DK145082B - Analogifremgangsmaade til fremstilling af (methylsulfonylmethylphenyl)-ethanolaminforbindelser eller syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af (methylsulfonylmethylphenyl)-ethanolaminforbindelser eller syreadditionssalte deraf Download PDFInfo
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- DK145082B DK145082B DK139673AA DK139673A DK145082B DK 145082 B DK145082 B DK 145082B DK 139673A A DK139673A A DK 139673AA DK 139673 A DK139673 A DK 139673A DK 145082 B DK145082 B DK 145082B
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- DK
- Denmark
- Prior art keywords
- compounds
- acid addition
- preparation
- addition salts
- methylsulphonylmethylphenyl
- Prior art date
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- 239000002253 acid Substances 0.000 title description 7
- 238000000034 method Methods 0.000 title description 7
- 238000002360 preparation method Methods 0.000 title description 6
- 150000003839 salts Chemical class 0.000 title description 6
- UPRKDTUSQUUERJ-UHFFFAOYSA-N CS(=O)(=O)CC1=CC=CC=C1C(CN)O Chemical class CS(=O)(=O)CC1=CC=CC=C1C(CN)O UPRKDTUSQUUERJ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- -1 2- (4-hydroxyphenyl) -1-methylethyl Chemical group 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 241000700199 Cavia porcellus Species 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LAMHAMBOLINJML-UHFFFAOYSA-N 1-[3-(chloromethyl)-4-hydroxyphenyl]ethanone Chemical compound CC(=O)C1=CC=C(O)C(CCl)=C1 LAMHAMBOLINJML-UHFFFAOYSA-N 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 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 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- NSFUOQCLHUVYCH-UHFFFAOYSA-L magnesium;methanesulfinate Chemical compound [Mg+2].CS([O-])=O.CS([O-])=O NSFUOQCLHUVYCH-UHFFFAOYSA-L 0.000 description 1
- XNEFVTBPCXGIRX-UHFFFAOYSA-N methanesulfinic acid Chemical compound CS(O)=O XNEFVTBPCXGIRX-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 description 1
- DLSOILHAKCBARI-UHFFFAOYSA-N n-benzyl-2-methylpropan-2-amine Chemical compound CC(C)(C)NCC1=CC=CC=C1 DLSOILHAKCBARI-UHFFFAOYSA-N 0.000 description 1
- MMNNFMKNCOKXLZ-UHFFFAOYSA-N n-benzyl-2-methylpropan-2-amine;hydrobromide Chemical compound Br.CC(C)(C)NCC1=CC=CC=C1 MMNNFMKNCOKXLZ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000005062 tracheal ring Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Pulmonology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(φ) (19) DANMARK \ξ£/ © (12) FREMLÆGGELSESSKRIFT ου 145082 Β
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENET
(21) Ansøgning nr. 1396/73 (51) |ntCL* C 07 C 147/02 (22) Indleveringsdag 1 5 · ®ar. 1973 (24) Løbedag 15. mar. 1973 (41) Aim. tilgængelig 21. sep. 1973 (44) Fremlagt 23· aug. 1982 (86) International ansøgning nr. - (86) International indleveringadag (85) Videreførelsesdag - (62) Stamansøgning nr. -
(30) Prioritet 20. mar. 1972, 236177, US
(71) Ansøger SMITH KLINE & FRENCH LABORATORIES, Philadelphia, US.
(72) Opfinder Carl Kaiser, US! Stephen Torey Ross, US.
(74) Fuldmægtig Firmaet Chas. Hude.
(54) Analogifremgangsmåde til frera= stilling af (methylsulfonylme» thylphenyl) -ethanolaminf orbinp® delser eller syreadditionssal» te deraf.
Denne opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte (methylsulfonylmethylphenyl)-ethanolaminforbindelser eller syreadditionssalte deraf, hvilken fremgangsmåde er ejendommelig ved det i kravets kendetegnende del angivne, og hvilke forbindelser tt har nyttig farmakodynamisk virkning. Forbindelserne er specielt an- ^ vendelige som β-adrenergisk stimulerende midler med relativ større
CO
O virkning på respirationsglatmusklen end på cardialmusklen. Disse for- bindeiser har derfor direkte bronchodilatorvirknlng med minimal car» -a- τ— dialstimulering, som påvist ved farmakologiske standardundersøgel- ^ sesmetode.
Q
145082 2
To in vitro testsystemer anvendt til bestemmelse af selektiv β-sti-muleringsvirkning er: (1) virkningen på spontan tonus af marsvine-trachealkædepræparater som et mål for β-stimulerende (direkte afslappende) virkning på luftvejsglatmusklen og (2) virkningen på hastigheden af spontant slående højre aterie hos marsvin som et mål for β-stimulerende virkning på cardialmusklen. Forbindelserne ifølge denne opfindelse har selektive bronchodilaterende egenskaber, da de er virksomme i (l) ovenfor i en lavere dosis end der kræves i (2) ovenfor, hvilket resulterer i et positivt separationsf orhold.
De ifølge opfindelsen fremstillede forbindelser kan illustreres ved hjælp af den følgende almene formel: o?
CHr,0oCEo—f^' ^|—C-C-NHR1 ^ ά HH
Formel I
hvori R·*" er tertiær butyl, cyklobutyl eller 2-(4-hydroxyphenyl) -1-methylethyl, eller syreadditionssalte deraf.
Forbindelserne fremstillet ifølge denne opfindelse kan anvendes i fhrm af et farmaceutisk acceptabelt^ syreadditionssalt, der er anvendeligt som den fri base. Sådanne salte,fremstillet ved hjælp af i og for sig velkendte metoder, dannes med både uorganiske eller organiske syrer, f.eks. maleinsyre, fumarsyre, benzoesyre, ascorbinsyre, pamoicsyre, ravsyre, bismethylensalicylsyre, methansulfonsyre, ethandisulfonsy= re, eddikesyre, oxalsyre, propionsyre, vinsyre, salicylsyre, ci= tronsyre, glyconsyre, asparaginsyre, stearinsyre, palmitinsyre, itaconsyre, glycolsyre, p-aminobenzoesyre, glutaminsyre, benzensul= fonsyre, saltsyre, hydrogenbromidsyre, svovlsyre, cyclohexylsulfa= minsyre, phosphorsyre og salpetersyre.
3 165082
Forbindelserne fremstillet ifølge denne opfindelse indeholder ét asymmetrisk carbonatom og kan derfor spaltes i d- og 1- optiske isomere. Medmindre andet er anført i den foreliggende beskrivelse drejer det sig overalt om alle isomere, separerede eller blandinger deraf.
En foretrukket forbindelse fremstillet ifølge denne opfindelse er a-t-butyl=' aminomethy1-4-hydroxy-3-(methylsulfonylmethyl)-benzylalkohol, som virker afslappende på den spontane tonus af marsvinetrachealring-præparat ved en ED^0 på 0,0051 mcg/ml, medens den forøger kontraktionshastigheden af marsvins højre aterie ved en EDgtj på 8,28 mcg/ ml. Disse virkninger giver et absolut separationsforhold på 1.620, hvilket er en forbedring på 5.340 gange i sammenligning med den tilsvarende virkning af d, 1-isoproterenol (absolut separationsforhold = 0,5) i lignende in vitro præparater.
De i den efterfølgende tabel anførte farmakologiske data for fem forbindelser, nemlig tre ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med formlen I:
H
O H
/ I I i
CH,SO.,CH0_y -C - C - NHR
J 2 ^ I Η H
HO
hvor R·*" har den ovennævnte betydning, og et kendt isopropylaminoderivat med formlen II:
H
H / ? ch3so2n —sy n—c - ch2 - nhch(ch3)2
HO
og en fra patentansøgning nr. 6226/68 kendt forbindelse med formlen III:
H
H ? CH3S02N-CH2 —o' —c - CH2 - NH - C(CH3)3
HO
4 145082 godtgør, at de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser har en væsentlig forøget farmakodynamisk virkning i sammenligning med de nærmest beslægtede kendte forbindelser med samme virkningsretning.
Tabel
Separationsforhold Forbedring i forarterie ED--/ hold til isopro= 1 . , , terenol
r tracheal ed5Q
tertiær butyl 1650,0 3375,00 cyklobutyl 2170,0 4520,00 4-HOPhCH2CH(Me) 244,0 508,00
Formel II 2,9 6,04 (kendt teknik)
Formel III 86,4 180,00 (kendt teknik)
Forbindelserne fremstillet ifølge denne opfindelse og deres udgangsmaterialer fremstilles som angivet i det følgende reaktionsskema: / ° 0 rrs_CH2H hci cicH2"-f^ y-c-ch2h CHo0 X 7* H0—2 HO—eller OLj-SO^g 0 0 Br CE^-SO^ H C6H5CH2C1 ^3^2^2-y' C6H5CH20—^ 5 145082 O s ch3-so2ch2 —j^^^n-C-CH-N-R1
CgH^CH^HR1 CH9C^ Pd~C
Τ' c6h5ch2o-I^^J 3H2 X
„ formel II
OH H -
CH,-S0oCHo —^1—C—C-NHR1 622 HH
H0_ hvori R"*· har den tidligere anførte betydning og ΗΤΓ er betegnelsen for pyrrolidon= hydrotribromid. Som vist ovenfor bliver således en 4-hydroxyphenon chlormethyleret med formaldehyd og saltsyre og behandlet med natrium- eller magniumsaltet af en methyl-sulfinsyre til dannelse af methylsulf ony lmethy Ider ivatet. Sidstnævnte bromeres og den resulterende α-bromphenon omsættes med en N-benzylamin til dannelse af den tilsvarende α-benzylaminphenon. Dette derivat hydrogeneres katalytisk, fortrinsvis med palladium-på-carbon til dannelse af det debenzylerede methylsulfonylmethylbenzylalkoholprodukt.
De ifølge opfindelsen fremstillede forbindelser kan administreres oralt eller parenteralt i sædvanlige former for doseringsenheder, såsom tabletter, kapsler, injicerbare portioner eller aerosoler, ved at inkorporere den passende dosis af en forbindelse med formlen I med bærere i overensstemmelse med accepteret farmaceutisk praksis.
De følgende eksempler illustrerer fremgangsmåden ifølge opfindelsen. Eksempel 1.
Til en blanding af 260 cnr5 37 #ig formaldehyd og 1800 cm^ koncentreret saltsyre tilsættes 400 g p-hydroxyacetophenon ved en temperatur på ca. 45°C. Blandingen holdes ved 50°C i 2 timer, filtreres Og vaskes med vand, hvilket giver 3-chlormethyl-4-hydroxyacetophenon, smeltepunkt 154°C, dekomponering.
En blanding af 40 g 3-chlormethyl-4-hydroxyacetophenon og 26 g magniummethylsulfinat i 500 ml ethanol tilbagesvales under omrøring 6 H5082 i 3 timer. Reaktionsblandingen koncentreres derpå i vakuum. Den resulterende olie opløses igen i chloroform og vaskes med vand. Chlo= roformet tørres og inddampes, hvilket giver 4-hydroxy-3-methylsul= fonylmethylacetophenon, smeltepunkt 206,5 - 208,5°C.
En blanding af 14,0 g 4-hydroxy-3-methylsulfonylmethylacetophenon, 9,3 g kaliumcarbonat, 7,8 ml benzylchlorid og en katalytisk mængde natriumiodid i 250 ml acetone og 250 ml vand tilbagesvales under omrøring i 16 timer. Acetonen fjernes, og den vandige fase ekstra-heres med chloroform, vaskes med vand,tørres og inddampes, hvilket giver en olie, der omkrystalliseres i isopropylalkohol, hvilket giver krystallinsk 4-benzyloxy-3-methylsulfonylmethylacetophenon, smeltepunkt 94-97°G.
Til en omrørt opløsning af 7,7 g 4-benzyloxy-3-methylsulfonylmethyl= acetophenon og 2,15 g 2-pyrrolidon i 300 ml tetrahydrofuran tilsættes 12,5 g pyrrolidonhydrotribromid (PHT) og omrøringen fortsættes i 56 timer ved stuetemperatur. Blandingen filtreres, og filtratet koncentreres i vakuum, hvilket giver en olie, der krystalliserer ved henstand. Krystallerne opløses igen i chloroform. Chloroform-opløsningen vaskes med vand, tørres og koncentreres, hvilket giver et fast stof, der omkrystalliseres fra acetonitril. Herved fås 4-benzyloxy-oc-brom-3-methylsulfonylmethylacetophenon, smeltepunkt 143-144°C. Sidstnævnte (100 g) opløses i 1 liter acetonitril og 82 g N-benzyl-N-t-butylamin tilsættes. Blandingen omrøres og til- bagesvales i 4 timer, afkøles og fortyndes med ether. Krystallinsk N-benzyl-N-t-butylaminhydrobromid filtreres. Filtratet syrnes med etherisk hydrogenchlorid og ether tilsættes, hvilket giver 4-ben= zyloxy-a(N-benzyl-N-t-butylamino)-3-methylsulfonylmethylacetophe= nonhydrochlorid, smeltepunkt 152-154°C.
En blanding af 20 g 4-benzyloxy-a(N-benzyl-N-t-butylamino)-3-methyl= sulfonylmethylacetophenonhydrochlorid, 10 g 5$ palladium-på-carbon og 125 ml ethanol hydrogeneres på Parr-apparatet ved stuetemperatur, idet der anvendes et hydrogenbegyndelsestryk på 4218 g/cm . Reaktionsblandingen filtreres og filtratet koncentreres i vakuum. Resten krystalliseres med ether/ethanol, hvilket giver a-(t-butylaminome= thyl) -4-hydr oxy-3-(methylsulf onylmethyl) -benzylalkoholhydrochlorid, smeltepunkt 219-220°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23617772A | 1972-03-20 | 1972-03-20 | |
| US23617772 | 1972-03-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK145082B true DK145082B (da) | 1982-08-23 |
| DK145082C DK145082C (da) | 1983-03-21 |
Family
ID=22888442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK139673A DK145082C (da) | 1972-03-20 | 1973-03-15 | Analogifremgangsmaade til fremstilling af (methylsulfonylmethylphenyl)-ethanolaminforbindelser eller syreadditionssalte deraf |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS5636188B2 (da) |
| AR (1) | AR196924A1 (da) |
| AU (1) | AU469666B2 (da) |
| BE (1) | BE796894A (da) |
| BR (1) | BR7301986D0 (da) |
| CA (1) | CA1007662A (da) |
| CH (1) | CH576435A5 (da) |
| DE (1) | DE2313625C2 (da) |
| DK (1) | DK145082C (da) |
| ES (1) | ES412799A1 (da) |
| FI (1) | FI58326C (da) |
| FR (1) | FR2183681B1 (da) |
| GB (2) | GB1386029A (da) |
| HU (1) | HU166931B (da) |
| IE (1) | IE38206B1 (da) |
| IL (1) | IL41758A (da) |
| IT (1) | IT1061426B (da) |
| LU (1) | LU67220A1 (da) |
| NL (1) | NL7303715A (da) |
| PH (1) | PH9436A (da) |
| SE (1) | SE403773B (da) |
| ZA (1) | ZA731903B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966770A (en) * | 1975-03-25 | 1976-06-29 | Smithkline Corporation | 4-Hydroxy-α-[(3,4-methylenedioxyphenyl)isopropylaminoethyl]-3-(methylsulfonylmethyl)benzyl alcohol |
| ATE89262T1 (de) * | 1987-03-26 | 1993-05-15 | Ciba Geigy Ag | Neue alpha-aminoacetophenone als photoinitiatoren. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE34545B1 (en) * | 1969-10-01 | 1975-06-11 | Continental Pharma | Amino-alcohols,their salts and process for preparing the same |
| ZA723611B (en) * | 1971-06-01 | 1973-03-28 | Smith Kline French Lab | N,n'-bis(2-(3-substituted-4-hydroxyphenyl)-ethyl or-2-hydroxyethyl)-polymethylene-diamines |
-
1973
- 1973-03-06 GB GB2471474A patent/GB1386029A/en not_active Expired
- 1973-03-06 GB GB1076873A patent/GB1386028A/en not_active Expired
- 1973-03-13 IL IL41758A patent/IL41758A/en unknown
- 1973-03-13 IE IE409/73A patent/IE38206B1/xx unknown
- 1973-03-14 SE SE7303544A patent/SE403773B/xx unknown
- 1973-03-14 FR FR7309051A patent/FR2183681B1/fr not_active Expired
- 1973-03-14 FI FI778/73A patent/FI58326C/fi active
- 1973-03-15 LU LU67220A patent/LU67220A1/xx unknown
- 1973-03-15 JP JP3048873A patent/JPS5636188B2/ja not_active Expired
- 1973-03-15 IT IT21683/73A patent/IT1061426B/it active
- 1973-03-15 CA CA166,212A patent/CA1007662A/en not_active Expired
- 1973-03-15 HU HUSI1298A patent/HU166931B/hu unknown
- 1973-03-15 AR AR247078A patent/AR196924A1/es active
- 1973-03-15 DK DK139673A patent/DK145082C/da active
- 1973-03-16 BE BE128895A patent/BE796894A/xx not_active IP Right Cessation
- 1973-03-16 NL NL7303715A patent/NL7303715A/xx unknown
- 1973-03-16 PH PH14433*UA patent/PH9436A/en unknown
- 1973-03-16 AU AU53410/73A patent/AU469666B2/en not_active Expired
- 1973-03-17 ES ES412799A patent/ES412799A1/es not_active Expired
- 1973-03-19 CH CH396473A patent/CH576435A5/xx not_active IP Right Cessation
- 1973-03-19 DE DE2313625A patent/DE2313625C2/de not_active Expired
- 1973-03-19 ZA ZA731903A patent/ZA731903B/xx unknown
- 1973-03-20 BR BR731986A patent/BR7301986D0/pt unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE38206L (en) | 1973-09-20 |
| NL7303715A (da) | 1973-09-24 |
| PH9436A (en) | 1975-11-26 |
| DE2313625A1 (de) | 1973-10-25 |
| HU166931B (da) | 1975-06-28 |
| IL41758A0 (en) | 1973-05-31 |
| GB1386028A (en) | 1975-03-05 |
| FR2183681B1 (da) | 1976-10-22 |
| IE38206B1 (en) | 1978-01-18 |
| JPS5636188B2 (da) | 1981-08-22 |
| ES412799A1 (es) | 1976-06-01 |
| FI58326C (fi) | 1981-01-12 |
| FI58326B (fi) | 1980-09-30 |
| SE403773B (sv) | 1978-09-04 |
| AR196924A1 (es) | 1974-02-28 |
| ZA731903B (en) | 1974-01-30 |
| FR2183681A1 (da) | 1973-12-21 |
| LU67220A1 (da) | 1973-05-22 |
| CA1007662A (en) | 1977-03-29 |
| BR7301986D0 (pt) | 1974-07-25 |
| CH576435A5 (da) | 1976-06-15 |
| IT1061426B (it) | 1983-02-28 |
| DK145082C (da) | 1983-03-21 |
| GB1386029A (en) | 1975-03-05 |
| DE2313625C2 (de) | 1986-03-13 |
| JPS4911846A (da) | 1974-02-01 |
| IL41758A (en) | 1976-03-31 |
| AU469666B2 (en) | 1976-02-19 |
| BE796894A (fr) | 1973-09-17 |
| AU5341073A (en) | 1974-09-19 |
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