HRP20231308T1 - Postupak za proizvodnju ozanimoda - Google Patents
Postupak za proizvodnju ozanimoda Download PDFInfo
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- HRP20231308T1 HRP20231308T1 HRP20231308TT HRP20231308T HRP20231308T1 HR P20231308 T1 HRP20231308 T1 HR P20231308T1 HR P20231308T T HRP20231308T T HR P20231308TT HR P20231308 T HRP20231308 T HR P20231308T HR P20231308 T1 HRP20231308 T1 HR P20231308T1
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- 238000000034 method Methods 0.000 title claims 15
- XRVDGNKRPOAQTN-FQEVSTJZSA-N 5-[3-[(1s)-1-(2-hydroxyethylamino)-2,3-dihydro-1h-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile Chemical compound C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C=2C=3CC[C@@H](C=3C=CC=2)NCCO)=NO1 XRVDGNKRPOAQTN-FQEVSTJZSA-N 0.000 title claims 7
- 229950008141 ozanimod Drugs 0.000 title claims 7
- 238000004519 manufacturing process Methods 0.000 title claims 2
- -1 benzyloxymethyl Chemical group 0.000 claims 46
- 150000001875 compounds Chemical class 0.000 claims 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 9
- 239000000203 mixture Substances 0.000 claims 9
- 239000003960 organic solvent Substances 0.000 claims 8
- 125000006239 protecting group Chemical group 0.000 claims 8
- 239000002904 solvent Substances 0.000 claims 8
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims 8
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical class COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 7
- 230000002378 acidificating effect Effects 0.000 claims 7
- 239000002585 base Substances 0.000 claims 7
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 7
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims 6
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 6
- 150000008064 anhydrides Chemical class 0.000 claims 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 4
- 239000007864 aqueous solution Substances 0.000 claims 4
- 239000011541 reaction mixture Substances 0.000 claims 4
- 150000003839 salts Chemical class 0.000 claims 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 3
- 239000003849 aromatic solvent Substances 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 150000007530 organic bases Chemical class 0.000 claims 3
- 239000008096 xylene Substances 0.000 claims 3
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims 2
- RTCVLCCTDCZTLE-UHFFFAOYSA-N 3-cyano-4-propoxybenzoic acid Chemical compound CCCOC1=CC=C(C(O)=O)C=C1C#N RTCVLCCTDCZTLE-UHFFFAOYSA-N 0.000 claims 2
- 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 class 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 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- 238000009835 boiling Methods 0.000 claims 2
- 150000001718 carbodiimides Chemical class 0.000 claims 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- LCFXLZAXGXOXAP-QPJJXVBHSA-N ethyl (2e)-2-cyano-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=N\O)\C#N LCFXLZAXGXOXAP-QPJJXVBHSA-N 0.000 claims 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims 2
- 239000000243 solution Substances 0.000 claims 2
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 claims 1
- HAOOCAKHSFYDBU-BDQAORGHSA-N 5-[3-[(1s)-1-(2-hydroxyethylamino)-2,3-dihydro-1h-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile;hydrochloride Chemical compound Cl.C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C=2C=3CC[C@@H](C=3C=CC=2)NCCO)=NO1 HAOOCAKHSFYDBU-BDQAORGHSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 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 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 230000004913 activation Effects 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 239000013078 crystal Substances 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000012074 organic phase Substances 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000012266 salt solution Substances 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 239000012047 saturated solution Substances 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- 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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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Claims (15)
1. Postupak za proizvodnju formula
[image]
ozanimoda ili njegovih kiselinskih adicijskih soli, naznačen time što se zaštitna skupina ili skupine koje se mogu ukloniti u kiselom mediju uklanjaju u organskom otapalu iz
a.) spoja opće formule
[image]
u kojoj R predstavlja zaštitnu skupinu koja se može ukloniti u kiselom mediju koji služi za privremenu zaštitu hidroksilne skupine, ili
b.) iz spoja formule
[image]
ili
c.)
iz smjese bilo kojeg omjera spoja opće formule (IV) i spoja formule (V), i formule (I); ozanimod dobiven na ovaj način se po izboru transformira u kiselinsku adicijsku sol.
2. Postupak prema zahtjevu 1, naznačen time što spojevi tipa supstituiranog metil etera, poželjno metoksimetil, benziloksimetil, p-metoksibenziloksimetil ili [(3,4-dimetoksibenzil)oksi] metil skupine, tetrahidropiranil skupine ili skupine tipa supstituiranog etil etera, po mogućnosti etoksietil, ili 1-[2-(trimetilsilil)etoksi]etil skupine, skupine sililnog tipa, po mogućnosti trimetilsilil, triizopropilsilil, t-butildimetilsilil ili trifenilsilil skupine, koriste se kao zaštitne skupine koje se mogu ukloniti u kiselom mediju koji služi za privremenu zaštitu hidroksilne skupine u spoju opće formule (IV).
3. Postupak prema bilo kojem od zahtjeva 1 ili 2, naznačen time što se koristi otapalo eterskog tipa, poželjno dioksan, alkohol s 1 do 4 atoma ugljika, poželjno 2-propanol, etanol ili metanol, najpoželjnije 2-propanol, ili aromatsko otapalo, poželjno toluen ili ksilen, poželjnije da se toluen koristi kao organsko otapalo, i/ili naznačen time da se kiselina koristi za cijepanje zaštitne skupine koja se može ukloniti u kiselom mediju koji služi za privremenu zaštitu hidroksilne skupine, po mogućnosti vodena otopina solne kiseline, klorovodična kiselina, bromovodik, jodovodik, fluorovodik (HF), sumporna kiselina, dušična kiselina ili njihove soli, tetrabutilamonijev fluorid (TBAF), smjesa TBAF i octene kiseline, vodena smjesa HF i THF, ili 1 M vodeni HIO4 otopljen u THF, pri čemu se kiselina poželjno koristi u vodenoj otopini, u smjesi organskog otapala i vode ili otopljena u otapalu, poželjno upotrebom dioksana, 2-propanola, etanola ili metanola, poželjno 2-propanola, etanol ili metanol, najpoželjnije 2-propanol kao otapalo.
4. Postupak prema bilo kojem od zahtjeva 1 do 3, naznačen time da se proizvodi spoj opće formule
[image]
u kojoj R predstavlja zaštitnu skupinu koja se može ukloniti u kiselom mediju služeći za privremenu zaštitu hidroksilne skupine, po mogućnosti skupine tipa supstituiranog metil etera, poželjnije metoksimetila, benziloksimetila, p-metoksibenziloksimetila ili [(3,4 -dimetoksibenzil)oksi]metil skupine, tetrahidropiranil skupine, ili supstituirane etil eterske skupine, poželjno etoksietil, ili 1-[2-(trimetilsilil)etoksi]etil skupine, skupine sililnog tipa, poželjno trimetilsilil, triizopropilsilil, t-butildimetilsilil ili trifenilsilil skupine, najpoželjnije t-butildimetilsilil skupine, ili spoja formule (V), ili smjese spoja opće formule (IV) i spoja formule (V) provodi se tako da
a.) spoj opće formule
[image]
3-cijano-4-(i-propiloksi)benzojeva kiselina se aktivira u organskom otapalu, zatim reagira sa spojem opće formule
[image]
u kojoj spoj R predstavlja zaštitnu skupinu koja se može ukloniti u kiselom mediju služeći za privremenu zaštitu hidroksilne skupine, poželjno skupine tipa supstituiranog metil etera, poželjnije metoksimetil, benziloksimetil, p-metoksibenziloksimetil ili [(3,4-dimetoksibenzil)oksi]metil skupine, tetrahidropiranil skupine ili skupine tipa supstituiranog etil etera, poželjno etoksietil, ili 1-[2-(trimetilsilil)etoksi]etil skupine, skupine sililnog tipa, poželjno trimetilsilil, triizopropilsilil, t-butildimetilsililne ili trifenilsililne skupine, najpoželjnije t-butildimetilsililne skupine, zatim po izboru
b.) dobiveni spoj opće formule (IV) i spoj formule (V) su međusobno izolirani.
5. Postupak prema zahtjevu 4, naznačen time što se kao otapala koriste amid, poželjno dimetilformamid, aromatska, poželjno ksilen ili toluen, najpoželjnije toluen, eter, poželjno tetrahidrofuran ili dioksan, ester, nitril, poželjno acetonitril, ili sulfoksid, poželjno da se koristi tip otapala dimetil sulfoksida kao organsko otapalo, po mogućnosti toluen ili otapala tipa estera, najpoželjnije se koristi etil acetat kao organsko otapalo, i/ili
naznačen time što je benzojeva kiselina formule (VIII) poželjno aktivirana disupstituiranim karbodiimidom, poželjno dicikloheksilkarbodiimidom, 1-etil-3-(3-dimetilaminopropil)karbodiimidom u prisutnosti organske baze, poželjnije u prisutnosti DIPEA, TEA, ili s karbonil-diimidazolom u prisutnosti hidroksibenzotriazola ili etil cijano glioksilat-2-oksima, ili s anhidridom propanfosfonske kiseline (T3P), najpoželjnije aktiviranim s anhidridom propanfosfonske kiseline (T3P).
6. Postupak prema bilo kojem od zahtjeva 4 do 5, naznačen time što se spojevi opće formule (IV) ili (V), ili njihova smjesa pretvaraju u ozanimod bez izolacije, ili bilo kakvog daljnjeg pročišćavanja.
7. Postupak prema zahtjevu 6, naznačen time što spoj opće formule (III), poželjno spoj opće formule (III/A) reagira sa spojem formule (VIII) u aromatskom otapalu, poželjno toluenu ili ksilenu, najpoželjnije toluenu, tako da se spoj formule (VIII) poželjno aktivira disupstituiranim karbodiimidom, poželjno dicikloheksilkarbodiimidom, 1-etil-3-(3-dimetilaminopropil)karbodiimidom u prisutnosti organske baze, poželjnije u prisutnosti DIPEA, TEA, ili s karbonil-diimidazolom u prisutnosti hidroksibenzotriazola ili etil cijano glioksilat-2-oksima, ili s anhidridom propanfosfonske kiseline (T3P), najpoželjnije s anhidridom propanfosfonske kiseline (T3P), zatim nakon što reakcija završi, reakcijska smjesa se ispere ako je potrebno s vodenom bazom i/ili zasićenom otopinom soli, zatim se koncentrirana klorovodična kiselina doda u aromatsko otapalo, poželjno otopinu toluena i istaloženi ozanimod hidroklorid se izolira, i po izboru pročisti.
8. Postupak prema zahtjevu 7, naznačen time što se spoj opće formule (III), poželjno spoj formule (III/A) i spoj formule (VIII), baza i reagensi za aktiviranje pomiješaju na temperaturi između 20 °C. -30 °C, poželjno između 20-25 °C, tada se temperatura reakcijske smjese podigne poželjno između 60 °C i vrelišta otapala, poželjno između 65-100 °C, najpoželjnije između 80-85 °C i održava se na toj temperaturi dok reakcija ne završi, zatim se reakcijska smjesa ohladi i zatim, ako je potrebno, ispere vodenom otopinom lužine, po mogućnosti otopinom natrijevog ili kalijevog hidrokarbonata, i ako je potrebno, zasićenom otopinom natrijevog klorida, tada organska faza reagira s koncentriranom vodenom otopinom klorovodične kiseline (37%) poželjno na temperaturi između 60 °C i vrelišta otapala, poželjno između 65-85 °C, najpoželjnije između 70-75 °C, zatim se nakon toga reakcijska smjesa ohladi, istaloženi kristali se odfiltriraju, osuše i po izboru transformiraju u bazu.
9. Postupak prema bilo kojem od zahtjeva 1 do 8, naznačen time što se ozanimod taloži u obliku hidrokloridne soli, a kristalni ozanimod se transformira u bazu.
10. Postupak prema bilo kojem od zahtjeva 4 do 6, naznačen time što se spoj opće formule (III) korišten u postupku, u kojoj je formula R definirana kao u zahtjevu 4 i najpoželjnije predstavlja t-butildimetilsililnu skupinu, proizvodi se tako da spoj opće formule
[image]
u kojem je R definiran kao u zahtjevu 4 i najpoželjnije predstavlja t-butildimetilsililnu skupinu, reagira s hidroksilamin hidrokloridom u organskom otapalu u prisutnosti baze i/ili je naznačen time da se proizvodi derivat opće formule (III) iz spoja formule (VI) na takav način da međuprodukt opće formule (II) nije izoliran.
11. Postupak prema zahtjevu 10, naznačen time što se spoj opće formule (II) proizvodi tako da spoj formule
[image]
reagira s bazom u organskom otapalu, zatim reagira sa spojem formule
[image]
u kojoj je formula R definirana kao u zahtjevu 4, poželjno t-butildimetilsilil skupina, a X predstavlja Cl, Br ili I, najpoželjnije (2-bromoetoksi)-t-butildimetilsilan reagira kao spoj (VII).
12. Postupak prema zahtjevu 1, naznačen time što
a.) spoj ili spojevi opće formule
[image]
u kojoj R predstavlja t-butildimetilsililnu skupinu, ili
b.) spoj formule
[image]
ili
c.) smjesa u bilo kojem omjeru spoja opće formule (IV) (R predstavlja t-butildimetilsililnu skupinu) i spoj formule (V) reagira u alkoholu s 1 do 4 atoma ugljika, poželjno 2-propanola, s anorganskom kiselinom, poželjno klorovodičnom kiselinom i dobiveni ozanimod se po izboru transformira u sol, poželjno hidrokloridnu sol.
13. Postupak prema zahtjevu 1, naznačen time što spoj opće formule (IV), u kojoj R predstavlja skupinu tipa supstituiranog metil etera, poželjnije metoksimetil, benziloksimetil, p-metoksibenziloksimetil ili [(3,4-dimetoksibenzil)oksi ]metil skupinu, tetrahidropiranil skupinu ili skupinu tipa supstituiranog etil etera, poželjno etoksietil, ili 1-[2-(trimetilsilil)etoksi]etil skupinu, skupinu sililnog tipa, poželjno trimetilsilil, triizopropilsilil, t-butildimetilsilil ili trifenilsilil skupinu, najpoželjnije t-butildimetilsilil skupinu, ili spoj formule (V) ili se smjesa istih proizvodi tako da
a.) spoj formule
[image]
reagira u organskom dimetilformamidu koristeći natrijev hidrid kao bazu sa spojem formule
[image]
u kojoj R predstavlja skupinu tipa supstituiranog metil etera, poželjnije metoksimetil, benziloksimetil, p-metoksibenziloksimetil ili [(3,4-dimetoksibenzil)oksi]metil skupinu, tetrahidropiranil skupinu ili skupinu tipa supstituiranog etil etera, po mogućnosti etoksietil, ili 1-[2-(trimetilsilil)etoksi]etil skupina, skupina sililnog tipa, poželjno trimetilsilil, triizopropilsilil, t-butildimetilsilil ili trifenilsilil skupina, najpoželjnije t-butildimetilsilil skupina, X predstavlja Cl, Br ili I, zatim
b.) dobiveni spoj formule
[image]
u kojoj R predstavlja skupinu tipa supstituiranog metil etera, poželjnije metoksimetil, benziloksimetil, p-metoksibenziloksimetil ili [(3,4-dimetoksibenzil)oksi]metil skupinu, tetrahidropiranil skupinu ili skupinu tipa supstituiranog etil etera, poželjno etoksietilnu ili 1-[2-(trimetil silil)etoksi] etilnu skupinu, skupinu sililnog tipa, poželjno trimetilsililnu, triizopropilsililnu, t-butildimetilsililnu ili trifenilsililnu skupinu, najpoželjnije t-butildimetilsililnu skupinu, reagira s hidroksilamin hidrokloridom u alkoholu s 1 do 4 atoma ugljika, poželjno etanolu u prisutnosti trietilamina kao organske baze, zatim
c.) dobiveni spoj opće formule
[image]
reagira s formulom (VIII) 3-cijano-4-(i-propiloksi)benzojeva kiselina aktivirana s anhidridom propanfosfonske kiseline (T3P) u etil acetatu.
14. Spoj opće formule
[image]
ili
[image]
ili
[image]
ili
[image]
ili
[image]
ili
[image]
u kojoj R predstavlja zaštitnu skupinu koja se može ukloniti u kiselom mediju služeći za privremenu zaštitu hidroksilne skupine, poželjno je da je R supstituirana skupina metil etera, kao što je metoksimetil, benziloksimetil, p-metoksibenziloksimetil ili [(3,4-dimetoksibenzil)oksi]metil skupina, tetrahidropiranil skupina ili supstituirana etil eterska skupina, kao što je etoksietil, ili 1-[2-(trimetilsilil)etoksi]etil skupina, skupina sililnog tipa, poput trimetilsilil triizopropilsililna, t-butildimetilsililna ili trifenilsililna skupina, najpoželjnije t-butildimetilsililna skupina.
15. Smjesa spojeva koji imaju formulu (IV) prema zahtjevu 14 i spojeva koji imaju formulu (V)
[image]
ili spojeva koji imaju formulu (IVA) prema zahtjevu 14 i spojeva koji imaju formulu (V) u bilo kojem omjeru.
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| HUP1700216 | 2017-05-22 | ||
| EP18806925.6A EP3630738B1 (en) | 2017-05-22 | 2018-05-18 | Process for the production of ozanimod |
| PCT/HU2018/050019 WO2018215807A1 (en) | 2017-05-22 | 2018-05-18 | Process for the production of ozanimod |
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| ES2962211T3 (es) * | 2018-12-07 | 2024-03-18 | Synthon Bv | Proceso mejorado para preparar ozanimod |
| WO2020152718A1 (en) * | 2019-01-25 | 2020-07-30 | Mylan Laboratories Limited | Polymorphic forms 5-[3-[(1s)-2,3-dihydro-1-[(2-hydroxyethyl) amino]-1h-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-(1-methylethoxy)benzonitrile |
| CN112062785B (zh) * | 2019-06-11 | 2023-06-27 | 广东东阳光药业有限公司 | 奥扎莫德及其中间体的制备方法 |
| EP3999495A1 (en) | 2019-07-16 | 2022-05-25 | Synthon B.V. | Improved process for preparing ozanimod |
| CN114599363A (zh) | 2019-10-31 | 2022-06-07 | 爱杜西亚药品有限公司 | Cxcr7拮抗剂与s1p1受体调节剂的组合 |
| EP4126826A1 (en) * | 2020-04-02 | 2023-02-08 | Synthon B.V. | Crystalline form of ozanimod hydrochloride |
| EP4212156A1 (en) | 2022-01-13 | 2023-07-19 | Abivax | Combination of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with a s1p receptor modulator |
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| WO2015066515A1 (en) * | 2013-11-01 | 2015-05-07 | Receptos, Inc. | Selective sphingosine 1 phosphate receptor modulators and combination therapy therewith |
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| MA48798A (fr) | 2020-04-08 |
| SI3630738T1 (sl) | 2024-02-29 |
| MA48798B1 (fr) | 2023-10-31 |
| CN110997645B (zh) | 2023-10-10 |
| WO2018215807A1 (en) | 2018-11-29 |
| EA201992421A1 (ru) | 2020-03-27 |
| US20200087269A1 (en) | 2020-03-19 |
| EP3630738A1 (en) | 2020-04-08 |
| PL3630738T3 (pl) | 2024-04-08 |
| EP3630738A4 (en) | 2021-03-10 |
| PT3630738T (pt) | 2023-10-24 |
| HUE064642T2 (hu) | 2024-04-28 |
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