7.90 (s, IH); 7.78-7.80 (d, IH); 7.48-7.52 (m, IH); 7.40-7.41 (m, 2H); 4.36-4.38 (d, 4H); 4.30 (s, IH); 3.75-3.81 (d, 4H); 3.61 (s, 4H);
Example 18 Synthesis of Compound CI
3g compound B, 4.4g N, N-dimethyl formamide diisopropyl acetal was dissolved in 140ml dioxane was heated to reflux, tlc monitoring the progress of the reaction, the reaction time of approximately 11-12 hours after the completion of the reaction, was cooled to room temperature, the reaction solution was spin-dry to give 2.4g of the compound Cl.
The implementation of the synthesis of Example 19 Icotinib
3g compound Cl, 1.3 g inter-aminophenyl acetylene, 130 ml of acetic acid was added 250 ml reaction flask and heated to 70-80
V, TLC monitoring of the reaction. Spin dry the reaction system, methanol was added, and shock dispersion, filtered, and the methanol wash was 2.8g Icotinib. Implementation of Example 20 Icotinib synthesis
C1 Icotinib
8g compound Cl, 3.5g inter-aminophenyl acetylene, dissolved in 380ml of acetic acid, heated to 100-120 ° C, TLC monitoring of the reaction. Spin dry the reaction system, by adding ethanol shock dispersion, filter, the ethanol wash 7.2g Icotinib. Implementation of Example 21 Icotinib Synthesis
The C1 Exeter erlotinib reaction temperature of 120-15CTC Example 4 was 2.2 g Icotinib.
Example 22 Icotinib Synthesis
3g compound Cl, 1.8 g inter-aminophenyl acetylene and 130 ml of acetic acid was added 250 ml reaction flask and heated to 90-100C, TLC monitoring of the reaction. Spin dry the reaction system, isopropanol shock dispersion, filtration, isopropyl alcohol wash was 2.9g Icotinib.
The implementation of the synthesis of Example 23 Icotinib
3G compound CI and 1.3 g of m-aminophenyl acetylene dissolved in 130ml of formic acid was heated to 80-90 ° C, TLC monitoring of the reaction. Spin dry the reaction system, methanol was added, and shock dispersion, filtered, and the methanol wash was 2.7g Icotinib.
Example 24 Icotinib synthesis
3g of compound C1 and 1.3g aminophenyl acetylene dissolved in 130ml of trifluoroacetic acid was heated to 70-80 ° C, TLC monitoring of the reaction.Spin dry the reaction system, methanol was added, and shock dispersion, filtered, and the methanol wash was 2.7g Icotinib. Example 25 Icotinib Hydrochloride synthesis
Icotinib Hydrochloride
The 500mg Icotinib Add to a 100 ml reaction flask, add 30ml of ethanol was stirred under hydrogen chloride gas was passed into the after, filtered crude hydrochloride Icotinib recrystallized from isopropanol to give 515mg hydrochloride Icotinib. Example 26 Icotinib Hydrochloride Synthesis
500mg Icotinib Add 100 ml reaction flask, add 40 ml of tetrahydrofuran was stirred under hydrogen chloride gas was passed into the after, filtered crude hydrochloride Icotinib recrystallized from isopropanol to give 500mg hydrochloride Icotinib. EXAMPLE 27 Icotinib Hydrochloride Synthesis
Exeter erlotinib erlotinib hydrochloride Exeter
500mg Icotinib Add 100 ml reaction flask, add 50 ml of isopropanol and stirred under hydrogen chloride gas was passed into the after, filtered crude hydrochloride Icotinib recrystallized from isopropanol to give 500mg hydrochloride Icotinib. Example 28 Icotinib Hydrochloride synthesis
Icotinib
Icotinib Hydrochloride
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