NO144422B - ANALOGY PROCEDURE FOR PREPARATION OF 10,11-DIHYDRO-3-CARBOXYCYPROHEPTADINE - Google Patents
ANALOGY PROCEDURE FOR PREPARATION OF 10,11-DIHYDRO-3-CARBOXYCYPROHEPTADINE Download PDFInfo
- Publication number
- NO144422B NO144422B NO753562A NO753562A NO144422B NO 144422 B NO144422 B NO 144422B NO 753562 A NO753562 A NO 753562A NO 753562 A NO753562 A NO 753562A NO 144422 B NO144422 B NO 144422B
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- Norway
- Prior art keywords
- dihydro
- methyl
- cyclohepten
- dibenzo
- compound
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 20
- 150000001204 N-oxides Chemical class 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 2
- 150000004795 grignard reagents Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- LDIOQSOJLJYUJK-UHFFFAOYSA-N 11-(1-methylpiperidin-4-ylidene)-5,6-dihydrodibenzo[1,3-e:1',2'-f][7]annulene-2-carboxylic acid;hydrochloride Chemical compound Cl.C1CN(C)CCC1=C1C2=CC(C(O)=O)=CC=C2CCC2=CC=CC=C21 LDIOQSOJLJYUJK-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- -1 1-methyl-4-piperidylmagnesium halide Chemical class 0.000 description 4
- 239000000739 antihistaminic agent Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- PLJQZAYZHIYLDP-UHFFFAOYSA-N 4-(2-bromo-5,6-dihydrodibenzo[1,3-e:1',2'-f][7]annulen-11-ylidene)-1-methylpiperidine Chemical compound C1CN(C)CCC1=C1C2=CC(Br)=CC=C2CCC2=CC=CC=C21 PLJQZAYZHIYLDP-UHFFFAOYSA-N 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000002948 appetite stimulant Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- VNSDQOCKNPJFDL-UHFFFAOYSA-N 11-(1-methylpiperidin-4-ylidene)-5,6-dihydrodibenzo[1,3-e:1',2'-f][7]annulene-2-carboxylic acid Chemical compound C1CN(C)CCC1=C1C2=CC(C(O)=O)=CC=C2CCC2=CC=CC=C21 VNSDQOCKNPJFDL-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 229940029995 appetite stimulants Drugs 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 2
- 229960001140 cyproheptadine Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZCQVEMXIVISDLV-UHFFFAOYSA-M magnesium;1-methylpiperidin-4-ide;chloride Chemical compound [Mg+2].[Cl-].CN1CC[CH-]CC1 ZCQVEMXIVISDLV-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000007943 positive regulation of appetite Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- HZTASHQRDOBMFD-UHFFFAOYSA-N 11-(1-methylpiperidin-4-ylidene)dibenzo[1,3-e:1',2'-f][7]annulene-2-carboxylic acid;hydrochloride Chemical compound Cl.C1CN(C)CCC1=C1C2=CC(C(O)=O)=CC=C2C=CC2=CC=CC=C21 HZTASHQRDOBMFD-UHFFFAOYSA-N 0.000 description 1
- QLVKECUOHNDWOI-UHFFFAOYSA-N 2-oxo-1,3,2$l^{5}-diazaphosphonan-2-amine Chemical compound NP1(=O)NCCCCCCN1 QLVKECUOHNDWOI-UHFFFAOYSA-N 0.000 description 1
- MYGXGCCFTPKWIH-UHFFFAOYSA-N 4-chloro-1-methylpiperidine Chemical compound CN1CCC(Cl)CC1 MYGXGCCFTPKWIH-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
Classifications
-
- 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
-
- 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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Saccharide Compounds (AREA)
Description
Foreliggende oppfinnelse angår analogifremgangsmåter ved fremstilling av 10,ll-dihydro-3-carboxycyproheptadin (1-methyl-4-(3-carboxy-10,ll-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin) som er en appetittstimulant og et anti-histaminmiddel. Oppfinnelsen omfatter også fremstilling av de farmasøytisk godtagbare salter og N-oxyd av denne forbindelse . The present invention relates to analogous methods for the production of 10,11-dihydro-3-carboxycyproheptadine (1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-ylidene) -piperidine) which is an appetite stimulant and an antihistamine. The invention also includes the preparation of the pharmaceutically acceptable salts and N-oxide of this compound.
Den frie syreform av 10,ll-dihydro-3-carboxycyproheptadin som fremstilles ifølge oppfinnelsen, har følgende struktur-formel: The free acid form of 10,11-dihydro-3-carboxycyproheptadine produced according to the invention has the following structural formula:
Det er ganske uventet blitt oppdaget at 10,11-dihydro-3-carboxycyproheptadinene som fremstilles ifølge oppfinnelsen, er appetittstimulanter og antihistaminer med i det vesentlige samme styrke som dihydrocyproheptadin og cyproheptadin, men er i det vesentlige frie for andre farmakologiske virkninger som anticholinergisk aktivitet, hvilken sistnevnte aktivitet er så karakteristisk for forbindelser strukturelt beslektet med cyproheptadin, innbefattende dihydro-derivatene derav. Det er følgelig et mål ved foreliggende oppfinnelse å fremskaffe 10,ll-dihydro-3-carboxycyproheptadin og dets farmasøytisk godtagbare salt- og N-oxyd-derivater for anvendelse som appetittstimulanter og antihistaminmidler. It has quite unexpectedly been discovered that the 10,11-dihydro-3-carboxycyproheptadines produced according to the invention are appetite stimulants and antihistamines with essentially the same potency as dihydrocyproheptadine and cyproheptadine, but are essentially free of other pharmacological effects such as anticholinergic activity, which latter activity is so characteristic of compounds structurally related to cyproheptadine, including its dihydro derivatives. Accordingly, it is an object of the present invention to provide 10,11-dihydro-3-carboxycyproheptadine and its pharmaceutically acceptable salt and N-oxide derivatives for use as appetite stimulants and antihistamines.
10,11-dihydro-3-carboxycyproheptadinene kan ifølge oppfinnelsen bekvemt fremstilles fra 3-brom-10,ll-dihydro-5H-dibenzo-! a,d]-cyclohepten-5-on (se f.eks. US patenter 3-306.934 og 3.014-911) ved omsetning med l-methyl-4—piperidylmagnesiumhalo-genid i et passende oppløsningsmiddel som tetrahydrofuran og lignende, ved 0°C til værelsetemperatur for å få 1-methyl-4-(3-brom-lO,11-dihydro-5-hydroxy-5H-dibenzo-[a,d j-cyclohepten-5-yl)-piperidin, som dehydratiseres ved behandling med et passende de-hydratiseringsmiddel som en mineralsyre, carboxylsyre, klorid eller anhydrid og lignende, enten alene eller i et oppløsnings-middel som kloroform eller iseddik for å få l-methyl-4-(3-brom-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin, som ved overføring til 3-cyanoforbindelsen ved behandling med cuprocyanid i et oppløsningsmiddel som dimethylformamid eller hexamethylenfosforamid ved 50 - 200°C i 2 - 12 timer, fulgt av hydrolyse med en sterk mineralsyre ved tilbakeløpstemperatur i 1-24 timer gir det ønskede 1 -methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin(IO,11-dihydro-3-carboxycyproheptadin). Alternativt kan Grignard-reaksjonen følge reaksjonen med cuprocyanid på ketonet, hvorved den nest følgende behandling med mineralsyre således ikke bare dehydratiserer, men også overfører 3-cyanosubstituenten til den ønskede 3-carboxyl-funksjon. According to the invention, the 10,11-dihydro-3-carboxycyproheptadines can be conveniently prepared from 3-bromo-10,11-dihydro-5H-dibenzo-! a,d]-cyclohepten-5-one (see, for example, US patents 3-306,934 and 3,014-911) by reaction with 1-methyl-4-piperidylmagnesium halide in a suitable solvent such as tetrahydrofuran and the like, at 0° C to room temperature to give 1-methyl-4-(3-bromo-10,11-dihydro-5-hydroxy-5H-dibenzo-[α,d j-cyclohepten-5-yl)-piperidine, which is dehydrated on treatment with a suitable dehydrating agent such as a mineral acid, carboxylic acid, chloride or anhydride and the like, either alone or in a solvent such as chloroform or glacial acetic acid to obtain 1-methyl-4-(3-bromo-10,11-dihydro- 5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine, which upon transfer to the 3-cyano compound by treatment with cuprocyanide in a solvent such as dimethylformamide or hexamethylene phosphoramide at 50 - 200°C for 2 - 12 hours, followed of hydrolysis with a strong mineral acid at reflux temperature for 1-24 hours gives the desired 1 -methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)- piperidine (10,11-dihyd ro-3-carboxycyproheptadine). Alternatively, the Grignard reaction can follow the reaction with cuprocyanide on the ketone, whereby the next treatment with mineral acid thus not only dehydrates, but also transfers the 3-cyano substituent to the desired 3-carboxyl function.
Det dannede 10,11-dihydro-3-carboxycyproheptadin kan så oxyderes til det ønskede N-oxyd. Fortrinnsvis utføres imidlertid oxydasjonen på en passende lavere alkylester av det fri-syre-mellomprodukt som fremstilles ved konvensjonelle metoder. Eksem-pelvis kan ethylesteren bekvemt fremstilles ved å omsette den frie syre i ethanol i nærvær av BF^ (CH^CH2) 20. Hydrogenperoxyd er et passende oxydasjonsmiddel, og reaksjonen kan utføres i et hvilket som helst passende inert protisk oppløsningsmiddel som vandig methanol, vandig ethanol eller lignende, ved en temperatur fra 0° til tilbakeløpstemperaturen i fra 1 til 72 timer. Forbindelse I kan også bekvemt fremstilles ved reduksjon av 3-carboxycyproheptadin, forbindelse X, med hydrogen ved 1,5 - 7 kg/cm2 og væreIsetemperåtur i nærvær av en edelmetallkatalysator som palladium, særlig 5%-ig palladium-på-carbon i et fortynnet mineral-syreoppløsningsmiddel som 0,1 N saltsyre. The 10,11-dihydro-3-carboxycyproheptadine formed can then be oxidized to the desired N-oxide. Preferably, however, the oxidation is carried out on a suitable lower alkyl ester of the free acid intermediate which is prepared by conventional methods. For example, the ethyl ester may be conveniently prepared by reacting the free acid in ethanol in the presence of BF 2 (CH 2 CH 2 ) 20 . Hydrogen peroxide is a suitable oxidizing agent, and the reaction may be carried out in any suitable inert protic solvent such as aqueous methanol, aqueous ethanol or the like, at a temperature from 0° to the reflux temperature for from 1 to 72 hours. Compound I can also be conveniently prepared by reduction of 3-carboxycyproheptadine, compound X, with hydrogen at 1.5 - 7 kg/cm2 and ice temperature in the presence of a noble metal catalyst such as palladium, especially 5% palladium-on-carbon in a dilute mineral-acid solvent such as 0.1 N hydrochloric acid.
En videre fremgangsmåte ved fremstilling av forbindelse I omfatter dannelsen av et Grignard-reagens fra magnesium og 3~brom-10,11-dihydrocyproheptadin i et oppløsningsmiddel som vanligvis anvendes ved Grignard-reaksjoner, som ether, tetrahydrofuran eller lignende, ved -5° til 20°C, fulgt av behandling med tørr car-bondioxydgass ved de samme temperaturer inntil reaksjonen er fullstendig. A further method for the preparation of compound I comprises the formation of a Grignard reagent from magnesium and 3-bromo-10,11-dihydrocyproheptadine in a solvent that is usually used in Grignard reactions, such as ether, tetrahydrofuran or the like, at -5° to 20°C, followed by treatment with dry carbon dioxide gas at the same temperatures until the reaction is complete.
En annen fremgangsmåte ved fremstilling av en forbindelse med formel I eller dens estere omfatter alkoholyse av enten forbindelse V eller VII med svovelsyre i en lavere alkanol, særlig methanol. Om ønskes, kan den dannede ester avestres med syre eller alkali ved standardmetoder. De følgende diagrammer illustrerer disse fremgangsmåter. Another method for preparing a compound of formula I or its esters comprises alcoholysis of either compound V or VII with sulfuric acid in a lower alkanol, especially methanol. If desired, the ester formed can be removed with acid or alkali by standard methods. The following diagrams illustrate these procedures.
Passende farmasøytiske salter og N-oxyd av 10,11-dihydro-3-carboxycyproheptadin kan fremstilles ifølge oppfinnelsen ved konvensjonelle metoder. Saltformer er de mest foretrukne og innbefatter (i forhold til nitrogenatomet av_piperidyl-gruppen): hydrokloridet, sulfatet, fosfatet, citratet, tartratet, succinatet og lignende. Med hensyn til salter basert på carboxyfunksjonen foretrekkes salter avledet av alkali- og jordalkalimetaller som natrium og kalium. Disse salter er i alminnelighet ekvivalente i styrke med den frie syreform tatt i betraktning de anvendte støkiometriske mengder. Suitable pharmaceutical salts and N-oxide of 10,11-dihydro-3-carboxycyproheptadine can be prepared according to the invention by conventional methods. Salt forms are the most preferred and include (relative to the nitrogen atom of the piperidyl group): the hydrochloride, the sulfate, the phosphate, the citrate, the tartrate, the succinate and the like. With regard to salts based on the carboxy function, salts derived from alkali and alkaline earth metals such as sodium and potassium are preferred. These salts are generally equivalent in strength to the free acid form given the stoichiometric amounts used.
Ved siden av oppfinnelsen som angår fremgangsmåter ved behandling og farmasøytiske preparater, skal det bemerkes at den presise enhetsdoseform og dosemengde avhenger av sykdoms-historien for individet som behandles og overlates til den be-handlende leges bedømmelse. I alminnelighet gir fremgangsmåte-forbindelsene den ønskede virkning av appetittstimulering når de gies ved fra 0,01 til 10,0 mg pr. kg legemsvekt pr. dag. Alongside the invention which relates to methods of treatment and pharmaceutical preparations, it should be noted that the precise unit dosage form and dosage amount depends on the disease history of the individual being treated and is left to the judgment of the treating physician. In general, the method compounds provide the desired effect of appetite stimulation when administered at from 0.01 to 10.0 mg per kg body weight per day.
Den foretrukne administrasjonsform for fremgangsmåteforbind-elsene for appetittstimulering av husdyr er ved oppløsning i drikkevann eller for-forblandinger. For menneske- og dyre-administrasjon kan en hvilken som helst av de vanlige farma-søytiske orale former anvendes som tabletter, eliksirer og vandige suspensjoner inneholdende fra 0,01 til 10,0 mg av frem-gangsmåteforbindelsene pr. kg legemsvekt gitt daglig. Således er f.eks. tabletter gitt 2-4 ganger daglig inneholdende fra 0,5 til 50 mg fremgangsmåteforbindelse egnet for menneskebehandling. Sterile oppløsninger (som representativt gies ved menneskebehandling) for injeksjon inneholdende fra 0,1 til 10,0 mg fremgangsmåteforbindelse gitt to til fire ganger daglig er også en egnet administrasjonsmåte. Når en anti-histaminvirkning er indikert, er også de ovennevnte doseformer og mengder passende. The preferred form of administration for the method compounds for appetite stimulation of domestic animals is by dissolution in drinking water or premixtures. For human and animal administration, any of the usual pharmaceutical oral forms can be used as tablets, elixirs and aqueous suspensions containing from 0.01 to 10.0 mg of the process compounds per kg body weight given daily. Thus, e.g. tablets given 2-4 times daily containing from 0.5 to 50 mg of process compound suitable for human treatment. Sterile solutions (representatively given in human treatment) for injection containing from 0.1 to 10.0 mg of method compound given two to four times daily are also a suitable mode of administration. When an antihistamine effect is indicated, the above dosage forms and amounts are also appropriate.
De følgende eksempler illustrerer representativt foreliggende oppfinnelse. The following examples representatively illustrate the present invention.
Eksempel 1 Example 1
Fremstilling av 1-methyl-4-(3-carboxy-10,ll-dihydro-5H-dibenzo-[ a,dj-cyclohepten-5-yliden)-piperidin Preparation of 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[α,dj-cyclohepten-5-ylidene)-piperidine
Trinn A: 1-methyl-4-(3-brom-10,11-dihydro-5H-dibenzo-fa ,d]-cyclohepten- 5- yliden) - piperidin Step A: 1-methyl-4-(3-bromo-10,11-dihydro-5H-dibenzo-pha,d]-cyclohepten-5-ylidene)-piperidine
Til en isavkjølt oppløsning av 15,0 g (0,0523 mol) 3-brom-10,11-dihydro-5H-dibenzo-(a,dj-cyclohepten-5-on i 150 ml tørt tetrahydrofuran tilsettes dråpevis i løpet av 0,5 timer 100 ml 0,53 M l-methyl-4-piperidyl-magnesiumklorid i tetrahydrofuran. Oppløsningen omrøres i 1 time, og derpå fjernes tetrahydrofuranet på en roterende fordamper. Det røde oljeaktige residuum oppløses i benzen, og vann tilsettes dråpevis inntil et klart benzen-overstående skikt og en gelatinøs vannfase fåes. Benzenet fradekanteres, og den gelatinøse vannfase ekstraheres med 2 x 100 ml varm benzen. De forenede benzenfaser vaskes med 6 x 200 ml vann, og derpå inndampes benzenfasen på en roterende fordamper. Residuet tritureres med acetonitril. Det krystallinske produkt fjernes ved filtrering, vaskes med ytterligere acetonitril, oppsamles og tørres ved 6o°C. Produktet, 1-methyl-4-(3-brom-10,ll-dihydro-5-hydroxy-5H-dibenzo-[a,d]-cyclohepten-5-yl)-piperidin som fåes i en mengde av 9,66 g (65%), smelter ved 203 - 207°C. To an ice-cooled solution of 15.0 g (0.0523 mol) of 3-bromo-10,11-dihydro-5H-dibenzo-(a,dj-cyclohepten-5-one) in 150 ml of dry tetrahydrofuran is added dropwise over 0 .5 hours 100 ml of 0.53 M 1-methyl-4-piperidyl-magnesium chloride in tetrahydrofuran. The solution is stirred for 1 hour, and then the tetrahydrofuran is removed on a rotary evaporator. The red oily residue is dissolved in benzene, and water is added dropwise until a clear benzene upper layer and a gelatinous water phase are obtained. The benzene is decanted off, and the gelatinous water phase is extracted with 2 x 100 ml of hot benzene. The combined benzene phases are washed with 6 x 200 ml of water, and then the benzene phase is evaporated on a rotary evaporator. The residue is triturated with acetonitrile. The crystalline product is removed by filtration, washed with additional acetonitrile, collected and dried at 60° C. The product, 1-methyl-4-(3-bromo-10,11-dihydro-5-hydroxy-5H-dibenzo-[ a,d]-cyclohepten-5-yl)-piperidine which is obtained in an amount of 9.66 g (65%), melting at 203 - 207°C .
En blanding av 9,66 g 1-methyl-4-(3-brom-10,11-dihydro-5~ hydroxy-5H-dibenzo-[a,d]-cyclohepten-5-yl)-piperidin og 130 ml 6 N saltsyre omrøres og kokes under tilbakeløp i 1/2 time. Hoved-mengden av saltsyren fjernes på en roterende fordamper, og residuet fordeles mellom 5%-ig vandig natriumhydroxyd og ether. Etherfasen fjernes, vaskes med vann, tørres over magnesiumsulfat, filtreres, og etheren fjernes, hvorved man får 9,17 g l-methyl-4-(3-brom-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden) - piper idin. A mixture of 9.66 g of 1-methyl-4-(3-bromo-10,11-dihydro-5~ hydroxy-5H-dibenzo-[a,d]-cyclohepten-5-yl)-piperidine and 130 ml 6 N hydrochloric acid is stirred and boiled under reflux for 1/2 hour. The main amount of the hydrochloric acid is removed on a rotary evaporator, and the residue is distributed between 5% aqueous sodium hydroxide and ether. The ether phase is removed, washed with water, dried over magnesium sulfate, filtered, and the ether is removed, whereby 9.17 g of 1-methyl-4-(3-bromo-10,11-dihydro-5H-dibenzo-[a,d] -cyclohepten-5-ylidene) - piper idine.
Trinn B: 1-methyl-4-(3-cyano-IO,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten- 5- yliden) - piperidin Step B: 1-methyl-4-(3-cyano-10,11-dihydro-5H-dibenzo-[α,dJ-cyclohepten-5-ylidene)-piperidine
En blanding av 9,17 g (0,0249 mol) 1-methyl-4-(3-brom-lO,11-dihydro-5H-dibenzo- f a,d]-cyclohepten-5-yliden)-piperidin, 4,58 9 (0,0498 mol) cuprocyanid og 30 ml tørt dimethylformamid omrøres og oppvarmes under tilbakeløp i 6,5 timer. Til den avkjølte oppløs-ning (25°C) tilsettes 54 ml vann, 27 ml av en mettet vandig oppløs-ning av natriumcyanid og 75 ml benzen. Blandingen omrøres inntil et to-fasesystem fåes. Benzenfasen fjernes, og vannfasen ekstraheres med 2 x 75 ml benzen. De forenede benzenfaser vaskes med 100 ml vandig 0,1 M nat riumcyanid, 3 x 100 ml vann og tørres over magnesiumsulfat. Efter filtrering gir fordampning av benzenet 7,40 g av et krystallinsk residuum. Dette materialet oppløses i det minimale volum kloroform og føres over en aluminiumoxydkolonne (38 cm x 2,5 cm) pakket i kloroform. Fordampning av kloroformen gir et krystallinsk produkt som omkrystalliseres fra isopropyl-alkohol, hvorved man får ren 1-methy1-4-(3-cyano-10,11-dihydro-5H-dibenzo-ja,d]-cyclohepten-5-yliden)-piperidin, smp. 152 - 154°C. A mixture of 9.17 g (0.0249 mol) 1-methyl-4-(3-bromo-10,11-dihydro-5H-dibenzo-fa,d]-cyclohepten-5-ylidene)-piperidine, 4, 58 9 (0.0498 mol) of cuprocyanide and 30 ml of dry dimethylformamide are stirred and heated under reflux for 6.5 hours. 54 ml of water, 27 ml of a saturated aqueous solution of sodium cyanide and 75 ml of benzene are added to the cooled solution (25°C). The mixture is stirred until a two-phase system is obtained. The benzene phase is removed, and the water phase is extracted with 2 x 75 ml of benzene. The combined benzene phases are washed with 100 ml of aqueous 0.1 M sodium cyanide, 3 x 100 ml of water and dried over magnesium sulphate. After filtration, evaporation of the benzene gives 7.40 g of a crystalline residue. This material is dissolved in the minimal volume of chloroform and passed over an aluminum oxide column (38 cm x 2.5 cm) packed in chloroform. Evaporation of the chloroform gives a crystalline product which is recrystallized from isopropyl alcohol, whereby pure 1-methyl-4-(3-cyano-10,11-dihydro-5H-dibenzo-ja,d]-cyclohepten-5-ylidene) is obtained -piperidine, m.p. 152 - 154°C.
Analyse beregn..for: C22<H>22<N2:>Analysis calc..for: C22<H>22<N2:>
Beregnet: C 84,04; H 7,05; N 8,91. Calculated: C 84.04; H 7.05; N 8.91.
Funnet: C 83,87; H 7,4l; N 8,73- Found: C 83.87; H 7.4l; N 8.73-
Trinn C: 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,dJ-cyclohepten-5-yliden)-piperidin-hyydroklorid En blanding av 1,0 g (O,00318 mol) l-methyl-4-(3-cyano-10,11-dihydro-5H-dibenzo-|a,d]-cyclohepten-5-yliden)-piperidin og 20 ml 6 N saltsyre omrøres og kokes under tilbakeløp i 18 timer. Efter avkjøling filtreres blandingen, og det oppsamlede faste stoff vaskes med 6 N saltsyre og derpå med ethanol. Det tørrede materiale veier 1,03 g (87%). Omkrystallisasjon fra absolutt ethanol gir rent 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[ a,d]-cyclohepten-5-yliden)-piperidin-hydroklorid, smp. 304 - 307°C. Step C: 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[α,dJ-cyclohepten-5-ylidene)-piperidine hydrochloride A mixture of 1.0 g (0.00318 mol) 1-methyl-4-(3-cyano-10,11-dihydro-5H-dibenzo-|a,d]-cyclohepten-5-ylidene)-piperidine and 20 ml of 6 N hydrochloric acid are stirred and refluxed for 18 hours. After cooling, the mixture is filtered, and the collected solid is washed with 6 N hydrochloric acid and then with ethanol. The dried material weighs 1.03 g (87%). Recrystallization from absolute ethanol gives pure 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine hydrochloride, m.p. 304 - 307°C.
Analyse beregn, for: C22H23N02*HC1:Analysis calculate, for: C22H23N02*HC1:
Beregnet: C 71,43; H 6,54; N 3,79; Cl 9,59. Calculated: C 71.43; H 6.54; N 3.79; Cl 9.59.
Funnet: c 71,01; H 6,87; N 3,73; Cl 9,44. Found: c 71.01; H 6.87; N 3.73; Cl 9.44.
Eksempel 2 Example 2
Fremstilling av 1-methy1-1-oxo-4-(3-carboxy-10,11-dihydro-5H-dibenzo-i a,dj-cyclohepten-5-yliden)-piperidin Preparation of 1-methyl-1-oxo-4-(3-carboxy-10,11-dihydro-5H-dibenzo-i a,dj-cyclohepten-5-ylidene)-piperidine
En oppløsning av 4,13 g (0,0177 mol) 3-cyano-10,11-dihydro-5H-dibenzo-; a,d ;-cyclohepten-5-on (fremstilt fra 3-bromketonet ved omsetning med cuprocyanid ved fremgangsmåten i eksempel 1, trinn B, når den passende substitusjon av reaktanter er gjort) i 40 ml tetrahydrofuran behandles med 42 ml 0,43 M l-methyl-4-piperidyl-magnesiumklorid. Oppløsningen omrøres i 1 time, og derpå fjernes tetrahydrofuranet på en roterende fordamper. Det røde oljeaktige residuum oppløses i benzen, og 'vann tilsettes dråpevis inntil mari får en klar benzen-overstående væske og en geia-tinøs vannfase. Benzenet fradekanteres, og den gelatinøse vannfase ekstraheres med 2 x 100 ml varm benzen. De forenede benzenfaser vaskes med 6 x 200 ml vann, og derpå inndampes benzenfasen på en roterende fordamper. Residuet tritureres med acetonitril. Det krystallinske produkt fjernes ved filtrering, vaskes med ytterligere acetonitril, oppsamles og tørres ved 6o°C, hvorved man får 2,88 g (49%) krystallinsk forbindelse VII (skjema II) som blandes med 60 ml 6 N saltsyre og kokes under tilbakeløp i 24 timer, hvorved man får 2,80 g av forbindelse I (skjema II). En blanding av 2,80 g av forbindelse I og 2 ml bortrifluorid- A solution of 4.13 g (0.0177 mol) of 3-cyano-10,11-dihydro-5H-dibenzo-; a,d ;-cyclohepten-5-one (prepared from the 3-bromoketone by reaction with cuprocyanide by the procedure of Example 1, step B, when the appropriate substitution of reactants has been made) in 40 ml of tetrahydrofuran is treated with 42 ml of 0.43 M 1-methyl-4-piperidyl magnesium chloride. The solution is stirred for 1 hour, and then the tetrahydrofuran is removed on a rotary evaporator. The red oily residue is dissolved in benzene, and water is added dropwise until a clear benzene supernatant liquid and a gelatinous water phase are obtained. The benzene is decanted off, and the gelatinous water phase is extracted with 2 x 100 ml of hot benzene. The combined benzene phases are washed with 6 x 200 ml of water, and then the benzene phase is evaporated on a rotary evaporator. The residue is triturated with acetonitrile. The crystalline product is removed by filtration, washed with additional acetonitrile, collected and dried at 6o°C, whereby 2.88 g (49%) of crystalline compound VII (Scheme II) is obtained which is mixed with 60 ml of 6 N hydrochloric acid and refluxed for 24 hours, whereby 2.80 g of compound I (scheme II) is obtained. A mixture of 2.80 g of compound I and 2 ml of boron trifluoride
etherat i 200 ml absolutt ethanol kokes under tilbakeløp i 8 timer. Oppløsningen inndampes til tørrhet, og residuet fordeles mellom ether og vandig nat riumcarbonatoppløsning. Etherfasen fjernes, tørres over magnesiumsulfat, filtreres, og etheren fjernes ved fordampning. Man får 2,7 g av ethylesteren VIII (skjema II) som oppløses i lOO ml methanol, 10 ml vann og 10 ml 30%-ig hydrogenperoxyd. Efter omrøring i 48 timer ved værelsetemperatur tilsettes en liten skje 5%-ig Pt/C, og blandingen omrøres i ytterligere 2 timer for å spalte overskudd av hydrogenperoxyd. Blandingen filtrerers, og oppløsningsmidlet fordampes, hvorved man får kromatograf isk rent ethylester-N-oxyd IX (skjema II). 1 g av ethylester-N-oxyd IX oppløses i IO ml methanol inneholdende 2 ml 2 N kaliumhydroxyd. Oppløsningen oppvarmes på dampbad i 2 timer. Methanolen fjernes, 10 ml vann tilsettes til residuet, og under omrøring tilsettes iseddik dråpevis inntil intet ytterligere bunn-fall dannes. Det hvite, faste stoff som dannes, fjernes ved filtrering og vaskes omhyggelig med vann. Produktet oppsamles og tørres, hvorved man får I-N-oxyd-seskvihydrat, smp. 208 - 209°C (spaltning, skummer), tynnskiktskromatografisk homogent. etherate in 200 ml of absolute ethanol is boiled under reflux for 8 hours. The solution is evaporated to dryness, and the residue is distributed between ether and aqueous sodium carbonate solution. The ether phase is removed, dried over magnesium sulfate, filtered, and the ether is removed by evaporation. 2.7 g of the ethyl ester VIII (scheme II) is obtained, which is dissolved in 100 ml of methanol, 10 ml of water and 10 ml of 30% hydrogen peroxide. After stirring for 48 hours at room temperature, a small spoonful of 5% Pt/C is added, and the mixture is stirred for a further 2 hours to decompose excess hydrogen peroxide. The mixture is filtered, and the solvent is evaporated, thereby obtaining chromatographically pure ethyl ester N-oxide IX (scheme II). 1 g of ethyl ester N-oxide IX is dissolved in 10 ml of methanol containing 2 ml of 2 N potassium hydroxide. The solution is heated on a steam bath for 2 hours. The methanol is removed, 10 ml of water is added to the residue, and glacial acetic acid is added dropwise while stirring until no further precipitate forms. The white solid that forms is removed by filtration and washed thoroughly with water. The product is collected and dried, whereby I-N-oxyde sesquihydrate is obtained, m.p. 208 - 209°C (decomposition, foaming), thin layer chromatography homogeneous.
Analyse beregn, for C^H^NO^-l 1/2 H20: Analysis calculate, for C^H^NO^-l 1/2 H20:
Beregnet: C 70,19; H 6,96; N 3,72. Calculated: C 70.19; H 6.96; N 3.72.
Funnet: C 70,30; H 6,77; N 3,51. Found: C 70.30; H 6.77; N 3.51.
Eksempel 3 Example 3
Fremstilling av l-methyl-4-(3-carboxy-10,ll-dihydro-5H-dibenzo-[ a, d]- cyclohepten- 5- yliden)- piperidin- hydroklorid Preparation of 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine hydrochloride
En oppløsning av 0,43 g (0,00162 mol) l-methyl-4-(3-carboxy-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin-hydroklorid i 25 ml 0,1N saltsyre hydrogeneres over 50 mg 5%-ig palladium-på-trekull ved værelsetemperatur ved et begynnelses-hydrogentrykk på 2,8 kg/cm" i 12 timer. 15 ml vann tilsettes, og blandingen filtreres for å fjerne katalysatoren. Filtratet inndampes til tørrhet under vakuum, og residuet omkrystalliseres fra 10 ml absolutt ethanol. Produktet oppsamles og tørres ved 100°C under vakuum, hvorved man får 0,16 g l-methyl-4-(3-carboxy-10,ll-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin-hydroklorid med smp. 307 - 310°C. A solution of 0.43 g (0.00162 mol) of 1-methyl-4-(3-carboxy-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine hydrochloride in 25 ml of 0.1N hydrochloric acid is hydrogenated over 50 mg of 5% palladium-on-charcoal at room temperature at an initial hydrogen pressure of 2.8 kg/cm" for 12 hours. 15 ml of water is added and the mixture is filtered to remove the catalyst. The filtrate is evaporated to dryness under vacuum, and the residue is recrystallized from 10 ml of absolute ethanol. The product is collected and dried at 100° C. under vacuum, whereby 0.16 g of 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo is obtained -[α,d]-cyclohepten-5-ylidene)-piperidine hydrochloride with mp 307 - 310°C.
Eksempel 4 Example 4
Fremstilling av l-methyl-4-(3-carboxy-10,ll-dihydro-5H-dibenzo-[ a, d]- cyclohepten- 5- yliden)- piperidin- hydroklorid Preparation of 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine hydrochloride
I en flammetørret, nitrogenspylt kolbe forsynt med rører, kjøler med et calciumklorid-tørrerrør, og dråpetrakt innføres 0,68 g (0,02 8 mol) magnesiumspon og 2 ml tørr tetrahydrofuran. Blandingen oppvarmes til tilbakeløp, og 0,81 g l-methyl-4-klor-piperidin og en krystall av jod tilsettes. Grignard-reaksjonen begynner straks. En oppløsning av 5,0 g (0,0136 mol) l-methyl-4-(3-brom-10,ll-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin i 25 ml tetrahydrofuran tilsettes dråpevis til den under tilbakeløp svakt kokende oppløsning i løpet av 1 time. Efter at tilsetningen er avsluttet, kokes blandingen under tilbakeløp i 4 timer, avkjøles til værelsetemperatur og helles så i et overskudd av knust tørr-is. Blandingen omrøres og får lov til å oppvarmes til værelsetemperatur. 150 ml ether og 150 ml 6N saltsyre tilsettes, og blandingen omrøres inntil et to-fasesystem er erholdt. Den vandige syrefase trekkes av og vaskes nok en gang med ether. Den vandige syrefase gjøres basisk ved tilsetning av 40%-ig natriumhydroxydoppløsning, hvorefter oppløsningen filtreres. Den klare vannfase ekstraheres med 200 ml ether og gjøres derpå sur ved tilsetning av 6N saltsyre. Oppløsningen inndampes på en roterende inndamper ved 60-70°C til et volum på ca. 100 ml. Under denne inndampning krystalliserer l-methyl-4-(3-carboxy-10,ll-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin-hydroklorid fra oppløsningen. Væsken dekanteres fra det faste stoff, og det krystallinske residuum oppslemmes med 50 ml vann. Dette vann fradekanteres, og residuet tritureres med 50 ml absolutt ethanol. Produktet oppsamles ved filtrering, vaskes med kold absolutt ethanol og tørres, hvorved man får 1,30 g (26%) l-methyl-4-(3-carboxy-10,ll-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-yliden)-piperidin-hydroklorid med smp. 304 - 307°C. Blandet smeltepunkt med autentisk materiale fremstilt tidligere, var 304 - 307°C. Produktet er homogent ved tynnskiktskromatografi i fluorescerende silicagel under anvendelse av n-butanol, eddik-syre, vann (5:2:3) og er homogent ved tynnskiktskromatografi når blandet med autentisk materiale tidligere fremstilt. Into a flame-dried, nitrogen-flushed flask fitted with a stirrer, cooled with a calcium chloride drying tube, and dropwise introduced 0.68 g (0.02 8 mol) of magnesium shavings and 2 ml of dry tetrahydrofuran. The mixture is heated to reflux, and 0.81 g of 1-methyl-4-chloro-piperidine and a crystal of iodine are added. The Grignard reaction begins immediately. A solution of 5.0 g (0.0136 mol) of 1-methyl-4-(3-bromo-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine in 25 ml of tetrahydrofuran is added dropwise to the gently boiling solution under reflux over the course of 1 hour. After the addition is finished, the mixture is refluxed for 4 hours, cooled to room temperature and then poured into an excess of crushed dry ice. The mixture is stirred and allowed to warm to room temperature. 150 ml of ether and 150 ml of 6N hydrochloric acid are added, and the mixture is stirred until a two-phase system is obtained. The aqueous acid phase is drawn off and washed once more with ether. The aqueous acid phase is made basic by adding a 40% sodium hydroxide solution, after which the solution is filtered. The clear water phase is extracted with 200 ml of ether and then made acidic by adding 6N hydrochloric acid. The solution is evaporated on a rotary evaporator at 60-70°C to a volume of approx. 100 ml. During this evaporation, 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5-ylidene)-piperidine hydrochloride crystallizes from the solution. The liquid is decanted from the solid, and the crystalline residue is slurried with 50 ml of water. This water is decanted off, and the residue is triturated with 50 ml of absolute ethanol. The product is collected by filtration, washed with cold absolute ethanol and dried, thereby obtaining 1.30 g (26%) of 1-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-[a,d] -cyclohepten-5-ylidene)-piperidine hydrochloride with m.p. 304 - 307°C. Mixed melting point with authentic material prepared earlier was 304 - 307°C. The product is homogeneous by thin-layer chromatography in fluorescent silica gel using n-butanol, acetic acid, water (5:2:3) and is homogeneous by thin-layer chromatography when mixed with authentic material previously prepared.
Fremstilling av utgangsmateriale, 3-carboxy-10,11-dihydrocyproheptadin- hydroklorid Preparation of starting material, 3-carboxy-10,11-dihydrocyproheptadine hydrochloride
En oppløsning av 1,27 g av ethylesteren av 3-carboxy-10,11-dihydrocyproheptadin (smp. 85 - 87°C) i 5 ml ethanol inneholdende 1 ml 2N kaliumhydroxyd omrøres og oppvarmes på dampbad i 2 timer. Ethanolen fjernes ved fordampning under redusert trykk. Residuet oppløses i 5 ml vann, og 6N saltsyre tilsettes inntil blandingen er sur. Bunnfallet som dannes, oppsamles ved filtrering, vaskes med koldt vann, absolutt ethanol og tørres i en 60°C vakuumovn, hvorved man får 0,80 g 3-carboxy-10,11-dihydrocyproheptadin-hydroklorid med smp. 306 - 310°C, som er homogent ved tynnskiktskromatografi. A solution of 1.27 g of the ethyl ester of 3-carboxy-10,11-dihydrocyproheptadine (m.p. 85 - 87°C) in 5 ml of ethanol containing 1 ml of 2N potassium hydroxide is stirred and heated on a steam bath for 2 hours. The ethanol is removed by evaporation under reduced pressure. The residue is dissolved in 5 ml of water, and 6N hydrochloric acid is added until the mixture is acidic. The precipitate that forms is collected by filtration, washed with cold water, absolute ethanol and dried in a 60°C vacuum oven, whereby 0.80 g of 3-carboxy-10,11-dihydrocyproheptadine hydrochloride with m.p. 306 - 310°C, which is homogeneous by thin layer chromatography.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US52267674A | 1974-11-11 | 1974-11-11 | |
US56328575A | 1975-03-28 | 1975-03-28 |
Publications (3)
Publication Number | Publication Date |
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NO753562L NO753562L (en) | 1976-05-12 |
NO144422B true NO144422B (en) | 1981-05-18 |
NO144422C NO144422C (en) | 1981-08-26 |
Family
ID=27060901
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO753562A NO144422C (en) | 1974-11-11 | 1975-10-23 | ANALOGUE PROCEDURE FOR THE PREPARATION OF 10,11-DIHYDRO-3-CARBOXYCYPROHEPTADINE. |
Country Status (19)
Country | Link |
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JP (1) | JPS6011029B2 (en) |
AR (1) | AR211108A1 (en) |
AT (1) | AT352126B (en) |
CA (1) | CA1082177A (en) |
CH (1) | CH621114A5 (en) |
DE (1) | DE2550395C3 (en) |
DK (1) | DK474575A (en) |
ES (1) | ES442375A1 (en) |
FI (1) | FI59583C (en) |
FR (1) | FR2290203A1 (en) |
IE (1) | IE42220B1 (en) |
IL (1) | IL48365A (en) |
LU (1) | LU73771A1 (en) |
NL (2) | NL173398B (en) |
NO (1) | NO144422C (en) |
NZ (1) | NZ179080A (en) |
PH (1) | PH13443A (en) |
SE (1) | SE424990B (en) |
YU (1) | YU273475A (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US4195091A (en) * | 1978-11-15 | 1980-03-25 | Merck & Co., Inc. | Appetite stimulating pyrrolo[2,1-b][3]benzazepines |
US4412999A (en) * | 1982-04-14 | 1983-11-01 | Merck & Co., Inc. | Anti-emetic esters of cyproheptadine-3-carboxylic acid and structurally related compounds |
US5250681A (en) * | 1988-06-02 | 1993-10-05 | Ajinomoto Co., Inc. | Piperidine derivatives and hypotensives containing the same |
-
0
- NL NLAANVRAGE7512384,A patent/NL173398C/en active
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1975
- 1975-10-20 FI FI752920A patent/FI59583C/en not_active IP Right Cessation
- 1975-10-21 SE SE7511792A patent/SE424990B/en unknown
- 1975-10-22 DK DK474575A patent/DK474575A/en unknown
- 1975-10-22 NL NLAANVRAGE7512384,A patent/NL173398B/en not_active IP Right Cessation
- 1975-10-23 NO NO753562A patent/NO144422C/en unknown
- 1975-10-27 CA CA238,610A patent/CA1082177A/en not_active Expired
- 1975-10-27 PH PH17702A patent/PH13443A/en unknown
- 1975-10-27 IL IL48365A patent/IL48365A/en unknown
- 1975-10-28 NZ NZ179080A patent/NZ179080A/en unknown
- 1975-10-29 YU YU02734/75A patent/YU273475A/en unknown
- 1975-11-05 ES ES442375A patent/ES442375A1/en not_active Expired
- 1975-11-05 IE IE2406/75A patent/IE42220B1/en unknown
- 1975-11-06 AT AT843975A patent/AT352126B/en not_active IP Right Cessation
- 1975-11-07 FR FR7534117A patent/FR2290203A1/en active Granted
- 1975-11-10 CH CH1453475A patent/CH621114A5/en not_active IP Right Cessation
- 1975-11-10 AR AR261126A patent/AR211108A1/en active
- 1975-11-10 LU LU73771A patent/LU73771A1/xx unknown
- 1975-11-10 DE DE2550395A patent/DE2550395C3/en not_active Expired
- 1975-11-11 JP JP50134784A patent/JPS6011029B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
IL48365A (en) | 1978-10-31 |
CA1082177A (en) | 1980-07-22 |
FR2290203B1 (en) | 1980-05-30 |
YU273475A (en) | 1983-04-27 |
DK474575A (en) | 1976-05-12 |
ES442375A1 (en) | 1977-08-16 |
DE2550395A1 (en) | 1976-05-13 |
NO144422C (en) | 1981-08-26 |
FI59583C (en) | 1981-09-10 |
FI59583B (en) | 1981-05-29 |
PH13443A (en) | 1980-04-23 |
AR211108A1 (en) | 1977-10-31 |
AU8605775A (en) | 1977-05-05 |
SE424990B (en) | 1982-08-23 |
CH621114A5 (en) | 1981-01-15 |
JPS5170769A (en) | 1976-06-18 |
SE7511792L (en) | 1976-05-12 |
NL173398B (en) | 1983-08-16 |
AT352126B (en) | 1979-09-10 |
NZ179080A (en) | 1978-07-10 |
IE42220B1 (en) | 1980-07-02 |
JPS6011029B2 (en) | 1985-03-22 |
DE2550395C3 (en) | 1979-08-09 |
NL173398C (en) | |
IL48365A0 (en) | 1975-12-31 |
IE42220L (en) | 1976-05-11 |
DE2550395B2 (en) | 1978-11-30 |
FR2290203A1 (en) | 1976-06-04 |
NL7512384A (en) | 1976-05-13 |
NO753562L (en) | 1976-05-12 |
FI752920A (en) | 1976-05-12 |
LU73771A1 (en) | 1976-09-06 |
ATA843975A (en) | 1979-02-15 |
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