# US 10,501,483 B2 · Enamines and diastereo-selective reduction of enamines > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,501,483 B2 - Document ID: US10501483B2 - Status: Granted - Kind: B2 - Application number: 16/168,548 - Filed: 2018-10-23 - Published: 2019-04-25 - Granted: 2019-12-10 - Earliest claimed: 2017-10-24 - Assignees: Allergan, Inc. - Applicants: Allergan, Inc. - Inventors: Danny T. Dinh; William R. Perrault - Web page: https://patentgrep.com/patent/US10501483B2 ## CPC - C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 - C07D 471/10: Spiro-condensed systems - C07D 498/10: Spiro-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract Described herein is a compound having a chemical structure of Formula A: wherein m, p, q, W, Z, Y, X1, X2, R1, R2, R3 and R4 are as defined herein. A diastereo-selective reduction of the compound comprising contacting the compound of Formula A with a reducing agent in an aprotic polar or non-polar solvent is also described. ## Claims ### Claim 1 An isolated compound of Formula A: wherein: m is 1 or 2; p is 0, 1, or 2; q is 0; W is C; Z is CH2; Y is NH, O, S, or CH2; X1 and X2 are hydrocarbons which together contain a total of five to nine carbon atoms and which link together such that the moiety: forms a bridged bicyclic ring system; R1, R2 and R3 are independently H or C1-3 alkyl; R4 is H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl, or C3-6 cycloalkenyl, each of the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl is optionally substituted with at least one group selected from OH, halo, CN, C1-3 alkoxy, and NH2. ### Claim 2 An isolated compound which is selected from the following compounds: ### Claim 3 An isolated compound which is selected from the following compounds ### Claim 4 An isolated compound which is selected from the following compounds ### Claim 5 A method of synthesizing a compound of Formula B or a salt thereof, comprising: contacting an isolated compound of Formula A with a reducing agent in an aprotic polar or non-polar solvent optionally comprising an acid and, optionally, purifying the compound of Formula B, wherein the compound of Formula B is: or a salt thereof, and wherein the compound of Formula A is: ### Claim 6 (depends on 5) The method of claim 5, wherein the reducing agent is selected from boron hydrides and silicon hydrides. ### Claim 7 (depends on 6) The method of claim 6, wherein the silicon hydride is selected from Et3SiH, HSiCl3, HSiPh3, and HSiPh(CH3)2. ### Claim 8 (depends on 7) The method of claim 7, wherein the silicon hydride is Et3SiH. ### Claim 9 (depends on 7) The method of claim 7, wherein the silicon hydride is HSiCl3. ### Claim 10 (depends on 7) The method of claim 7, wherein the silicon hydride is HSiPh3. ### Claim 11 (depends on 7) The method of claim 7, wherein the silicon hydride is HSiPh(CH3)2. ### Claim 12 (depends on 6) The method of claim 6, wherein the boron hydride is selected from NaBH4, NaBH(OAc)3, NBu4BH4, NaBH(OAc)3, NaCNBH3, and NMe4BH(OAc)3. ### Claim 13 (depends on 12) The method of claim 12, wherein the boron hydride is NaBH4. ### Claim 14 (depends on 12) The method of claim 12, wherein the boron hydride is NaBH(OAc)3. ### Claim 15 (depends on 12) The method of claim 12, wherein the boron hydride is NBu4BH4. ### Claim 16 (depends on 12) The method of claim 12, wherein the boron hydride is NaBH(OAc)3. ### Claim 17 (depends on 12) The method of claim 12, wherein the boron hydride is NaCNBH3. ### Claim 18 (depends on 12) The method of claim 12, wherein the boron hydride is NMe4BH(OAc)3. ### Claim 19 (depends on 5) The method of claim 5, wherein the aprotic polar or non-polar solvent is selected from xylenes, toluene, alkanes, CHCl3, CH2Cl2, methyl tert-butyl ether, acetonitrile, propionitrile, tetrahydrofuran, and 2-methyl tetrahydrofuran. ### Claim 20 (depends on 5) The method of claim 5, wherein the optional acid is a C1 to C10 carboxylic acid. ### Claim 21 (depends on 20) The method of claim 20, wherein the C1 to C10 carboxylic acid is acetic acid or hexanoic acid. ### Claim 22 (depends on 5) The method of claim 5, wherein the compound of Formula B obtained before the optional purification has an exo:endo isomer ratio greater than or equal to 70:30, greater than or equal to 75:25, greater than or equal to 80:20, greater than or equal to 85:15, greater than or equal to 90:10, greater than or equal to 95:5, or greater than or equal to 99:1. ### Claim 23 (depends on 5) The method of claim 5, wherein the compound of Formula B obtained before the optional purification has an endo:exo isomer ratio greater than or equal to 70:30, greater than or equal to 75:25, greater than or equal to 80:20, greater than or equal to 85:15, greater than or equal to 90:10, greater than or equal to 95:5, or greater than or equal to 99:1. ### Claim 24 (depends on 5) The method of claim 5, wherein the compound of Formula B is further converted to a pharmaceutically acceptable salt. ### Claim 25 An isolated compound which is: ### Claim 26 (depends on 5) The method of claim 5, wherein the method also comprises contacting at reflux a mixture of a ketone of Formula C, a secondary amine of Formula D or a salt thereof, and an acidic catalyst in a non-polar solvent to obtain the compound of Formula A: ### Claim 27 (depends on 26) The method of claim 26, wherein the non-polar solvent is xylenes. ### Claim 28 (depends on 26) The method of claim 26, wherein the catalytic acid hexanoic acid. ### Claim 29 (depends on 26) The method of claim 26, wherein the water produced by the reaction between the ketone of Formula C and the amine of Formula D is removed using a sieve dryer or Dean-Stark apparatus. ### Claim 30 (depends on 26) The method of claim 26, wherein the compound of Formula A is isolated by crystallization. ### Claim 31 (depends on 30) The method of claim 30, wherein the crystallization is accomplished by cooling the reaction mixture to room temperature, adding another non-polar solvent, optionally seeding the mixture with the previously formed compound of Formula A, and collecting the solid compound of Formula A. ### Claim 32 (depends on 26) The method of claim 26, wherein the non-polar solvent is hexane, heptane, or octane.