# US 7,608,740 B2 · Method of synthesizing key intermediates for the production of camptothecin derivatives > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,608,740 B2 - Document ID: US7608740B2 - Status: Granted - Kind: B2 - Application number: 11/997,688 - Filed: 2005-09-27 - Published: 2008-09-11 - Granted: 2009-10-27 - Earliest claimed: 2005-08-03 - Assignees: Avra Laboratories Pvt. Ltd - Inventors: Ramakrishna Rao; Venkata Rama Rao Alla - Web page: https://patentgrep.com/patent/US7608740B2 ## CPC - C07C 221/00: Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton - C07C 29/40: with compounds containing carbon-to-metal bonds - C07C 45/305: {with halogenochromate reagents, e.g. pyridinium chlorochromate} - C07C 201/08: by substitution of hydrogen atoms by nitro groups - C07C 201/12: by reactions not involving the formation of nitro groups - C07C 205/45: the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group - C07D 491/22: in which the condensed system contains four or more hetero rings - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The present invention discloses a process for efficient production of 2-amino-5-hydroxypropiophenone corresponding to the AB ring part of camptothecin (CPT) skeleton, which is a key intermediate useful for the total synthesis of camptothecin analogs including 7-Ethyl-10-hydroxy camptothecin and novel intermediates thereof. ## Claims ### Claim 1 A process for preparing 2-amino-5-hydroxypropiophenone to synthesize camptothecin analogs, wherein compound (13) is produced by dropping a Grignard reagent under an inert atmosphere to compound (12) wherein compound (14) is produced by mixing compound (13) with an oxidizing agent and stirring the mixture in a solvent; wherein compound (15) is produced by dropping a nitrating agent to compound (14); wherein compound (16) is produced by mixing compound (15), a metal hydroxide and an alcohol, and stirring the mixture; wherein compound (17) is produced by deprotection of compound (16), or by stirring a mixture of compound (15) and an aqueous base; wherein compound (11) is produced by reduction of compound (17) by mixing with a base and a reducing agent, and stirring the mixture in an aqueous alcoholic solution; and wherein X is a halogen, and R is hydrogen or a protective group which can be deprotected. ### Claim 2 (depends on 1) The process as claimed in claim 1, wherein the halogen is fluoro and the protective group is a methyl or ethyl group. ### Claim 3 (depends on 1) The process according to claim 1, wherein the Grignard reagent is ethyl magnesium bromide. ### Claim 4 (depends on 1) The process according to claim 1, wherein the oxidizing agent is Jones reagent, active manganese dioxide or TEMPO-sodium hypochlorite. ### Claim 5 (depends on 1) The process according to claim 1, wherein the nitrating agent is fuming nitric acid, or a nitrating mixture of nitric acid and sulfuric acid. ### Claim 6 (depends on 1) The process according to claim 1, wherein the metal hydroxide is sodium hydroxide. ### Claim 7 (depends on 1) The process according to claim 1, wherein the alcohol is methyl alcohol or ethyl alcohol. ### Claim 8 (depends on 1) The process according to claim 1, wherein the deprotection is carried out using a metal salt in polar solvent, or using Lewis acid, when the protective group is methyl. ### Claim 9 (depends on 1) The process according to claim 1, wherein the deprotection is carried out using zinc chloride in an acid, when the protective group is ethyl. ### Claim 10 (depends on 8) The process according to claim 8, wherein the polar solvent is DMF, DMSO, DMA or N-methylpyrrolidine. ### Claim 11 (depends on 9) The process according to claim 9, wherein the acid is hydrochloric acid, when the protective group is ethyl. ### Claim 12 (depends on 1) The process according to claim 1, wherein the reducing agent is sodium dithionite. ### Claim 13 (depends on 1) The process according to claim 1, wherein the base in the last step is sodium carbonate. ### Claim 14 (depends on 1) The process according to claim 1, wherein the aqueous alcoholic solution is aqueous methanolic solution. ### Claim 15 (depends on 4) The process according to claim 4, wherein the oxidizing agent is Jones reagent. ### Claim 16 (depends on 5) The process according to claim 5, wherein the nitrating agent is fuming nitric acid. ### Claim 17 (depends on 8) The process according to claim 8, wherein the metal salt is lithium chloride. ### Claim 18 (depends on 10) The process according to claim 10, wherein the solvent is DMF. ### Claim 19 (depends on 1) A method of preparing a camptothecin analog, comprising the step of reacting 2-amino-5-hydroxypropiophenone, prepared by the process according to claim 1, with a tricyclic ketone, ### Claim 20 5-Fluoro-2-nitropropiophenone, a novel intermediate for the manufacture of camptothecin, prepared by mixing a nitrating agent with 5-fluoropropiophenone. ### Claim 21 5-Alkoxy-2-nitropropiophenone, a novel intermediate for the manufacture of camptothecin, prepared by mixing compound (15), a metal hydroxide and alkanol, and stirring the mixture; wherein alkoxy is methoxy when alkanol is methanol, and alkoxy is ethoxy when alkanol is ethanol.