NO802173L - PROCEDURE FOR THE PREPARATION OF OXO CHOIC-XANTINES - Google Patents
PROCEDURE FOR THE PREPARATION OF OXO CHOIC-XANTINESInfo
- Publication number
- NO802173L NO802173L NO802173A NO802173A NO802173L NO 802173 L NO802173 L NO 802173L NO 802173 A NO802173 A NO 802173A NO 802173 A NO802173 A NO 802173A NO 802173 L NO802173 L NO 802173L
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- residue
- oxoalkyl
- methyl
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims description 8
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000005188 oxoalkyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- -1 5-oxohexyl residue Chemical group 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CNAULKGFZUMSBZ-UHFFFAOYSA-N 5-oxohexyl 4-methylbenzenesulfonate Chemical compound CC(=O)CCCCOS(=O)(=O)C1=CC=C(C)C=C1 CNAULKGFZUMSBZ-UHFFFAOYSA-N 0.000 description 3
- XBWPXAGHBDBODX-UHFFFAOYSA-N 8-(5-oxohexyl)-3,7-dihydropurine-2,6-dione Chemical class N1C(=O)NC(=O)C2=C1N=C(CCCCC(=O)C)N2 XBWPXAGHBDBODX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- QVMZOLZGAZBZJS-UHFFFAOYSA-N 5-oxohexyl methanesulfonate Chemical compound CC(=O)CCCCOS(C)(=O)=O QVMZOLZGAZBZJS-UHFFFAOYSA-N 0.000 description 2
- UALYCKSVHDYQRP-UHFFFAOYSA-N 6-hydroxyhexan-2-one Chemical compound CC(=O)CCCCO UALYCKSVHDYQRP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- RBQOQRRFDPXAGN-UHFFFAOYSA-N Propentofylline Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCC RBQOQRRFDPXAGN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- XBEDAMVJWVPVDS-UHFFFAOYSA-N 1,3-dimethyl-7-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CCCCC(=O)C XBEDAMVJWVPVDS-UHFFFAOYSA-N 0.000 description 1
- YOTSOUGNZSULJR-UHFFFAOYSA-N 1-hexyl-3-methyl-7-(5-oxohexyl)purine-2,6-dione Chemical compound O=C1N(CCCCCC)C(=O)N(C)C2=C1N(CCCCC(C)=O)C=N2 YOTSOUGNZSULJR-UHFFFAOYSA-N 0.000 description 1
- DNGNNURPARKSKM-UHFFFAOYSA-N 3-ethyl-1-(5-oxohexyl)-7-propylpurine-2,6-dione Chemical compound CCN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCC DNGNNURPARKSKM-UHFFFAOYSA-N 0.000 description 1
- SCWBBXYWLYSKGK-UHFFFAOYSA-N 3-methyl-7-(5-oxohexyl)-1-propylpurine-2,6-dione Chemical compound O=C1N(CCC)C(=O)N(C)C2=C1N(CCCCC(C)=O)C=N2 SCWBBXYWLYSKGK-UHFFFAOYSA-N 0.000 description 1
- MHNVSFOURBQRPK-UHFFFAOYSA-N 3-methyl-7-propylpurine-2,6-dione Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2CCC MHNVSFOURBQRPK-UHFFFAOYSA-N 0.000 description 1
- SOCYNBJTSAFFQI-UHFFFAOYSA-N 7-butyl-3-methyl-1-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCCC SOCYNBJTSAFFQI-UHFFFAOYSA-N 0.000 description 1
- RTYRGIMUXABCRT-UHFFFAOYSA-N 7-decyl-3-methyl-1-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCCCCCCCCC RTYRGIMUXABCRT-UHFFFAOYSA-N 0.000 description 1
- MROQSUMVRJJJLI-UHFFFAOYSA-N 7-ethyl-3-methyl-1-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CC MROQSUMVRJJJLI-UHFFFAOYSA-N 0.000 description 1
- SAEKTFXZAVNNEC-UHFFFAOYSA-N 7-hexyl-3-methyl-1-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCCCCC SAEKTFXZAVNNEC-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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Description
Oppfinnelsen vedrorer en fremgangsmåte til fremstilling av oksoalkyl-xantiner hvor xantiner omsettes med alkylfulf onyloksyalkanoner eller med arylsulfonyloksyal-kanoner. The invention relates to a process for producing oxoalkylxanthines where xanthines are reacted with alkylsulfonyloxyalkanones or with arylsulfonyloxyalkanones.
Det er kjent at man kan få (5-oksoheksyl)-xantiner av xantiner og 6-halogenheksan-2-oner. Også ved omsetning av N-(3-halogenpropyl)-xantiner med natriumacet-eddikestere, etterfølgende forsåpning og dekarboksylering ble det dannet (5-oksbheksyl)-xantiner. It is known that (5-oxohexyl)-xanthines can be obtained from xanthines and 6-halohexan-2-ones. Also by reacting N-(3-halopropyl)-xanthines with sodium acetoacetic esters, subsequent saponification and decarboxylation, (5-oxhexyl)-xanthines were formed.
Oppfinnelsens gjenstand er en fremgangsmåte til fremstilling av forbindelser med den generelle formel I The object of the invention is a method for preparing compounds of the general formula I
hvori R"*" og betyr en rettlinjet (w-l)r-oksoalkylrest med 4-8 karbonatomer eller (C^-C-j^-alkyl og R betyr (C-^-Cg)-alkyl, idet imidlertid minst én av restene R"<*>"eller R^ betyr en oksoalkylgruppe og idet Rp og R^ikke samtidig er metyl, når oksoalkylgruppen er en 5-oksoheksylrest. Fremgangsmåten erkarakterisert vedat man for innforing av oksoalkylresten omsetter salter av 3-alkylxantiner, 1,3- resp. 3,-7-dialkylxantiner eller av 1-oksoalkyl-3-alkyl resp. 3-alkyl-7-oksoalkyl-xantiner med alkylsulfonyloksyalkan-2-oner eller arylsulfonyloksyal-r kan-2-oner med den generelle formel in which R"*" and means a linear (w-1)r-oxoalkyl residue with 4-8 carbon atoms or (C^-C-j^-alkyl and R means (C-^-Cg)-alkyl, however at least one of the residues R" <*>" or R^ means an oxoalkyl group and since Rp and R^ are not at the same time methyl, when the oxoalkyl group is a 5-oxohexyl residue. The method is characterized by introducing the oxoalkyl residue by reacting salts of 3-alkylxanthines, 1,3- or 3,-7-dialkylxanthines or of 1-oxoalkyl-3-alkyl or 3-alkyl-7-oxoalkyl-xanthines with alkylsulfonyloxyalkan-2-ones or arylsulfonyloxyalkan-2-ones of the general formula
idet R betyr en alifatisk rest, fortrinnsvis en alkylrest med 1-4 C-atomer som CH^-, 0,^.^-, CF-^- eller en aro- wherein R means an aliphatic residue, preferably an alkyl residue with 1-4 C atoms such as CH^-, O,^.^-, CF-^- or an aro-
matisk rest som fenyl, p-tolyl, p-bromfenyl, fortrinnsvis imidlertid metyl og p-tolyl og n er 6 - 6 og fortrinnsvis 4. De enkelte utgangsstoffer kan anvendes i stbkiometriske eller også i ikke-stokiometriske mengder. Man kan anvende saltene av xåntinene, fortrinnsvis alkalisaltene, i ferdig form. Fortrinnsvis frembringer man disse salter imidlertid i reaksjonsblandingen, fortrinnsvis med kalium-karbonat. matic residue such as phenyl, p-tolyl, p-bromophenyl, preferably, however, methyl and p-tolyl and n is 6 - 6 and preferably 4. The individual starting substances can be used in stoichiometric or also in non-stoichiometric amounts. You can use the salts of the xanthines, preferably the alkali salts, in finished form. Preferably, however, these salts are produced in the reaction mixture, preferably with potassium carbonate.
Fremgangsmåten ifolge oppfinnelsen lar seg gjen-nomføre på teknisk enkel måte vanligvis ved en temperatur på fra 20 - 160°C, fortrinnsvis fra 60 - 140°C, eventuelt ved forhoyet eller nedsatt trykk, men vanligvis ved atmos-færetrykk. Som opplosningS" eller fordelingsmiddel egner, det seg under reaksjonsbetingelsene inerte forbindelser, som f.eks. dimetylformamid, dimetylsulfoksyd, aceton, butan-2-on eller acetonitril. Alkylsulfonyloksyalkan-2-oner og arylsulfonyloksyalkan-2-oner med formel II lar seg oppnå etter kjente metoder, fra hydroksyalkan-2-oner og halogenid-er av tilsvarende sulfonsyrer (sammenlign f.eks. Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1976, side 683<ff.>).The method according to the invention can be carried out in a technically simple manner, usually at a temperature of from 20 - 160°C, preferably from 60 - 140°C, optionally at increased or reduced pressure, but usually at atmospheric pressure. Compounds that are inert under the reaction conditions are suitable as solvents or dispersants, such as, for example, dimethylformamide, dimethylsulfoxide, acetone, butan-2-one or acetonitrile. Alkylsulfonyloxyalkan-2-ones and arylsulfonyloxyalkan-2-ones of formula II can be obtained by known methods, from hydroxyalkan-2-ones and halides of corresponding sulfonic acids (compare e.g. Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1976, page 683<ff.>).
De ifolge oppfinnelsen oppnådde (5-oksoheksyl)-xantiner er kjent og virker befordrende på den cerebrale og perifere gjennomblodning og/eller bronkosparmolytisk og/eller fibrinolytisk. The (5-oxohexyl)-xanthines obtained according to the invention are known and have a promoting effect on cerebral and peripheral blood flow and/or bronchosparmolytic and/or fibrinolytic.
Eksempler Examples
1. 1-( 5- oksoheksyl)- 3- metyl- 7- propylxantin 1. 1-(5-oxohexyl)-3-methyl-7-propylxanthine
a) Til 34,9 g 6-hydroksyheksan-2-on og 36,4 g tri-etylamin i 500 ml metylenklorid dryppes under omroring a) Add 34.9 g of 6-hydroxyhexan-2-one and 36.4 g of triethylamine in 500 ml of methylene chloride dropwise while stirring
ved 0 - 5°C indre temperatur 36,1 g metansulfonsyreklorid. Det etteromrbres 1 time ved værelsetemperatur, utfellingen frafiltreres og filtratet vaskes noytralt og saltfritt med NaHCO^-opplbsning og vann. Etter tbrking over Na2S0^ fjer-ner man metylenkloridet ved nedsatt trykk og får 57,4 g 6-mesyloksyheksan-2-on, som er tynnsjiktkromatografisk en-hetlig (kiselgel, elueringsmiddel: dietyleter, fremkalling at 0 - 5°C internal temperature 36.1 g methanesulfonic acid chloride. It is then stirred for 1 hour at room temperature, the precipitate is filtered off and the filtrate is washed neutrally and salt-free with NaHCO3 solution and water. After evaporation over Na2S0^, the methylene chloride is removed under reduced pressure and 57.4 g of 6-mesyloxyhexan-2-one is obtained, which is homogeneous by thin-layer chromatography (silica gel, eluent: diethyl ether, development
iseddik/I^SO^, volumforhold 1:1). Produktet kunne anvendes direkte til innfbring av (5-oksoheksyl)-resten i xantiner, IR- spektrum ( kap.): 1710 cm'<1>(C=0), 1360 cm'1, 1180 cm'<1>(mesylat) glacial acetic acid/I^SO^, volume ratio 1:1). The product could be used directly to introduce the (5-oxohexyl) residue in xanthines, IR spectrum (cap.): 1710 cm'<1>(C=0), 1360 cm'1, 1180 cm'<1>(mesylate )
''• H- k. ierneresonansspektrum ( i CDCl^) : ''• H- k. iron resonance spectrum (in CDCl^) :
(m, -(CH2)2-) (m, -(CH2)2-)
b) 10,4 g 3-metyl-7-propyl-xantin og 7,1 g ^CO^i 175 ml dimetylformamid oppvarmes under omrbring ved 120°C. b) 10.4 g of 3-methyl-7-propyl-xanthine and 7.1 g of ^CO^ in 175 ml of dimethylformamide are heated with stirring at 120°C.
I lopet av en halv time tildryppes 10 g 6-mesyloksyheksan-2-on i 20 ml dimetylformamid og omrbres videre i 7 timer ved 120°C. Etter blandingens inndampning ved nedsatt trykk innstilles residuet med IN natronlut på pH 13 - 14 og ekstraheres flere ganger med metylenklorid. De samlede metylenkloridekstrakter inndampes ved nedsatt trykk og residuet oppvarmes, i 1 time i__50 ml IN saltsyre ved til-bakelbpstemperatur. Etter avkjbling innstiller man med IN natronlut på pH 13 - 14, ekstraherer flere ganger med metylenklorid, vasker de samlede metylenkloridfaser.nbytralt, tbrker og inndamper. Fra residuet fås etter rens-ning ved omkrystallisering fra isopropanol/petroleter (volumforhold 1:2) 11,5 g l-(5-oksoheksyl)-3-metyl-7-propylxantin med smeltepunkt 70 - 71°C. Fremgangsmåteproduktet er ifolge blandingssmeltepunkt, tynnsjiktkromatogram, infrarbdt- og kjerneresonansspektrene identisk med det autentiske stoff. Over the course of half an hour, 10 g of 6-mesyloxyhexan-2-one are added dropwise to 20 ml of dimethylformamide and further stirred for 7 hours at 120°C. After the mixture has been evaporated under reduced pressure, the residue is adjusted to pH 13 - 14 with 1N caustic soda and extracted several times with methylene chloride. The combined methylene chloride extracts are evaporated under reduced pressure and the residue is heated for 1 hour in __50 ml 1N hydrochloric acid at reflux temperature. After cooling, adjust to pH 13 - 14 with 1N caustic soda, extract several times with methylene chloride, wash the combined methylene chloride phases with neutral, dry and evaporate. After purification by recrystallization from isopropanol/petroleum ether (volume ratio 1:2), 11.5 g of 1-(5-oxohexyl)-3-methyl-7-propylxanthine with a melting point of 70 - 71°C are obtained from the residue. According to the mixture melting point, thin-layer chromatogram, infrared and nuclear resonance spectra, the process product is identical to the authentic substance.
2. 1, 3- dimetyl- 7-( 5- oksoheksyl) xantin 2. 1, 3-dimethyl-7-(5-oxohexyl)xanthine
a) 6- tosyloksyheksan- 2- on a) 6-tosyloxyhexan-2-one
Til 23,5 g 6-hydroksyheksan-2-on i 200 ml abso-lutt pyridin setter man ved -5°C på en gang 38,8 p-toluen-sulfoklorid, omrbrer 215 timer ved 0 - -5°C og tildrypper i lbpet av en halv time ved maks. 0°C 20 ml rL>0. Etter blanding med 500 g is utrystes med 3 x 250 ml metylenklorid. De samlede metylenkloridekstrakter^vaskes pyridinfrie med 2N saltsyre og noytrale med mettet NaHCO^-opplbsning og H2O, tbrkes over Na2S0^-_o.g inndampes ved nedsatt trykk. To 23.5 g of 6-hydroxyhexan-2-one in 200 ml of absolute pyridine, 38.8 g of p-toluene sulphochloride are added at -5°C at once, stirred for 215 hours at 0 - -5°C and added dropwise in the lbpet of half an hour at max. 0°C 20 ml rL>0. After mixing with 500 g of ice, shake with 3 x 250 ml of methylene chloride. The combined methylene chloride extracts are washed free of pyridine with 2N hydrochloric acid and neutralized with saturated NaHCO^ solution and H2O, dried over Na2S0^ and evaporated under reduced pressure.
Man får 40,8 g 6-tosyloksyheksan-2-on som kunne anvendes direkte til irmforing av (5-oksoheksyl)-resten i xantin. IR- spektrum ( kap.): 1710 cm<-1>(C=0), I36O cm"<1>, 1190 cm"1, 1180 cm'1 (tosylat) 40.8 g of 6-tosyloxyhexan-2-one is obtained, which could be used directly to form the (5-oxohexyl) residue in xanthine. IR spectrum ( ch.): 1710 cm<-1>(C=0), 1360 cm"<1>, 1190 cm"1, 1180 cm'1 (tosylate)
•^ H- k. ierneresonansspektrum ( i CDCl-^): •^ H- k. iron resonance spectrum (in CDCl-^):
1,9 (m, -(CH2)2-) 1.9 (m, -(CH2)2-)
b) Til opplosningen av 9 g teofyllin i 175 ml dimetylformamid settes ved 120°C under omroring 7,1 g K^CO^b) Add 7.1 g of K^CO^ to the solution of 9 g of theophylline in 175 ml of dimethylformamide at 120°C with stirring
og i lbpet av en halv time tildryppes 14,2 g 6-tosyloksyheksan-2-on i 20 ml dimetylformamid. Etter ytterligere 5 timers omrbring ved 120°C inndamper man ved nedsatt trykk, blander residuet med 55 ml IN natronlut og ekstraherer med metylenklorid. De samlede metylenkloridfaser behandles med 30 ml IN natronlut, vaskes nbytralt med ILpO, tbrkes over Na2S0^ og inndampes. Fra residuet får man en rens-ning ved omkrystallisering fra isopropanol/petroleter (volumforhold 1:2) 9,3 g k,3-dimetyl-7-(5-oksoheksyl)-xantin av smeltepunkt 76 - 77°C. and over the course of half an hour, 14.2 g of 6-tosyloxyhexan-2-one are added dropwise in 20 ml of dimethylformamide. After stirring for a further 5 hours at 120°C, the mixture is evaporated under reduced pressure, the residue is mixed with 55 ml of 1N caustic soda and extracted with methylene chloride. The combined methylene chloride phases are treated with 30 ml of 1N caustic soda, washed neutrally with ILpO, dried over Na2SO4 and evaporated. From the residue, a purification by recrystallization from isopropanol/petroleum ether (volume ratio 1:2) yields 9.3 g of k,3-dimethyl-7-(5-oxohexyl)-xanthine of melting point 76 - 77°C.
Fremgangsmåteproduktet er ifolge blandingssmeltepunkt, tynnsjiktkromatogram,. infrarbdt spektrum og kjerneresonansspektrum identisk med det autentiske stoff. The process product is according to mixture melting point, thin layer chromatogram. infrared spectrum and nuclear resonance spectrum identical to the authentic substance.
Etter arbeidsmåten ifolge ovennevnte eksempler fremstilles fblgende (5-oksoheksyl)-xantiner og identifiser-es på samme måte som ovenfor. 3. l-propyl-3-metyl-7-(5-oksoheksyl)-xantin, smeltepunkt: 76 -78°C. 4. l-heksyl-3-metyl-7-(5-oksoheksyl)-xantin, smelte-r punkt: 35 - 38°C. 5.. l-(5-oksoheksyl)-3-metyl-7-etylxantin, smeltepunkt: 102 - 103°C 6. 1-(5-oksoheksyl)-3-metyl-7-butylxantin, smeltepunkt: 79 - 80°C. 7. 1-(5-oksoheksyl)-3-metyl-7-heksylxantin, smeltepunkt: 52°C. 8. 1-(5-oksoheksyl)-3-metyl-7-decylxantin, smeltepunkt: 64 - 66°C. 9. 1-(5-oksoheksyl)-3-etyl-7-propylxantin, smeltepunkt: 81 - 82°C. 10. l-metyl-3-t>utyl-7-(5-oksoheksyl)-xantin, n^ PO 1,5308. Following the procedure according to the above-mentioned examples, the following (5-oxohexyl)-xanthines are prepared and identified in the same way as above. 3. 1-propyl-3-methyl-7-(5-oxohexyl)-xanthine, melting point: 76-78°C. 4. 1-hexyl-3-methyl-7-(5-oxohexyl)-xanthine, melting point: 35 - 38°C. 5.. 1-(5-oxohexyl)-3-methyl-7-ethylxanthine, melting point: 102 - 103°C 6. 1-(5-oxohexyl)-3-methyl-7-butylxanthine, melting point: 79 - 80° C. 7. 1-(5-oxohexyl)-3-methyl-7-hexylxanthine, melting point: 52°C. 8. 1-(5-oxohexyl)-3-methyl-7-decylxanthine, melting point: 64 - 66°C. 9. 1-(5-oxohexyl)-3-ethyl-7-propylxanthine, melting point: 81 - 82°C. 10. 1-Methyl-3-t>util-7-(5-oxohexyl)-xanthine, n^ PO 1.5308.
Claims (7)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792929596 DE2929596A1 (en) | 1979-07-21 | 1979-07-21 | METHOD FOR PRODUCING OXOALKYL XANTHINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO802173L true NO802173L (en) | 1981-01-22 |
Family
ID=6076378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO802173A NO802173L (en) | 1979-07-21 | 1980-07-18 | PROCEDURE FOR THE PREPARATION OF OXO CHOIC-XANTINES |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0023032A1 (en) |
| JP (1) | JPS5616486A (en) |
| AR (1) | AR227645A1 (en) |
| DE (1) | DE2929596A1 (en) |
| DK (1) | DK311580A (en) |
| ES (1) | ES8105005A1 (en) |
| FI (1) | FI802267A (en) |
| GR (1) | GR69741B (en) |
| NO (1) | NO802173L (en) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0042706B1 (en) * | 1980-06-21 | 1985-12-27 | BEECHAM - WUELFING GmbH & Co. KG | Xanthine derivatives, pharmaceutical compositions containing them and a process for their preparation |
| GB8418430D0 (en) * | 1984-07-19 | 1984-08-22 | Beecham Wuelfing Gmbh & Co Kg | Treatment |
| GB8501488D0 (en) * | 1985-01-21 | 1985-02-20 | Beecham Group Plc | Treatment |
| US4851060A (en) * | 1987-08-12 | 1989-07-25 | Essex Group, Inc. | Multilayer wrapped insulated magnet wire |
| CA2030112A1 (en) * | 1989-11-24 | 1991-05-25 | Yasuo Ito | Xanthine compound, method for preparing thereof, and a pharmaceutical composition comprising the same |
| DE3942872A1 (en) * | 1989-12-23 | 1991-06-27 | Hoechst Ag | METHOD FOR THE ENANTIOSELECTIVE PRESENTATION OF ((OMEGA) -1) -HYDROXYALKYLXANTHINES |
| EP0570831A2 (en) * | 1992-05-20 | 1993-11-24 | Hoechst Aktiengesellschaft | Use of Xanthinderivatives for treatment of cerebral nerve dammages after disruption of the blood circulation |
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
| DE102004054054A1 (en) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines |
| DE102005035891A1 (en) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals |
| PE20080251A1 (en) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | USES OF DPP IV INHIBITORS |
| KR101541791B1 (en) | 2006-05-04 | 2015-08-04 | 베링거 인겔하임 인터내셔날 게엠베하 | Polymorphs |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| AR071175A1 (en) | 2008-04-03 | 2010-06-02 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INHIBITOR OF DIPEPTIDIL-PEPTIDASA-4 (DPP4) AND A COMPARING PHARMACO |
| KR20200118243A (en) | 2008-08-06 | 2020-10-14 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment for diabetes in patients inappropriate for metformin therapy |
| UY32030A (en) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN" |
| AU2009290911A1 (en) | 2008-09-10 | 2010-03-18 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| NZ592924A (en) | 2008-12-23 | 2014-05-30 | Boehringer Ingelheim Int | Salt forms of a xanthine derivative |
| TW201036975A (en) | 2009-01-07 | 2010-10-16 | Boehringer Ingelheim Int | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy |
| KR20210033559A (en) | 2009-11-27 | 2021-03-26 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
| US9186392B2 (en) | 2010-05-05 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
| BR112012032579B1 (en) | 2010-06-24 | 2021-05-11 | Boehringer Ingelheim International Gmbh | use of linagliptin and pharmaceutical composition comprising linagliptin and long-acting basal insulin |
| AR083878A1 (en) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | VASOPROTECTORA AND CARDIOPROTECTORA ANTIDIABETIC THERAPY, LINAGLIPTINA, TREATMENT METHOD |
| EP3517539B1 (en) | 2011-07-15 | 2022-12-14 | Boehringer Ingelheim International GmbH | Substituted dimeric quinazoline derivative, its preparation and its use in pharmaceutical compositions for the treatment of type i and ii diabetes |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| US20130303462A1 (en) | 2012-05-14 | 2013-11-14 | Boehringer Ingelheim International Gmbh | Use of a dpp-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| JP2019517542A (en) | 2016-06-10 | 2019-06-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Combination of linagliptin and metformin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2336403A1 (en) * | 1975-12-24 | 1977-07-22 | Bruneau & Cie Lab | Theophyllin-substd. propanesulphonic acid prepn. - by reaction of theophyllin with a disubstituted propane |
| GB1527543A (en) * | 1976-04-15 | 1978-10-04 | Degussa | Basically substituted xanthine derivatives |
| DE2714953C2 (en) * | 1977-04-02 | 1986-09-25 | Hoechst Ag, 6230 Frankfurt | drug |
-
1979
- 1979-07-21 DE DE19792929596 patent/DE2929596A1/en not_active Withdrawn
-
1980
- 1980-01-28 GR GR62506A patent/GR69741B/el unknown
- 1980-07-15 ES ES493385A patent/ES8105005A1/en not_active Expired
- 1980-07-17 FI FI802267A patent/FI802267A/en not_active Application Discontinuation
- 1980-07-17 EP EP80104171A patent/EP0023032A1/en not_active Withdrawn
- 1980-07-18 DK DK311580A patent/DK311580A/en unknown
- 1980-07-18 AR AR281813A patent/AR227645A1/en active
- 1980-07-18 NO NO802173A patent/NO802173L/en unknown
- 1980-07-21 JP JP9883880A patent/JPS5616486A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ES493385A0 (en) | 1981-05-16 |
| DK311580A (en) | 1981-01-22 |
| DE2929596A1 (en) | 1981-02-05 |
| GR69741B (en) | 1982-07-12 |
| AR227645A1 (en) | 1982-11-30 |
| ES8105005A1 (en) | 1981-05-16 |
| FI802267A (en) | 1981-01-22 |
| JPS5616486A (en) | 1981-02-17 |
| EP0023032A1 (en) | 1981-01-28 |
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