HRP20100239T1 - Poboljšana šema sinteze za lakozamid - Google Patents
Poboljšana šema sinteze za lakozamid Download PDFInfo
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- HRP20100239T1 HRP20100239T1 HR20100239T HRP20100239T HRP20100239T1 HR P20100239 T1 HRP20100239 T1 HR P20100239T1 HR 20100239 T HR20100239 T HR 20100239T HR P20100239 T HRP20100239 T HR P20100239T HR P20100239 T1 HRP20100239 T1 HR P20100239T1
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- Prior art keywords
- compound
- substituted
- unsubstituted
- formula
- methoxypropionamide
- Prior art date
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- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 title claims abstract 13
- 229960002623 lacosamide Drugs 0.000 title claims abstract 9
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract 33
- 150000001875 compounds Chemical class 0.000 claims abstract 15
- 238000007069 methylation reaction Methods 0.000 claims abstract 8
- 238000006243 chemical reaction Methods 0.000 claims abstract 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract 5
- 239000012071 phase Substances 0.000 claims 10
- 230000007704 transition Effects 0.000 claims 10
- 229910052757 nitrogen Inorganic materials 0.000 claims 9
- 125000005842 heteroatom Chemical group 0.000 claims 8
- 229910052760 oxygen Inorganic materials 0.000 claims 8
- 229910052717 sulfur Inorganic materials 0.000 claims 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 6
- WPLANNRKFDHEKD-SNVBAGLBSA-N Descarbonyl-lacosamide Chemical compound COC[C@@H](N)C(=O)NCC1=CC=CC=C1 WPLANNRKFDHEKD-SNVBAGLBSA-N 0.000 claims 5
- 239000007864 aqueous solution Substances 0.000 claims 5
- 150000002900 organolithium compounds Chemical class 0.000 claims 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 4
- 238000006555 catalytic reaction Methods 0.000 claims 4
- -1 hexafluoroantimonate Chemical group 0.000 claims 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims 3
- 125000003118 aryl group Chemical group 0.000 claims 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 3
- 239000012022 methylating agents Substances 0.000 claims 3
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 2
- 239000012190 activator Substances 0.000 claims 2
- 239000008346 aqueous phase Substances 0.000 claims 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 230000011987 methylation Effects 0.000 claims 2
- 238000005580 one pot reaction Methods 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 2
- FHOAKXBXYSJBGX-RXMQYKEDSA-N (2r)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](CO)C(O)=O FHOAKXBXYSJBGX-RXMQYKEDSA-N 0.000 claims 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims 1
- 229930195711 D-Serine Natural products 0.000 claims 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 229910006069 SO3H Inorganic materials 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims 1
- 238000006640 acetylation reaction Methods 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000001718 carbodiimides Chemical class 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 239000000945 filler Substances 0.000 claims 1
- 150000004820 halides Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Chemical group SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical group OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 235000010755 mineral Nutrition 0.000 claims 1
- 239000012074 organic phase Substances 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical group OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 235000011181 potassium carbonates Nutrition 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/10—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Postupak za proizvodnju (R)-2-acetamido-N-benzil-3-metoksipropionamida (lakozamida) koji sadrži O-metilaciju spoja formule Ida bi se proizveo spoj formule IIu kojoj je Rx - N-zaštitna grupa, naznačen time štose O-metilacija izvodi u reakciji od jednog koraka i pri čemu se spoj formule II dobija kao R-enantiomer čistoće od najmanje 88% ipostupak se izvodi ili (a) kao kataliza faznog prelaza ili (b) dodavanjem metilacijskog sredstva i organo litijkog spoja spoju formule I. Patent sadrži još 28 patentnih zahtjeva.
Claims (29)
1. Postupak za proizvodnju (R)-2-acetamido-N-benzil-3-metoksipropionamida (lakozamida) koji sadrži O-metilaciju spoja formule I
[image]
da bi se proizveo spoj formule II
[image]
u kojoj je Rx - N-zaštitna grupa,
naznačen time što
se O-metilacija izvodi u reakciji od jednog koraka i pri čemu se spoj formule II dobija kao R-enantiomer čistoće od najmanje 88% i
postupak se izvodi ili (a) kao kataliza faznog prelaza ili (b) dodavanjem metilacijskog sredstva i organo litijkog spoja spoju formule I.
2. Postupak prema patentnom zahtjevu 1, naznačen time što taj postupak sadrži dodavanje metilacijskog sredstva u reakcijski sustav faznog prelaza koji sadrži spoj formule I, vodenu fazu, organsku fazu i katalizator faznog prelaza.
3. Postupak prema patentnom zahtjevu 2, naznačen time što se kao katalizator faznog prelaza koristi piridinij, fosfonij, amonij ili sulfonijeva sol.
4. Postupak prema bilo kojem od patentnih zahtjeva 2-3, naznačen time što je katalizator faznog prelaza izabran od spojeva:
(a) opće formule IV
[image]
(b) opće formule V
[image]
ili
(c) opće formule VI
[image]
u kojima
R, R’, R" i R"’, ako su prisutni, nezavisno se mogu izabrati od alkil, aril ili aralkil grupa;
Q, u spojevima formule IV, je dušik ili fosfor; i
X je halid, acetat, p-toluensulfonat, trifluorometansulfonat, heksafluoroantimonat, hidroksid, perhlorat, hidrogensulfat, tiocijanat ili tetrafluoroborat grupa.
5. Postupak prema bilo kojem od patentnih zahtjeva 2-4, naznačen time što je katalizator faznog prelaza tetrabutilamonijev bromid.
6. Postupak prema bilo kojem od patentnih zahtjeva 2-5, naznačen time što je metilacijsko sredstvo koje se koristi u katalizi faznog prelaza izabrano od dimetil sulfata, trimetil fosfata ili metil jodida.
7. Postupak prema bilo kojem od patentnih zahtjeva 2-6, naznačen time što je vodena faza vodena otopina natrijeva hidroksida, vodena otopina litijeva hidroksida, vodena otopina kalijeva hidroksida, vodena otopina natrijeva katbonata ili vodena otopina kalijeva karbonata.
8. Postupak prema bilo kojem od patentnih zahtjeva 2-7, naznačen time što je organski otapalo toluen, heksan, metilen klorid ili metil t-butil eter.
9. Postupak prema bilo kojem od patentnih zahtjeva 1-8, naznačen time što se kataliza faznog prelaza izvodi na 0- najmanje 30 minuta.
10. Postupak prema patentnom zahtjevu 1, naznačen time što je metilacijski spoj kojt se koristi sa organo litijevim spojem - dimetilsulfat.
11. Postupak prema bilo kojem od patentnih zahtjeva 1 ili 10, naznačen time što je organolitijski spoj butil litij.
12. Postupak prema patentnim zahtjevima 1 ili 10 do 11, naznačen time što se O-metilacija u prisustvu organolitijevog spoja odigrava na temperaturi od 0- najmanje 5 sati.
13. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što dalje sadrži reakciju spoja II sa benzilaminom da bi se dobio spoj formule III,
[image]
i zatim zamjenu zaštitne grupe Rx sa metil karbonilom da bi se dobio (R)-2-acetamido-N-benzil-3-metoksipropionamid (lakozamid).
14. Postupak prema patentnom zahtjevu 13, naznačen time što se reakcija spoja formule II sa benzilaminom odigrava u prisustvu aktivatora karboksil grupe i baze.
15. Postupak prema patentnom zahtjevu 14, naznačen time što je baza 4-metilmorfolin, trietilamin, diizopropiletilamin, 1.8-diazabiciklo[5.4.0]undec-7-en ili kalijey bikarbonat i aktivator karboksil grupe je alkil hloroformiat ili karbodiimid.
16. Postupak prema bilo kojem od patentnih zahtjeva 13-15, naznačen time što je N-zaštitna grupa Rx zamijenjena sa metil karbonilom putem uzastopnog
(a) odvajanja zaštitne grupe Rx od spoja formule III dodavanjem (i) mineralne kiseline ili (ii) H2/Pd-C da bi se proizveo (R)-2-amino-N-benzil-3-metoksipropionamid i zatim
(b) dodavanja metil karbonil grupe u (R)-2-amino-N-benzil-3-metoksipropionamid reakcijom (R)-2-amino-N-benzil-3-metoksipropionamida sa anhidridom octene kiseline.
17. Postupak prema patentnom zahtjevu 16, naznačen time što se korak (b) izvodi u odsustvu piridina.
18. Postupak prema bilo kojem od patentnih zahtjeva 13-15, naznačen time što je N-zaštitna grupa Rx odvojena da bi se dobio (R)-2-amino-N-benzil-3-metoksipropionamid.
19. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što je lakozamid izoliran iz krajnje reakcijske smjese kristalizacijom.
20. Postupak prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što je N-zaštitna grupa - t-butiloksi karbonil (Boc).
21. Postupak prema bilo kojem od prethodnih patentnih zahtjeva naznačen time što sadrži korak N-acetilacije (R)-2-amino-N-benzil-3-metoksipropionamida sa anhidridom octene kiseline u odsustvu baze, posebno u odsustvu piridina.
22. Postupak prema bilo kojem od prethodnih patentnih zahtjeva naznačen time što je spoj formule II - (R)-2-N-Boc-amino-3-metoksipropionska kiselina (C-936) ili njene soli.
23. Postupak prema bilo kojem od patentnih zahtjeva 13-18, naznačen time što je spoj formule III - (R)-N-benzil-2-N-Boc-amino-3-metoksipropionamid (C-937) ili bilo koja njegova sol.
24. Primjena (R)-N-benzil-2-N-Boc-amino-3-metoksipropionamida (C-937) ili bilo koje njegove soli u postupku prema patentnim zahtjevima 1 do 22, naznačen time što se koristi za proizvodnju (R)-2-acetamido-N-benzil-3-metoksipropionamida (lakozamid).
25. Postupak za proizvodnju farmaceutske formulacije koja sadrži lakozamid, naznačen time što se vrši putem uzastopnih koraka:
(a) proizvodnje lakozamida prema bilo kojem od patentnih zahtjeva 1 do 22 i
(b) miješanja lakozamida sa farmaceutski prihvatljivim inertnim puniteljima.
26. Postupak prema bilo kojem od patentnih zahtjeva 1 do 22, naznačen time što dodatno sadrži proizvodnju N-Boc-D-serina reakcijom D-serina sa di-t-butil dikarbonatom u reakciji faznog prelaza.
27. Postupak za proizvodnju spoja formule VIII, koji sadrži O-metilaciju spoja formule VII,
[image]
da bi se proizveo spoj formule VIII,
[image]
pri čemu su R1, R2 i R3 nezavisno su izabrani iz grupe koju čine vodik, -OH, -SH, -NH2, -NO2, -CN, -COOH, -SOH, -SO2H, -SO3H, halogen, -OR10, -SR10, -NR10R11, -SOR10, -SO2R10, -SO3R10, supstituirani ili nesupstituirani alkil, supstituirani ili nesupstituirani C2-C6-alkenil, supstituirani ili nesupstituirani C2-C6-alkinil, -(CO)-R10, -(CO)-O-R10, -O-(CO)-R10, supstituirani ili nesupstituirani aril, supstituirani ili nesupstituirani C3-C13-hetaril koji ima 1-3 heteroatoma nezavisno izabrana od N, S, O, supstituirani ili nesupstituirani aralkil, supstituirani ili nesupstituirani C7-C15-alkaril, supstituirani ili nesupstituirani C4-C14-hetaralkil koji ima 1-3 heteroatoma nezavisno izabrana od N, S, O; supstituirani ili nesupstituirani C4-C14-alkhetaril koji ima 1-3 heteroatoma nezavisno izabrana od N, S, O; i supstituirani ili nesupstituirani C3-C12-cikloalkil koji ima 0-3 heteroatoma nezavisno izabrana od N, S, O, pri čemu je R4 izabran od R1 i N-zaštitnih grupa i pri čemu su R10 i R11 nezavisno izabrani iz grupe koju čine vodik, supstituirani ili nesupstituirani alkil, supstituirani ili nesupstituirani C2-C6-alkenil, supstituirani ili nesupstituirani C2-C6-alkinil, supstituirani ili nesupstituirani aril, supstituirani ili nesupstituirani C3-C13-hetaril koji ima 1-3 heteroatoma nezavisno izabrana od N, S, O, supstituirani ili nesupstituirani aralkil, supstituirani ili nesupstituirani C7-C15-alkaril, supstituirani ili nesupstituirani C4-C14-hetaralkil koji ima 1-3 heteroatoma nezavisno izabrana od N, S, O; supstituirani ili nesupstituirani C4-C14-alkhetaril koji ima 1-3 heteroatoma nezavisno izabrana od N, S, O; i supstituirani ili nesupstituirani C3-C12-cikloalkil koji ima 0-3 heteroatoma nezavisno izabrana od N, S, O,
naznačen time što se O-metilacija izvodi u reakciji od jednog koraka pri čemu se spoj formule VIII dobija u istoj konfiguraciji kao spoj VII u najmanje 88% čistoće i postupak se izvodi ili (a) kao kataliza faznog prelaza ili (b) dodavanjem sredstva za metilaciju i organolitijumskog spoja spoju formule VII.
28. Postupak prema patentnom zahtjevu 27, naznačen time što je R1 jednako H, R2 je H, R3 je H i R4 je N-zaštitna grupa.
29. Postupak prema bilo kojem od patentnih zahtjeva 27 ili 28, naznačen time što je spoj VII u R-konfiguraciji.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| EP04023556A EP1642889A1 (en) | 2004-10-02 | 2004-10-02 | Improved synthesis scheme for lacosamide |
| PCT/EP2005/010603 WO2006037574A1 (en) | 2004-10-02 | 2005-09-30 | Improved synthesis scheme for lacosamide |
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| Publication Number | Publication Date |
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| HRP20100239T1 true HRP20100239T1 (hr) | 2010-06-30 |
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ID=34926827
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| Application Number | Title | Priority Date | Filing Date |
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| HR20100239T HRP20100239T1 (hr) | 2004-10-02 | 2010-04-26 | Poboljšana šema sinteze za lakozamid |
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| US (2) | US7884134B2 (hr) |
| EP (2) | EP1642889A1 (hr) |
| JP (1) | JP5128281B2 (hr) |
| KR (1) | KR101246169B1 (hr) |
| CN (2) | CN1989102B (hr) |
| AT (1) | ATE457975T1 (hr) |
| AU (1) | AU2005291456B2 (hr) |
| BR (1) | BRPI0516735B8 (hr) |
| CA (1) | CA2570598C (hr) |
| CY (1) | CY1109994T1 (hr) |
| DE (1) | DE602005019437D1 (hr) |
| DK (1) | DK1799635T3 (hr) |
| EA (1) | EA012588B1 (hr) |
| ES (1) | ES2341470T3 (hr) |
| HR (1) | HRP20100239T1 (hr) |
| IL (1) | IL180479A (hr) |
| MX (1) | MX2007001253A (hr) |
| NO (1) | NO336765B1 (hr) |
| NZ (1) | NZ552076A (hr) |
| PL (1) | PL1799635T3 (hr) |
| SI (1) | SI1799635T1 (hr) |
| UA (1) | UA95600C2 (hr) |
| WO (1) | WO2006037574A1 (hr) |
| ZA (1) | ZA200610000B (hr) |
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| US20070048372A1 (en) * | 2005-08-18 | 2007-03-01 | Srz Properties, Inc. | Method for treating non-inflammatory osteoarthritic pain |
| EP1754476A1 (en) * | 2005-08-18 | 2007-02-21 | Schwarz Pharma Ag | Lacosamide (SPM 927) for treating myalgia, e.g. fibromyalgia |
| US20070043120A1 (en) * | 2005-08-18 | 2007-02-22 | Bettina Beyreuther | Therapeutic combination for painful medical conditions |
| EP1873527A1 (en) * | 2006-06-30 | 2008-01-02 | Schwarz Pharma Ag | Method for identifying CRMP modulators |
| CN101466390B (zh) * | 2006-06-15 | 2014-03-12 | 优时比制药有限公司 | 用于治疗难治性癫痫持续状态的肽类化合物 |
| EP2037965B1 (en) * | 2006-06-15 | 2017-08-30 | UCB Pharma GmbH | Pharmaceutical composition with synergistic anticonvulsant effect |
| WO2009053070A1 (en) * | 2007-10-23 | 2009-04-30 | Schwarz Pharma Ag | Compounds for treating demyelination conditions |
| EP2468261A1 (en) * | 2010-12-02 | 2012-06-27 | UCB Pharma GmbH | Formulation of lacosamide |
| AU2011335415B2 (en) * | 2010-12-02 | 2016-05-19 | Ucb Pharma Gmbh | Once daily formulation of lacosamide |
-
2004
- 2004-10-02 EP EP04023556A patent/EP1642889A1/en not_active Withdrawn
-
2005
- 2005-09-30 CN CN2005800241755A patent/CN1989102B/zh not_active Expired - Fee Related
- 2005-09-30 AU AU2005291456A patent/AU2005291456B2/en not_active Ceased
- 2005-09-30 ES ES05794396T patent/ES2341470T3/es active Active
- 2005-09-30 BR BRPI0516735A patent/BRPI0516735B8/pt not_active IP Right Cessation
- 2005-09-30 MX MX2007001253A patent/MX2007001253A/es active IP Right Grant
- 2005-09-30 DE DE602005019437T patent/DE602005019437D1/de active Active
- 2005-09-30 NZ NZ552076A patent/NZ552076A/en not_active IP Right Cessation
- 2005-09-30 EA EA200700746A patent/EA012588B1/ru not_active IP Right Cessation
- 2005-09-30 WO PCT/EP2005/010603 patent/WO2006037574A1/en active Application Filing
- 2005-09-30 PL PL05794396T patent/PL1799635T3/pl unknown
- 2005-09-30 AT AT05794396T patent/ATE457975T1/de active
- 2005-09-30 CA CA2570598A patent/CA2570598C/en not_active Expired - Fee Related
- 2005-09-30 KR KR1020077002247A patent/KR101246169B1/ko active IP Right Grant
- 2005-09-30 DK DK05794396.1T patent/DK1799635T3/da active
- 2005-09-30 CN CN2010101835217A patent/CN101928230B/zh not_active Expired - Fee Related
- 2005-09-30 JP JP2007533955A patent/JP5128281B2/ja active Active
- 2005-09-30 US US11/664,316 patent/US7884134B2/en not_active Expired - Fee Related
- 2005-09-30 UA UAA200704328A patent/UA95600C2/ru unknown
- 2005-09-30 SI SI200530992T patent/SI1799635T1/sl unknown
- 2005-09-30 EP EP05794396A patent/EP1799635B1/en active Active
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2006
- 2006-11-30 ZA ZA200610000A patent/ZA200610000B/xx unknown
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- 2007-01-01 IL IL180479A patent/IL180479A/en active IP Right Grant
- 2007-04-30 NO NO20072250A patent/NO336765B1/no not_active IP Right Cessation
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- 2010-04-30 CY CY20101100383T patent/CY1109994T1/el unknown
- 2010-12-07 US US12/961,705 patent/US8809585B2/en active Active
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