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(12) Patent Application Publication (10) Pub. No.: US 2010/0292475A1 Magnus Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0292475A1 Magnus Et Al US 2010O292475A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0292475A1 Magnus et al. (43) Pub. Date: Nov. 18, 2010 (54) EFFICIENTSYNTHESIS OF MORPHINE AND Related U.S. Application Data CODEINE (60) Provisional application No. 61/177,500, filed on May 12, 2009. (75) Inventors: Philip D. Magnus, Austin, TX s (US); Benjamin P. Fauber, San Publication Classification Francisco, CA (US); Neeraj Sane, (51) Int. Cl. Pune (IN) C07D 489/00 (2006.01) C07D 3II/78 (2006.01) Correspondence Address: (52) U.S. Cl. ........................................... 546/45; 549/384 MEDLEN & CARROLL, LLP Suite 350, 101 Howard Street (57) ABSTRACT San Francisco, CA 94105 (US) The present invention relates to methods for the synthesis of morphine, intermediates, salts and derivatives thereof. In pre (73) Assignee: Board of Regents The University ferred embodiments, the invention relates to methods for of Texas System improving the efficiency and overall yield of said morphine, morphine related derivatives and intermediates thereof. In (21) Appl. No.: 12/778,466 further embodiments, the invention relates to methods for improving the efficiency and overall yield of galanthamine (22) Filed: May 12, 2010 and intermediates thereof. MeO RO MeO HO 1, (R)-reticulineOH 2, salutaridine 3 , codeinone 4.5, S(R = MSE-Y-rnrai Patent Application Publication Nov. 18, 2010 Sheet 1 of 17 US 2010/02924.75 A1 FIGURE 1 MeO HO Y MeO OH 3 4. 1, (R)-reticuline 2, salutaridine , Codeinone S. SSEE Patent Application Publication Nov. 18, 2010 Sheet 2 of 17 US 2010/02924.75 A1 FIGURE 2 Atom and ring numbering for morphine Patent Application Publication Nov. 18, 2010 Sheet 3 of 17 US 2010/02924.75 A1 FIGURE 3A Ar obo RO A-Boyar RO RO -------r-rrrrrr-e- O Hawaaaa--1OR/X, PraNEt O HO CHO Pd2(dba) (1 mol%) HO CHO CH2Cl2 0°C i. CHO Br PCy BHT, K2CO3 dioxane/H2O180°C O ... O Ar = OR2 OR2 Csf/DMF/130°C, 1.5h O CHO A 1:1 mixture of stereoisomers at C-16 RO16 O which are mirror images of one another O Patent Application Publication Nov. 18, 2010 Sheet 4 of 17 US 2010/02924.75 A1 FIGURE 3B Ar B MeO MeO MeO AroAir C 21 OEt/Braj PraNEt C HO CHO Pa2(dba) (1mol%) HO CHO O CHO Br PCy3, BHT, KCO CH2Cl2 0°C EtO} 8 dioxane/H2O1800C O 10 (R = TIPS, 96%) O 11 (R = TBDMS, 99%) Br -K)-oys OR2 OR2 an At = -()-OBDMS CsS F/DMFJ 130°C, 1.5h 12 (R2 = TIPS, 99%) 9a 13 (R = TBDMS, 99%) CHO EtO 16 A 1: mixture of stereoisomers at C-16 which are mirror images of one anohter 14 (90% from 12, and 96% from 13) Patent Application Publication Nov. 18, 2010 Sheet 5 of 17 US 2010/02924.75 A1 FIGURE 4A RO RO where R7-H CHO C NaCNBH3 ACOH2h reflux phosphate RO O Ro 16 NO25ufferimeOH O R7CH2NO2 O Reduction LiAlH4 THFI-78°C to RT18 1M HCl, dioxane RO2CC O reflux CH2Cl2/EtN . NaCNBH Pn 40 Patent Application Publication Nov. 18, 2010 Sheet 6 of 17 US 2010/02924.75 A1 FIGURE 4B MeO MeO C O CHO NaCNBH3 MeNO2/NH4OAC O P40 ACOH2.5h reflux NO phosphate EtO O EtO 16 NV2 buffer?MeoH O O 14 MeNO2 15 (97%) Reductio 16 (88%) LiAlH4 THF1-78 oC to RT/8h EtO2CC 1M HCl, dioxane CH2Cl2EtN reflux 2 3 NaCNBH Ph 40 19 (89.6%) 18 (66%) OH 17 (72%) e Patent Application Publication Nov. 18, 2010 Sheet 7 of 17 US 2010/02924.75 A1 FIGURE 5A Y. acetone, H2O RO -Ho1. H2O2/(CF3)2CHOH 2. PhMe/NaHCO3 c. 4, (R1 = Me, R = H, 87%) (E)-codeine 5, (R = H, R = H) (t)-morphine Patent Application Publication Nov. 18, 2010 Sheet 8 of 17 US 2010/02924.75 A1 FIGURE SB 21 (93%) (91% from 19) Br 20 (97%) PhSNa/EtOH (also ArSH and RSH) e-H 2. PhMe/NaHCO3 4 (R1 = Me, 87%) (E)-codeine 23 (93%) SPh 22 (99%) 5, (R = H) (E)-morphine Patent Application Publication Nov. 18, 2010 Sheet 9 of 17 US 2010/02924.75 A1 FIGURE 6 1 (E)-Galanthamine 2 (E)-Narwedine Atom numbering for galanthamine Patent Application Publication Nov. 18, 2010 Sheet 10 of 17 US 2010/0292475A1 FIGURE 7A RO CHO Reductive -rror2MHCIdioxane O OH amination RO O reflux R11 NH2 RO 11 L-Selectride O 1 (-)-Galanthamine 2 (+)-Narwedine (R=Me, RFMe) (R=Me, R=Me) Patent Application Publication Nov. 18, 2010 Sheet 11 of 17 US 2010/02924.75 A1 FIGURE 7B MeO MeO O CHO CHO Reductive 2M HCldioxane O OH amination to O reflux CH3NH2 O O 24 (93%) MeO NMe re-SS-.L-Selectride OH 1 (-)-Galanthamine (99%) 2 (E)-Narwedine (74%) Patent Application Publication Nov. 18, 2010 Sheet 12 of 17 US 2010/0292475A1 FIGURE 7C MeO O CHO CHO 2M HCl/dioxane O RNH3CINEPr2/dioxane EtO O reflux ACOH/NaCNBH3/23°C/5h O O 14 24 (93%) MeO MeO MeO tion NMe NR O L-Selectride O 1M MeSOH 2. dioxane 40min 80°C . OH OH 1 (-)-Galanthamine (99%) 2 (t)-Narwedine (R = Me, 72% over 2 steps) 27 (R = Me) Patent Application Publication Nov. 18, 2010 Sheet 13 of 17 US 2010/0292475A1 FIGURE 8A O CHORCHNO2 RO Patent Application Publication Nov. 18, 2010 Sheet 14 of 17 US 2010/0292475A1 FIGURE 8B MeO OH reduction reduction EtO NO2 Patent Application Publication Nov. 18, 2010 Sheet 15 of 17 US 2010/0292475A1 FIGURE 9A Oxidizing agent acidic alcohol Patent Application Publication Nov. 18, 2010 Sheet 16 of 17 US 2010/0292475A1 FIGURE 9B 21 (93% from 19) Me 22 (99%) PhSNa/EtOH HR-R-e-H2O2 hexafluoro isopropanol SPh 22 (99%) G) SPh Patent Application Publication Nov. 18, 2010 Sheet 17 of 17 US 2010/0292475A1 FIGURE 10 N-allyinorgalanthamine N-(14-methylally)norgalanthamine R=Me, R2 =OH, R13=H R1=Me, R12 -OH, R13=H 1 (-)-Galanthamine Norgalanthamine Narwedine R=Me, R=Me, R =Me, REH, R=Me, R=Me, R12=OH, R13=H R12 =OH, R13 H R12 + R13 = O US 2010/0292475 A1 Nov. 18, 2010 EFFICIENT SYNTHESIS OF MORPHINE AND it is contemplated that one or more oxygen atom(s) of a CODENE compound of the present invention may be replaced by a Sulfur or selenium atom(s). FIELD OF THE INVENTION 0005. Other non-carbon groups contemplated by the present invention as candidates for Substituting into the com 0001. The present invention relates to methods for the pounds described herein include, but are not limited to oxy, synthesis of morphine and precursors, intermediates, and amino, amido, imino, thio, thiol, Sulfonyl, ammonium, Sulfo derivatives thereof. In preferred embodiments, the invention nium, silyl and the Substituted versions of these groups. relates to methods for improving the efficiency and overall 0006. In some embodiments the terms alkyl, aryl, yield of said morphine, morphine related derivatives and alkanediyl, alkynyl, arenediyl, aralkyl, heteroarenediyl, het intermediates thereof. In further embodiments, the invention eroaralkyl, heteroaryl, alkenyl, alkenediyl, alkynediyl, acyl, relates to methods for improving the efficiency and overall alkylidene, or a Substituted version of any of these groups, yield of galanthamine and intermediates thereof. refer to groups with a number of carbonss20. In some embodiments the terms alkyl, aryl, alkanediyl, alkynyl, are BACKGROUND OF THE INVENTION nediyl, aralkyl, heteroarenediyl, heteroaralkyl, heteroaryl, 0002 Morphine is one of the most important analgesics alkenyl, alkenediyl, alkynediyl, acyl, alkylidene, or a Substi worldwide. The majority of the world's morphine supply is tuted version of any of these groups, refer to groups with a derived from poppy plants found in some of the more politi number of carbonsis 12. In some embodiments the terms cally turbulent areas of western Asia. A related compound, alkyl, aryl, alkanediyl, alkynyl, arenediyl, aralkyl, heteroare galanthamine, has shown efficacy in the treatment of inter nediyl, heteroaralkyl, heteroaryl, alkenyl, alkenediyl. alia, Alzheimer's disease. However, while morphine remains alkynediyl, acyl, alkylidene, or a Substituted version of any of in high demand worldwide, the lack of effective synthetic these groups refer to groups with a number of carbonss 10. In methods coupled with the aforementioned instability in areas Some embodiments the terms alkyl, aryl, alkanediyl, alkynyl, largely responsible for the natural production of morphine arenediyl, aralkyl, heteroarenediyl, heteroaralkyl, heteroaryl, illustrates the tenuous state of current means for obtaining the alkenyl, alkenediyl, alkynediyl, acyl, alkylidene, or a Substi compound. Similarly, overall yields for galanthamine using tuted version of any of these groups, refer to groups with a current synthetic routes remain poor. Thus, there is a need to number of carbonss8. In some embodiments, the present develop improved methods for synthesizing morphine and invention contemplates allyl, propargyl, and cyclopropyl related derivatives for use in pharmaceutical compositions carbinol derivatives. and other medical applications. 0007. In some embodiments (FIG. 3A), the invention relates to a method for forming a cross-conjugated 2.5-cyclo hexadienone, comprising i) providing a Substituted biphenyl: SUMMARY OF THE INVENTION ii) treating said biphenyl to create an ether. In further embodi 0003. The present invention relates to methods and com ments, said biphenyl is treated with an alkenylether or positions for the synthesis of galanthamine, morphine and vinylether (e.g. ethylvinyl ether) under a set of conditions to precursors, intermediates (including but not limited to create a biphenyl ether. In one embodiment, the method fur codeine), salts, and derivatives thereof. In addition, pharma ther comprises iii) treating said ether under conditions (e.g. ceutical formulations comprising Such compositions, as well with a phenol alkylating catalyst) to cause intramolecular as methods of treatment comprising administering said com phenol alkylation so as to produce a cross-conjugated 2.5- positions), are contemplated.
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