WO2015007897A1 - Method of racemisation of undesired enantiomers - Google Patents
Method of racemisation of undesired enantiomers Download PDFInfo
- Publication number
- WO2015007897A1 WO2015007897A1 PCT/EP2014/065539 EP2014065539W WO2015007897A1 WO 2015007897 A1 WO2015007897 A1 WO 2015007897A1 EP 2014065539 W EP2014065539 W EP 2014065539W WO 2015007897 A1 WO2015007897 A1 WO 2015007897A1
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- WO
- WIPO (PCT)
- Prior art keywords
- group
- racemisation
- formula
- configuration
- substituted
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 101
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 title description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 230000008569 process Effects 0.000 claims abstract description 28
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 18
- 238000013459 approach Methods 0.000 claims abstract description 17
- -1 amino, hydroxyl Chemical group 0.000 claims abstract description 15
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 claims abstract description 10
- 229960005060 lorcaserin Drugs 0.000 claims abstract description 10
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 61
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 53
- 230000003287 optical effect Effects 0.000 claims description 40
- 239000000047 product Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 23
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 125000004122 cyclic group Chemical group 0.000 claims description 23
- 239000011734 sodium Substances 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 238000002955 isolation Methods 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 10
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 10
- 239000011591 potassium Substances 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 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 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000001181 organosilyl group Chemical class [SiH3]* 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 102000004190 Enzymes Human genes 0.000 claims description 7
- 108090000790 Enzymes Proteins 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000004703 alkoxides Chemical class 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 238000004587 chromatography analysis Methods 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 7
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003880 polar aprotic solvent Substances 0.000 claims description 6
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 6
- 238000004804 winding Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 230000006340 racemization Effects 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000006227 byproduct Substances 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 4
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 4
- 150000004692 metal hydroxides Chemical class 0.000 claims description 4
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 3
- 230000002860 competitive effect Effects 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical class [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 abstract description 14
- 150000001298 alcohols Chemical class 0.000 abstract description 12
- 238000005516 engineering process Methods 0.000 abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 125000005842 heteroatom Chemical group 0.000 abstract description 8
- 125000001743 benzylic group Chemical group 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 68
- 239000002904 solvent Substances 0.000 description 25
- 239000007858 starting material Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 15
- 238000012360 testing method Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000012267 brine Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 11
- 238000004296 chiral HPLC Methods 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- CUOBYVASRNWRRD-SSDOTTSWSA-N (2s)-2-(3-chlorophenyl)propan-1-amine Chemical compound NC[C@@H](C)C1=CC=CC(Cl)=C1 CUOBYVASRNWRRD-SSDOTTSWSA-N 0.000 description 5
- 0 **CC(*)c1ccccc1 Chemical compound **CC(*)c1ccccc1 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- AJUMGSLQADLWKL-UHFFFAOYSA-N 1h-azepine;hydrochloride Chemical compound Cl.N1C=CC=CC=C1 AJUMGSLQADLWKL-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- VDMAQVANUGNDOM-UHFFFAOYSA-N 3-methyl-2-phenylbutan-1-amine Chemical compound CC(C)C(CN)C1=CC=CC=C1 VDMAQVANUGNDOM-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003821 enantio-separation Methods 0.000 description 3
- 231100001261 hazardous Toxicity 0.000 description 3
- 239000012263 liquid product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- 230000007306 turnover Effects 0.000 description 3
- CUOBYVASRNWRRD-ZETCQYMHSA-N (2r)-2-(3-chlorophenyl)propan-1-amine Chemical compound NC[C@H](C)C1=CC=CC(Cl)=C1 CUOBYVASRNWRRD-ZETCQYMHSA-N 0.000 description 2
- RNDNSYIPLPAXAZ-MRVPVSSYSA-N (2s)-2-phenylpropan-1-ol Chemical compound OC[C@@H](C)C1=CC=CC=C1 RNDNSYIPLPAXAZ-MRVPVSSYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000001358 L(+)-tartaric acid Substances 0.000 description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- AXORVIZLPOGIRG-QMMMGPOBSA-N R-BETA-METHYLPHENYLETHYLAMINE Chemical compound NC[C@H](C)C1=CC=CC=C1 AXORVIZLPOGIRG-QMMMGPOBSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000006276 transfer reaction Methods 0.000 description 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 1
- UYJSCLFFKWVEME-UHFFFAOYSA-N 1,1'-biphenyl;potassium Chemical group [K].C1=CC=CC=C1C1=CC=CC=C1 UYJSCLFFKWVEME-UHFFFAOYSA-N 0.000 description 1
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical group N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000854350 Enicospilus group Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- HRKQOINLCJTGBK-UHFFFAOYSA-N dihydroxidosulfur Chemical class OSO HRKQOINLCJTGBK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- QLUMLEDLZDMGDW-UHFFFAOYSA-N sodium;1h-naphthalen-1-ide Chemical compound [Na+].[C-]1=CC=CC2=CC=CC=C21 QLUMLEDLZDMGDW-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
- C07C209/88—Separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/56—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by isomerisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to the field of organic synthesis, in particular to the racemisation of chiral by-products in the synthesis of optically active compounds.
- Racemisation techniques represent a practical method for regeneration of undesirable enantiomers.
- a-amines and a-alcohols There are a number of processes for racemisation of such chiral compounds unlimitedly listed in the following items.
- Transition metal catalyzed hydrogen transfer is the most often used approach for racemisation of ⁇ -amines or alcohols.
- the process utilizes a conversion of optically active a-benzyl amine compound to an imine by reaction with a metal catalyst (hydride storage), followed by recovery of the amine by in situ hydrogenation of the imine to get the racemic mixture.
- a metal catalyst hydrogen storage
- the process undergoes via the ketone intermediate (see Scheme 1 ).
- Such methodology is efficient but suffers especially from the use of hazardous and carcinogenic polycyclic hydrocarbon aromatics and also from the difficult handling of alkali metal complexes (low stability, toxicity etc.) and as such it is not so convenient for industrial applications especially in pharmaceutical development. It is also less suitable for cyclic amines where substrates under single electron transfer reduction conditions could follow cycle-cleavage reactions.
- the present invention provides a novel efficient, simple and economic racemisation methodology suitably adapted and applicable for the target compounds of optically active ⁇ -benzyl amine, hydroxy and thiol compound including cyclic ⁇ -benzazepines like lorcaserin.
- the present invention also provides new methods for inversion of the chirality and a method for increasing the yield of a desired enantiopure product, suitably used in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt.
- the present invention further provides novel intermediates of such new methods preferably applied in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt.
- R is represented by a linear, branched or cyclic Ci-Ci 2 -alkyl
- R' is selected from hydrogen or a group selected from a Ci-Ci 2 -alkyl group, a d- Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a Ci-C 4 - alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;
- X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';
- one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C 6 -alkoxy group, a unsubstituted or Ci-Ci 2 -alkyl mono- or di-substituted amino group, a Ci-Ci 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a Ci-C 6 - alkyloxy carbonyl group, a CrC 4 -alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl- sub
- R is preferably represented by hydrogen, an acetyl group, a trifluoracetyl group, a benzyloxycarbonyl, an allyloxycarbonyl group, a mesyl group, or a tosyl group.
- a high boiling polar aprotic solvent preferably selected from a group of amides, sulfoxides, and sulfones, more preferably ⁇ , ⁇ -dimethylacetamide (DMA), N,N- dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), and most preferably dimethylsulfoxide.
- DMA ⁇ , ⁇ -dimethylacetamide
- DMF N,N- dimethylformamide
- DMSO dimethylsulfoxide
- the strong base is selected from alkali or earth alkali hydroxides (preferably selected from alkali metal hydroxides, more preferably sodium or potassium hydroxide), alkali or earth alkali alkoxides (preferably alkali metal alkoxides, more preferably sodium or potassium ie f-butoxide), or alkali or earth alkali amides (preferably silylamides, more preferably sodium hexamethyldisilazane (NaHMDS)).
- alkali or earth alkali hydroxides preferably selected from alkali metal hydroxides, more preferably sodium or potassium hydroxide
- alkali or earth alkali alkoxides preferably alkali metal alkoxides, more preferably sodium or potassium ie f-butoxide
- alkali or earth alkali amides preferably silylamides, more preferably sodium hexamethyldisilazane (NaHMDS)
- R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ⁇ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;
- step (f) isolating the product of the step (e'), which is preferably a racemate, according to the above step (b') to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively. 18. The method according to item 17, wherein the steps (b') to (f) are successively repeated several times.
- the present invention provides a very simple, efficient and economic technology for racemisation of amine, alcohol or thioalcohol compounds having chirality in the ⁇ - position. It was surprisingly found that this simple technology based on the use of appropriate base in appropriate solvent, enables efficient racemisation of amines, alcohols or thioalcohols where the chiral carbon (benzylic position) is located at the ⁇ -position of the heteroatom (amino, hydroxyl or mercapto group) or even more distant therefrom.
- enantiomerically enriched mixture/product/compound or “enantiomerical enrichment” as used herein mean a mixture, a product, a compound or a process having or achieving an enantiomerical excess by 10 to 70 % e.e, preferably 30 to 70 % e.e, more preferably 50 to 70 % e.e.
- enantiomerically pure means a compound having an enantiomerical excess by at least 70 % e.e., preferably having at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.
- racemization refers to the converting of an enantiomerically enriched or enantiopure compound into a mixture where the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is reduced at least by one-third, more preferably at least by half, and still more preferably by at least by two- third. Most preferably, the racemization results in a mixture where the enantiomers are present in equal quantity (racemic or a racemate).
- salt refers to any suitable salt form from the respective compound.
- the salt is pharmaceutically acceptable.
- the invention provides a method for racemisation of a compound according to the formula la or lb:
- R is represented by a linear, branched or cyclic Ci-Ci 2 -alkyl
- R' is selected from hydrogen or a group selected from a Ci-Ci 2 -alkyl group, a d- Ci2-alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a C1-C4- alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;
- X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';
- one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C 6 -alkoxy group, a unsubstituted or Ci-Ci 2 -alkyl mono- or di-substituted amino group, a Ci-Ci 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a Ci-C 6 - alkyloxy carbonyl group, a CrC 4 -alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl- sub
- the racemisation treatment reduces the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration at least by one-third, more preferably at least by half, and still more preferably by at least by two-third. It is most preferred that no enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is detectable after the racemisation treatment thus achieving a racemic mixture of 0% e.e.
- the racemization method thus preferably yields the compound according to the formula Ha or Mb, respectivel :
- the winding line ⁇ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the enantiomerically enriched or enantiopure starting configuration.
- the racemisation treatment is preferably carried out in a high boiling polar aprotic solvent, which is preferably selected from the group of amides, sulfoxides, and sulfones
- the preferred solvents are ⁇ , ⁇ -dimethylacetamide (DMA), N,N-dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), the most preferred one is dimethylsulfoxide.
- the solvent preferably consists only of high boiling polar aprotic solvents, which are preferably used anhydrous.
- One high boiling polar aprotic solvent may be used alone or a mixture of high boiling polar aprotic solvents may be used.
- the racemisation treatment is preferably carried out at elevated temperature, preferably at 80 °C or more, more preferably at 90 °C or more, most preferably 100 °C or more.
- the upper limit of the reaction temperature is not especially limited provided that the reaction temperature is lower than the degradation/decomposition temperature of the educts in the reaction mixture.
- the racemisation treatment is suitably accomplished in the presence of metal hydroxides, metal alkoxides or metal amides which are selected from bases the corresponding acid having a pKb of at least 12 in DMSO.
- the base is selected from alkali or earth alkali hydroxides, alkali or earth alkali alkoxides or alkali or earth alkali amides. More preferably the base is selected from alkali metal hydroxides (preferably sodium or potassium hydroxide), alkali metal alkoxides (preferably sodium or potassium ie f-butoxide), or alkali metal silylamides (preferably sodium hexamethyldisilazane (NaHMDS)).
- alkali metal hydroxides preferably sodium or potassium hydroxide
- alkali metal alkoxides preferably sodium or potassium ie f-butoxide
- alkali metal silylamides preferably sodium hexamethyldisilazane (NaHMDS)
- the strong base is added in an amount enabling suitable racemisation turnover.
- the conversion can be performed by submolar, equimolar or excess amounts of the base, but in order to increase the turnover and/or speed up the reaction time, it is preferred to apply the strong base at least equimolar, preferably with a molar excess of 1.25 or more, with respect to the compound according to formula la or lb.
- the upper limit of the amount of strong base is not particular limited provides that the used amount avoids the decomposition or degradation of the compound to be racemised. However, in the individual case, it may even be desirable to apply such an amount of strong base that leads to racemisation and de-protection of a protecting group at the heteroatom O, N, or S (i.e. groups R', R", R b or R c ) in one concerted reaction.
- the reaction of conversion is preferably prolonged to a full racemisation, in the case of very slow conversion a skilled person can optionally stop the reaction, when a reasonably reduced enantiomeric access, such 50 % e.e. or below, preferably 20 % e.e. or below, is reached.
- a full racemisation is usually achieved within 48 hours, preferably it takes 12 to 36 hours.
- the benzene ring may be substituted as defined above. If one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are substituted, at least one of the substituents is preferably selected from an electron withdrawing group selected from halo, nitro, nitroso, cyano, or a group selected from a Ci-Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxycarbonyl group, a Ci-C 4 -alkanesulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups and optional substituents of the carbon atoms are defined as above.
- Such electron withdrawing groups may have beneficial impact on the racemisation turnover in the racemisation treatment of the present invention. It is most preferred that a chloro substituent is present in the meta-position (i.e. position 3 or 5) of the benzene ring of formula la or lb with no further substitution on the benzene ring being present.
- R is preferably represented by methyl, ethyl, isopropyl, more preferably methyl.
- R' is preferably represented by hydrogen.
- R' is hydrogen
- R" is selected from hydrogen or a group selected from a Ci-Ci 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a CrC 4 -alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-substituted and/or aryl-substit
- R" may be suitably selected to be the same or different from R', while such amine compounds being substituted by R' and R" may be represented by alkylamides, alkylsulfonamides, tertiary amines, etc.
- I a H, F, CI, Br, I, OH, MeO, N0 2 ; preferably H or CI (preferably in meta-position);
- R" is selected from hydrogen or a group selected from a CrCi 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a CrC 4 -alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-substituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one
- n is 1.
- the compound according to the formula lb features a benzazepine skeleton having a 7-membered ring annealed to the benzene ring.
- A is represented by -CH 2 -CH 2 -, -CH 2 -CO- or -CO-CH 2 -, more preferably -CH 2 -CH 2 -.
- Scheme 4 Another typical but not limited set of the cyclic benzylic compounds according to the formula lb for successful racemisation according to the invention is shown in Scheme 4 with respect to the compound according to the formula lb". Experimental details are more precisely shown in the example section, while table 1 in Example 10 teaches optimal conditions and reagents for racemisation.
- the substituents R b or R c may beneficially influence on ease and duration of racemisation conversion.
- the influence is empirical, a skilled person may decide according to experimental results whether the substitution of the heteroatom X, preferably nitrogen, is done in order to make racemisation easier, the reaction time shorter or temperature lower.
- the substituent(s) R a may also influence on ease and duration of racemisation conversion. Electron withdrawing substituents, such as chloro have a beneficial effect on duration and completeness of the racemisation, because they enhance acidity of the proton on the carbon atom attached to the aromatic ring.
- the heteroatom can be substituted by protecting groups from previous steps of the synthesis.
- a skilled person can decide whether the racemisation is performed on the substituted derivative or by an approach wherein the intermediate is first deprotected and then racemised.
- the present invention provides novel compounds according to the formulae 2* to 7* as shown in Scheme 5, wherein the compounds shown in Scheme 5 are enantiomerically enriched or enantiopure in (S) or (R) configuration, preferably the (R) configuration. More preferably, such compounds have an enantiomeric excess of 98 % e.e. or more.
- Such novel compounds represent suitable intermediates for the synthesis of pharmaceutically active agents, especially lorcaserin, or a salt thereof, preferably the hydrochloride salt thereof.
- Such intermediates can be achieved by substitution of the heteroatom, which can be done by routine methods well known to a skilled person using reactive alkylation or acylation reagents in the presence of a base or by dehydration techniques using dehydration reagents such as carbodiimides.
- the invention provides a method for inverting the chirality of a compound according to the formula la or lb
- the starting compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.
- the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.
- step (b) Following the steps (a) and (b) in a repeating manner, it is possible to successively convert almost all starting compound to the desired compound having inverted chirality.
- step (b) there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).
- the invention provides a method for increasing the yield of a desired enantiopure product according to the formula la or lb
- R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ⁇ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;
- step (f) isolating the product of the step (e'), which is preferably a racemate, according to the procedure of the above step (b') in order to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively.
- the resulting desired compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.
- the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.
- the steps (b') to (f) are preferably successively repeated several times. Thereby, it is possible to batch-wise increase the yield of the compound having the desired chirality.
- step (b') there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).
- the above methods of the present invention can be suitable used in the synthesis of lorcaserin according to the formula (R)-" , or a salt thereof, preferably the hydrochloride salt thereof.
- the present invention is illustrated more precisely based on the following examples and with the table which presents a study of the effect of the reaction conditions on racemisation process using novel technology.
- the optical purity of the starting compounds and final products is indicated by enantiomeric excess (% e.e.).
- the enantiomeric excess as mentioned herein means an excess of one enantiomer over the racemic mixture.
- Optical purity is determined using chiral HPLC analysis or by chiral GC-FID.
- the % e.e. is calculated from percentage ratio of enantiomers x:y, wherein y>x by the mathematical formula 100 - 2x.
- the testing compound of the formula (S)-9 is commercially available.
- the testing compound (S)-2-(3-chlorophenyl)propan-1 -amine ⁇ (S)-5) was prepared according to the literature (J. Med. Chem. 56, 4786 (2013)) followed by separation of enantiomers by column chromatography on chiral supporter to its (S)- and (R)- enantiomer.
- Example 7 Racemisation of optical active (S)-/V-2-(3-chlorophenyl)propyl)-2- phenylacetamide in the presence of potassium ie f-butoxide
- the compound of the formula ⁇ (S)- ) was prepared following the procedures of examples 8, 9, 10, and 12 in WO 05/019179.
- the obtained crude racemate of the compound according to the formula 1 was submitted to triple crystallisation through the salt with D-(-)-tartaric acid according to the Example 13 of the same publication to give the title compound in 16 % yield and optical purity of over 98 % e.e.
- Example 10 Efficient racemisation of optical pure (S)-8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 /-/-benzo/c//azepine
- Example 12 Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone using sodium hydroxide
- Example 13 Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone in the presence of potassium ie f-butoxide
- Example 15 Racemisation of optical pure allyl (S)-8-chloro-1 -methyl-4,5-dihyd benzo[c/]azepine-3-(2/-/)-carboxylate in the presence of potassium ie f-butoxide
- Example 17 Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[d]azepine-3-(2H)-yl)-2-phenylethanone)-2-phenylethanone
- a skilled person may combine different approaches of recovery, for example he may racemise only the liquor from tartaric salt preparation, which is much more enriched in undesired isomer and may treat recrystallisation liquors, which are rich in the desired isomer by other approaches. By repeatable recovery the yield may exceed 50 % before one crop of liquors must be discarded due to accumulation of degradation products.
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Abstract
The present invention provides a very simple, efficient and economic technology for racemisation of amines, alcohols or thioalcohols where the chiral carbon (benzylic position) is located at the β-position of the heteroatom (amino, hydroxyl or mercapto group) or even more distant therefrom. Special focus is oriented in efficient and simple racemisation of an undesired enantiomer of a chiral pharmaceutically active ingredient, preferably lorcaserin or a salt thereof, preferably the hydrochloride salt thereof. The approach according to the invention enables a use of cheaper and shorter racemic synthetic schemes not requiring expensive and toxic reagents and catalysts. Present methodology enables industrialy convenient process.
Description
Method of Racemisation of Undesired Enantiomers
The present invention relates to the field of organic synthesis, in particular to the racemisation of chiral by-products in the synthesis of optically active compounds.
Background of the Invention
The preparation of enantiomerically pure amines and alcohols represents a challenging task for industrial production. In recent literature, there are reported several enantioselective methods how to obtain optically active amines and alcohols with low content of the undesired enantiomer. In most cases cheap and simple reagents are not sufficient for obtaining a high enantiomeric excesses, but usually very expensive, hazardous and toxic chiral transition metal catalyzed approaches are used. On the other hand, it is possible to obtain optically pure amines or alcohols from easier available racemic mixtures using a) chiral separation chromatographic techniques; b) classical optical resolution approach through formation of salts; or c) kinetic resolution using enzymes. It is important to know, that a yield of a process is then consequently lower (max. 50%) and at least 50% of the material (undesirable enantiomer) represents losses/waste. This problem is even more expressed if the resolution is carried out on expensive or high-volume products. In order to have an economic and industrial applicable process there is a need for simple and efficient technologies to minimize losses by an undesirable enantiomer or for significantly improving the efficiency to yield the target/desirable enantiomer.
Racemisation techniques represent a practical method for regeneration of undesirable enantiomers. Most of the chiral amines, alcohols and ethers on which racemisation techniques are applied, possess the asymmetric carbon directly attached to the amino or hydroxyl group (a-amines and a-alcohols). There are a number of processes for racemisation of such chiral compounds unlimitedly listed in the following items.
1 ) Transition metal catalyzed hydrogen transfer is the most often used approach for racemisation of α-amines or alcohols. The process utilizes a conversion of optically active a-benzyl amine compound to an imine by reaction with a metal catalyst (hydride storage), followed by recovery of the amine by in situ hydrogenation of the imine to get the racemic mixture. In the case of alcohols the process undergoes via the ketone intermediate (see Scheme 1 ).
?H H metal M metalH ?H OH
^^CH3 Ph-^CH3 V Ph^*CH3 Ph^'"ci
' metal H metal
NH2 metal NH metalH NH, NH
^CH
"3 V Ph-^CH, P ^CHs Ph^
N ·»■ metalH 3 r "
^ metal J
Scheme 1 : Racemisation of a-amines and a-alcohols catalyzed by transition metal catalyst via hydrogen transfer reaction.
The method is not limitedly reviewed in the publications such as Ahn, Y. et al., Coord. Chem. Rev. 2008, 647; Blacker, A. J. et al., Org. Proc. Res. Dev. 2007, 11, 642; Samec, J. S. M. et. al., Chem. Eur. J. 2005, 11, 2327; Parvulescu, A. et al. Chem. Commun. 2005, 42, 5307; US 6576795). Predominantly, the use of expensive, toxic and hazardous metal catalyst based on Ir, Ru, Rh, Pd, Ni, Zn for hydrogen transfer reaction is described therein.
2. ) Racemisation with special alkali metal polyaromatic complexes (US 4246424);
3. ) Base induced process (strongly requiring acidic hydrogen atom abstraction reaction on the oposition from amino group, only; US 5183939);
4. ) Enzymatic racemisation (US 2009/0098623; Koszelewski, D., et. al. Chem. Eur. J. 201 1 , 17, 378.; Musa, M. et. al. Org. Biomol. Chem. 2013, 1 1 , 291 1 ).
Most of publications are strongly limited to racemisation of obenzyl amines and obenzyl alcohols.
These methods are ineffective if the chiral carbon atom is in a distant position from amino or hydroxyl groups. For example, the racemisation of amines and alcohols wherein the chiral center is located on the β-position from the amino or hydroxy group (optically active β-amines or alcohols) is a very problematic and challenging task. The activating amino or hydroxy group is too far from the chiral center and consequently the possibility and reactivity for the racemisation is low. There is only one literature example found, wherein a method of racemisation was tested on optically active 3-methyl-2-phenylbutylamine showing full racemisation (US 5969186). The method applies highly reactive alkali metal polyaromatic complexes (sodium naphthalide, potassium biphenyl, sodium anthracide etc.) via single electron transfer process (see Scheme 2).
Scheme 2: Racemisation of 3-methyl-2-phenylbutylamine using sodium napthalenide complex.
Such methodology is efficient but suffers especially from the use of hazardous and carcinogenic polycyclic hydrocarbon aromatics and also from the difficult handling of alkali metal complexes (low stability, toxicity etc.) and as such it is not so convenient for industrial applications especially in pharmaceutical development. It is also less suitable for cyclic amines where substrates under single electron transfer reduction conditions could follow cycle-cleavage reactions.
Therefore, there is a strong need for a simple, economical, industrially friendly and generally applicable racemisation technology, especially for the racemisation of β-aryl substituted amines, alcohols, ethers, thiols or thioethers and derivatives, wherein the chiral center is in the β-position relative to the heteroatom.
Summary of the invention
In order to solve the above objects, the present invention provides a novel efficient, simple and economic racemisation methodology suitably adapted and applicable for the target compounds of optically active β-benzyl amine, hydroxy and thiol compound including cyclic β-benzazepines like lorcaserin. The present invention also provides new methods for inversion of the chirality and a method for increasing the yield of a desired enantiopure product, suitably used in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt. The present invention further provides novel intermediates of such new methods preferably applied in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt.
The following items summarize in more detail aspects and preferred features embodiments, which contribute to solve the objects of the present invention alone or combination.
1 . Method for racemisation of a compound according to the formula la or lb:
wherein * in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure;
wherein
R is represented by a linear, branched or cyclic Ci-Ci2-alkyl;
R' is selected from hydrogen or a group selected from a Ci-Ci2-alkyl group, a d- Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxy carbonyl group, a Ci-C4- alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;
X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';
A is selected from -CH2-, -CR1R2- (wherein R1 and R2 are same or different and are selected from linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH2-CH2-, CR1R2-CR3R4- (wherein R1, R2, R3 and R4 are same or different and are selected from linear, branched or cylic, substituted or unsubstituted C Ci2-alkyl), -CR5=CR6- (wherein R5 and R6 are same or different and are selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH2-CO-, -CO-CH2-, >C=0, -S02-, and -NR7- (wherein R7 is selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted Ci-Ci2-alkyl);
n represents 0 or 1 , wherein X is directly linked to the benzene ring by a single bond if n is 0;
one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C6-alkoxy group, a unsubstituted or Ci-Ci2-alkyl mono- or di-substituted amino group, a Ci-Ci2-alkyl group, a Ci-Ci2-alkanoyl group, a benzoyl group, a Ci-C6- alkyloxy carbonyl group, a CrC4-alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl- subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, and wherein bonds between the positions 2 and 3, or 3 and 4, or 4 and 5 are optionally condensed with another six-membered aromatic ring optionally containing one or two nitrogen atoms or with a five-membered aromatic ring containing one oxygen, or one sulfur or 1 to 3 nitrogen atoms or a combination of one oxygen and one nitrogen atom; by treatment with a strong base, which is selected from metal hydroxides, metal alkoxides or metal amides, in order to reduce the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration.
2. The method according to item 1 , wherein the racemization method yields compound according to the formula Ha or lib, respectively:
wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above, and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the enantiomerically enriched or enantiopure starting configuration.
3. The method according to item 1 or 2, wherein if one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are substituted, at least one of the substituents is selected from an electron withdrawing group selected from halo, nitro, nitroso, cyano, or a group selected from a Ci-Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxycarbonyl group, a Ci-C4-alkanesulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups and optional substituents of the carbon atoms are defined as above.
4. The method according to any one of items 1 to 3, wherein R is represented by methyl, ethyl, isopropyl, preferably methyl.
5. The method according to any of items 1 to 4, wherein R' is represented by hydrogen.
6. The method according to any of items 1 to 5, wherein A is represented by -CH2-CH2-, -CH2-CO-, or -CO-CH2-, preferably -CH2-CH2-.
7. The method according to any of items 1 to 6, wherein X is represented by N-R", and wherein R" is preferably selected from hydrogen or one of the above defined C1-C12- alkanoyl group (preferably represented by an acetyl or a trifluoracetyl group), Ci-C6- alkyloxy carbonyl group (preferably represented by a benzyloxycarbonyl or an allyloxycarbonyl group), Ci-C4-alkylsulfonyl group (preferably represented by a mesyl group) or benzenesulfonyl group (preferably represented by a tosyl group).
8. The method according to any of items 1 to 7, wherein only the meta-position (3 or 5) in the benzene ring of formulae la and lb is substituted with chloro.
9. The method according to any of items 1 to 8, wherein the compound lb is represented by the following formula lb':
lb' wherein * and R" are defined as above, and wherein R" is preferably represented by hydrogen, an acetyl group, a trifluoracetyl group, a benzyloxycarbonyl, an allyloxycarbonyl group, a mesyl group, or a tosyl group.
10. The method according to any of items 1 to 9, wherein the racemisation process is carried out in a high boiling polar aprotic solvent, preferably selected from a group of amides, sulfoxides, and sulfones, more preferably Ν,Ν-dimethylacetamide (DMA), N,N- dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), and most preferably dimethylsulfoxide.
1 1 . The method according to any of items 1 to 10, wherein the racemisation process is carried out at elevated temperature, preferably 80 °C or more, more preferably 90 °C or more, and most preferably 100 °C or more.
12. The method according to any of items 1 to 1 1 , wherein the strong base is selected from alkali or earth alkali hydroxides (preferably selected from alkali metal hydroxides, more preferably sodium or potassium hydroxide), alkali or earth alkali alkoxides (preferably alkali metal alkoxides, more preferably sodium or potassium ie f-butoxide), or alkali or earth alkali amides (preferably silylamides, more preferably sodium hexamethyldisilazane (NaHMDS)).
13. The method according to any of items 1 to 12, wherein the strong base is added at least equimolar, preferably with a molar excess of 1.25 or more, with respect to the compound according to formula la or lb.
14. Method according to any of items 1 to 13, wherein the enantiomerically enriched or enantiopure starting configuration is the (S) configuration.
15. Compound according to any of formulae 2* to 7*,
2* 3* 4*
6* 7*
wherein * in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure, preferably enantiopure.
16. Method for inverting the chirality of a compound according to the formula la or lb
wherein * donates the enantiopure (R) or (S) configuration and R, R\ X, A and n are defined as above, and wherein the enantiopure starting configuration is preferably the (S) configuration;
by applying
(a) a racemisation treatment as defined by any of items 1 to 14, thereby at least partially inverting the chirality of the enantiopure starting configuration;
(b) an isolation process for isolating the enantiopure enantiomer according to the formula la or lb, respectively, having inverted chirality by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes,
(c) repeating at least once the above steps (a) and (b) for treatment of the residual non-inverted enantiomer having the starting configuration to successively yield the desired enantiomer having inverted chirality.
17. Method for increasing the yield of a desired enantiopure product according to the formula la or lb
wherein * donates the enantiopure (R) or (S) configuration and R, R\ X, A and n are defined as above, and wherein the desired configuration is preferably the (R) configuration,
by applying the steps of:
(a') preparation of a racemic intermediate according to a competitive industrially applicable synthesis or preparation of a chiral intermediate, which is enantiomerically enriched in the desired enantiomer by insufficient enantiomeric excess when applying a synthesis of insufficient enantioselectivity;
(b') isolation of a first batch of enantiomerically pure desired enantiomer according to the formula la or lb, respectively, by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes;
(c') collecting the undesired enantiomer according to the formula la or lb from side fractions, mother liquors or other process side products resulting from the isolation of the desired enantiomer;
(d')optionally isolation of the undesired enantiomer;
(e') racemising the undesired enantiomer by a racemisation treatment as defined by any of items 1 to 14 to afford a compound according to the formula Ha or lib, respectively:
wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;
(f) isolating the product of the step (e'), which is preferably a racemate, according to the above step (b') to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively.
18. The method according to item 17, wherein the steps (b') to (f) are successively repeated several times.
19. Method for synthesizing lorcaserin according to the formula (R)-" , or a salt thereof, preferably the hydrochloride salt thereof:
applying a method as defined by any of items 1 to 1 1 , 13 or 14.
Detailed description of the invention
Hereinafter, the present invention is described in more detail by referring to further preferred and further advantageous embodiments and examples which supplement the above items and which shall not be understood as being limiting.
The present invention provides a very simple, efficient and economic technology for racemisation of amine, alcohol or thioalcohol compounds having chirality in the β- position. It was surprisingly found that this simple technology based on the use of appropriate base in appropriate solvent, enables efficient racemisation of amines, alcohols or thioalcohols where the chiral carbon (benzylic position) is located at the β-position of the heteroatom (amino, hydroxyl or mercapto group) or even more distant therefrom. Up to now it has been only possible to racemise obenzyl amines or o benzyl alcohols where heteroatom (N, O, S) is directly located/bound at asymmetric benzylic position and very strongly increase the reactivity of the compound towards racemisation.
Special focus is oriented in efficient and simple racemisation of an undesired enantiomer of a chiral pharmaceutically active ingredient, preferably lorcaserin or a salt thereof, preferably the hydrochloride salt, or an intermediate for the preparation thereof, wherein the chiral benzylic position is located at the β-position of the amino group. The approach according to the invention enables the use of cheaper and shorter racemic synthetic schemes not requiring expensive and toxic reagents and catalysts, followed
by final resolution of enantiomers with chiral chromatography or using classical optical resolution approach without unavoidable loss of more than 50 % of consumed material and energy by wasting the undesired enantiomer. Using this technology, it is possible to almost quantitatively obtain pure enantiomer with simple combination of resolution followed by efficient racemisation of undesirable enantiomer in a cyclic process.
The terms "enantiomerically enriched mixture/product/compound" or "enantiomerical enrichment" as used herein mean a mixture, a product, a compound or a process having or achieving an enantiomerical excess by 10 to 70 % e.e, preferably 30 to 70 % e.e, more preferably 50 to 70 % e.e.
The term "enantiomerically pure", "enantiopure" or "optically pure" compound as used herein means a compound having an enantiomerical excess by at least 70 % e.e., preferably having at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.
The term "racemization" as used herein refers to the converting of an enantiomerically enriched or enantiopure compound into a mixture where the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is reduced at least by one-third, more preferably at least by half, and still more preferably by at least by two- third. Most preferably, the racemization results in a mixture where the enantiomers are present in equal quantity (racemic or a racemate).
The term "salt" as used herein refers to any suitable salt form from the respective compound. Preferably, the salt is pharmaceutically acceptable.
In the first embodiment, the invention provides a method for racemisation of a compound according to the formula la or lb:
wherein * in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure;
wherein
R is represented by a linear, branched or cyclic Ci-Ci2-alkyl;
R' is selected from hydrogen or a group selected from a Ci-Ci2-alkyl group, a d- Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxy carbonyl group, a C1-C4- alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;
X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';
A is selected from -CH2-, -CR1R2- (wherein R1 and R2 are same or different and are selected from linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH2-CH2-, CR1R2-CR3R4- (wherein R1, R2, R3 and R4 are same or different and are selected from linear, branched or cylic, substituted or unsubstituted C Ci2-alkyl), -CR5=CR6- (wherein R5 and R6 are same or different and are selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH2-CO-, -CO-CH2-, >C=0, -S02-, and -NR7- (wherein R7 is selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted Ci-Ci2-alkyl); n represents 0 or 1 , wherein X is directly linked to the benzene ring by a single bond if n is 0;
one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C6-alkoxy group, a unsubstituted or Ci-Ci2-alkyl mono- or di-substituted amino group, a Ci-Ci2-alkyl group, a Ci-Ci2-alkanoyl group, a benzoyl group, a Ci-C6- alkyloxy carbonyl group, a CrC4-alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl- subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, and wherein bonds between the positions 2 and 3, or 3 and 4, or 4 and 5 are optionally condensed with another six-membered aromatic ring optionally containing one or two nitrogen
atoms or with a five-membered aromatic ring containing one oxygen, or one sulfur or 1 to 3 nitrogen atoms or a combination of one oxygen and one nitrogen atom; by treatment with a strong base, which is selected from metal hydroxides, metal alkoxides or metal amides, in order to reduce the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration.
The racemisation treatment reduces the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration at least by one-third, more preferably at least by half, and still more preferably by at least by two-third. It is most preferred that no enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is detectable after the racemisation treatment thus achieving a racemic mixture of 0% e.e.
The racemization method thus preferably yields the compound according to the formula Ha or Mb, respectivel :
wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above. The winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the enantiomerically enriched or enantiopure starting configuration.
The racemisation treatment is preferably carried out in a high boiling polar aprotic solvent, which is preferably selected from the group of amides, sulfoxides, and sulfones The preferred solvents are Ν,Ν-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), the most preferred one is dimethylsulfoxide. The solvent preferably consists only of high boiling polar aprotic solvents, which are preferably used anhydrous. One high boiling polar aprotic solvent may be used alone or a mixture of high boiling polar aprotic solvents may be used. Preferably, only DMSO is used.
The racemisation treatment is preferably carried out at elevated temperature, preferably at 80 °C or more, more preferably at 90 °C or more, most preferably 100 °C or more. The upper limit of the reaction temperature is not especially limited provided that the reaction temperature is lower than the degradation/decomposition temperature of the educts in the reaction mixture.
The racemisation treatment is suitably accomplished in the presence of metal hydroxides, metal alkoxides or metal amides which are selected from bases the corresponding acid having a pKb of at least 12 in DMSO. Preferably, the base is selected from alkali or earth alkali hydroxides, alkali or earth alkali alkoxides or alkali or earth alkali amides. More preferably the base is selected from alkali metal hydroxides (preferably sodium or potassium hydroxide), alkali metal alkoxides (preferably sodium or potassium ie f-butoxide), or alkali metal silylamides (preferably sodium hexamethyldisilazane (NaHMDS)). The strong base is added in an amount enabling suitable racemisation turnover. The conversion can be performed by submolar, equimolar or excess amounts of the base, but in order to increase the turnover and/or speed up the reaction time, it is preferred to apply the strong base at least equimolar, preferably with a molar excess of 1.25 or more, with respect to the compound according to formula la or lb. The upper limit of the amount of strong base is not particular limited provides that the used amount avoids the decomposition or degradation of the compound to be racemised. However, in the individual case, it may even be desirable to apply such an amount of strong base that leads to racemisation and de-protection of a protecting group at the heteroatom O, N, or S (i.e. groups R', R", Rb or Rc) in one concerted reaction.
The reaction of conversion is preferably prolonged to a full racemisation, in the case of very slow conversion a skilled person can optionally stop the reaction, when a reasonably reduced enantiomeric access, such 50 % e.e. or below, preferably 20 % e.e. or below, is reached. A full racemisation is usually achieved within 48 hours, preferably it takes 12 to 36 hours.
In the compound according to the formula la or lb applied in the method of the present invention, the benzene ring may be substituted as defined above. If one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are substituted, at least one of the substituents is preferably selected from an electron withdrawing group selected from halo, nitro, nitroso, cyano, or a group selected from a Ci-Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxycarbonyl group, a Ci-C4-alkanesulfonyl group and a
benzenesulfonyl group, wherein the alkyl chain of these groups and optional substituents of the carbon atoms are defined as above. Such electron withdrawing groups may have beneficial impact on the racemisation turnover in the racemisation treatment of the present invention. It is most preferred that a chloro substituent is present in the meta-position (i.e. position 3 or 5) of the benzene ring of formula la or lb with no further substitution on the benzene ring being present.
In the compound according to the formula la or lb applied in the method of the present invention, R is preferably represented by methyl, ethyl, isopropyl, more preferably methyl.
In the compound according to the formula la applied in the method of the present invention, R' is preferably represented by hydrogen. In case of X being O or S, it is especially preferred that R' is represented by hydrogen. In case of X being N-R", it is preferred that R' is hydrogen, while R" is selected from hydrogen or a group selected from a Ci-Ci2-alkyl group, a Ci-Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxy carbonyl group, a CrC4-alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl-substituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, while R" is preferably selected from hydrogen or one of the above defined C Ci2-alkanoyl group (preferably represented by an acetyl or a trifluoracetyl group), d- C6-alkyloxy carbonyl group (preferably represented by a benzyloxycarbonyl or an allyloxycarbonyl group), Ci-C4-alkylsulfonyl group (preferably represented by a mesyl group) or benzenesulfonyl group (preferably represented by a tosyl group). In case of X being N-R" and R' being different from hydrogen, R" may be suitably selected to be the same or different from R', while such amine compounds being substituted by R' and R" may be represented by alkylamides, alkylsulfonamides, tertiary amines, etc.
A typical but not limited set of the open chained chiral benzylic compounds according to the formula la for successful racemisation according to the invention is shown in Scheme 3 with respect to the compound according to the formula la". Experimental details are more precisely shown in the example section.
base
T X solvent
CH3 CH3 la" Ma" optically pure/enriched racemate
I a= H, F, CI, Br, I, OH, MeO, N02; preferably H or CI (preferably in meta-position);
X= NH, 0, S;
Rb= -H if X = 0, S and Rb = -H, -COCH2Ph, -COCH3 or -COOCH2CH=CH2 if X = NH;
base= NaOH, KOH, NaOfBu, KOfBu, NaHMDS
solvent= DMSO, sulfolane, DMA, DMF
Scheme 3: Illustrative examples of racemisation technology on preferred open chained chiral benzylic compounds according to formula la".
Further, in the compound according to the formula lb applied in the method of the present invention, R" is selected from hydrogen or a group selected from a CrCi2-alkyl group, a Ci-Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxy carbonyl group, a CrC4-alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl-substituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, while R" is preferably selected from hydrogen or one of the above defined Ci-Ci2- alkanoyl group (preferably represented by an acyl or a trifluoracyl group), Ci-C6- alkyloxy carbonyl group (preferably represented by a benzyloxycarbonyl or an allyloxycarbonyl group), d-C4-alkylsulfonyl group (preferably represented by a mesyl group) or benzenesulfonyl group (preferably represented by a tosyl group).
Additionally, it is preferred that n is 1. Furthermore, it is preferred that the compound according to the formula lb features a benzazepine skeleton having a 7-membered ring annealed to the benzene ring. In this case, it is preferred that A is represented by -CH2-CH2-, -CH2-CO- or -CO-CH2-, more preferably -CH2-CH2-.
Another typical but not limited set of the cyclic benzylic compounds according to the formula lb for successful racemisation according to the invention is shown in Scheme 4 with respect to the compound according to the formula lb". Experimental details are more precisely shown in the example section, while table 1 in Example 10 teaches optimal conditions and reagents for racemisation.
lb" Mb
Rc= -H, -COCH3, -COCF3, -COOCH2CH=CH2, -COCH2Ph;
Scheme 4: Illustrative examples of racemisation technology on cyclic chiral benzylic compounds
The substituents Rb or Rc (and R' or R", respectively) may beneficially influence on ease and duration of racemisation conversion. The influence is empirical, a skilled person may decide according to experimental results whether the substitution of the heteroatom X, preferably nitrogen, is done in order to make racemisation easier, the reaction time shorter or temperature lower.
The substituent(s) Ra (i.e. the substituent(s) on positions 2 to 6 of the benzene ring) may also influence on ease and duration of racemisation conversion. Electron withdrawing substituents, such as chloro have a beneficial effect on duration and completeness of the racemisation, because they enhance acidity of the proton on the carbon atom attached to the aromatic ring.
Applying the racemisation method in a total synthesis of a desired compound the heteroatom can be substituted by protecting groups from previous steps of the synthesis. In such case, a skilled person can decide whether the racemisation is performed on the substituted derivative or by an approach wherein the intermediate is first deprotected and then racemised.
In another embodiment of the invention, the present invention provides novel compounds according to the formulae 2* to 7* as shown in Scheme 5, wherein the compounds shown in Scheme 5 are enantiomerically enriched or enantiopure in (S) or
(R) configuration, preferably the (R) configuration. More preferably, such compounds have an enantiomeric excess of 98 % e.e. or more.
6* 7*
Scheme 5: Novel compounds representing suitable intermediates for preparation of optically active pharmaceutics, preferably lorcaserin, or a salt thereof.
Such novel compounds represent suitable intermediates for the synthesis of pharmaceutically active agents, especially lorcaserin, or a salt thereof, preferably the hydrochloride salt thereof. Such intermediates can be achieved by substitution of the heteroatom, which can be done by routine methods well known to a skilled person using reactive alkylation or acylation reagents in the presence of a base or by dehydration techniques using dehydration reagents such as carbodiimides.
In another embodiment, the invention provides a method for inverting the chirality of a compound according to the formula la or lb
wherein * donates the enantiopure (R) or (S) configuration and R, R', X, A and n are defined as above, and wherein the enantiopure starting configuration is preferably the (S) configuration;
by applying
(a) a racemisation treatment as defined by any of items 1 to 14, thereby at least partially inverting the chirality of the enantiopure starting configuration;
(b) an isolation process for isolating the enantiopure enantiomer according to the formula la or lb, respectively, having inverted chirality by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes,
(c) repeating at least once the above steps (a) and (b) for treatment of the residual non-inverted enantiomer having the starting configuration to successively yield the desired enantiomer having inverted chirality.
In the method for inverting the chirality of a compound according to the formula la or lb, the starting compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e. Besides, the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.
Following the steps (a) and (b) in a repeating manner, it is possible to successively convert almost all starting compound to the desired compound having inverted chirality. For the isolation process in step (b), there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).
In another embodiment, the invention provides a method for increasing the yield of a desired enantiopure product according to the formula la or lb
wherein * donates the enantiopure (R) or (S) configuration and R, R\ X, A and n are defined as above, and wherein the desired configuration is preferably the (R) configuration,
by applying the steps of:
(a') preparation of a racemic intermediate according to a competitive industrially applicable synthesis or preparation of a chiral intermediate, which is enantiomerically enriched in the desired enantiomer by insufficient enantiomeric excess when applying a synthesis of insufficient enantioselectivity;
(b') isolation of a first batch of enantiomerically pure desired enantiomer according to the formula la or lb, respectively, by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes;
(c') collecting the undesired enantiomer according to the formula la or lb from side fractions, mother liquors or other process side products resulting from the isolation of the desired enantiomer;
(d')optionally isolation of the undesired enantiomer;
(e') racemising the undesired enantiomer by a racemisation treatment as defined by any of items 1 to 14 to afford a compound according to the formula Ha or lib, respectively:
wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;
(f) isolating the product of the step (e'), which is preferably a racemate, according to the procedure of the above step (b') in order to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively.
In the method for increasing the yield of a desired enantiopure product according to the formula la or lb, the resulting desired compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e. Besides, the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.
In this method of the present invention, the steps (b') to (f) are preferably successively repeated several times. Thereby, it is possible to batch-wise increase the yield of the compound having the desired chirality.
For the isolation process in step (b'), there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).
Applying the racemisation technology according to the invention, it is possible to enhance the weight gain of a target chiral product for more than 20 %, preferably for more than 50 % in one step and to enhance the yield by single or multiple recovery over 50 %, preferably over 70 %.
Such protocol is very useful for industrial preparation of pharmaceutically applicable compounds according to the formula la or lb. For example, the (RJ-enantiomer of the compound according to the formula lb' or lb", wherein Rc and R", respectively, are hydrogen was recently introduced to medical practice as an antiobesity drug (the compound of the formula (R)A .
In the literature, several processes for the preparation of the racemic compound according to the formula lib", wherein Rc is hydrogen, have been reported (see WO 03/086306, WO 05/019179, WO 08/0701 1 1 ). The preparation of the compound
according to the formula (RjA is achieved by using a resolution via a diastereomeric salt with L-(+)-tartaric acid (see WO 05/019179). By triple precipitation from wet tert- butanol enantiomerically pure compound of the formula (R)-" in the form of tartrate is obtained in 98.7 % e.e., but the yield is only 15 %. An amount of 85 % of material, obtained after several troublesome synthetic steps is therefore unrecurrently lost.
By using the process of racemisation according to the invention most of material, which has been removed in the form of the mirror isomer represented by the formula (S)-" and the lost part of the desired (RJ-isomer can be returned to the process losing only the material due to degradation and technical losses.
Therefore, the above methods of the present invention can be suitable used in the synthesis of lorcaserin according to the formula (R)-" , or a salt thereof, preferably the hydrochloride salt thereof.
Detailed description of the ways of carrying out the invention (examples) in a way that examples can be reproduced.
The present invention is illustrated more precisely based on the following examples and with the table which presents a study of the effect of the reaction conditions on racemisation process using novel technology.
In all examples, the optical purity of the starting compounds and final products is indicated by enantiomeric excess (% e.e.). The enantiomeric excess as mentioned herein means an excess of one enantiomer over the racemic mixture. Optical purity is determined using chiral HPLC analysis or by chiral GC-FID. The % e.e. is calculated from percentage ratio of enantiomers x:y, wherein y>x by the mathematical formula 100 - 2x.
Example 1 : Racemisation of optically active (R)-2-phenylpropan-1 -amine using potassium ie f-butoxide
(R)-B 8
The testing compound of the formula {R)-S is commercially available.
Starting material (R)-2-(3-chlorophenyl)propan-1 -amine {{R)-S, 1 mmol; 136 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 1 .25 mmol) was added in two portions in 30 min intervals and the closed reaction system was stirred at 100 °C for 36 hours. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (123 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 136; CI).
Example 2: Racemisation of optically active (R)-2-phenylpropan-1 -amine using potassium hydroxide
(R)-8
Starting material (R)-2-(3-chlorophenyl)propan-1 -amine ((R)-8, 1 mmol; 136 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOH (fresh powder; 2 mmol) was added in four portions in 30 min intervals and the closed reaction system was stirred at 100 °C for 48 hours. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (1 16 mg) was analysed with chiral HPLC where 60 % e.e. was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 136; CI).
Example 3: Racemisation of optically active (S)-2-phenyl-propan-1 -ol in the presence of potassium ie f-butoxide
fSj-9 9
The testing compound of the formula (S)-9 is commercially available.
Starting material (S)-2-phenyl-propan-1 -ol ((S)-8; 1 mmol; 137 mg; > 99% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 1 .5 mmol) was added in four portions in one hour intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (1 12 mg) was analysed with chiral GC-FID where 50 % e.e. was detected.
Example 4: Racemisation of optically active (S)-2-(3-chlorophenyl)propan-1 -amine using potassium hydroxide
(S)-5 5
The testing compound (S)-2-(3-chlorophenyl)propan-1 -amine {(S)-5) was prepared according to the literature (J. Med. Chem. 56, 4786 (2013)) followed by separation of enantiomers by column chromatography on chiral supporter to its (S)- and (R)- enantiomer.
Starting material (S)-2-(3-chlorophenyl)propan-1 -amine ((S)-5, 1 mmol; 169 mg; > 95% optical purity) was dissolved in anhydrous DMSO (0.8 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOH (fresh powder;
1 .25 mmol) was added in three portions in 30 min intervals and the closed the reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (155 mg) was analysed with chiral HPLC where 28 % e.e. was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 169; CI) and 1H NMR.
1H NMR (500 MHz, CDCI3) δ 8.25 (bs, NH2), 7.25-7.10 (m, 4ArH), 3.15 (m, 1 H), 2.92 (m, 2H), 1 .15 (d, J= 9 Hz, 3H).
Example 5: Racemisation of optically active (S)-2-(3-chlorophenyl)propan-1 -amine using potassium ie f-butoxide
(S)-5 5
Starting material (S)-2-(3-chlorophenyl)propan-1 -amine {(S)-5, 0.5 mmol; 85 mg; > 95% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 0.625 mmol) was added in three portions in 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted with n-hexane (60 mL) for few times. The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (81 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions was analysed also with GC-MS (m/z = 169; CI) and 1H NMR.
Example 6: Synthesis of (S)-/V-2-(3-chlorophenyl)propyl)-2-phenylacetamide {(S)-7)
(S)S (S)-7
Starting material (^^-(S-chloropheny^propan-l -amine {(S)-5, 2.5 mmol; > 96% optical purity) was suspended in acetone (10 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards an aqueous solution of K2C03 (1 .25 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of phenylacetyl chloride (2.8 mmol). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH2CI2, washed with saturated NaHC03, the organic phases were dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained oily product (680 mg; 94% yield) was analysed with GC-MS (m/z = 287) and 1 H, 13C NMR spectroscopy.
1 H N MR (500 MHz, CDCI3) δ 7.41 -7.30 (m, 4ArH), 7.28-7.19 (m, 3ArH), 7.17-7.09 (m, 2ArH), 5.40 (bs, NH), 3.55 (m, 1 H), 3.50 (s, 2H), 3.18 (m, 1 H), 2.85 (m, 1 H), 1 .18 (d, J= 9.2 Hz, 3H);
13C N MR (125 MHz, CDCI3) δ 170.9, 147.3, 146.0, 134.4, 129.8, 129.1 , 127.5, 126.8, 126.6, 125.6, 125.3, 46.0, 43.8, 40.2, 39.4, 19.1 .
Example 7: Racemisation of optical active (S)-/V-2-(3-chlorophenyl)propyl)-2- phenylacetamide in the presence of potassium ie f-butoxide
(S)-7 7
Starting material (S)-/V-2-(3-chlorophenyl)propyl)-2-phenylacetamide {(S)-7, 0.5 mmol; 143.5 mg; > 95% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (fresh powder; 0.625 mmol) was added in three portions in 30 min intervals and the closed reaction system was stirred at 100 °C for 24 hours. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (100 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (133 mg) was analysed with chiral HPLC where 45 % e.e. was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 287; CI).
Example 8: Synthesis of allyl (RJ-(2-(3-chlorophenyl)propyl)carbamate
Starting material (/^.-(S-chloropheny propan-l -amine {(R)-5, 12.2 mmol; > 98% optical purity) dissolved in CH2CI2 (25 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards Et3N (1 .2 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of allyl chloroformate (1 .05 equiv.). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH2CI2, washed with saturated NaHC03, the organic phases were dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained liquid product (2.61 g; 84% yield) was analysed and confirmed with GC-MS (m/z = 253) and 1H NMR spectroscopy.
1H NMR (500 MHz, CDCI3) δ 7.33-7.12 (m, 3ArH), 7.07 (m, 1ArH), 5.85 (m, 1 H), 5.25 (m, 2H), 4.51 (m, 2H), 3.45 (m, 1 H), 3.30 (m, 1 H), 2.90 (m, 1 H), 1.27 (d, J = 9 Hz, 3H).
Example 9: Synthesis of (S)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine
(fs;-i)
The compound of the formula {(S)- ) was prepared following the procedures of examples 8, 9, 10, and 12 in WO 05/019179. The obtained crude racemate of the compound according to the formula 1 was submitted to triple crystallisation through the salt with D-(-)-tartaric acid according to the Example 13 of the same publication to give the title compound in 16 % yield and optical purity of over 98 % e.e.
Example 10: Efficient racemisation of optical pure (S)-8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 /-/-benzo/c//azepine
fs -i
optical pure racemate
Starting material (S)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine ((SJ-1 , 1 mmol; 198 mg; >98% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), an appropriate base (1 .25 mmol; see Table 1 ) was added in three portions in 30 min intervals and the closed reaction system was stirred at 90-100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane or n-heptane (60 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (185 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the
product under such conditions were analysed with GC-MS (m/z = 195; CI) and 1H NMR.
1H NMR (500 MHz, CDCI3) δ 7.04 (m, 2H), 6.98 (m, J = 9.1 Hz, 1 H), 6.22 (d, J = 9.7 Hz, 1 H), 5.06 (1 H, J = 9.7 Hz, 1 H), 3.32 (m, 1 H), 3.24 (m, 1 H), 1.18 (d, J = 7.1 Hz, 3H).
In a similar reaction protocol as described above, the effect of the reaction conditions on the racemisation process was studied. Several reactions were carried out at various reaction conditions (effect of a base; solvent; temperature). The results are presented in Table 1 .
Table 1.
Example 11 : Synthesis of optical pure 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[c/]azepin-3(2H)-yl)ethanone {{(S)-2)
(S)-VHC\ (S)-2
Starting material 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine hydrochloride ((S)-V C\, 2.5 mmol; > 98% optical purity) was dissolved in anhydrous CH2CI2 (5 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards Et3N (1 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of acetyl chloride (2.8 mmol). Such reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH2CI2, washed with saturated NaHC03, the organic phases were dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained oily product (570 mg; 96% yield) was analysed with GC-MS (m/z = 237) and 1H NMR spectroscopy.
1H NMR (500 MHz, DMSO, 75 °C) δ 7.31 -7.05 (m, 3ArH), 3.85 (m, 2H), 3.55 (m, 2H), 3.25-2.86 (m, 3H), 1 .97 (s, 3H), 1 .20 (bs, 3H).
Example 12: Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone using sodium hydroxide
(S)-2
Starting material (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[c/]azepin-3(2/-/)- yl)ethanone {(S)-2, 0.5 mmol; 120 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar.
During slow heating (10 °C/min), NaOH (fresh powder; 0.625 mmol) was added in two portions in 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (120 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 237; CI) and 1H NMR. 22% of hydrolysed product (m/z = 195) was also observed.
Example 13: Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone in the presence of potassium ie f-butoxide
(S)-2 2
Starting material (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[c/]azepin-3(2/-/)- yl)ethanone {{(S)-2, 0.5 mmol; 120 mg; > 98% optical purity) was dissolved in anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (0.625 mmol) was added in two portions in 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and solvent was evaporated under reduced pressure. The obtained residue (120 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 237; CI) and 1H NMR (two conformers). 12% of hydrolysed product (m/z = 195) was also observed.
Example 14: Synthesis of optical pure allyl 8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[c/]azepine-3-(2H)-carboxylate {(S)-3)
Starting material 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine hydrochloride (((S)-V C\, 2.5 mmol; > 98% optical purity) was dissolved in anhydrous CH2CI2 (5 mL) in a 100 mL flask equipped with magnetic stir bar. Afterwards Et3N (1 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of allyl chloroformate (2.75 mmol). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the reaction system was diluted with CH2CI2, washed with saturated NaHC03, the organic phases were dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained liquid product (600 mg; 86% yield) was analysed with GC-MS (m/z = 279) and 1H NMR spectroscopy.
1H NMR (500 MHz, CDCI3) δ 7.28-7.17 (m, 2ArH), 7.06-6.97 (m, 1ArH), 5.93 (m, 1 H), 5.32 (m, 1 H), 5.25 (m, 1 H), 4.60 (m, 2H), 3.82-3.30 (m, 4H), 3.05 (m, 2H), 2.86 (m, 1 H), 1 .28 (d, J = 7.0 Hz, 3H).
Example 15: Racemisation of optical pure allyl (S)-8-chloro-1 -methyl-4,5-dihyd benzo[c/]azepine-3-(2/-/)-carboxylate in the presence of potassium ie f-butoxide
Starting material (S)-allyl 8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[c ]azepine-3-(2/-/)- carboxylate {{(S)-3, 0.5 mmol; 1 17 mg; > 98% optical purity) was dissolved in
anhydrous DMSO (0.75 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), KOiBu (0.625 mmol) was added in two portions in an 30 min intervals and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (1 1 1 mg) was analysed with chiral HPLC where 25 % e.e. was detected. Purity and stability of the product under such conditions were analysed also with GC-MS (m/z = 279; CI) and 1 H NMR. 28% of hydrolysed product (m/z = 195) was also observed.
Example 16: Synthesis of optical pure 1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[d]azepine-3-(2H)-yl)-2-phenylethanone)-2-phenylethanone {(S)-4)
(S)-V C\ (S)-4
Starting material 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/-benzo/c//azepine hydrochloride {(S)-1* C\, 3 mmol; > 98% optical purity) was suspended in acetone (15 mL) in a 50 mL flask equipped with magnetic stir bar. Afterwards an aqueous solution of K2C03 (2 equiv. according to starting compound) was added and the reaction system was cooled down to 0 °C followed by slow addition of phenylacetyl chloride (3.15 mmol). The reaction mixture was vigorously stirred at room temperature. After the completion of the reaction, the organic solvent was evaporated, the residue was extracted with CH2CI2, washed with saturated NaHC03, the organic phases were dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained liquid product (865 mg; 92% yield) was analysed with GC-MS (m/z = 313) and 1 H, 13C NMR spectroscopy.
1 H N MR (500 MHz, DMSO, 70 °C) δ 7.35-7.05 (m, 8ArH), 4.75-4.85 (m, 5H), 3.30 (s, 2H) 2.85 (m, 2H), 1 .16 (d, J= 7.2 Hz, 3H); 13C N MR (125 MHz, DMSO) δ 169.8, 146.7,
145.9, 138.1 , 137.5, 132.0, 131 .7, 131 .0, 128.9, 128.3, 127.8, 126.3, 125.8, 54.9, 51 .8, 48.3, 43.7, 33.7, 17.7.
Example 17: Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[d]azepine-3-(2H)-yl)-2-phenylethanone)-2-phenylethanone
(S)-A 4
Starting material (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H-benzo[d]azepine-3-(2H)-yl)-2- phenylethanone)-2-phenylethanone {(S)-4, 0.5 mmol; 156 mg; > 99% optical purity) was dissolved in anhydrous DMSO (0.9 mL) in a 10 mL test tube equipped with magnetic stir bar. During slow heating (10 °C/min), NaOH (fresh powder; 0.625 mmol) was added and the closed reaction system was stirred at 100 °C overnight. After the completion of the reaction, the reaction system was cooled down to room temperature and extracted several times with n-hexane (60 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure. The obtained residue (135 mg) was analysed with chiral HPLC where 0 % e.e. (full racemisation) was detected. Purity and stability of the product under such conditions were analysed with GC-MS (m/z = 313; CI). 25% of hydrolysed product (m/z = 195) was also detected.
Example 18: Preparation of optical pure (R)-8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 /-/- benzo/c//azepine {(R)- ) in an improved yield
Crude product (15.09 g) prepared according to Example 9 was dissolved in ie f-butanol (70 mL), followed by addition of aqueous solution of L-(+)-tartaric acid (2.35 g of acid in 3,5 mL of water) and seed crystals were added. The solution was stirred at room temperature for 10 hours. The resulting suspension was filtered and the precipitate was washed with acetone. The obtained precipitate was twice recrystallised from wet tert-
butanol (60 ml of ie f-butanol/water 6:1 ) and dried to give 4.0 g of tartaric salt of (RjA in >98 % e.e.
Mother liquors from the preparation of tartaric salt and two recrystallisations from wet ie f-butanol (220 mL) were collected and concentrated to about 20 % of volume. First methylene chloride was added followed by 10 % aqueous NaOH. Phases are stirred, separated and the aqueous layer was extracted again with methylene chloride. The organic layers were collected and evaporated to dryness. The residue contains a mixture of both enantiomers with an excess of the undesired (S)-enantiomer in a form of base (35 % e.e.).
The residue (Sj-λ (1 1.5 g, 35 % e.e.) from the previous step was dissolved in anhydrous DMSO (42 mL). During slow heating (10 °C/min), potassium ie f-butoxide (8.0 g) was added in three portions in 30 min intervals. The mixture was then stirred in inert atmosphere at 90-100 °C overnight. After the completion of the reaction, the mixture was cooled down to room temperature and extracted several times with n-heptane (60 mL). The organic phases were washed with brine, dried over anhydrous Na2S04 and the solvent was evaporated under reduced pressure to give a residue (10.5 g, with < 2 % e.e. of (Sj-isomer).
The residue was treated as described in the first paragraph of this example to give 2.52 g of L-(+)-tartaric salt of (R)-" in >98 % e.e. The crop was added to the original crop to give 6.52 g of tartaric salt (overall yield 24 %).
The L-(+)-tartaric acid salt of (R)-" (6.52 g) was dissolved in aqueous NaOH (5 g in 40 ml of water), stirred for 10 minutes at room temperature and was then twice treated with 100 of methylene chloride. The combined organic extracts were washed with water (100 mL) and evaporated to dryness on the pump to get free amine (R)-" (4.72 g crude weight).
To a clean, dry 25 mL round bottom flask were added the free amine (R)-" (4.72 g), 65 mL of methylene chloride, and 40 mL of ether, which is saturated with HCI. The mixture was stirred for 5 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid, the HCI salt. The salt was re-dissolved in methylene chloride (65 mL) and an additional 40 mL of with ether saturated with HCI was added and the solution was again stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to give the desired hydrochloride salt of 8-chloro-1 -methyl-2,3,4,5-tetrahydro-1 H-3-benzazapine {(R)-V C\) (3.88 g).
A gain by applying the process according to the invention reaches about 60 % (6.52 g comparing to 4.0 g of tartaric salt was obtained). It is possible to re-racemise mother liquors from tartaric salt preparation and recrystallisation liquors of the second crop of the product with further improvement of yield. A skilled person may combine different approaches of recovery, for example he may racemise only the liquor from tartaric salt preparation, which is much more enriched in undesired isomer and may treat recrystallisation liquors, which are rich in the desired isomer by other approaches. By repeatable recovery the yield may exceed 50 % before one crop of liquors must be discarded due to accumulation of degradation products.
Claims
1 . Method for racemisation of a compound according to the formula la or lb:
wherein * in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure;
wherein
R is represented by a linear, branched or cyclic Ci-Ci2-alkyl;
R' is selected from hydrogen or a group selected from a Ci-Ci2-alkyl group, a d- Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxy carbonyl group, a Ci-C4- alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;
X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';
A is selected from -CH2-, -CR1R2- (wherein R1 and R2 are same or different and are selected from linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH2-CH2-, CR1R2-CR3R4- (wherein R1, R2, R3 and R4 are same or different and are selected from linear, branched or cylic, substituted or unsubstituted C Ci2-alkyl), -CR5=CR6- (wherein R5 and R6 are same or different and are selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted C1-C12- alkyl), -CH2-CO-, -CO-CH2-, >C=0, -S02-, and -NR7- (wherein R7 is selected from hydrogen or linear, branched or cyclic, substituted or unsubstituted Ci-Ci2-alkyl); n represents 0 or 1 , wherein X is directly linked to the benzene ring by a single bond if n is 0;
one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C6-alkoxy group, a unsubstituted or Ci-Ci2-alkyl mono- or di-substituted amino group, a Ci-Ci2-alkyl group, a Ci-Ci2-alkanoyl group, a benzoyl group, a Ci-C6- alkyloxy carbonyl group, a CrC4-alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC6-alkoxy, unsubstituted or substituted amino, CrC6-alkyl- subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond, and wherein bonds between the positions 2 and 3, or 3 and 4, or 4 and 5 are optionally condensed with another six-membered aromatic ring optionally containing one or two nitrogen atoms or with a five-membered aromatic ring containing one oxygen, or one sulfur or 1 to 3 nitrogen atoms or a combination of one oxygen and one nitrogen atom; by treatment with a strong base, which is selected from metal hydroxides, metal alkoxides or metal amides, in order to reduce the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration.
2. The method according to claim 1 , wherein the racemization method yields the compound according to the formula Ha or lib respectively:
wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above, and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the enantiomerically enriched or enantiopure starting configuration.
3. The method according to claim 1 or 2, wherein if one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are substituted, at least one of the substituents is selected from an electron withdrawing group selected from halo, nitro, nitroso, cyano, or a group
selected from a Ci-Ci2-alkanoyl group, a benzoyl group, a CrC6-alkyloxycarbonyl group, a Ci-C4-alkanesulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups and optional substituents of the carbon atoms are defined as above.
4. The method according to any one of claims 1 to 3, wherein R is represented by methyl, ethyl, isopropyl, preferably methyl.
5. The method according to any of claims 1 to 4, wherein R' is represented by hydrogen.
6. The method according to any of claims 1 to 5, wherein A is represented by -CH2-CH2-, -CH2-CO-, or -CO-CH2-, preferably -CH2-CH2-.
7. The method according to any of claims 1 to 6, wherein X is represented by N-R", and wherein R" is preferably selected from hydrogen or one of the above defined C Ci2-alkanoyl group (preferably represented by an acyl or a trifluoracyl group), Ci-C6- alkyloxy carbonyl group (preferably represented by a benzyloxycarbonyl or an allyloxycarbonyl group), Ci-C4-alkylsulfonyl group (preferably represented by a mesyl group) or benzenesulfonyl group (preferably represented by a tosyl group).
8. The method according to any of claims 1 to 7, wherein only the meta-position (3 or 5) in the benzene ring of formulae la and lb is substituted with chloro, and/or wherein the compound lb is represented by the following formula lb':
lb' wherein * and R" are defined as above, and wherein R" is preferably represented by hydrogen, an acetyl group, a trifluoracyl group, a benzyloxycarbonyl, an allyloxycarbonyl group, a mesyl group, or a tosyl group.
9. The method according to any of claims 1 to 8, wherein the racemisation process is carried out in a high boiling polar aprotic solvent, preferably selected from a group of amides, sulfoxides, and sulfones, more preferably Ν,Ν-dimethylacetamide (DMA), N,N- dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), and most preferably dimethylsulfoxide, and/or wherein the racemisation process is carried out at
elevated temperature, preferably at 80 °C or more, more preferably at 90 °C or more, and most preferably at 100 °C or more.
10. The method according to any of claims 1 to 9, wherein the strong base is selected from alkali or earth alkali hydroxides (preferably selected from alkali metal hydroxides, more preferably sodium or potassium hydroxide), alkali or earth alkali alkoxides (preferably alkali metal alkoxides, more preferably sodium or potassium ie f-butoxide), or alkali or earth alkali amides (preferably silylamides, more preferably sodium hexamethyldisilazane (NaHMDS)), and/or wherein the strong base is added at least equimolar, preferably with an molar excess of 1.25 or more, with respect to the compound according to formula la or lb.
1 1 . Method according to any of claims 1 to 10, wherein the enantiomerically enriched or enantiopure starting configuration is the (S) configuration.
12. Compound according to any of formulae 2* to 7*,
6* 7*
wherein * in the formulae donates an asymmetric chiral carbon atom in (R) or (S) configuration being enantiomerically enriched or enantiopure.
13. Method for inverting the chirality of a compound according to the formula la or lb
la lb
wherein * donates the enantiopure (R) or (S) configuration and R, R\ X, A and n are defined as above, and wherein the enantiopure starting configuration is preferably the (S) configuration;
by applying
(a) a racemisation treatment as defined by any of claims 1 to 1 1 , thereby at least partially inverting the chirality of the enantiopure starting configuration;
(b) an isolation process for isolating the enantiopure enantiomer according to the formula la or lb, respectively, having inverted chirality by chiral separation chromatographic techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes,
(c) repeating at least once the above steps (a) and (b) for treatment of the residual non-inverted enantiomer having the starting configuration to successively yield the desired enantiomer having inverted chirality.
14. Method for increasing the yield of a desired enantiopure product according to the formula la or lb
wherein * donates the enantiopure (R) or (S) configuration and R, R', X, A and n are defined as above, and wherein the desired configuration is preferably the (R) configuration,
by applying the steps of:
(a') preparation of a racemic intermediate according to a competitive industrially applicable synthesis or preparation of a chiral intermediate, which is enantiomerically enriched in the desired enantiomer by insufficient enantiomeric excess when applying a synthesis of insufficient enantioselectivity;
(b') isolation of a first batch of enantiomerically pure desired enantiomer according to the formula la or lb, respectively, by chiral separation chromatographic
techniques, by optical resolution approach through the formation of diastereomeric derivatives, salts or complexes or by kinetic resolution using enzymes;
(c') collecting the undesired enantiomer according to the formula la or lb from side fractions, mother liquors or other process side products resulting from the isolation of the desired enantiomer;
(d')optionally isolation of the undesired enantiomer;
(e') racemising the undesired enantiomer by a racemisation treatment as defined by any of items 1 to 1 1 to afford a compound according to the formula Ha or lib, respectively:
wherein R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ~ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;
(f) isolating the product of the step (e'), which is preferably a racemate, according to the above step (b') to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively;
and wherein the steps (b') to (f) are optionally successively repeated several times.
15. Method for synthesizing lorcaserin according to the formula (R)-" , or a salt thereof, preferably the hydrochloride salt thereof:
(R) applying a method as defined by any of claims 1 to 1 1 , 13 or 14.
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Cited By (7)
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CN105777750A (en) * | 2016-04-13 | 2016-07-20 | 江西中德诚信科技有限公司 | Synthesis method for moxifloxacin side chain |
EP3210975A1 (en) | 2016-02-24 | 2017-08-30 | Enantia, S.L. | Cocrystals of lorcaserin |
CN114728884A (en) * | 2019-09-26 | 2022-07-08 | Fmc农产品国际有限公司 | Process for the preparation of (R)-4-aminoindans and corresponding amides |
CN114804989A (en) * | 2022-05-06 | 2022-07-29 | 华中科技大学 | Purification method and racemization recycling of rivastigmine key chiral intermediate |
WO2023181054A1 (en) * | 2022-03-19 | 2023-09-28 | Aarti Industries Limited | Improved process for synthesis of benazepril intermediate |
WO2023158722A3 (en) * | 2022-02-16 | 2023-12-21 | Teva Pharmaceuticals International Gmbh | Processes for preparation of avacopan and intermediates thereof |
WO2024233603A1 (en) * | 2023-05-09 | 2024-11-14 | Icagen, Llc | Novel carboxamide derivatives |
Families Citing this family (1)
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CN112047906A (en) * | 2019-06-07 | 2020-12-08 | 帝斯曼知识产权资产管理有限公司 | Racemization method of pantoyl lactone |
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WO2009105206A1 (en) * | 2008-02-19 | 2009-08-27 | Arena Pharmaceuticals, Inc. | Modulators of the histamine h3 receptor useful for the treatment of disorders related thereto |
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US6953787B2 (en) * | 2002-04-12 | 2005-10-11 | Arena Pharmaceuticals, Inc. | 5HT2C receptor modulators |
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US5969186A (en) * | 1996-03-28 | 1999-10-19 | Nagase & Company, Ltd. | Process for racemizing of optically active amines |
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EP3210975A1 (en) | 2016-02-24 | 2017-08-30 | Enantia, S.L. | Cocrystals of lorcaserin |
WO2017144598A1 (en) | 2016-02-24 | 2017-08-31 | Enantia, S.L. | Cocrystals of lorcaserin |
CN105777750A (en) * | 2016-04-13 | 2016-07-20 | 江西中德诚信科技有限公司 | Synthesis method for moxifloxacin side chain |
CN114728884A (en) * | 2019-09-26 | 2022-07-08 | Fmc农产品国际有限公司 | Process for the preparation of (R)-4-aminoindans and corresponding amides |
WO2023158722A3 (en) * | 2022-02-16 | 2023-12-21 | Teva Pharmaceuticals International Gmbh | Processes for preparation of avacopan and intermediates thereof |
WO2023181054A1 (en) * | 2022-03-19 | 2023-09-28 | Aarti Industries Limited | Improved process for synthesis of benazepril intermediate |
CN114804989A (en) * | 2022-05-06 | 2022-07-29 | 华中科技大学 | Purification method and racemization recycling of rivastigmine key chiral intermediate |
CN114804989B (en) * | 2022-05-06 | 2023-12-26 | 华中科技大学 | Purification method and racemization recycling of rivastigmine key chiral intermediate |
WO2024233603A1 (en) * | 2023-05-09 | 2024-11-14 | Icagen, Llc | Novel carboxamide derivatives |
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