WO1998052921A1 - Processes and intermediates for resolving piperidyl acetamide stereoisomers - Google Patents
Processes and intermediates for resolving piperidyl acetamide stereoisomers Download PDFInfo
- Publication number
- WO1998052921A1 WO1998052921A1 PCT/US1998/010131 US9810131W WO9852921A1 WO 1998052921 A1 WO1998052921 A1 WO 1998052921A1 US 9810131 W US9810131 W US 9810131W WO 9852921 A1 WO9852921 A1 WO 9852921A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- threo
- acetamide
- piperidyl
- stereoisomers
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 56
- SXESBRNYONQKLV-UHFFFAOYSA-N n-piperidin-1-ylacetamide Chemical class CC(=O)NN1CCCCC1 SXESBRNYONQKLV-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 239000000543 intermediate Substances 0.000 title abstract description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical group O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical group OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- SEJJYFSKEXRWOZ-UHFFFAOYSA-N acetamide;piperidine Chemical compound CC(N)=O.C1CCNCC1 SEJJYFSKEXRWOZ-UHFFFAOYSA-N 0.000 claims 2
- 125000005233 alkylalcohol group Chemical group 0.000 claims 2
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 claims 1
- 125000005936 piperidyl group Chemical group 0.000 claims 1
- -1 2-substituted piperidines Chemical class 0.000 abstract description 12
- 150000003053 piperidines Chemical class 0.000 abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 102
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000013078 crystal Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000000463 material Substances 0.000 description 17
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- 229960001033 methylphenidate hydrochloride Drugs 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012458 free base Substances 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 8
- 239000002002 slurry Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 229960001344 methylphenidate Drugs 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 150000003892 tartrate salts Chemical class 0.000 description 6
- LJLMNWPXAYKPGV-UHFFFAOYSA-N 2-phenylpiperidine-2-acetamide Chemical compound C=1C=CC=CC=1C(C(=O)N)C1CCCCN1 LJLMNWPXAYKPGV-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
- 238000006345 epimerization reaction Methods 0.000 description 5
- 0 *[C@@]([C@]1(*CCCC1)N)C(N)=O Chemical compound *[C@@]([C@]1(*CCCC1)N)C(N)=O 0.000 description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 4
- 229910003446 platinum oxide Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 206010001513 AIDS related complex Diseases 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CAXNYFPECZCGFK-UHFFFAOYSA-N 2-phenyl-2-pyridin-2-ylacetonitrile Chemical compound C=1C=CC=NC=1C(C#N)C1=CC=CC=C1 CAXNYFPECZCGFK-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000002743 euphoric effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JUMYIBMBTDDLNG-QNTKWALQSA-N methyl (2s)-2-phenyl-2-[(2s)-piperidin-2-yl]acetate;hydrochloride Chemical compound Cl.C([C@H]1[C@@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-QNTKWALQSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- This invention is directed to novel processes for resolution of piperidyl acetamide stereoisomers.
- the invention additionally is directed to synthetic intermediates and reaction products useful in such processes.
- Substituted piperidines have found use in the treatment of many nervous system disorders. For example, methylphenidate has been used to treat Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD) and cognitive decline in Acquired Ijrnmunodeficiency Syndrome (AIDS) and AIDS Related Complex (ARC) patients.
- ADD Attention Deficit Disorder
- ADHD Attention Deficit Hyperactivity Disorder
- AIDS Acquired Ijrnmunodeficiency Syndrome
- ARC AIDS Related Complex
- racemic methylphenidate often results in notable side effects such as anorexia, weight loss, insomnia, dizziness and dysphoria. Additionally, racemic
- methylphenidate produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for substance abuse in patients.
- U.S. Patent Nos. 2,507,631 and 2,957,880 disclose synthetic procedures wherein methylphenidate, alternatively known as methyl ⁇ -piperid-2-ylphenylacetate, is prepared through a multi-step process in which 2-chloropyridine and phenylacetonitrile initially are coupled to form -pyrid-2-ylphenylacetonitrile.
- c.-pyrid-2-ylphenylacetamide which, in turn, is either: (a) catalytically hydrogenated to yield o.-piperid-2-ylphenylacetamide and then converted to methyl c.-piperid-2-ylphenylacetate, or (b) converted to methyl ⁇ -pyrid-2- ylphenylacetate which, in turn, is hydrogenated to yield methyl ⁇ -piperid-2-ylphenylacetate.
- ⁇ -piperid-2-ylphenylacetamide is first separated into the threo and erythro diastereomeric racemates. This is accomplished through evaporation of the solvent utilized in the hydrogenation (i.e., acetic acid), addition of sodium hydroxide to precipitate the ⁇ -piperid-2-ylphenylacetamide free base, recrystallization of this amide from ethyl acetate, and preferential crystallization of the erythro form by passing gaseous hydrogen
- the isolated erythro racemate then is resolved through formation of the /-tartrate salt, repeated recrystallizations of this salt from 96% ethanol are performed until a constant rotation is obtained, and the l-erythro form of -piperid-2-ylphenylacetamide is precipitated with sodium hydroxide.
- the l-erythro form of -piperid-2-ylphenylacetamide thus obtained is said to be subjected to epimerization to yield the desired d-threo diastereomer of ⁇ -piperid- 2-ylphenylacetamide through treatment with 6 M potassium hydroxide.
- Patent Nos. 2,507,631 and 2,957,880 do, in fact, produce the desired d-threo isomer. Indeed, J.R. Soares, "Stereochemical Studies On Potential Central Nervous System Active Agents and Studies On The Chemistry Of Some 3-Benzoylpiperidines," 1971 , Columbia University Ph.D. dissertation, p. 115, discloses that "all attempts to epimerize the resolved eryt/Vo-amides to the corresponding threo-amides by the procedure outlined in [U.S. 2,957,880] failed completely.”
- the processes of the invention comprise reacting d,l-threo piperidyl acetamide stereoisomers having formulas Ila and lib:
- This invention provides novel processes for stereoselective synthesis of a variety 2- substituted piperidine stereoisomers.
- the invention is directed to synthetic methods involving hydrogenation of pyridines having formula I:
- R ! is aryl having about 6 to about 28 carbon atoms.
- Aryl groups as used herein, are aromatic groups containing a delocalized ⁇ -electron cloud. Such aromatic groups can be
- aryl groups include phenyl, naphthyl, xylyl, chlorophenyl, fluorophenyl, trifluoromethylphenyl, and bromophenyl. Phenyl groups are preferred.
- This hydrogenation can be effected by any of the numerous techniques known in the art.
- One preferred hydrogenation technique involves reacting the pyridine with hydrogen gas in the presence of a suitable catalyst in an alkanoic acid having 1 to about 10 carbon atoms. The hydrogenation preferably run at 25 °C and 40 psi. Representative catalysts contain platinum, with platinum oxide being particularly preferred.
- One preferred alkanoic acid is acetic acid. Hydrogenation of pyridine I provides a mixture of piperidine diastereomers Ila-d:
- this mixture is treated with an organic base in an organic solvent to epimerize the erythro stereoisomers into threo forms.
- the epimerization can, for example, be effected in an aromatic hydrocarbon solvent such as toluene using an alkali metal alkoxide such as potassium tert-butoxide.
- the epimerization is effected at 70 °C in an aromatic hydrocarbon solvent such as toluene using two equivalents of an alkali metal alkoxide such as potassium tert-butoxide.
- Alkyl groups according to the invention are hydrocarbons which are straight, branched, or cyclic. Such hydrocarbons can be substituted with one or more substituents, such as, for example, halo, hydroxy, alkoxy, and carboxy groups.
- Exemplary alkyl groups include methyl, ethyl, isopropyl, ⁇ -butyl, t-butyl, n-pentyl, acetyl, trifiuoromethyl, chloromethyl, and hexyl groups.
- Representative solvents include alcohols, alkyl alkanoates (e.g., ethyl acetate), ketones (e.g., acetone), and ethers (e.g., tetrahydrofuran, dioxane).
- Preferred solvents are alcohols having 1 to about 5 carbon atoms, include branched and straight chain compounds such as ethyl, propyl and tert-butyl alcohol, with isopropanol being particularly preferred.
- the reaction of piperidyl acetamide stereoisomers with acid resolving agents preferably is performed with stirring at room temperature.
- Representative acid resolving agents include L-(+)- or D-(-)- tartaric acid, dipivaloyl-D-tartaric acid, (lS)-(+)-10-camphorsulphonic acid, L-(-)-malic acid, (S)-(+)- mandelic acid, N-acetyl-/-aspartic acid (and other N-protected amino acids), (R)-(+)-l ,l'-bi-s- napthol, (+)-camphoric acid, D-glucuronic acid, and derivatives thereof.
- Those believed to be useful for forming d-threo stereoisomers preferentially with respect to l-threo isomers include (+)-dibenzoyl-D-tartaric acid.
- Derivatives of D-(-)-tartaric acid are preferred, including those having formula (III): HO 2 CCH[OC(O)R 3 ]CH[OC(O)R 3 ]CO 2 H (III) where each R 3 , independently, is aryl having 6 to about 28 carbon atoms or aralkyl having 7 to about 28 carbon atoms.
- Aralkyl groups according to the invention are those (such as, for example, benzyl groups, which both aryl and alkyl portions and are covalently bound to a core molecule (such as the above-noted carbonyl-functionalized tartaric acid) through the alkyl
- the piperidyl acetamide stereoisomers having formulas Ila and lib are reacted with an acid resolving agent in an organic solvent to form acid salts of the l-threo stereoisomers preferentially with respect to the d-threo stereoisomers.
- Resolving agents believed to be useful for forming l-threo stereoisomers preferentially with respect to d-threo isomers include (-)-dibenzoyl-L-tartaric acid. Derivatives of L-(-)-tartaric acid are preferred, including those having formula (III). Crystallization preferably is performed at ambient temperature.
- the acid salts obtained via resolution typically are dissolved in water and treated with an aqueous base such as a carbonate, bicarbonate, or hydroxide to precipitate the corresponding piperidyl amide free base in substantially pure form. They then can be reacted with an alcohol having, for example, 1 to about 5 carbon atoms in the presence of acid to form the corresponding ester.
- an aqueous base such as a carbonate, bicarbonate, or hydroxide
- the reactor was charged with cone. H 2 SO 4 , and cooled to ⁇ 10°C.
- ⁇ -Phenyl-oc- pyridyl-(2)-acetonitrile (from Example I.A) was added portionwise, keeping the temperature below 30°C.
- the reaction was stirred at ambient temperature for 16h.
- the reaction mixture then was cooled to 10°C, at which point water was added.
- the NaOH then was added to a pH of 12, keeping the temperature below 30 °C.
- the resulting crystals were
- NH 4 OH can be substituted for NaOH to adjust the pH to 12.
- One advantage of using NH 4 OH is that the by-product that is formed (ammonium sulfate) is more soluble in water then the by-product (sodium sulfate) formed when NaOH is used as the base. Thus, the product crystals are less likely to be contaminated with inorganic salts.
- the reactor was charged with 2-chloropyridine, benzyl cyanide, and toluene (0.59 L).
- Sodium amide powder was added over a lh period via a solid-addition funnel, keeping the reaction temperature below 300 °C.
- the reaction mixture was stirred for 16h at ambient temperature.
- the reaction was cooled to ⁇ 10°C, and quenched with 0.52 L water.
- Ethyl acetate (0.26 L) was added to solubilize the precipitated product.
- the organic layer was separated and washed once with 0.26 L brine, and solvent was removed from the organic layer on a rotovap. Toluene (0. 10 L), followed by hexanes (0.94 L) were added to the resulting residue.
- the reactor was charged with 2-chloropyridine, benzyl cyanide, and toluene
- the reactor was charged with cone. H 2 SO 4 , and cooled to ⁇ 10°C.
- ⁇ -Phenyl- ⁇ - pyridyl-(2)-acetonitrile (from Example 3. A) was added portionwise, keeping the temperature below 30 °C.
- the reaction was stirred at ambient temperature for 16h.
- the reaction mixture then was cooled to 10°C, the water was added, and the NaOH was added to a pH of 12, keeping the temperature below 30°C.
- the resulting crystals were filtered, the filter cake was washed with water, and dried under vacuum to give 289 g (100%)) of ⁇ -phenyl- ⁇ -pyridyl-(2)-acetamide.
- Dibenzoyl-L-tartaric acid and (i,/-t/zre ⁇ - ⁇ -phenyl- ⁇ -piperidyl-(2)-acetamide (from Example 3.D) is dissolved in isopropanol by warming the reaction mixture to ⁇ 50°C.
- the resulting clear solution is stirred at ambient temperature for 16h, whereby the tartrate salt of /-t/zre ⁇ -acetamide crystallizes out.
- the crystals are filtered, and the filter cake washed with isopropanol and dried in a vacuum oven at 40 °C.
- This tartrate salt is added in portions to a stirred solution of 6N aq. HCl, and the resultant slurry is stirred at ambient temperature for 4h.
- the slurry is filtered, and the filter cake (containing free dibenzoyl-L-tartaric acid) is washed with water.
- Solid NaCl is added to the filtrate (which contains /-t/zre ⁇ -acetamide hydrochloride salt) and the mixture is cooled to ⁇ 10°C.
- the NaOH is added to this mixture to a pH of 12, whereby the free base of /- t/zre ⁇ -acetamide precipitates out.
- the precipitated crystals are filtered, washed with water and dried to give /-t zre ⁇ - -phenyl- ⁇ -piperidyl-(2)- acetamide.
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- Organic Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (7)
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DK98922398T DK0983238T3 (en) | 1997-05-22 | 1998-05-18 | Process and intermediates for cleavage of piperidylacetamide stereoisomers |
AT98922398T ATE273952T1 (en) | 1997-05-22 | 1998-05-18 | METHOD AND INTERMEDIATE PRODUCTS FOR SEPARATING PIPERIDYLACETAMIDE STEREOISOMERS |
DE69825746T DE69825746T2 (en) | 1997-05-22 | 1998-05-18 | Process and intermediates for the separation of piperidylacetamide stereoisomers |
CA002291170A CA2291170C (en) | 1997-05-22 | 1998-05-18 | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
AU74955/98A AU735353B2 (en) | 1997-05-22 | 1998-05-18 | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
EP98922398A EP0983238B1 (en) | 1997-05-22 | 1998-05-18 | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
JP55049098A JP4439595B2 (en) | 1997-05-22 | 1998-05-18 | Methods and intermediates for the separation of piperidylacetamide stereoisomers |
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US08/861,988 | 1997-05-22 | ||
US08/861,988 US5936091A (en) | 1997-05-22 | 1997-05-22 | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
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PCT/US1998/010131 WO1998052921A1 (en) | 1997-05-22 | 1998-05-18 | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
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EP (2) | EP0983238B1 (en) |
JP (1) | JP4439595B2 (en) |
AT (2) | ATE273952T1 (en) |
AU (1) | AU735353B2 (en) |
CA (1) | CA2291170C (en) |
CY (1) | CY1113023T1 (en) |
DE (1) | DE69825746T2 (en) |
DK (2) | DK1506961T3 (en) |
ES (2) | ES2226131T3 (en) |
HK (1) | HK1071895A1 (en) |
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US9233924B2 (en) | 2014-03-11 | 2016-01-12 | Ampac Fine Chemicals Llc | Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof |
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US5922736A (en) * | 1995-12-04 | 1999-07-13 | Celegene Corporation | Chronic, bolus administration of D-threo methylphenidate |
US5837284A (en) * | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
US6486177B2 (en) * | 1995-12-04 | 2002-11-26 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
US6962997B1 (en) * | 1997-05-22 | 2005-11-08 | Celgene Corporation | Process and intermediates for resolving piperidyl acetamide steroisomers |
US6395752B1 (en) * | 1999-03-04 | 2002-05-28 | Pharmaquest Limited | Method of treating depression using 1-threo-methylphenidate |
US6127385A (en) * | 1999-03-04 | 2000-10-03 | Pharmaquest Limited | Method of treating depression using l-threo-methylphenidate |
US20020187192A1 (en) * | 2001-04-30 | 2002-12-12 | Yatindra Joshi | Pharmaceutical composition which reduces or eliminates drug abuse potential |
US6638533B2 (en) | 2002-01-03 | 2003-10-28 | George Krsek | Pulse dosage formulations of methylphenidate and method to prepare same |
CH712083B1 (en) * | 2003-02-05 | 2017-07-31 | Siegfried Ag | Process for the preparation of d-threo-2-phenyl-2-piperidin-2-yl-acetic acid esters. |
US20050239830A1 (en) * | 2004-04-26 | 2005-10-27 | Vikram Khetani | Methods of diminishing co-abuse potential |
EP1830648A4 (en) * | 2004-12-09 | 2008-03-12 | Celgene Corp | Treatment using d-threo methylphenidate |
CN101786982A (en) * | 2010-03-30 | 2010-07-28 | 华东师范大学 | Method for synthetizing 2-pyridyl benzyl cyanide |
ES2542433T3 (en) | 2010-12-17 | 2015-08-05 | Rhodes Technologies | Synthesis at low temperature of methylphenidate hydrochloride |
EP3484850A4 (en) | 2016-07-18 | 2019-12-11 | Harman Finochem Limited | An improved process for the preparation of dexmethyl phenidate hydrochloride |
CN115322141B (en) * | 2022-09-01 | 2024-04-16 | 凯特立斯(深圳)科技有限公司 | Method for preparing chiral methylphenidate compound through asymmetric hydrogenation |
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US2507631A (en) * | 1944-01-19 | 1950-05-16 | Ciba Pharm Prod Inc | Pyridine and piperidine compounds and process of making same |
US2957880A (en) * | 1953-12-23 | 1960-10-25 | Ciba Pharm Prod Inc | Process for the conversion of stereoisomers |
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Cited By (2)
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US9233924B2 (en) | 2014-03-11 | 2016-01-12 | Ampac Fine Chemicals Llc | Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof |
US9573896B2 (en) | 2014-03-11 | 2017-02-21 | Ampac Fine Chemicals Llc | Methods for preparing d-threo-methylphenidate using diazomethane, and compositions thereof |
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EP1506961B1 (en) | 2012-02-22 |
PT983238E (en) | 2004-10-29 |
EP0983238A4 (en) | 2001-08-08 |
HK1071895A1 (en) | 2005-08-05 |
ES2381361T3 (en) | 2012-05-25 |
US5936091A (en) | 1999-08-10 |
CY1113023T1 (en) | 2016-04-13 |
JP4439595B2 (en) | 2010-03-24 |
CA2291170A1 (en) | 1998-11-26 |
DK0983238T3 (en) | 2004-11-29 |
EP0983238B1 (en) | 2004-08-18 |
ATE273952T1 (en) | 2004-09-15 |
JP2002515066A (en) | 2002-05-21 |
ES2226131T3 (en) | 2005-03-16 |
DK1506961T3 (en) | 2012-05-21 |
EP1506961A3 (en) | 2007-01-03 |
AU735353B2 (en) | 2001-07-05 |
EP1506961A2 (en) | 2005-02-16 |
PT1506961E (en) | 2012-05-07 |
CA2291170C (en) | 2008-09-16 |
EP0983238A1 (en) | 2000-03-08 |
DE69825746T2 (en) | 2005-08-18 |
ATE546429T1 (en) | 2012-03-15 |
AU7495598A (en) | 1998-12-11 |
DE69825746D1 (en) | 2004-09-23 |
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