# US 5,349,064 A · Production of pyrrolopyrimidines > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,349,064 A - Document ID: US5349064A - Status: Granted - Kind: A - Application number: 08/029,310 - Filed: 1993-03-08 - Granted: 1994-09-20 - Earliest claimed: 1989-06-14 - Assignees: Takeda Chemical Industries, Ltd. - Inventors: Hiroshi Akimoto; Takenori Hitaka; Tetsuo Miwa - Web page: https://patentgrep.com/patent/US5349064A ## CPC - C07D 239/48: Two nitrogen atoms - A61P 35/00: Antineoplastic agents - C07D 239/50: Three nitrogen atoms - C07D 487/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract There is provided an improved process for producing novel compounds represented by the general formula: ##STR1## wherein the ring A represents a pyrrole ring which may be hydrogenated; X represents an amino, hydroxyl or mercapto group; R.sup.1, R.sup.2 and R.sup.3 each being the same as or different from the other, represents hydrogen or an alkyl, alkenyl or alkynyl group which may be substituted; R.sup.4 represents OR.sup.5 wherein R.sup.5 represents hydrogen or a hydrocarbon group which may be substituted or NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 wherein R.sup.6 and R.sup.7 each represents hydrogen or a hydrocarbon group which may be substituted; and n represents an integer of 1 to 4, or a salt thereof from compounds represented by the general formula: ##STR2## wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are the same as defined above; Y.sup.1 and Y.sup.2 each represents oxygen or sulfur atom; R.sup.8 and R.sup.9 each, being the same as or different from the other, represents a hydrocarbon group which may be substituted, or salts thereof by an intramolecular ring closure reaction to form a pyrrolopyrimidine ring and, if necessary, reducing the pyrrole ring thus formed to a pyrroline ring. The compounds are useful as antitumor agents. ## Claims ### Claim 1 A process for producing a compound represented by the formula: ##STR15## The ring A represents a pyrrole ring which may be hydrogenated; X represents an amino, hydroxyl or mercapto group; R.sup.1 represents hydrogen or a C.sub.1-6 alkyl group which may be substituted; R.sup.2 and R.sup.3 each, being the same or different, represents hydrogen or a C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl group which may be substituted; R.sup.4 represents OR.sup.5 wherein R.sup.5 represents hydrogen or a hydrocarbon group selected from the group consisting of C.sub.1-5 alkyl, benzyl and phenyl which may be substituted or NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 wherein R.sup.6 and R.sup.7 each represents hydrogen or a hydrocarbon group selected from the group consisting of C.sub.1-5 alkyl, benzyl and phenyl which may be substituted; and n represents an integer of i to 4, or a nontoxic salt thereof, said process comprising contacting a compound of the formula: ##STR16## wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are the same as defined above; Y.sup.1 and Y.sup.2 each represents oxygen or sulfur atom; R.sup.8 and R.sup.9 each, being the same or different, represents a hydrocarbon group selected from the group consisting of C.sub.1-5 alkyl, benzyl and phenyl which may be substituted, or a salt thereof, with an acid in a water-containing organic solvent to undergo a ring-closure reaction, wherein during said ring-closure reaction the group ##STR17## is converted to a carbonyl, hemiacetal or hemiketal group, said carbonyl, hemiacetal or hemiketal group condensing with the amino group on the pyrimidine ring to form the pyrrolo(2,3-d)pyrimidine ring, and optionally, reducing the pyrrole ring of ring A into a pyrroline ring, or converting OR.sup.5 of R.sup.4, where R.sup.5 is the same as defined above, into, NHCH(COOR.sup.6)CH.sub.2 CH.sub.2 COOR.sup.7 where R.sup.6 and R.sup.7 are the same as defined above, wherein in the above formulae, the substituted alkyl, substituted alkenyl and substituted alkynyl groups of R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are substituted with one to three substituents selected from the group consisting of halogen, nitro, cyano, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms, trifluoromethyl, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms and alkylsulfonyl of 1 to 4 carbon atoms; and wherein the substituted phenyl and substituted benzyl groups of R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are substituted with one to three substituents selected from the group consisting of halogen, nitro, cyano, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms, trifluoromethyl, alkythio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 3 carbon atoms and alkynyl of 2 to 3 carbon atoms. ### Claim 2 (depends on 1) A process as claimed in claim 1, wherein the water-containing organic solvent is a mixture of an alcohol, an acetic acid ester, an ether, a ketone, an amide, a sulfoxide or a nitrile with water. ### Claim 3 (depends on 1) A process as claimed in claims 1, wherein the acid is selected from the group consisting of hydrogen chloride, hydrogen bromide, perchloric acid, sulfuric acid, nitric acid and phosphoric acid. ### Claim 4 (depends on 1) A process as claimed in claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 each is a hydrogen atom. ### Claim 5 (depends on 1) A process as claimed in claim 1, wherein Y.sup.1 and Y.sup.2 and both are an oxygen atom. ### Claim 6 (depends on 1) A process as claimed in claim 1, wherein R.sup.8 and R.sup.9 each is a C.sub.1-3 alkyl group. ### Claim 7 (depends on 1) A process as claimed in claim 1, wherein R.sup.5, R.sup.6 and R.sup.7 each is a C.sub.1-5 alkyl group or benzyl group.