# US 8,785,669 B2 · Taxane compounds, compositions and methods > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,669 B2 - Document ID: US8785669B2 - Status: Granted - Kind: B2 - Application number: 13/170,830 - Filed: 2011-06-28 - Published: 2012-01-05 - Granted: 2014-07-22 - Earliest claimed: 2010-06-30 - Assignees: Gfv, LLC - Applicants: John K. Thottathil; Raymond P. Warrell, Jr. - Inventors: John K. Thottathil; Raymond P. Warrell, Jr. - Web page: https://patentgrep.com/patent/US8785669B2 ## CPC - C07D 493/08: Bridged systems - A61P 35/00: Antineoplastic agents - C07D 205/08: with one oxygen atom directly attached in position 2, e.g. beta-lactams - C07D 305/14: condensed with carbocyclic rings or ring systems - C07D 401/04: directly linked by a ring-member-to-ring-member bond - C07D 407/02: containing two hetero rings - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention provides a method for the preparation of orally available pentacyclic taxane compounds, as well as intermediates useful in their preparation. ## Claims ### Claim 1 A compound having a formula ### Claim 2 (depends on 1) A method of making a taxane compound comprising coupling a taxane side chain precursor compound to a C13 hydroxyl group of the compound of claim 1 to produce a protected taxane reaction product, deprotecting the protected taxane reaction product, and isolating the taxane compound. ### Claim 3 (depends on 2) The method of claim 2, wherein the taxane side chain precursor compound has a formula wherein R2 is an alkoxy group having from 1 to 6 carbon atoms or a halogen atom and R33 is a protected hydroxyl group. ### Claim 4 (depends on 3) The method of claim 3, wherein the hydroxyl group is protected by a triisopropylsilyl (TIPS) or 2-methoxy propyl (MOP) group. ### Claim 5 (depends on 3) The method of claim 3, wherein R2 is fluorine. ### Claim 6 (depends on 5) The method of claim 5, wherein fluorine is at the 3-position of pyridine. ### Claim 7 (depends on 3) The method of claim 3, wherein the side chain precursor compound has a formula wherein Me is methyl and BOC is tert-butoxycarbonyl. ### Claim 8 (depends on 1, 2) The method of claim 2, wherein the compound according to claim 1 is derived from a compound having a formula (Ib): or from a compound having a formula (III): ### Claim 9 (depends on 8) The method of claim 8, wherein the compound having the formula (III) or the compound having a formula (Ib) is derived from a compound having a formula (VII): ### Claim 10 (depends on 9) The method of claim 9, wherein the compound having the formula (VII) is converted to ### Claim 11 (depends on 9) The method of claim 9, wherein the compound having the formula (VII) is derived from a compound having a formula (X): or from a compound having a formula (IX): ### Claim 12 (depends on 1, 2) The method of claim 2, wherein the compound according to claim 1 is synthesized by a process comprising: formylating C10 of 10-DAB III to produce a first intermediate comprising a C10 formyl ester; reacting a C7 hydroxyl of the first intermediate with triflic anhydride to produce a second intermediate; forming a C6-7 double bond in the second intermediate and hydrolyzing the C10 formyl ester to produce a third intermediate; reducing a C9 ketone of the third intermediate to form a diol compound having hydroxyls at C9 and C10; forming a C9-C10 cyclic acetal from the diol, wherein the cyclic acetal is attached to a terminal olefin group; oxidatively cleaving the terminal olefin group to form an aldehyde; reductively aminating the aldehyde; and hydrogenating the C6-7 double bond. ### Claim 13 (depends on 1, 2) The method of claim 2, wherein the compound according to claim 1 is synthesized by a process comprising: formylating C10 of 10-DAB III to produce a first intermediate comprising a C10 formyl ester; reacting a C7 hydroxyl of the first intermediate with triflic anhydride to produce a second intermediate; forming a C6-7 double bond in the second intermediate and hydrolyzing the C10 formyl ester to produce a third intermediate; reducing a C9 ketone of the third intermediate to form a diol compound having hydroxyls at C9 and C10; hydrogenating the C6-7 double bond; forming a C9-C10 cyclic acetal from the diol, wherein the cyclic acetal is attached to a terminal olefin group; oxidatively cleaving the terminal olefin group to form an aldehyde; and reductively aminating the aldehyde. ### Claim 14 (depends on 1, 2) The method of claim 2, wherein the compound according to claim 1 is synthesized by a process comprising: reacting a C7 hydroxyl of 10-DAB III with triflic anhydride to produce a first intermediate; forming a C6-7 double bond in the first intermediate by base elimination; reducing the C6-7 double bond to produce a reduced first intermediate; reducing a C9 ketone of the reduced first intermediate to form a diol compound having hydroxyls at C9 and C10; forming a cyclic acetal from the diol, wherein the cyclic acetal is attached to a terminal olefin group; oxidatively cleaving the terminal olefin group to an aldehyde; and reductively aminating the aldehyde. ### Claim 15 (depends on 1, 2) The method of claim 2, wherein the compound according to claim 1 is synthesized by a process comprising: reducing a C9 ketone of 10-DAB III to produce a triol first intermediate; forming a C9-C10 cyclic acetal from the triol first intermediate to produce a second intermediate, wherein the cyclic acetal is attached to a terminal olefin group; reacting a C7 hydroxyl of the second intermediate with triflic anhydride; forming a C6-C7 double bond by base elimination; oxidatively cleaving the terminal olefin group to an aldehyde; reductively aminating the aldehyde; and hydrogenating the C6-C7 double bond. ### Claim 16 (depends on 1, 2) The method of claim 2, wherein the compound according to claim 1 is synthesized by a process comprising: reducing a C9 ketone of 10-DAB III to produce a triol first intermediate having hydroxyls at C9 and C10; reacting a C7 hydroxyl of the first intermediate with triflic anhydride to produce a second intermediate; forming a C6-C7 double bond in the second intermediate by base elimination to produce a third intermediate; forming a C9-C10 cyclic acetal from the diol of the third intermediate, wherein the cyclic acetal is attached to a terminal olefin group; oxidatively cleaving the terminal olefin group to an aldehyde; reductively aminating the aldehyde; and hydrogenating the C6-C7 double bond. ### Claim 17 (depends on 11) The method of claim 11, wherein 10-DAB III is converted to the compound represented by formula (IX) by reacting a C7 hydroxyl of 10-DAB III with triflic anhydride and treating with base to form a C6-C7 double bond. ### Claim 18 (depends on 2) The method of claim 2, wherein the side chain precursor compound is coupled to C13 using a hindered soluble alkaline metal base. ### Claim 19 (depends on 2) The method of claim 2, further comprising converting the taxane compound to a pharmaceutically acceptable acid salt form. ### Claim 20 (depends on 2) The method of claim 2, wherein the taxane compound is tesetaxel.