HRP20000793A2 - Improved method for preparing pharmaceutically valuable norbenzomorphane derivatives - Google Patents
Improved method for preparing pharmaceutically valuable norbenzomorphane derivatives Download PDFInfo
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- HRP20000793A2 HRP20000793A2 HR20000793A HRP20000793A HRP20000793A2 HR P20000793 A2 HRP20000793 A2 HR P20000793A2 HR 20000793 A HR20000793 A HR 20000793A HR P20000793 A HRP20000793 A HR P20000793A HR P20000793 A2 HRP20000793 A2 HR P20000793A2
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- Prior art keywords
- acid
- piperidine
- aluminum
- derivative
- reaction
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 27
- -1 C1-C8-alkoxy Chemical group 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000000203 mixture Chemical class 0.000 claims description 6
- 150000003053 piperidines Chemical class 0.000 claims description 6
- 239000012429 reaction media Substances 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- UQDFPUOBXNBENB-UHFFFAOYSA-N 2-[(3-methoxyphenyl)methyl]-3,3-dimethyl-4-methylidenepiperidine Chemical compound COC1=CC=CC(CC2C(C(=C)CCN2)(C)C)=C1 UQDFPUOBXNBENB-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 150000001555 benzenes Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DNNGHKHJLRIZJA-UHFFFAOYSA-N 2-[(2-methoxyphenyl)methyl]-3,3-dimethyl-4-methylidenepiperidine Chemical compound COC1=CC=CC=C1CC1C(C)(C)C(=C)CCN1 DNNGHKHJLRIZJA-UHFFFAOYSA-N 0.000 description 2
- LPKIGDXRQSIQBA-UHFFFAOYSA-N 4-methylidenepiperidine Chemical class C=C1CCNCC1 LPKIGDXRQSIQBA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 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 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 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
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/26—Benzomorphans
-
- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
Predloženi izum odnosi se na novi postupak za proizvodnju derivata norbenzomorfana opće formule 1, (na slikama 1a i 1b prikazani su odgovarajući stereoizomeri, a opis se odnosi samo na proizvodnju R-enantiomera - S-enantiomeri se proizvode na analogan način):
[image]
u kojoj
R1 = može značiti H, C1-C8-alkil, C1-C8-alkoksi, hidroksi ili halogen.
Ako u pojedinačnim navodima nije navedeno odstupanje, opće definicije koriste se u slijedećem smislu:
C1-C8-alkil predstavlja općenito razgranati ili nerazgranati ugljikovodični ostatak koji ima 1 do 8 ugljikovih atoma, i koji prema potrebi može biti supstituiran s jednim ili više halogenih atoma – ponajprije s fluorom, i koji međusobno mogu biti jednaki ili različiti. Kao primjeri navode se slijedeći ugljikovodični ostaci:
metil, etil, propil, 1-metiletil (izopropil), butil, 1-metilpropil, 2-metilpropil, 1,1-dimetiletil, pentil, 1-metilbutil, 2-metilbutil, 3-metilbutil, 1,1-dimetilpropil, 1,2-dimetilpropil, 2,2-dimetilpropil, 1-etilpropil, heksil, 1-metilpentil, 2-metilpentil, 3-metilpentil, 4-metilpentil, 1,1-dimetilbutil, 1,2-dimetilbutil, 1,3-dimetilbutil, 2,2,-dimetilbutil, 2,3-dimetilbutil, 3,3-dimetilbutil, 1-etil-butil, 2-etilbutil, 1,1,2-trimetilpropil, 1, 2, 2-trimetil-propil, 1-etil-l-metilpropil i 1-etil-2-metilpropil. Ako nije navedeno drugačije, to su ponajprije niži alkilni ostaci koji imaju 1 do 3 ugljikova atoma, kao metil, etil, propil, izopropil.
C1-C8-alkoksi predstavlja općenito razgranati ili nerazgranati i preko kisikovog atoma povezani ugljikovodični ostatak koji ima 1 do 8 ugljikovih atoma, i koji prema potrebi može biti supstituiran s jednim ili više halogenih atoma - ponajprije s fluorom, i koji međusobno mogu biti jednaki ili različiti. Kao primjeri navode se slijedeći ugljikovodični ostaci:
metoksi, etoksi, propoksi, 1-Metiletil (izopropil) , butoksi, 1-metilpropoksi, 2-metilpropoksi, 1,1-dimetil-etoksi, pentoksi, 1-metilbutoksi, 2-metilbutoksi, 3-metil-butoksi, 1,1-dimetilpropoksi, 1,2-dimetilpropoksi, 2,2-dimetilpropoksi, 1-etilpropoksi, heksoksi, 1-metilpentoksi, 2-metilpentoksi, 3-metilpentoksi, 4-metilpentoksi, 1,1-dimetilbutoksi, 1,2-dimetilbutoksi, 1,3-dimetilbutoksi, 2,2,-dimetilbutoksi, 2,3-dimetilbutoksi, 3,3-dimetil-butoksi, 1-etilbutoksi, 2-etilbutoksi, 1,1,2-trimetil-propoksi, 1,2,2-trimetilpropoksi, 1-etil-1-metilpropoksi i 1-etil-2-metilpropoksi. Ako nije navedeno drugačije, to su ponajprije niži alkilkosi ostaci koji imaju 1 do 3 ugljikova atoma, kao metoksi, etoksi, propoksi, izopropoksi.
Halogen, u smislu predloženih spojeva znači fluor, klor, brom, jod, pri čemu se kao supstituentima daje prednost fluoru i kloru. Kao anioni u aluminijevim spojevima prednosni su brom i klor - posebno potonji.
Postupak se može primijeniti za sintezu racemičnih spojeva, kao i za sintezu odgovarajućih enantiomerno čistih spojeva. U usporedbi s postupkom opisanim u njemačkoj publikaciji 195 28 472, postupak prema izumu ima prednost da su ušteđena dva stupnja - naime uvođenje kao i kasnije odstranjivanje N-formilne zaštitne skupine. U slučaju 4’-metoksi substituiranog norbenzomorfana (R1 = 4’-OMe), koji predstavlja dragocjeni međuproizvod za farmaceutski učinkovite derivate norbenzomorfana, time se dobije značajno bolje iskorištenje željenog spoja.
U uvodno navedenom stanju tehnike opisan je postupak po kojem se odgovarajući derivat 4-metilen-piperidina 2, nakon uvođenja N-formilne zaštitne skupine - 3 - ciklizira u odgovarajući derivat benzomorfana 4. Da bi se došlo do odgovarajućeg norbenzomorfana 5, u daljnjem stupnju postupka treba ponovno odcijepiti formilnu zaštitnu skupinu.
Na kraju, ako je poželjno, substituent R2 prevede se na poznati način u R1, u skladu sa ciljnim spojem 1. Tako se, ako R2 predstavlja alkoksi skupinu, kao npr. metoksi, etoksi, n-propoksi ili izopropoksi - tijekom eterskog odcjepljivanja - npr. pretvorbom s halogenovodičnom kiselinom, kao što je HBr - može dobiti hidroksi spoj (R1 = OH).
Iznenađujuće je nađeno, da se postupkom prema izumu može izbjeći uvođenje formilne zaštitne skupine. Prema izumu se derivat piperidina 2 može ciklizirati u protoniranom obliku izravno s AlCl3 u derivat benzomorfana 5. U shemi 1 prikazana je sinteza odgovarajućeg 1R-enantiomera. Ona se također može analogno provesti s odgovarajućim 1S-enantiomerom ili s racemičnim polaznim spojem.
Shema 1:
[image]
Tako se, postupkom opisanim u stanju tehnike, u slučaju 2-(2-metoksifenil)metil-3, 3-diinetil-4-metilen-piperidina 2a (R2 je 2-OMe), dobije željeni derivat benzomorfana samo do 20%.
Nasuprot tome, po novom postupku, željeni derivat benzomorfana, tip 5 - u primjeru sa R2 = OCHs - izolira se s iskorištenjem iznad 80%. Inačice uvjeta pokusa (tablica 1) pokazuju da se za uspješnu ciklizaciju 4-metilen-piperidin 2 treba najprije samo prevesti u sol, jer se ciklizacijom slobodne baze dobije pretežno proizvod rasipanja nepoznate prirode.
Postupak prema izumu provodi se svrhovito u reakcijskom mediju. Pri tome, kao reakcijski mediji posebno su prikladni halogenirani alifatski ili aromatski ugljikovodici ili također i kiselinski amidi, između ostalog, posebno su prikladni mono- ili poliklorirani alkani s 1 do 3 C-atoma ili klorirani derivati benzola ili kiselinski amidi karbonskih kiselina s 1 do 3 C-atoma u karboksilnoj skupini. Posve posebnu prednost daje se diklormetanu (metilenklorid), 1,2-dikloretanu, klorbenzolu i dimetilacetamidu. Mogu se, međutim, upotrijebiti također i mješavine navedenih otapala.
Reakcijska temperatura za reakcije prema izumu u širokom području nije kritična. Ona se u prvom redu podešava prema učincima u reakciji, pri čemu se gornju granicu postavlja prema vrelištu otapala, ako se reakcija ne provodi u autoklavu. Tako se reakcija prema izumu može provesti, ovisno o upotrijebljenom otapalu, u temperaturnom intervalu od 0 do 150°C. Povoljno je područje od 20 do 100°C, pri čemu se posebnu prednost daje intervalu od 40 do 70°C.
Upotrijebljena količina aluminijevog(III) halogenida -ponajprije aluminijevog tribromida i posebno povoljno aluminijevog triklorida - također se može mijenjati u širokom području. Ona se tipično kreće u rasponu od 2 do 12 ekvivalenata aluminijevog klorida u odnosu prema eduktu. Posebno povoljan je omjer u području od 3 do 10 ekvivalenata, pri čemu se posebnu prednost daje omjeru u rasponu od 3 do 5 ekvivalenata.
Upotrijebljeni oblik soli, što se tiče povoljne mogućnosti provedbe reakcije prema izumu, također nije kritičan. Upotrebljavaju se ponajprije soli derivata piperidina tipa 2 s anorganskim kiselinama - naročito s mineralnim kiselinama. Povoljne su neutralne soli s halogenovodičnim kiselinama ili sa sumpornom kiselinom. Osim neutralnih sulfata (u tablici 1 označene su kraticom "SU1"), za upotrebu posebno dolaze u obzir hidrokloridi (Cl) ili hidrobromidi (Br).
Predloženi opisani izum objasnit će se također u slijedećem primjeru pisanog postupka. Iz predloženog opisa stručnjaku će biti jasne različite druge izvedbe postupka prema izumu. Ipak se izričito naglašava da su primjer i opis predviđeni samo za objašnjenje i ne smiju se smatrati ograničenjem izuma.
PRIMJERI
Primjer 1
(-)-4'-metoksi-5,9,9-trimetil-6,7-benzomorfan-tartarat ((-)-5aTA)
4,9 g (20 mmolova) (+)-2-(2-metoksifenil)metil-3,3-di-metil-4-metilen-piperidina (2a) otopi se u 20 ml acetona i pomiješa s 1 g konz. sumporne kiseline. Izlučeni kristali se odsisaju i suspendiraju u 6 ml diklormetana1),2). K tome se uz hlađenje pri 10-20°C doda 9 g (68 mmolova) AlCl3. Nastane bistra otopina, koju se zatim kuha 2 h (unutrašnja temperatura 46 °C). Crveno smeđu reakcijsku smjesu ohladi se na sobnu temperaturu, razrijedi se s 25 ml diklormetana i stavi se pribl. 100 g leda. K tome se, uz hlađenje, pri 20 - 25°C dokaplje se 100 ml 20%-tne NaOH, organsku fazu se odvoji, a vodenu fazu ekstrahira s 25 ml diklormetana. Sjedinjeni organski ekstrakti se osuše preko magnezijevog sulfata i otapalo se izdestilira u vakuumu. Ostatak se preuzme u 10 ml metanola i pomiješa s 3,1 g L-(+)-vinske kiseline3 u 2 ml H2O. Pusti se 10 minuta kristalizirati na ledenoj kupelji, razrijedi se s pribl. 40 ml acetona i odsisa. Iskorištenje: 6,5 g (82,3%), talište: 236°C.
1 Alternativnom upotrebom 1,2-dikloretana, nakon inverznog dodatka AlCl3 i nakon 30 minuta pri 55 °C, dobije se 78 % benzomorfana.
2 Reakcijom u diklormetanu pri 55°C, pod pritiskom, nakon 1,5 sata, dobije benzomorfan s iskorištenjem od 82%.
3 Alternativno se za kristalizaciju može upotrijebiti 62%-tnu HBr. Izolira se odgovarajući hidrobromid s iskorištenjem od 77%.
Tablica 1:
[image]
Primjer 2
(-)-3’-metoksi-5,9,9-trimetil-6,7-benzomorfan-tartarat ((-)-5bTA)
8,6 g (35 mmolova) (+)-2-(3-metoksifenil) metil-3,3-dimetil-4-metilen-piperidina (2b) otopi se u 35 ml acetona i pomiješa s 1,8 g konz. sumporne kiseline. Izlučeni kristali se odsisaju i suspendiraju u 10,5 ml 1,2-dikloretana. K tome se uz hlađenje pri 20-30°C doda 16 g (120 mmolova) AlCl3. Smjesu se brzo zagrije na 55-70°C. Nakon 30 minuta pusti se ohladiti na sobnu temperaturu, razrijedi se sa 100 ml diklormetana i pomiješa s 200 g ledene vode. K tome se, uz hlađenje, pri 20 - 25°C dokaplje se 300 ml 20%-tne NaOH, zatim se organsku fazu odvoji i vodenu fazu se ekstrahira sa 150 ml diklormetana. Sjedinjeni organski ekstrakti se osuše preko magnezijevog sulfata i otapalo se izdestilira u vakuumu. Ostatak se preuzme u 20 ml metanola i pomiješa s 5,4 g L-(+)-vinske kiseline u 3 ml H2O. Pusti se kristalizirati 10 minuta na lednoj kupelji, razrijedi se s pribl. 40 ml acetona i odsisa. Iskorištenje: 10,9 g (79%), talište:186°C.
Claims (14)
1. Postupak za proizvodnju R~ odnosno S-norbenzo-morfana opće formule 1
[image]
u kojoj
R1 može predstavljati H, C1-C8-alkil, C1-C8-alkoksi, hidroksi, halogen, naznačen time, da se derivat 4-metilen-
[image]
piperidina opće formule 2 kiselinom prevede u odgovarajuću kiselinsku adicijsku sol i da se sol pretvori u reakcijskom mediju s aluminijevim(III) halogenidom, ponajprije aluminijevim tribromidom ili aluminijevim trikloridom pri temperaturi u intervalu od 0 do 150°C i reakcijski proizvod se izolira nakon potpune pretvorbe.
2. Postupak prema zahtjevu 1, naznačen time, da se kao reakcijski medij upotrebljava halogenirani alifatski ili aromatski ugljikovodik ili kiselinski amid ili mješavina navedenih otapala.
3. Postupak prema zahtjevu 2, naznačen time, da se kao reakcijski medij upotrebljava mono- ili poliklorirani alkan s 1 do 3 C-atoma, klorirani benzol ili derivat benzola ili amid karbonske kiseline s 1 do 3 C-atoma u karboksilnom ostatku ili mješavina navedenih otapala.
4. Postupak prema zahtjevu 3, naznačen time, da se kao reakcijski medij upotrebljava diklormetan, 1,2-diklor-etan, klorbenzol ili dimetilacetamid ili mješavina navedenih otapala.
5. Postupak prema bilo kojem zahtjevu 1 do 4, naznačen time, da se reakciju provodi u temperaturnom intervalu od 20 do 150 °C.
6. Postupak prema zahtjevu 5, naznačen time, da se reakciju provodi u temperaturnom intervalu od 40 do 70 °C.
7. Postupak prema bilo kojem zahtjevu 1 do 6, naznačen time, da se u odnosu na edukt upotrebljavaju 2 do 12 ekvivalenata aluminijevog(III) halogenida.
8. Postupak prema zahtjevu 7, naznačen time, da se u odnosu na edukt upotrebljavaju 3 do 10 ekvivalenata aluminijevog(III) halogenida.
9. Postupak prema zahtjevu 8, naznačen time, da se u odnosu na edukt upotrebljavaju 3 do 5 ekvivalenata aluminijevog(III) halogenida.
10. Postupak prema bilo kojem zahtjevu 1 do 9, naznačen time, da se kao derivat piperidina upotrebljava (+)-2-(3-metoksifenil)metil-3,3-dimetil-4-metilen-piperidin.
11. Postupak prema bilo kojem zahtjevu 1 do 9, naznačen time, da kao polazna baza upotrebljava (-)-2-(3-metoksifenil)metil-3,3-dimetil-4-metilen-piperidin.
12. Postupak prema bilo kojem zahtjevu 1 do 10, naznačen time, da se derivat piperidina upotrebljava u obliku adicijske soli s mineralnom kiselinom.
13. Postupak prema zahtjevu 12, naznačen time, da se derivat piperidina upotrebljava u obliku adicijske soli s halognovodičnom kiselinom ili sa sumpornom kiselinom.
14. Postupak prema zahtjevu 14, naznačen time, da se derivat piperidina upotrebljava u obliku adicijske soli sa solnom kiselinom, bromovodičnom kiselinom ili sa sumpornom kiselinom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19822822A DE19822822A1 (de) | 1998-05-20 | 1998-05-20 | Verbessertes Verfahren zur Herstellung von pharmazeutisch wertvollen Norbenzomorphanderivaten |
| PCT/EP1999/003142 WO1999059976A1 (de) | 1998-05-20 | 1999-05-07 | Verbessertes verfahren zur herstellung von pharmazeutisch wertvollen norbenzomorphanderivaten |
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| Publication Number | Publication Date |
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| HRP20000793A2 true HRP20000793A2 (en) | 2001-10-31 |
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| HR20000793A HRP20000793A2 (en) | 1998-05-20 | 2000-11-17 | Improved method for preparing pharmaceutically valuable norbenzomorphane derivatives |
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| US (1) | US6124459A (hr) |
| EP (1) | EP1080076B1 (hr) |
| JP (1) | JP4526185B2 (hr) |
| KR (1) | KR20010043703A (hr) |
| CN (1) | CN1113058C (hr) |
| AR (1) | AR016040A1 (hr) |
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| AU (1) | AU753563B2 (hr) |
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| BR (1) | BR9910603A (hr) |
| CA (1) | CA2330669C (hr) |
| CO (1) | CO5060460A1 (hr) |
| DE (2) | DE19822822A1 (hr) |
| DK (1) | DK1080076T3 (hr) |
| EA (1) | EA003059B1 (hr) |
| EE (1) | EE04305B1 (hr) |
| EG (1) | EG21526A (hr) |
| ES (1) | ES2211093T3 (hr) |
| HK (1) | HK1035728A1 (hr) |
| HR (1) | HRP20000793A2 (hr) |
| HU (1) | HUP0102034A3 (hr) |
| ID (1) | ID27014A (hr) |
| IL (1) | IL138998A0 (hr) |
| MY (1) | MY120806A (hr) |
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| SK (1) | SK283996B6 (hr) |
| TR (1) | TR200003360T2 (hr) |
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| US7405149B1 (en) * | 1998-12-21 | 2008-07-29 | Megica Corporation | Post passivation method for semiconductor chip or wafer |
| US10130615B2 (en) * | 2014-09-17 | 2018-11-20 | Purdue Pharma L.P. | Benzomorphan analogs and the use thereof |
| CN107089948B (zh) * | 2017-04-28 | 2020-07-17 | 云南大学 | 吗吩衍生物及其制备方法和应用 |
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| IE34235B1 (en) * | 1969-06-04 | 1975-03-19 | Acf Chemiefarma Nv | 6,7-benzomorphans and their preparation |
| US4255579A (en) * | 1974-05-20 | 1981-03-10 | Sterling Drug Inc. | 11-Substituted hexahydro-2,6-methano-3-benzazocines |
| US3932422A (en) * | 1974-05-20 | 1976-01-13 | Sterling Drug Inc. | 8-Methylene-3-azabicyclo[3.3.1]non-6-en-4-ones |
| DE19528472A1 (de) * | 1995-08-03 | 1997-02-06 | Boehringer Ingelheim Kg | Neues Verfahren zur Herstellung von Norbenzomorphan einer Zwischenstufe bei Herstellung von pharmazeutisch wertvollen Benzomorphanderivaten, insbesondere von (-)-(1R,5S,S"R)-3'-Hydroxy-2-(2-methoxypropyl-)-5,9,9-trimethyl-6,7 benzomorphan |
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