Process for the preparation of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(isopropylsulfonyl)azetidin-3-yl}acetonitrile
The present application relates to a preparation method for a pyrrolopyrimidine compound, comprising: obtaining a compound 3 from a compound 2, obtaining a compound 4P2 from the compound 3, and obtaining a pyrrolopyrimidine compound of formula I by removing a protecting group from the compound 4P2. The preparation method of the present application has the advantages of simple operation, mild reaction conditions and high yield, avoids the problems of low yield and a large amount of impurities and difficult separation of same in original routes, reduces production costs, and is suitable for industrial production. Furthermore, the product yield of each step is high, and basically reaches about 80%, and even the yield of some steps can reach 90% or more.
1 . A process for the preparation of a compound of formula 1:
wherein the process comprises the following steps:
(1) reacting a compound of formula 2:
wherein:
R 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)CF 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl; and
each R 3 is independently H or C 1 -C 4 alkyl; or
R 3 and R 3 , together with the nitrogen atom to which they are attached, form a C 3 - to C 8 -membered ring;
with a hydrazine compound selected from the group consisting of a salt of hydrazine, an aqueous solution of hydrazine, and an organic solution of hydrazine, and optionally, an acetal selected from the group consisting of an N,N-di(C 1 -C 4 alkyl)formamide di(C 1 -C 4 alkyl) acetal and a 5- or 6-membered azaheterocycle-N-formamide di(C 1 -C 4 alkyl) acetal, to obtain a compound of formula 3:
wherein:
R 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)CF 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl;
(2) reacting the compound of formula 3 obtained in step (1) above with a cyclic imide protecting agent selected from the group consisting of 1,2-cyclohexanedicarboxylic anhydride, glutaric anhydride, maleic anhydride, phthalic anhydride, 3,4-difluorophthalic anhydride, 3,6-difluorophthalic anhydride, 4-chlorophthalic anhydride, 3-methylphthalic anhydride, 4-methylphthalic anhydride, tetrahydrophthalic anhydride, 4-methyltetrahydrophthalic anhydride, 3,4-dimethylphthalic anhydride, 3-methoxyphthalic anhydride, 4-methoxyphthalic anhydride, methylhexahydrophthalic anhydride, succinic anhydride, methylsuccinic anhydride, 3,3-dimethylsuccinic anhydride, 3,4-dimethylsuccinic anhydride, and 3-bromotetrahydrofuran-2,5-dione, to obtain a compound of formula 3P:
wherein:
R 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)CF 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl; and
R 2 , together with the intervening atoms and the nitrogen atom to which they are attached, form a cyclic imide protecting group selected from the group consisting of 1,2-cyclohexanedicarboximide, glutarimide, maleimide, phthalimide, 3,4-difluorophthalimide, 3,6-difluorophthalimide, 4-chlorophthalimide, 3-methylphthalimide, 4-methylphthalimide, 3,4-dimethylphthalimide, 3-methoxyphthalimide, 4-methoxyphthalimide, tetrahydrophthalimide, 4-methyltetrahydrophthalimide, methylhexahydrophthalimide, succinimide, 2-bromosuccinimide, methylsuccinimide, 2,2-dimethylsuccinimide, or 2,3-dimethylsuccinimide;
(3) reacting the compound of formula 3P obtained in step (2) above with a compound of formula SM2:
wherein:
R 4 is CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl (THP);
in the presence of a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, tetramethylguanidine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), to obtain a compound of formula 4P1:
wherein:
R 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)CF 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl; and
R 2 , together with the intervening atoms and the nitrogen atom to which they are attached, form a cyclic imide protecting group selected from the group consisting of 1,2-cyclohexanedicarboximide, glutarimide, maleimide, phthalimide, 3,4-difluorophthalimide, 3,6-difluorophthalimide, 4-chlorophthalimide, 3-methylphthalimide, 4-methylphthalimide, 3,4-dimethylphthalimide, 3-methoxyphthalimide, 4-methoxyphthalimide, tetrahydrophthalimide, 4-methyltetrahydrophthalimide, methylhexahydrophthalimide, succinimide, 2-bromosuccinimide, methylsuccinimide, 2,2-dimethylsuccinimide, or 2,3-dimethylsuccinimide; and
R 4 is CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl (THP);
(4) reacting the compound of formula 4P1 obtained in step (3) above with a mineral acid or an organic acid, to obtain a compound of formula 5:
or a salt thereof,
wherein:
R 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)CF 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl; and
R 2 , together with the intervening atoms and the nitrogen atom to which they are attached, form a cyclic imide protecting group selected from the group consisting of 1,2-cyclohexanedicarboximide, glutarimide, maleimide, phthalimide, 3,4-difluorophthalimide, 3,6-difluorophthalimide, 4-chlorophthalimide, 3-methylphthalimide, 4-methylphthalimide, 3,4-dimethylphthalimide, 3-methoxyphthalimide, 4-methoxyphthalimide, tetrahydrophthalimide, 4-methyltetrahydrophthalimide, methylhexahydrophthalimide, succinimide, 2-bromosuccinimide, methylsuccinimide, 2,2-dimethylsuccinimide, or 2,3-dimethylsuccinimide;
(5) reacting the compound of formula 5 obtained in step (4) above, or a salt thereof, with an isopropylsulfonyl reagent selected from the group consisting of ClS(O) 2 CH(CH 3 ) 2 , BrS(O) 2 CH(CH 3 ) 2 , HOS(O) 2 CH(CH 3 ) 2 , CH 3 OS(O) 2 CH(CH 3 ) 2 , CH 3 CH 2 OS(O) 2 CH(CH 3 ) 2 , and (CH 3 ) 2 CHOS(O) 2 CH(CH 3 ) 2 , to obtain a compound of formula 4P2:
wherein:
R 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 (Bum), CH 2 OCH 2 -phenyl (Bom), C(O)OCH 2 CCl 3 (Troc), CH 2 OCH 2 CH 2 Si(CH 3 ) 3 (SEM), CH 2 OC(O)C(CH 3 ) 3 (POM), C(O)CH 3 , C(O)CF 3 , C(O)OCH 2 -phenyl (Cbz), C(O)OCH 2 CH 2 Si(CH 3 ) 3 (Teoc), C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl) (TSC), C(O)OC(CH 3 ) 3 (Boc), C(O)OCH[C(CH 3 ) 2 CH 3 ] 2 (Doc), C(O)O-(1-adamantyl) (Adoc), C(O)O-2-adamantyl (2-Adoc), C(phenyl) 3 (Tr), Si(CH 3 ) 3 (Tms), Si(phenyl) 3 (Ts), S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 phenyl, S(O) 2 -p-toluene, S(O) 2 -p-nitrophenyl, or 2-tetrahydropyranyl; and
R 2 , together with the intervening atoms and the nitrogen atom to which they are attached, form a cyclic imide protecting group selected from the group consisting of 1,2-cyclohexanedicarboximide, glutarimide, maleimide, phthalimide, 3,4-difluorophthalimide, 3,6-difluorophthalimide, 4-chlorophthalimide, 3-methylphthalimide, 4-methylphthalimide, 3,4-dimethylphthalimide, 3-methoxyphthalimide, 4-methoxyphthalimide, tetrahydrophthalimide, 4-methyltetrahydrophthalimide, methylhexahydrophthalimide, succinimide, 2-bromosuccinimide, methylsuccinimide, 2,2-dimethylsuccinimide, or 2,3-dimethylsuccinimide;
(6) reacting the compound of formula 4P2 obtained in step (5) above with a reagent selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, boron trifluoride, lithium tetrafluoroborate, sodium tetrafluoroborate, and potassium tetrafluoroborate, to obtain a compound of formula 6:
wherein:
R 2 , together with the intervening atoms and the nitrogen atom to which they are attached, form a cyclic imide protecting group selected from the group consisting of 1,2-cyclohexanedicarboximide, glutarimide, maleimide, phthalimide, 3,4-difluorophthalimide, 3,6-difluorophthalimide, 4-chlorophthalimide, 3-methylphthalimide, 4-methylphthalimide, 3,4-dimethylphthalimide, 3-methoxyphthalimide, 4-methoxyphthalimide, tetrahydrophthalimide, 4-methyltetrahydrophthalimide, methylhexahydrophthalimide, succinimide, 2-bromosuccinimide, methylsuccinimide, 2,2-dimethylsuccinimide, or 2,3-dimethylsuccinimide; and
(7) reacting the compound of formula 6 obtained in step (6) above with an elimination reagent selected from the group consisting of ammonia gas, ammonia water, ethylenediamine, propylenediamine, ethanolamine, propanolamine, hydrazine, hydrazine hydrate, a hydrazine salt, and an organic solution of hydrazine, or a combination thereof, to obtain the compound of formula 1:
2 . The process according to claim 1 , wherein in step (1), the acetal is selected from the group consisting of pyrrolidine-N-formamide diethyl acetal, piperidine-N-formamide dimethyl acetal, piperidine-N-formamide diethyl acetal, morpholine-N-formamide dimethyl acetal, and morpholine-N-formamide diethyl acetal.