EP2989099A1 - A process for the synthesis of maraviroc - Google Patents
A process for the synthesis of maravirocInfo
- Publication number
- EP2989099A1 EP2989099A1 EP14723973.5A EP14723973A EP2989099A1 EP 2989099 A1 EP2989099 A1 EP 2989099A1 EP 14723973 A EP14723973 A EP 14723973A EP 2989099 A1 EP2989099 A1 EP 2989099A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- process according
- reaction
- acid
- amine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 41
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 title claims abstract description 27
- 229960004710 maraviroc Drugs 0.000 title claims abstract description 27
- 230000008569 process Effects 0.000 title claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 title abstract description 26
- 238000003786 synthesis reaction Methods 0.000 title abstract description 17
- 238000002955 isolation Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 150000001412 amines Chemical class 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 239000000654 additive Substances 0.000 claims description 14
- 229910052723 transition metal Inorganic materials 0.000 claims description 13
- 150000003624 transition metals Chemical class 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- -1 sulfonate compound Chemical class 0.000 claims description 11
- 230000000996 additive effect Effects 0.000 claims description 10
- 235000009518 sodium iodide Nutrition 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 239000002808 molecular sieve Substances 0.000 claims description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- 229910052741 iridium Inorganic materials 0.000 claims description 5
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 15
- 239000001257 hydrogen Substances 0.000 abstract description 15
- 239000000126 substance Substances 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 5
- 238000013459 approach Methods 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 24
- 230000029936 alkylation Effects 0.000 description 18
- 238000005804 alkylation reaction Methods 0.000 description 18
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 17
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 229930004006 tropane Natural products 0.000 description 8
- 230000009467 reduction Effects 0.000 description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 150000003852 triazoles Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000007074 heterocyclization reaction Methods 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QQXLDOJGLXJCSE-KNVOCYPGSA-N tropinone Chemical compound C1C(=O)C[C@H]2CC[C@@H]1N2C QQXLDOJGLXJCSE-KNVOCYPGSA-N 0.000 description 2
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 1
- GSNHKUDZZFZSJB-HLMSNRGBSA-N 4,4-Difluoro-N-[(1S)-3-[(1R,5S)-3-[3-methyl-5-(propan-2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboximidic acid Chemical compound CC(C)C1=NN=C(C)N1C1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-HLMSNRGBSA-N 0.000 description 1
- PJWULPCWPCVQKD-UHFFFAOYSA-N 4,4-difluorocyclohexane-1-carbonyl chloride Chemical compound FC1(F)CCC(C(Cl)=O)CC1 PJWULPCWPCVQKD-UHFFFAOYSA-N 0.000 description 1
- HYIUDFLDFSIXTR-UHFFFAOYSA-N 4,4-difluorocyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(F)(F)CC1 HYIUDFLDFSIXTR-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- KGRVEPLJSQNWDY-UHFFFAOYSA-L I[Ir](C1(C(=C(C(=C1C)C)C)C)C)I Chemical compound I[Ir](C1(C(=C(C(=C1C)C)C)C)C)I KGRVEPLJSQNWDY-UHFFFAOYSA-L 0.000 description 1
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 1
- 238000006804 Parikh-Doering oxidation reaction Methods 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 238000007011 Robinson annulation reaction Methods 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003067 chemokine receptor CCR5 antagonist Substances 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical group C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
Definitions
- the invention relates to a new approach to synthesis of Maraviroc, a compound with the chemical name A/- ⁇ (1S)-3-[3-(3-isopropyl-5-methyl-4H-1 ,2,4-triazol-4-yl)-exo-8- azabicyclo-[3.2.1 ]oct-8-yl]-1 -phenylpropyl ⁇ -4,4-difluorocyclohexanecarboxamide and the structure of formula I, as well as to improved isolation and purification of the final product.
- Maraviroc (also known as UK-427,857) is a selective reversible non-competitive CCR5 receptor antagonist and it is used in the treatment of retroviral diseases, in particular it has found its therapeutic application in the treatment of HIV, a retroviral infection genetically related to HIV, AIDS, or inflammatory diseases. Its effect is based on preventing the virus from entering the cell.
- Maraviroc and its pharmaceutically acceptable salts or solvates were first described in patent application WO0190106 by Pfizer.
- Medicinal synthesis of Maraviroc described in patent application WO0190106, is shown in Scheme 1.
- the first step consists in the Robinson synthesis of the tropane core of formula II.
- the oxime of formula III is prepared and its subsequent reduction with sodium in penthanol under reflux leads to selective formation of the primary exo-amine of formula IV.
- a substituted 1 ,2,4-triazole cycle is built in two steps in the molecule of formula IV and, after deprotection of the benzyl group under transfer-hydrogenolysis conditions, the tropane triazole adduct of formula VII is prepared.
- Reductive amination of the aldehyde of formula VIII and subsequent deprotection of the ieri-butyloxycarbonyl group of the product under acidic catalysis conditions leads to formation of the amine of formula IX.
- the last step is acylation of the amine of formula IX with 4,4-difluorocyclohexylcarboxylic acid of formula X in the presence of a carbodiimide polymer.
- the chiral aldehyde of formula VIII was prepared from W-ferf-butyloxycarbonyl methyl ester of 1-amino-1-phenylpropionic acid of formula XII (Scheme 2) by hydride reduction under cryogenic conditions necessary to prevent over-reduction of the ester of formula XII to an alcohol.
- Scheme 2 Preparation of the aldehyde of formula VIII
- Alcohols represent very cheap and available starting materials; however, they are non-reactive (low electrophilicity of simple alcohols) with regard to their use as an alkylation agent. Therefore, their activation or transformation to more reactive intermediates such as alkyl sulfonates (mesylate, tosylate) or alkyl halides is usually necessary, the latter, however, representing a problem from the point of view of toxicity (many alkyl halides belong to genotoxic alkylation agents). Another problem is control of the selectivity of monoalkylation.
- the invention provides a new efficient process for the preparation of Maraviroc by reaction of the tropane triazole of formula VII with the (S)-amido alcohol of formula XVII, catalyzed by a transition metal complex, or using the catalytic system of a transition metal complex and an additive.
- the new process for the synthesis of Maraviroc is illustrated in Scheme 5 below.
- the invention further includes a method of isolation of Maraviroc from the reaction mixture.
- Table 1 summarizes examples of carrying out direct alkylation of the tropane triazole of formula VII with the (S)-amido alcohol of formula XVII.
- Table 1 summarizes examples of carrying out direct alkylation of the tropane triazole of formula VII with the (S)-amido alcohol of formula XVII.
- a side product of the reaction is water and therefore the benefit of the addition of 3A molecular sieves as a desiccant in the reaction was tested (Example 4), which brought an increase of the product yield to 54%.
- Example 4 When other catalytic systems based on rhodium or ruthenium were used (Examples 5 to 7; inspired by J. Am. Chem. Soc. 2009, 131 , 1766), product formation in very low yields (1.5 to 6%) was only observed.
- the catalyst was added in three portions 2.5 mol% each in the time intervals of 5h (second portion) and 24h (third portion) after addition of the first portion.
- the alkylation of the amine of formula XX proceeded with 100% conversion even at more moderate conditions (110°C, 18h) and with use of a lower amount of the catalyst (2.1 mol% [Cp * lrCI 2 ]2).
- the alkylation product of formula XXI was isolated by crystallization from the reaction mixture in the yield of 83% and purity of 97.5% (determined by UPLC). Subsequently, formation of the triazole (via imidoyl chloride, followed by reaction with acetic acid hydrazide and acid catalyzed cyclization according to the procedure published in Org. Process Res.
- cuprous iodide increased the conversion, but besides Maraviroc increased formation of side products was also observed (not identified, referred to as the sum of impurities in the table).
- a transition metal is used as the catalyst, preferably an iridium complex, advantageously dichloro(pentamethylcyclopentadienyl)iridium(lll) dimer or diiodo(pentamethylcyclopentadienyl)iridium ⁇ lll) dimer, in an amount of 0.1 to 4 mol%, preferably 2.5 mol%.
- an ion pair is used as an additive, wherein the cation is selected from the group of alkali metals or transition metals.
- the cation can be conveniently selected from the group of alkali metals.
- the sodium cation is an advantageous cation.
- the anion of the above-mentioned ion pair is selected from the group of halogens or sulfonates. Conveniently, the anion is selected from the group of halides.
- the iodide anion is a convenient anion. Conveniently, sodium iodide is used as the ion pair.
- the additive is used in an amount of 0.1 to 10 mol%, advantageously 5 mol%.
- the proportion of the catalyst (transition metal complex) and additive is 1:1 to 1:3, conveniently a 1 :2 proportion of the catalyst and additive is selected.
- a desiccant (with regard to the amine of formula VII) are added to the reaction, molecular sieves in the powder form with the particle size of 3A being conveniently used.
- the proportion of the alcohol of formula XVII and amine of formula VII is 1:1 to 1:1.3; conveniently, a 1 :1.2 proportion of the alcohol of formula XVII and amine of formula VII is selected.
- the reaction is carried out in an organic, high-boiling, non-polar solvent, toluene being conveniently used as the solvent.
- the reaction is carried out at a temperature higher than 100°C; the temperature of the reaction advantageously being 100 to 130°C.
- This invention also includes isolation of the product Maraviroc I from the reaction mixture and its purification.
- a purification procedure via a salt of Maraviroc with an acid has been applied.
- the acid is selected from the group of hydrochloric acid, hydrobromic acid, sulphuric acid, citric acid and tartaric acid; hydrochloric acid being the preferred option.
- the reaction mixture containing Maraviroc having purity of 60 to 90% is, after completion of the reaction time, filtered through kieselguhr, washed with a suitable solvent and carefully poured into a glacial 1M solution of HCI. After separation the acidic aqueous base is basified by gradual addition of the base up to pH 12 and subsequently the product is extracted with a suitable organic solvent and, after concentration, a crude product is obtained with purity higher than 85%, suitable for further purification by crystallization.
- the crystallization is conveniently carried out from a solution of a crude product with purity higher than 85% in a mixture of the organic solvents hexane and acetic acid ethyl ester, conveniently in acetic acid ethyl ester. After crystallization and drying a product in purity higher than 99% is obtained.
- the melting points were measured on a Kofler block.
- Example 1 Comparative example of TEMPO catalyzed oxidation of the alcohol of formula XVII (according to the method of Org. Process Res. Dev.. 2008, 12, 1104)
- the alcohol of formula XVII (10 g, 33.6 mmol), sodium bromide (3.57 g, 1.03 equivalents), sodium hydrogen carbonate (3.11 g, 1.1 equivalents) and TEMPO ⁇ (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, 0.05 g, 0.01 equivalents ⁇ were suspended in 100 ml of dichloromethane and 50 ml of water at the room temperature under an inert argon atmosphere.
- the two-phase reaction mixture was cooled down to 10 °C by means of an ice bath.
- the separated organic phase was concentrated (25 ml), heated up to 40°C, diluted with toluene (30 ml) and cooled down to 20°C; further, n-heptane (150ml) was added and the mixture was cooled to 0°C and stirred for 2 hours; then it was left to crystallize at the temperature of 8°C for 20 hours. Then it was filtered, washed with heptane and the crystalline product was dried in a vacuum drier at 40°C for 4 hours.
- the obtained crystalline material 4.79 g, was a mixture of at least three compounds; 30.1% of the (S)-amido aldehyde of formula XVIII and 39.1% of the (S)-amido acid of formula XIX were identified (determined by UPLC).
- the suspension was hot filtered through kieselguhr, washed with dichloromethane (100ml), concentrated to 150 ml and n- hexane (100 ml) was added dropwise to the solution at 40°C and the solution was left to freely cool down to the room temperature (accompanied by crystallization) and stirred for another 20 hours.
- the resulting suspension was cooled to 0 °C and stirred for 2 hours.
- the crystalline product was filtered and washed with n-hexane and dried in a vacuum drier at 45 °C for 3 hours.
- 4.0 g of a white crystalline product was obtained (melt, point 220 to 222°C, 97.5% purity, determined by UPLC) in the yield of 83%. Crystallization of the concentrated mother liquor provided another 0.48 g (melt, point 213.3 to 217,4°C, 92.02% purity, determined by UPLC).
- Example 4 (Borrowing hydrogen" alkylation of the amine of formula VII with the alcohol of formula XVII, Table 1 , Example 9)
- the suspension was filtered through kieselguhr and washed with dichloromethane (60 ml). Removal of the solvent by distillation at a reduced pressure provided a crude mixture containing 65.3% of Maraviroc I (determined by UPLC).
- the crude mixture was diluted with dichloromethane (15 ml) and carefully poured into a glacial 1M solution of HCI (10 ml). After separation of the phases the acidic aqueous phase was basified by addition of 2M Na 2 C0 3 dropwise up to pH 12 and subsequently the product I was extracted with dichloromethane (3x 20 ml). The combined_organic fractions were dried with Na 2 S0 4 and the solvent was evaporated at a reduced pressure.
- Example 5 (Borrowing hydrogen" alkylation of the amine of formula VII with the alcohol of formula XVI Table 3, Example 9)
- the suspension was filtered through kieselguhr and washed with dichloromethane (60 ml). Removal of the solvent by distillation at a reduced pressure provided a crude mixture containing 81.1% of Maraviroc of formula I (determined by UPLC).
- the crude mixture was diluted with dichloromethane (15 ml) and carefully poured into a glacial 1M solution of HCI (10 ml). After separation of the phases the acidic aqueous phase was basified by addition of 2M Na 2 CO 3 dropwise up to pH 12 and subsequently the product I was extracted with dichloromethane (3x 20 ml). The combined organic fractions were dried with Na 2 S0 4 and the solvent was evaporated at a reduced pressure.
- Example 7 (Borrowing hydrogen” alkylation of the amine of formula VII with the alcohol of formula XVII, Table 3.
- Example 13
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Abstract
A process for the synthesis of Maraviroc The invention relates to a new approach to synthesis of Maraviroc, a substance with the chemical name N-{(lS)-3-[3-(3-isopropy)-5- methyl-4 H-l,2,4-triazol-4-yl-exo-8-azabicyclo-[3.2.1]oct-8-yl]-l- phenylpropyl}-4,4-difluorocyclohexanecarboxamide and the structure of formula I using the "borrowing hydrogen" method also called "hydrogen autotransfer" method as well as improved isolation and purification of the final product.
Description
A process for the synthesis of Maraviroc
Technical Field
The invention relates to a new approach to synthesis of Maraviroc, a compound with the chemical name A/-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1 ,2,4-triazol-4-yl)-exo-8- azabicyclo-[3.2.1 ]oct-8-yl]-1 -phenylpropyl}-4,4-difluorocyclohexanecarboxamide and the structure of formula I, as well as to improved isolation and purification of the final product.
(I) Background Art
Maraviroc (also known as UK-427,857) is a selective reversible non-competitive CCR5 receptor antagonist and it is used in the treatment of retroviral diseases, in particular it has found its therapeutic application in the treatment of HIV, a retroviral infection genetically related to HIV, AIDS, or inflammatory diseases. Its effect is based on preventing the virus from entering the cell.
Maraviroc and its pharmaceutically acceptable salts or solvates were first described in patent application WO0190106 by Pfizer. Medicinal synthesis of Maraviroc, described in patent application WO0190106, is shown in Scheme 1. The first step consists in the Robinson synthesis of the tropane core of formula II. By a reaction of tropinone of formula II with hydroxylamine in pyridine, the oxime of formula III is prepared and its subsequent reduction with sodium in penthanol under reflux leads to selective formation of the primary exo-amine of formula IV. Further, a substituted 1 ,2,4-triazole cycle is built in two steps in the molecule of formula IV and, after deprotection of the benzyl group under transfer-hydrogenolysis conditions, the tropane triazole adduct of
formula VII is prepared. Reductive amination of the aldehyde of formula VIII and subsequent deprotection of the ieri-butyloxycarbonyl group of the product under acidic catalysis conditions leads to formation of the amine of formula IX. The last step is acylation of the amine of formula IX with 4,4-difluorocyclohexylcarboxylic acid of formula X in the presence of a carbodiimide polymer.
Scheme 1. Medicinal synthesis of Maraviroc according to patent application WO0190106
The chiral aldehyde of formula VIII was prepared from W-ferf-butyloxycarbonyl methyl ester of 1-amino-1-phenylpropionic acid of formula XII (Scheme 2) by hydride reduction under cryogenic conditions necessary to prevent over-reduction of the ester of formula XII to an alcohol.
Scheme 2. Preparation of the aldehyde of formula VIII
Optimization of this medicinal synthesis, focused on synthesis of Maraviroc in a larger scale, was published in Org. Process Res. Dev., 2008, 12, 1094. The publication describes the use of a new protecting group (Cbz-carbobenzyloxy) of the amino ester of formula XIII as well as elimination of the use of cryogenic conditions in the preparation of the aldehyde of formula XV (Scheme 3). This was achieved by reduction of the amino ester of formula XIII at the room temperature to the alcohol of formula XIV and its subsequent oxidation under Parikh-Doering conditions to the aldehyde of formula XV.
Scheme 3. A recent process for the preparation of the aldehyde of formula XV
S03.py
Et3N
DMSO
While the above mentioned method makes it possible to prepare the aldehyde in a larger scale, it introduces extra steps in the synthesis. The publication also describes an attempt to directly use a β-amino acid to produce an amide; however, the subsequent reduction of the carbonyl function was unsuccessful. Further, it describes an experiment with the use of an alcohol, its transformation to a mesylate and its subsequent use in a nucleophilic substitution reaction with the tropane triazole of formula VII; however, this method also ran into low yields of the substituted amine as well as low stability of the mesylate as an intermediate product.
In another work published in Org. Process Res. Dev., 2008, 12, 1104 a new approach to the synthesis is described, wherein the synthesis does not include the use of the protecting group due to addition of the step of combination of the chiral β-amino ester of formula XI with the 4,4-difluorocyclohexylcarboxylic acid chloride (prepared in situ from the acid of formula X) under the conditions of the Schotten-Baumann amidation at the beginning and production of the key intermediate of formula XVI (Scheme 4).
However, similarly to the previous process, the preparation of the aldehyde of formula XVIII, needed for the reductive amination with the tropane triazole of formula VII, was again made therein by an entirely impractical and synthetically demanding procedure of reducing the ester of formula XVI (this time by means of sodium borohydride in THF in the presence of methanol at the boiling point of the solvent) to the alcohol of formula XVII with subsequent oxidation to the desired aldehyde of formula XVIII by means of the TEMPO radical initiator with an excess of sodium hypochlorite. This two-step conversion of the requires isolation of both the alcohol of formula XVII and the aldehyde of formula XVIII, which introduces another isolated intermediate into the synthesis.
Scheme 4. Synthesis of Maraviroc of formula I according to the publication Process Res. Dev., 2008, 12, 1104
TEMPO/
NaCIO
An overview of the prior art clearly indicates the need of a simple, straightforward and procedurally applicable method for the synthesis of Maraviroc, especially eliminating the demanding preparation of the aldehyde of formula XVIII as an intermediate for indirect alkylation of the tropane triazole of formula VII.
For direct alkylation of amines by alcohol, a method has been developed recently that is known as "borrowing hydrogen" or "hydrogen autotransfer", which is alkylation of amines by means of alcohols, catalyzed with transition metals (review: Adv. Synth. Catal. 2007, 349, 1555; Dalton Trans., 2009, 753).
Alcohols represent very cheap and available starting materials; however, they are non-reactive (low electrophilicity of simple alcohols) with regard to their use as an alkylation agent. Therefore, their activation or transformation to more reactive
intermediates such as alkyl sulfonates (mesylate, tosylate) or alkyl halides is usually necessary, the latter, however, representing a problem from the point of view of toxicity (many alkyl halides belong to genotoxic alkylation agents). Another problem is control of the selectivity of monoalkylation.
Common methods of alkylation of amines also include reductive amination; however, this requires transformation of an alcohol to aldehyde and the use of hydride agents.
The principle of the "borrowing hydrogen" reaction is in situ oxidation (dehydrogenation) of an alcohol on a transition metal complex, producing an aldehyde and a hydrido-metallic species (Figure 1). In the presence of an amine as a reaction partner, the electrophilic aldehyde on the transition metal is transformed into an imine, which is reduced by "borrowed" hydrogen to an alkylated amine, which at the same time results in regeneration of the catalyst - transition metal complex for the next catalytic cycle.
Figure 1. Principle of the "borrowing hydrogen" reaction
R1^OH 1^NHR2
Disclosure of Invention
The invention provides a new efficient process for the preparation of Maraviroc by reaction of the tropane triazole of formula VII with the (S)-amido alcohol of formula XVII, catalyzed by a transition metal complex, or using the catalytic system of a transition metal complex and an additive. The new process for the synthesis of Maraviroc is illustrated in Scheme 5 below.
Scheme 5
The invention further includes a method of isolation of Maraviroc from the reaction mixture.
Detailed description of the invention
With regard to the existing synthesis (Scheme 4), published in Org. Process Res. Dev., 2008, 12, 1104, we have selected, as the main task for our improvement, finding a simpler synthetic alternative to the two-step and synthetically demanding process for the preparation of the aldehyde of formula XVIII.
In addition, in our reproduction of the published TEMPO catalyzed oxidation of the alcohol of formula XVII (comparative example 1 in the working examples) we have obtained inconsistent results in repeated preparation of the aldehyde of formula XVlll with regard to relatively low selectivity of the oxidation, wherein even formation of the product of subsequent oxidation of the aldehyde of formula XVlll to the carboxylic acid of formula XIX (Figure 2) was observed.
Figure 2. Side product of the TEMPO catalyzed oxidation
It has turned out that by application of the "borrowing hydrogen" method, i.e. direct alkylation of the amine of formula VII with the alcohol of formula XVII, it is possible to obtain Maraviroc of formula I effectively in one step with the use of technologically acceptable conditions.
Table 1 (Scheme 6) summarizes examples of carrying out direct alkylation of the tropane triazole of formula VII with the (S)-amido alcohol of formula XVII. In the first two mentioned experiments of direct alkylation we have been inspired by the conditions developed by Fujita et al (Tetrahedron Lett. 2003, 44, 2687, Tetrahedron 2008, 64, 1943), using the catalytic system [Cp*lrCI2]2/NaHC03 or [Cp*lrCI2]2/K2C03, respectively, at 110°C in toluene (Examples 1 and 2). In both the cases formation of the product of formula I was observed, but the conversion of the starting compounds was low and the product was detected at 16.1% and 29.9%, respectively (determined by the UPLC method, correction by means of response factors). It should be noted that no formation of any side product except water was observed.
In another experiment (Example 3) we implemented some changes, such as increasing the amounts of the catalyst and base, increasing the temperature (120°C) and shortening the reaction time to 22 h, increasing the amount of alcohol (1 ,3:1 = XVII:VII), and these changes finally resulted in an increase of the yield of the product 13%. A side product of the reaction is water and therefore the benefit of the addition of 3A molecular sieves as a desiccant in the reaction was tested (Example 4), which brought an increase of the product yield to 54%. When other catalytic systems based on rhodium or ruthenium were used (Examples 5 to 7; inspired by J. Am. Chem. Soc. 2009, 131 , 1766), product formation in very low yields (1.5 to 6%) was only observed.
We also verified the use of half the amount of the catalyst (2.5 mol% [Cp*lrCI2]2, Example 8) and a lower excess of the alcohol (1.2:1 = XVII.VII) and we have found out that this reduction did not lead to any significant reduction of the product yield. Finally, the reaction was also carried out in the absence of the base, which surprisingly increased the product yield to 65%.
Scheme 6. Optimization aimed at selection of the catalyst and base
Ph = phenyl Cy = cyclohexyl
Table 1. Optimization aimed at selection of the catalyst and base
UPLC analysis (% fraction in the reaction mixture) am- Catalyst/ XVII Base mol. t(°C)/ VII XVII I iigand (equi(equisieves time (h)
valent) valent) (nm)
1 7.5mol%1 1.05 0.05 - 110/48 32.1 44.5 16.1
[Cp*lrCl2]2 NaHC03
2 7.5mol%1 1.05 0.05 - 110/48 21.4 37.0 29.9
[Cp*lrCI2]2 K2CO3
3 5mol% 1.3 0.1 - 120/24 17.7 30.7 42.9
[Cp*lrC!2]2 K2C03
4 5mol% 1.3 0.1 0.3 120/22 13.6 26.1 54.0
[Cp*lrCl2]2 K2C03
5 5mol% 1.3 0.1 0.3 120/22 33.4 51.6 6.41
[Cp*RhCI2]2 K2C03
6 5mol% Ru 1.3 0.1 0.3 120/22 25.3 32.7 1.48 catalyst/ K2co3
DPEphos
7 5mol% Ru 1.3 0.1 0.3 120/22 36.2 40.4 5.76 catalyst ligand 1 K2C03
8 2.5mol% 1.2 0.1 0.3 120/26 12.3 36.1 49.4
[Cp*lrCl2]2 K2C03
9 2.5mol% 1.2 - 0.3 120/26 4.2 14.9 65.3
[Cp*lrCl2]2
1The catalyst was added in three portions 2.5 mol% each in the time intervals of 5h (second portion) and 24h (third portion) after addition of the first portion.
One of the assumptions that would explain the relatively low conversion of the reaction is inhibition of the reaction by the starting amine of formula VII. The substituted ,2,4-triazoie heterocycle is an excellent Iigand capable of strong coordination to the transition metal {Inorg. Chem. Commun. 2010, 13, 1576; Chem. Commun. 2006, 2442; J. Chem. Crystallogr. 2011 , 41, 127).
For confirmation of this theory, "borrowing hydrogen" alkylation of the amine of formula XX was performed (Scheme 7), whose benzylated form of formula V is the starting substance before closing of the triazole ring in the preparation of the tropane triazole of formula VI (Scheme 1).
Scheme 7. "Borrowing hydrogen" alkylation of the amine of formula XX
As expected, the alkylation of the amine of formula XX proceeded with 100% conversion even at more moderate conditions (110°C, 18h) and with use of a lower amount of the catalyst (2.1 mol% [Cp*lrCI2]2). The alkylation product of formula XXI was isolated by crystallization from the reaction mixture in the yield of 83% and purity of 97.5% (determined by UPLC). Subsequently, formation of the triazole (via imidoyl chloride, followed by reaction with acetic acid hydrazide and acid catalyzed cyclization according to the procedure published in Org. Process Res. Dev., 2008, 12, 1094) on the substituted tropane amide of formula XXI was verified, which would directly lead to the preparation of Maraviroc I (Scheme 8, Table 2). However, the presence of two amidic bonds in the adduct of formula XXI poses a risk from the chemical selectivity point of view. Table 2 presents experiments that refer to the possibilities of the influence of the selected conditions on the chemical selectivity of the reaction. The use of a three-equivalent excess of PCI5 in combination with a slight excess of acetic acid hydrazide (1.3 equivalents) provided relatively good conversion and selectivity (Example 2, Table 2).
Scheme 8. Final heterocyclization of the amide of formula XXI
XXli XXIII
Table 2. Final heterocyclization of the amide of formula XXI
Inspired by the fact that amination of the alcohol of formula XVII may be inhibited by the reaction partner of formula VII, we further investigated the influence of various additives (capable of quick, but not too strong coordination to the metal) on the course of the reaction (Scheme 9, Table 3). In recent literature, the use of silver trifluoromethanesulfonate as an additive was described (Chem. Eur. J. 2008, 14, 11474) but in the reaction of the amine of formula VII with the alcohol of formula XVII no positive effect has been proved (Example 1). Other candidates were four lithium salts, trifluoromethanesulfonate, bis(trifluoromethane)sulfonimide, bromide and iodide
(Examples 2 to 5). However, none of the above mentioned salts contributed to any improvement of the conversion of the reaction.
Then, the effect of the potassium salts, iodide and chloride was verified (Examples 6, 7), wherein in the use of potassium chloride a 60% conversion has been observed.
Still, two more salts were tested, cuprous iodide and sodium iodide. The addition of cuprous iodide (Example 8) increased the conversion, but besides Maraviroc increased formation of side products was also observed (not identified, referred to as the sum of impurities in the table).
Surprisingly, the addition of sodium iodide resulted in nearly 100% conversion, mainly for the benefit of the desired product Maraviroc (Example 9; 81.1% + 9.3% of unidentified impurities).
Scheme 9. Influence of various additives
equivalent
Table 3. Influence of various additives
11 2.5mol% rCp*!rC!2]2 Nal 0.5 11.7 35.4 46.9 6.0
12 2.5mol% [Cp*lrl2]2 - 11.8 30.4 49.1 8.7
13 2.5mol% [Cp*lrl2]2 Nal 0.05 5.1 19.1 67.8 7.9
The best candidate from the series of the tested additives is sodium iodide {Table 3, Example 9). Subsequently, the effect of the amount of sodium iodide was also investigated and it has been found out that further increasing of the amount led to gradual reduction of the conversion of the reagents (Table 3, Examples 10, 11).
A positive influence of the presence of a catalytic amount of sodium iodide in the reaction was also proved in the reaction of the alcohol of formula XVII with the amine of formula VII, catalyzed by the diiodo(pentamethylcyclopentadienyl)iridium catalyst, where 19% higher formation of the product was observed (Table 3, comparison of Examples 12 and 13). For the reaction of the alcohol of formula XVII with the amine of formula VII a transition metal is used as the catalyst, preferably an iridium complex, advantageously dichloro(pentamethylcyclopentadienyl)iridium(lll) dimer or diiodo(pentamethylcyclopentadienyl)iridium{lll) dimer, in an amount of 0.1 to 4 mol%, preferably 2.5 mol%.
To increase conversion of the reaction of the alcohol of formula XVII with the amine of formula VII, catalyzed by an iridium complex, an ion pair is used as an additive, wherein the cation is selected from the group of alkali metals or transition metals. The cation can be conveniently selected from the group of alkali metals. The sodium cation is an advantageous cation.
The anion of the above-mentioned ion pair is selected from the group of halogens or sulfonates. Conveniently, the anion is selected from the group of halides. The iodide anion is a convenient anion. Conveniently, sodium iodide is used as the ion pair.
The additive is used in an amount of 0.1 to 10 mol%, advantageously 5 mol%.
The proportion of the catalyst (transition metal complex) and additive is 1:1 to 1:3, conveniently a 1 :2 proportion of the catalyst and additive is selected.
To increase conversion of the reaction of the alcohol of formula XVII with the amine of formula VII, catalyzed by the iridium complex, 200 to 260% by weight of a desiccant (with regard to the amine of formula VII) are added to the reaction, molecular sieves in the powder form with the particle size of 3A being conveniently used.
The proportion of the alcohol of formula XVII and amine of formula VII is 1:1 to 1:1.3; conveniently, a 1 :1.2 proportion of the alcohol of formula XVII and amine of formula VII is selected. The reaction is carried out in an organic, high-boiling, non-polar solvent, toluene being conveniently used as the solvent.
The reaction is carried out at a temperature higher than 100°C; the temperature of the reaction advantageously being 100 to 130°C.
The reaction is carried out for the time required for the starting compounds to react (monitored by TLC or UPLC, HPLC); however, for 30 hours at the most. The reaction is conveniently carried out for 24 h. This invention also includes isolation of the product Maraviroc I from the reaction mixture and its purification. To purify the product I from the excess of the alcohol of formula XVII, as well as from the impurities, or unreacted triazole of formula VII, a purification procedure via a salt of Maraviroc with an acid has been applied. The acid is selected from the group of hydrochloric acid, hydrobromic acid, sulphuric acid, citric acid and tartaric acid; hydrochloric acid being the preferred option.
The reaction mixture containing Maraviroc having purity of 60 to 90% is, after completion of the reaction time, filtered through kieselguhr, washed with a suitable solvent and carefully poured into a glacial 1M solution of HCI. After separation the acidic aqueous base is basified by gradual addition of the base up to pH 12 and subsequently the product is extracted with a suitable organic solvent and, after concentration, a crude product is obtained with purity higher than 85%, suitable for further purification by crystallization. The crystallization is conveniently carried out
from a solution of a crude product with purity higher than 85% in a mixture of the organic solvents hexane and acetic acid ethyl ester, conveniently in acetic acid ethyl ester. After crystallization and drying a product in purity higher than 99% is obtained.
Examples
The melting points were measured on a Kofler block.
UPLC method
Column:
- dimensions: length 100 mm, inner diameter 2.1 mm
- stationary phase: UPLC BEH Shield C8 or equivalent (1.7 pm)
- temperature: 40°C Mobile phase:
- A: 10 mM of potassium dihydrogen phosphate, pH 7.8
- B: acetonitrile R1 Elution: gradient
Flow: 0.4 ml/min; Detection: UV, 215 nm; Feed volume: 1 μΙ
impurities:
Example 1 Comparative example of TEMPO catalyzed oxidation of the alcohol of formula XVII (according to the method of Org. Process Res. Dev.. 2008, 12, 1104) The alcohol of formula XVII (10 g, 33.6 mmol), sodium bromide (3.57 g, 1.03 equivalents), sodium hydrogen carbonate (3.11 g, 1.1 equivalents) and TEMPO {(2,2,6,6-tetramethylpiperidin-1-yl)oxyl, 0.05 g, 0.01 equivalents} were suspended in 100 ml of dichloromethane and 50 ml of water at the room temperature under an inert argon atmosphere. The two-phase reaction mixture was cooled down to 10 °C by means of an ice bath. Sodium hypochlorite was added dropwise to the reaction (27.5 ml, 10% aqueous solution, 1.1 equivalents) during 30 minutes, the temperature being maintained below 10°C. After addition the reaction mixture was stirred for another 20 min at 10°C. At the end, white precipitate separated from the reaction mixture (identified as the (S)-amido acid of formula XIX). Then, 25 ml of a 10% aqueous solution of Na2S2O3 was added dropwise to the reaction and the reaction mixture was stirred for another 15 minutes. The separated organic phase was concentrated (25 ml), heated up to 40°C, diluted with toluene (30 ml) and cooled down to 20°C; further, n-heptane (150ml) was added and the mixture was cooled to 0°C and stirred for 2 hours; then it was left to crystallize at the temperature of 8°C for 20 hours. Then it was filtered, washed with heptane and the crystalline product was dried in a vacuum drier at 40°C for 4 hours. The obtained crystalline material, 4.79 g, was a mixture of at least three compounds; 30.1% of the (S)-amido aldehyde of formula XVIII and 39.1% of the (S)-amido acid of formula XIX were identified (determined by UPLC).
Example 2 ("Borrowing hydrogen" alkylation of the amine of formula XX, Scheme 7)
The amine of formula XX (2 g, 10.2 mmol), the alcohol of formula XVII (3.7 g, 1.22 equivalents), [Cp*lrCI2]2 (0.17 g, 2.1 mol%), potassium carbonate (0.14 g, 0.1
equivalents) and molecular sieves (0.47 g) were suspended in toluene (50 ml) at the room temperature under an inert argon atmosphere. The reaction mixture was heated up to 110°C and stirred under a reflux condenser for 18 hours. Then, the reaction mixture was cooled to the room temperature under stirring, which resulted in crystallization of the product; this was supported by addition of n-hexane and cooling of the reaction mixture to 0°C and stirring for 5 hours. The crystallized product was filtered through frit, washed with hexane and, after separation of the filtrate, it was dissolved by means of dichloromethane (300 ml). Activated carbon (0.3 g) was added to the concentrated solution (100ml) and the solution was stirred at the boiling temperature of the solvent for 30 minutes. The suspension was hot filtered through kieselguhr, washed with dichloromethane (100ml), concentrated to 150 ml and n- hexane (100 ml) was added dropwise to the solution at 40°C and the solution was left to freely cool down to the room temperature (accompanied by crystallization) and stirred for another 20 hours. The resulting suspension was cooled to 0 °C and stirred for 2 hours. Then, the crystalline product was filtered and washed with n-hexane and dried in a vacuum drier at 45 °C for 3 hours. 4.0 g of a white crystalline product was obtained (melt, point 220 to 222°C, 97.5% purity, determined by UPLC) in the yield of 83%. Crystallization of the concentrated mother liquor provided another 0.48 g (melt, point 213.3 to 217,4°C, 92.02% purity, determined by UPLC).
Example 3 (Heterocvclization of the amide of formula XXI, Scheme 8, Table 2, Example 2)
A solution of the substituted amide of formula XXI (1 g, 2.1 mmol) in dichloromethane (22 ml) was added dropwise to a suspension of PCI5 (1.3 g, 3 equivalents) in dichloromethane, cooled to -5°C, during 45 minutes. After the addition the mixture was left to heat up to the room temperature and stirred for 3 hours. The reaction mixture was cooled down to -5°C and a solution of acetic acid hydrazide (0.2 g, 1.3 equivalents) in a mixture of acetonitrile/2-methyl-2-butanol (3 ml/6 ml) was added dropwise during 20 minutes, whereupon the reaction mixture was heated up to the room temperature and stirred still for 1 hour. Then, 2M NaOH was added dropwise to the reaction mixture up to pH 9 and the dichloromethane phase was separated. The aqueous phase was extracted with dichloromethane once again and the combined
organic layers were dried with Na2S04 and the solvent was evaporated at a reduced pressure. The evaporation residue was dissolved in 2-methyl-2-butanol (6 ml), 0.25 ml of acetic acid was added and the mixture was stirred at 80°C for 1 hour. Then the reaction mixture was cooled to the room temperature and 2M NaOH was added up to pH 12, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the combined organic fractions were dried with Na2S04 and the solvent was evaporated at a reduced pressure. 0.82 g of a crude product was obtained, the composition was determined by UPLC, see Table 2, Example 2.
Example 4 ("Borrowing hydrogen" alkylation of the amine of formula VII with the alcohol of formula XVII, Table 1 , Example 9)
The amine of formula VII (0.59 g, 2.5 mmol), alcohol of formula XVII (0.89 g, 1.2 equivalents), [Cp*lrCI2]2 (0.05 g, 2.5 mol%) and molecular sieves (1.5 g) were suspended in 20 ml of toluene at the room temperature, the reaction mixture was bubbled (2 to 5 mins) with argon and closed with a septum. The reaction mixture was heated up to 120°C and stirred for 26 hours. Then, the mixture was cooled down to 50°C, activated carbon (Norit A, 0.07 g) was added and the suspension was stirred for 15 minutes. The suspension was filtered through kieselguhr and washed with dichloromethane (60 ml). Removal of the solvent by distillation at a reduced pressure provided a crude mixture containing 65.3% of Maraviroc I (determined by UPLC). The crude mixture was diluted with dichloromethane (15 ml) and carefully poured into a glacial 1M solution of HCI (10 ml). After separation of the phases the acidic aqueous phase was basified by addition of 2M Na2C03 dropwise up to pH 12 and subsequently the product I was extracted with dichloromethane (3x 20 ml). The combined_organic fractions were dried with Na2S04 and the solvent was evaporated at a reduced pressure. 1.05 g of the product with the purity of 88.6% was obtained. The product was further dissolved in 10 ml of ethyl acetate at the temperature of 60°C, then it was cooled to the room temperature (accompanied by crystallization) and further stirred for 20 hours. The resulting suspension was cooled down to 0°C and stirred for 2 hours. Then the crystalline product was filtered and washed with a cooled mixture of ethyl acetate/n-hexane = 1 :1 and dried in a vacuum drier at 25°C for 24 hours. 0.76 g
of a white crystalline product was obtained (melt, point 193.7 to 195.2°C, 99.3% purity, determined by UPLC) in the yield of 60%.
Example 5 ("Borrowing hydrogen" alkylation of the amine of formula VII with the alcohol of formula XVI Table 3, Example 9)
The amine of formula VII (0.59 g, 2.5 mmol), alcohol of formula XVII (0.89 g, 1.2 equivalents), [Cp*lrCI2]2 (0.05 g, 2.5 mol%), sodium iodide (0.019 g, 5 mol%) and molecular sieves (1.5 g) were suspended in 20 ml of toluene at the room temperature, the reaction mixture was bubbled (2 to 5 mins) with argon and closed with a septum. The reaction mixture was heated up to 120°C and stirred for 26 hours. Then, the mixture was cooled down to 50°C, activated carbon (Norit A, 0.07 g) was added and the suspension was stirred for 15 minutes. The suspension was filtered through kieselguhr and washed with dichloromethane (60 ml). Removal of the solvent by distillation at a reduced pressure provided a crude mixture containing 81.1% of Maraviroc of formula I (determined by UPLC). The crude mixture was diluted with dichloromethane (15 ml) and carefully poured into a glacial 1M solution of HCI (10 ml). After separation of the phases the acidic aqueous phase was basified by addition of 2M Na2CO3 dropwise up to pH 12 and subsequently the product I was extracted with dichloromethane (3x 20 ml). The combined organic fractions were dried with Na2S04 and the solvent was evaporated at a reduced pressure. 1.18 g of the product with the purity of 90.1% was obtained. The product was further dissolved in 10 ml of ethyl acetate at the temperature of 60°C, then it was cooled to the room temperature (accompanied by crystallization) and further stirred for 20 hours. The resulting suspension was cooled down to 0°C and stirred for 2 hours. Then the crystalline product was filtered and washed with a cooled mixture of ethyl acetate/n-hexane = 1 :1 and dried in a vacuum drier at 25°C for 24 hours. 0.86 g of a white crystalline product was obtained (melt, point 193.5 to 196.4°C, 99.8% purity, determined by UPLC) in the yield of 67%.
Example 6 ("Borrowing hydrogen" alkylation of the amine of formula VII with the alcohol of formula XVII, Table 3, Example 12)
The amine of formula VII (0.29 g, 1.25 mmol), alcohol of formula XVII (0.45 g, 1.2 equivalents), [Cp*lrl2]2 (0.036 g, 2.5 mol%) and molecular sieves (0.75 g) were suspended in 10 ml of toluene at the room temperature, the reaction mixture was bubbled (2 to 5 min) with argon and closed with a septum. The reaction mixture was heated up to 120°C and stirred for 24 hours. Then, the mixture was cooled down to 50°C, activated carbon (Norit A, 0.03 g) was added and the suspension was stirred for 15 minutes. The suspension was filtered through kieselguhr and washed with dichloromethane (30 ml). Removal of the solvent by distillation at a reduced pressure provided a crude mixture containing 49.1 % of Maraviroc of formula I (determined by UPLC).
Example 7 ("Borrowing hydrogen" alkylation of the amine of formula VII with the alcohol of formula XVII, Table 3. Example 13)
The amine of formula VII (0.29 g, 1.25 mmol), alcohol of formula XVII (0.45 g, 1.2 equivalents), [Cp*lrl2]2 (0.036 g, 2.5 mol%), sodium iodide (0.019 g, 5 mol%) and molecular sieves (0.75 g) were suspended in 10 ml of toluene at the room temperature, the reaction mixture was bubbled (2 to 5 min) with argon and closed with a septum. The reaction mixture was heated up to 120°C and stirred for 24 hours. Then, the mixture was cooled down to 50°C, activated carbon (Norit A, 0.03 g) was added and the suspension was stirred for 15 minutes. The suspension was filtered through kieselguhr and washed with dichloromethane (30 ml). Removal of the solvent by distillation at a reduced pressure provided a crude mixture containing 67.8 % of Maraviroc of formula I (determined by UPLC).
Claims
Claims raviroc of formula I,
characterized in that it comprises
a) reaction of the amine of formula VII, or its salt or solvate
with the alcohol of formula XVII
catalyzed by a transition metal complex,
and
b) isolation of the product of formula I.
2) The process according to claim 1 , characterized in that the transition metal complex is a complex of iridium (III), preferably dichloro(pentamethyl- cyclopentadienyl)iridium(lll) dimer or diiodo(pentamethylcyclopentadienyl)- iridium(lll) dimer in an amount of 0.1 to 4 mol%, preferably 2.5 mol%.
3) The process according to claims 1 to 2, characterized in that the reaction is carried out in the presence of an additive selected from a halide or sulfonate compound of an alkali metal.
4) The process according to claim 3, characterized in that the alkali metal is sodium or potassium.
5) The process according to claims 3 and 4, characterized in that the additive is an alkali metal iodide, preferably sodium iodide.
6) The process according to claims 3 to 5, characterized in that the amount of the additive is in the range of 0.1 to 10 mol%, and preferably is 5 mol%.
7) The process according to claims 3 to 6, characterized in that the proportion of the transition metal complex and additive is in the range of 1 :1 to 1:3, and preferably is 1 :2.
8) The process according to claims 1 to 7, characterized in that the reaction is carried out in the presence of a desiccant in an amount of 100 to 260% by weight, related to the amount of amine of formula VII.
9) The process according to claim 8, characterized in that the desiccant is a powder molecular sieve in an amount of 200 to 260% by weight, related to the amine of formula VII, preferably with the particle size of 0.3 nm.
10) The process according to claims 1 to 9, characterized in that the proportion of the alcohol of formula XVII and amine of formula VII is in the range of 1:1 to 1 :1.5, preferably 1 :1.15 to 1.2.
11) The process according to claims 1 to 10, characterized in that the reaction is carried out in an organic, high-boiling, non-polar solvent, preferably in boiling toluene.
12) The process according to claims 1 to 11, characterized in that the isolation comprises extraction of the product with an aqueous solution of an acid to form a salt, followed by release of Maraviroc of formula I by means of a base and crystallization.
13) The process according to claim 12, characterized in that the acid is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, citric acid, and tartaric acid, and preferably is hydrochloric acid.
14) The process according to claims 12 or 13, characterized in that the crystallization is carried out from an organic solvent selected from hexane and acetic acid ethyl ester, or their mixture, preferably from acetic acid ethyl ester.
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PCT/CZ2014/000038 WO2014173375A1 (en) | 2013-04-26 | 2014-04-18 | A process for the synthesis of maraviroc |
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