Synthesis of n-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines
This invention is in the area of synthesizing pyrimidine-based compounds useful in the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
1. A process to prepare a 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine comprising: reacting a 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine with a heteroaryl amine, wherein the ratio of heteroaryl amine to 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is at least about 2 to 1 and the yield of the reaction is over about 50%, to afford the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine,
wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine is a compound of Formula:
wherein:
Z is —(CH 2 ) x —, wherein x is 1, 2, 3 or 4; or —O—(CH 2 ) z — wherein z is 2, 3 or 4;
R 2 is independently selected from the group consisting of hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;
each R 6 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 6 's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, 3 or 4;
R 12 is
R 7 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 8 R 9 , -(alkylene) m -C(O)—NR 8 R 9 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 10 , -(alkylene) m -S(O) n —R 10 , or -(alkylene) m -S(O) n —NR 8 R 9 ; any of which ma be optionally independently substituted with one or more R′ groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
R 8 and R 9 at each occurrence are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl, any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or
R 8 and R 9 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
R 10 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may be optionally independently substituted with one or more R x groups as allowed by valance;
R x at each occurrence is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl;
n is 0, 1, or 2; and
m is 0 or 1.
2. The process of claim 1 , wherein the process is conducted with a temperature that is maintained from about 0 to about 50° C.
3. The process of claim 1 , wherein the process is conducted with a temperature that is maintained from about 15 to about 30° C.
4. The process of claim 1 , wherein the process is conducted with a temperature that is maintained at or below 18° C.
5. The process of claim 1 , wherein the process is conducted with a temperature that is maintained at or below 10° C.
6. The process of claim 1 , wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is added over a time period of at least about 30 minutes.
7. The process of claim 6 , wherein the temperature is maintained from about 0 to about 50° C.
8. The process of claim 1 , wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is added portion wise.
9. The process of claim 1 further comprising: preparing the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine by selectively oxidizing a 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine with an oxidant in a solvent or mixture of solvents.
10. The process of claim 9 , wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine and 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine are compounds of Formula IV:
wherein:
represents the presence or absence of a double bond;
represents a carbocycle of 3 to 8 carbons connected in a spiro-fashion to the lactam ring wherein the spirocycle is optionally substituted;
R 1 is selected from: alkyl, aryl, haloalkyl, and arylalkyl; and
R 2 is selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl.
11. The process of claim 10 , wherein the oxidant is selected from: oxone, hydrogen peroxide, mCPBA, sodium hypochlorite, and sodium chlorite.
12. The process of claim 11 , wherein the oxidant is oxone.
13. The process of claim 10 , wherein the solvent or mixture of solvents is selected from: DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
14. The process of claim 13 , wherein the solvent or mixture of solvents is selected from ACN, water, and dioxane.
15. The process of claim 14 , wherein the mixture of solvents is water and ACN.
16. The process of claim 10 further comprising: preparing the 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine by removing the leaving group from a 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine with a suitable reagent.
17. The process of claim 16 , wherein the 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine is a compound of Formula IV and the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is a compound of Formula III:
wherein:
R 4 is selected from: hydrogen, silyl, haloalkyl, —C(O)alkyl, —S(O) 2 alkyl, —S(O) 2 haloalkyl, —S(O) 2 aryl, and —S(O) 2 arylalkyl.
18. The process of claim 17 further comprising a palladium catalyst.
19. The process of claim 17 , wherein the leaving group is tosylate (-OTs).
20. The process of claim 17 , wherein the leaving group is triflate (-OTf).
21. The process of claim 17 , wherein the suitable reagent is a trialkylsilane.
22. The process of claim 21 , wherein the trialkylsilane is triethylsilane.
23. The process of claim 17 further comprising: preparing the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine from a 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine with a suitable reagent.
24. The process of claim 23 wherein the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine are compounds of Formula III.
25. The process of claim 23 , wherein the leaving group is tosylate (-OTs).
26. The process of claim 23 , wherein the leaving group is triflate (-OTf).
27. The process of claim 23 , wherein the suitable reagent is triflic anhydride, Tf-Cl, tosyl anhydride, or Ts-Cl.
28. The process of claim 23 further comprising: preparing the 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine from an alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate by an intramolecular cyclization.
29. The process of claim 28 , wherein the 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is a compound of Formula III and the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is a compound of Formula II:
wherein:
R 5 is selected from: hydrogen, halogen, —N(alkyl)(alkoxy), —NCH 3 OMe, alkoxy, aryloxy, —OCH 2 aryl, —OC(O)alkyl, —OC(O)aryl, and —OC(O)arylalkyl.
30. The process of claim 29 further comprising: preparing the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate from an alkyl 4-halo-2-(alkylthio)pyrimidine-5-carboxylate by nucleophilic attack of a lactam amine.
31. The process of claim 30 , wherein the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5 carboxylate is a compound of Formula II and the lactam amine is a compound of Formula I:
wherein:
R 2 and R 3 is selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl.
32. The process of claim 1 wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is a 2′-(alkylsulfonyl)-lactam-pyrrolo[3,2-d]pyrimidine.
33. The process of claim 1 wherein Z is —(CH 2 ) 2 —.
34. The process of claim 33 wherein R 2 is hydrogen.
35. The process of claim 34 wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine of is selected from:
36. The process of claim 35 wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine is:
37. The process of claim 35 wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine is: