CA1210027A - Process for the preparation of 2-/e/phenyl- methylenecycloheptan-1-one-/e/-oxime - Google Patents
Process for the preparation of 2-/e/phenyl- methylenecycloheptan-1-one-/e/-oximeInfo
- Publication number
- CA1210027A CA1210027A CA000425105A CA425105A CA1210027A CA 1210027 A CA1210027 A CA 1210027A CA 000425105 A CA000425105 A CA 000425105A CA 425105 A CA425105 A CA 425105A CA 1210027 A CA1210027 A CA 1210027A
- Authority
- CA
- Canada
- Prior art keywords
- water
- ice
- alcohol
- reaction
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000012429 reaction media Substances 0.000 claims abstract description 15
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000002443 hydroxylamines Chemical class 0.000 claims abstract description 4
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 18
- 125000001931 aliphatic group Chemical group 0.000 claims 8
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000011541 reaction mixture Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BQCRDGOBIZRDJH-ACCUITESSA-N (2e)-2-benzylidenecycloheptan-1-one Chemical compound O=C1CCCCC\C1=C/C1=CC=CC=C1 BQCRDGOBIZRDJH-ACCUITESSA-N 0.000 description 1
- SDEBYHVDMCQKNZ-UHFFFAOYSA-N 4-methoxy-6-piperazin-1-ylpyrimidine;hydrochloride Chemical compound Cl.C1=NC(OC)=CC(N2CCNCC2)=N1 SDEBYHVDMCQKNZ-UHFFFAOYSA-N 0.000 description 1
- 241001502381 Budorcas taxicolor Species 0.000 description 1
- 101150041968 CDC13 gene Proteins 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
- 229930194542 Keto Natural products 0.000 description 1
- 101100536883 Legionella pneumophila subsp. pneumophila (strain Philadelphia 1 / ATCC 33152 / DSM 7513) thi5 gene Proteins 0.000 description 1
- 241000357437 Mola Species 0.000 description 1
- 101100240664 Schizosaccharomyces pombe (strain 972 / ATCC 24843) nmt1 gene Proteins 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- -1 hydroxylamine salts Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
The invention relates to a process for the preparation of 2-/E/-phenylmethylenecycloheptan-1-one-/E/-oxime of the formula /I/
/I/
free of other isomers.
According to the invention the compound of the formula /I/ is prepared by reacting 2-/E/-phenylmethylene-cycloheptzn-1-one of the formula /II/
with hydroxylamine obtained "in situ" from a hydroxylamine salt in the presence of a base. The reaction is carried out in water and/or in a lower, with water unrestrictedly miscible aliphatic alcohol, and subsequently the alcohol content of the reaction medium is adjusted to 40-60 %. The compound of the formula /I/ is isolated from the reaction mixture by known methods.
The 2-/E/-phenylmethylenecycloheptan-1-one-/E/-oxime of the formula /I/ serves as intermediate for the synthesis of compounds possessing valuable pharmaceutical properties.
The invention relates to a process for the preparation of 2-/E/-phenylmethylenecycloheptan-1-one-/E/-oxime of the formula /I/
/I/
free of other isomers.
According to the invention the compound of the formula /I/ is prepared by reacting 2-/E/-phenylmethylene-cycloheptzn-1-one of the formula /II/
with hydroxylamine obtained "in situ" from a hydroxylamine salt in the presence of a base. The reaction is carried out in water and/or in a lower, with water unrestrictedly miscible aliphatic alcohol, and subsequently the alcohol content of the reaction medium is adjusted to 40-60 %. The compound of the formula /I/ is isolated from the reaction mixture by known methods.
The 2-/E/-phenylmethylenecycloheptan-1-one-/E/-oxime of the formula /I/ serves as intermediate for the synthesis of compounds possessing valuable pharmaceutical properties.
Description
z~
PRO~ESS ~OR THE PREP~RATION O~ 2-/~/-P~Y~T~YL~N~-CY~LO~EPT~N-l-O~E~ O~I~E
~he i~Yention relate~ to a proces~ for the pxeparatio~
o~ 2-JE/-phenylmethylenecycloheptan-l-o~e-/E/-o~ime of the formula /I/
~ O H
\ ) ~ree of other i~omers. ~he compound o~ the for~ula /I/ 3erve~
a~ i~termediate u~e~ul i~ the ~ynthesi~ o~ deriYative3 ha~ing valuable pharmacautical propertie~, e.g~ in the ~ynthe~i~ o~
the compou~d~ de~cr~bed i~ Hungarian Patent Specification No. 1~ B~.
~o method ha3 bee~ ~o ~ar described i~ literature ~or 2Q the preparation of the compo~nd of ~or~lla ~
It 1~ known that ketona~ i~teract ~ith hydro~yl~mine obtalned "in ~itu" from ~ hydro~lamine ~alt i~ the pre~e~Ge of a ba~e~ The reactio~ r~ult~ in a~ o~ime. Takin~ th~
structural properti~ o~ the ~tarti~æ keto~e i~to account, two i~omer~ may be ~or~sd in the reaction. I~ 3impler case~ they are called ll~yn~ and "~ti9', re~pectively, while in ca~e of compound~ of more complicated ~tr~cture the designatio~ tfZ
- ~nd "~"~ re~pectively, are u~ed.
It is known that -the different isomers possess different biological properties. That is why in many instances it is necessary to prepare them in pure form, which can be accomplished only from intermediates free of isomers.
The aim of our investigations was to elaborate a method suitable for the production of the 2-[E]-phenylmethylenecycloheptan-l-one-[E]-oxime of the formula I substantially free of ot'ner isomers.
It has been found that when reacting the 2-[E]-phenyl-methylenecycloheptan~l~one of the formula [II]
~ ~ [II]
with hydroxylamine obtained "in situ" from a hydroxylamine salt in the presence of a base in water and/or in a lower, with water un-restrictedly miscible aliphatic alcohol and if necessary adjusting the alcohol content of the reaction medium to ~0-60%, preferably to 50%. The 2-[E]-phenylmethyleneacycloheptan-l-one-E-oxime can be isolated by known method~ The product contains at most 5% of other isomers, which can be removed, if desired, by known methods.
The starting compound of the formula [II] is known and can be prepared by methods described in iiterature [e.~.: Gazz.
Chim. Ital. 91, 326-48(1961)~. The hydroxylamine salts[sulfate, hydrochloride] are commercial products.
The reaction of the 2-[E]-phenylmethylenecycloheptan-1-one with the hydroxylamine obtained "in situ" from a hydroxylamine salt ~preferably sulfate or hydrochloride] is carried out in water and/or in an aqueous alcohol as medium. For this ~,:' ~z~
purpo3e straight or branched, with water u~restrictedly mlscible aliph~tic alcohol~ can be u3e~, such metha~ol, ethanol, n-propanol, isopropanol~ etc. '~he reactio~
i3 pre~erably performed i~ the ~ixtuxe of n alcohol and ~a-ter, preferably in ~ /50 98/:/2-50/ mixture of the~e Yol~enta.
When the reactio~ termi~ate~, the Qlcohol concentratio~ i3 adju~ted to 40-60, pre~erably to about 50 ~0 bg the addition o~ water /ice/ or ~lcoholO
The reactio~ i~ carried out in the presence of a ~a3e~
~or thi~ purpo~e organic base~ /pyridi~e or pyridine ba~es, that i~ the mi~ture~ of 2-, 3- and 4-picoline a~d lutidi~e, re~pectiYely/ or o~ ~ ic base~ ~alkali hydro~ide~, carbonate~
or hydrogan carbonate~J can be u~ed.
The reaction temperature doe~ not influence the yield e~e~ially and m~y be varied in a wide intarval. ~ne proceed~
generally between 20 C and 90 C, preferably betwee~ 75 ~
~nd 85 C.
~ha ~tereochemical purity of the th~s-obtained 2-/E/--phe~ylmethylenecyclohept~n~l one-/E/-o~ime depe~dq o~ that o~ the 2-/~/phenylmethylenecycloheptan-l-o~e u~ed for the reaction. ~amely, i~ thi3 latter compou~d i~ contami~ated with a greater amount of it~ 2-/Z/-iJomer, the number o~ the po~ible isomer co~taminations i~crea~es twofold, and the im~
purity of the thu~-obtained product may e~ceed the limit ~ive~
above~
If a particularl~ pure product i~ needed, the crude product obtai~ed in the re~ctio~ c~n be pured b~ methods knowm per 3e /e~g~ col~mn chromatogxaphy~ di~tillatio~, melti~g in zone3, cry3tallization from petroleum ether or from eth~nol~.
3 The inve~tion i~ illu~tr~ted by ~he ~ollowi~g E~mple3 o~ non-limiti~g character:
E~ample 1 20 g ~Ool mole/ o~ 2~/E/-phenylmethylenecycloheptan--l-one and 7.65 g /0.11 moles/ o~ hydroxylamine hydrochloride ~re di~olved in 100 cm3 of 96 /o ethanol, and ~.94 g /o~o56 mole ~ of ~odium carbo~ate a~e added to the raaction mixtuxe, under ~ti~ring. ~he~ it i.s heated to boiling and kept at the ~ame temperature until the gaq formation /carbon dioxide/
terminate~. Thereafter 98 g of crushed iC2 are added to the reaction mixture, and the 2~ phe~ylmethylenecycloheptan--l-one-/E/-o~ime 3eparated in ~orm of cry3t~1~ i3 filtered off.
Yield: 19~8 æ /92 ,'/ o~ white cry~tal~. M~p~o 67 C
Analy~ 4H17~0 /215.29f Calculated: C: 7~ . 7.96 ,'0 ~: 6.5 ,0 Fou~d: G: 78.0 -~0 H: 8.0 ,~0 ~: 6.5 Yo ~P~ /CDC13~: 6 . 95 pp~
6055 ppm 2020 5 ppm U-V-; ~ m~x 258 n~ mh /258/ ~ 740.23 EgamPle 2 To a 301ution of 20 g /0.1 mole/ of 2-/E/-phenylmethyle~e-cyclohepta~ one in 100 cm3 of methanol 7.64 g /0,11 moles/
of hydroxylamine hydrochloride a~d 8.7 g /0.11 mole~ o~ py-ridine are addedO The reaction mi~ture i~ ~tirred at room temperatu~e for 2 hour~, a~d 100 g o~ cru~hed ice a~e added.
The desired compound 3eparate~ i~ Porm oP while cryatal~O
Yield~ 16.55 g /76.97 ~! Mop~ 66-67 C
0`2~' ~naly3i3: the data are identical to tho~e give~ in E2ample 1.
E~ample 3 20 g /0.1 mole/ of 2-/E/-phenylmethylenecyclohepta~-:L--one, 7.64 g /0.11 mole~/ of hydroxylamine hydrochloride an~
5.83 g /0 D55 mole~/ of sodium carbonate are allowed to react in 200 cm o~ a ].:1 mi~ture o~ ethanol and water at the boil-ing point of the reaction mi~ture, the~ it i~ cooled ~o a temperature between 5 C and 10 C under ~igorou~ stirring.
~he crystalline 2-~E/-phe~ylmethylenec~cloheptan~l-one~
-o~ime i~ i~olated from the reaction mixture by filtrationD
Yield: 17.65 g /82 -~0/. M.p.: 66-67 C
~xample 4 20 g /Ool mole~ of 2-/E/-phenylmethyle~ecycloheptan--l o~e, 100 cm3 of water, 8.7 g ~0.11 mole3/ o~ pyridi ~ a~d 7.64 g ~0.11 ~ole3/ of hydroxyl~Ine hydrochloride are vigorou~-ly 3tirred at 80 C for a ~ew hours, the~ 100 cm3 o~ ethanol are added to the reaction mixture, ~nd it i~ stirxed u~til crystalli~tion~ under 310w cooli~gO
Yield: 15.7 g f72O92 5~/ of white, cry~talline 2-~E/-phenyl-methyl~necycloheptan-l-one /E/-o~ime. ~Op~` 65-67 C.
E:gamPle 5
PRO~ESS ~OR THE PREP~RATION O~ 2-/~/-P~Y~T~YL~N~-CY~LO~EPT~N-l-O~E~ O~I~E
~he i~Yention relate~ to a proces~ for the pxeparatio~
o~ 2-JE/-phenylmethylenecycloheptan-l-o~e-/E/-o~ime of the formula /I/
~ O H
\ ) ~ree of other i~omers. ~he compound o~ the for~ula /I/ 3erve~
a~ i~termediate u~e~ul i~ the ~ynthesi~ o~ deriYative3 ha~ing valuable pharmacautical propertie~, e.g~ in the ~ynthe~i~ o~
the compou~d~ de~cr~bed i~ Hungarian Patent Specification No. 1~ B~.
~o method ha3 bee~ ~o ~ar described i~ literature ~or 2Q the preparation of the compo~nd of ~or~lla ~
It 1~ known that ketona~ i~teract ~ith hydro~yl~mine obtalned "in ~itu" from ~ hydro~lamine ~alt i~ the pre~e~Ge of a ba~e~ The reactio~ r~ult~ in a~ o~ime. Takin~ th~
structural properti~ o~ the ~tarti~æ keto~e i~to account, two i~omer~ may be ~or~sd in the reaction. I~ 3impler case~ they are called ll~yn~ and "~ti9', re~pectively, while in ca~e of compound~ of more complicated ~tr~cture the designatio~ tfZ
- ~nd "~"~ re~pectively, are u~ed.
It is known that -the different isomers possess different biological properties. That is why in many instances it is necessary to prepare them in pure form, which can be accomplished only from intermediates free of isomers.
The aim of our investigations was to elaborate a method suitable for the production of the 2-[E]-phenylmethylenecycloheptan-l-one-[E]-oxime of the formula I substantially free of ot'ner isomers.
It has been found that when reacting the 2-[E]-phenyl-methylenecycloheptan~l~one of the formula [II]
~ ~ [II]
with hydroxylamine obtained "in situ" from a hydroxylamine salt in the presence of a base in water and/or in a lower, with water un-restrictedly miscible aliphatic alcohol and if necessary adjusting the alcohol content of the reaction medium to ~0-60%, preferably to 50%. The 2-[E]-phenylmethyleneacycloheptan-l-one-E-oxime can be isolated by known method~ The product contains at most 5% of other isomers, which can be removed, if desired, by known methods.
The starting compound of the formula [II] is known and can be prepared by methods described in iiterature [e.~.: Gazz.
Chim. Ital. 91, 326-48(1961)~. The hydroxylamine salts[sulfate, hydrochloride] are commercial products.
The reaction of the 2-[E]-phenylmethylenecycloheptan-1-one with the hydroxylamine obtained "in situ" from a hydroxylamine salt ~preferably sulfate or hydrochloride] is carried out in water and/or in an aqueous alcohol as medium. For this ~,:' ~z~
purpo3e straight or branched, with water u~restrictedly mlscible aliph~tic alcohol~ can be u3e~, such metha~ol, ethanol, n-propanol, isopropanol~ etc. '~he reactio~
i3 pre~erably performed i~ the ~ixtuxe of n alcohol and ~a-ter, preferably in ~ /50 98/:/2-50/ mixture of the~e Yol~enta.
When the reactio~ termi~ate~, the Qlcohol concentratio~ i3 adju~ted to 40-60, pre~erably to about 50 ~0 bg the addition o~ water /ice/ or ~lcoholO
The reactio~ i~ carried out in the presence of a ~a3e~
~or thi~ purpo~e organic base~ /pyridi~e or pyridine ba~es, that i~ the mi~ture~ of 2-, 3- and 4-picoline a~d lutidi~e, re~pectiYely/ or o~ ~ ic base~ ~alkali hydro~ide~, carbonate~
or hydrogan carbonate~J can be u~ed.
The reaction temperature doe~ not influence the yield e~e~ially and m~y be varied in a wide intarval. ~ne proceed~
generally between 20 C and 90 C, preferably betwee~ 75 ~
~nd 85 C.
~ha ~tereochemical purity of the th~s-obtained 2-/E/--phe~ylmethylenecyclohept~n~l one-/E/-o~ime depe~dq o~ that o~ the 2-/~/phenylmethylenecycloheptan-l-o~e u~ed for the reaction. ~amely, i~ thi3 latter compou~d i~ contami~ated with a greater amount of it~ 2-/Z/-iJomer, the number o~ the po~ible isomer co~taminations i~crea~es twofold, and the im~
purity of the thu~-obtained product may e~ceed the limit ~ive~
above~
If a particularl~ pure product i~ needed, the crude product obtai~ed in the re~ctio~ c~n be pured b~ methods knowm per 3e /e~g~ col~mn chromatogxaphy~ di~tillatio~, melti~g in zone3, cry3tallization from petroleum ether or from eth~nol~.
3 The inve~tion i~ illu~tr~ted by ~he ~ollowi~g E~mple3 o~ non-limiti~g character:
E~ample 1 20 g ~Ool mole/ o~ 2~/E/-phenylmethylenecycloheptan--l-one and 7.65 g /0.11 moles/ o~ hydroxylamine hydrochloride ~re di~olved in 100 cm3 of 96 /o ethanol, and ~.94 g /o~o56 mole ~ of ~odium carbo~ate a~e added to the raaction mixtuxe, under ~ti~ring. ~he~ it i.s heated to boiling and kept at the ~ame temperature until the gaq formation /carbon dioxide/
terminate~. Thereafter 98 g of crushed iC2 are added to the reaction mixture, and the 2~ phe~ylmethylenecycloheptan--l-one-/E/-o~ime 3eparated in ~orm of cry3t~1~ i3 filtered off.
Yield: 19~8 æ /92 ,'/ o~ white cry~tal~. M~p~o 67 C
Analy~ 4H17~0 /215.29f Calculated: C: 7~ . 7.96 ,'0 ~: 6.5 ,0 Fou~d: G: 78.0 -~0 H: 8.0 ,~0 ~: 6.5 Yo ~P~ /CDC13~: 6 . 95 pp~
6055 ppm 2020 5 ppm U-V-; ~ m~x 258 n~ mh /258/ ~ 740.23 EgamPle 2 To a 301ution of 20 g /0.1 mole/ of 2-/E/-phenylmethyle~e-cyclohepta~ one in 100 cm3 of methanol 7.64 g /0,11 moles/
of hydroxylamine hydrochloride a~d 8.7 g /0.11 mole~ o~ py-ridine are addedO The reaction mi~ture i~ ~tirred at room temperatu~e for 2 hour~, a~d 100 g o~ cru~hed ice a~e added.
The desired compound 3eparate~ i~ Porm oP while cryatal~O
Yield~ 16.55 g /76.97 ~! Mop~ 66-67 C
0`2~' ~naly3i3: the data are identical to tho~e give~ in E2ample 1.
E~ample 3 20 g /0.1 mole/ of 2-/E/-phenylmethylenecyclohepta~-:L--one, 7.64 g /0.11 mole~/ of hydroxylamine hydrochloride an~
5.83 g /0 D55 mole~/ of sodium carbonate are allowed to react in 200 cm o~ a ].:1 mi~ture o~ ethanol and water at the boil-ing point of the reaction mi~ture, the~ it i~ cooled ~o a temperature between 5 C and 10 C under ~igorou~ stirring.
~he crystalline 2-~E/-phe~ylmethylenec~cloheptan~l-one~
-o~ime i~ i~olated from the reaction mixture by filtrationD
Yield: 17.65 g /82 -~0/. M.p.: 66-67 C
~xample 4 20 g /Ool mole~ of 2-/E/-phenylmethyle~ecycloheptan--l o~e, 100 cm3 of water, 8.7 g ~0.11 mole3/ o~ pyridi ~ a~d 7.64 g ~0.11 ~ole3/ of hydroxyl~Ine hydrochloride are vigorou~-ly 3tirred at 80 C for a ~ew hours, the~ 100 cm3 o~ ethanol are added to the reaction mixture, ~nd it i~ stirxed u~til crystalli~tion~ under 310w cooli~gO
Yield: 15.7 g f72O92 5~/ of white, cry~talline 2-~E/-phenyl-methyl~necycloheptan-l-one /E/-o~ime. ~Op~` 65-67 C.
E:gamPle 5
2~ 20 ~ /0.1 mole/ o~ 2w/E/-phenylmethylenecycloheptan~l--one and 21.4~ g ¦0~11 molesf o~ hydxo~yl~;ne sul~t~ are mea~uxed to a mixture o~ 95 cm3 o~ propanol a~d 5 cm3 o~
water. ~hen 10.94 g /0.056 mole~/ o~ po-t~s~ium carbo~ate are added, under ~tirri~g. After boiling the mixture ~or a few - ~o hour~ the reactio~ te~minate~ he~ t~e mixture i~ cooled ~2~
to about 50 C~ 100 g of cru3hed ice are added, the cry~tal~
are fil-tered off and dxied4 Yield: 18.48 g /a7.5 ~io/ of white cry~tal~ cont~i~in~ at lea~t 95 ~o of 2~E/ phenylmethyle~ecycloheptan-l~one-/EI-o~ime.
M.p.: 67 C
An~ly`~i~ C14~17~ /215~29/
~alculat~d: C: 78~ 7096 v/0 ~: 6,5 ~
~ound: C: 77.91 ,~ H: 7,8 ~0 ~: 6.47 ~0 ExamPle 6 20 g J0.1 mole~ of 2-/~/ phenylm~thylQnecycloheptan-l-o~e ~nd 7.65 g /0.11 mole~/ of hydro~yl ~m; ne hydrochloride ~re heated to boiling in 100 c~3 of etha~ol, under vigorous stirring, and a solution of 6.17 g /0.11 mole3/ of pota~ium hydroxide in loo cm3 of water i~ dropped to the reactio~ mix-ture~ The~ it i9 allowed to react for hal~ an hour, ~lowly cooledl and the separated 2-/E/-phenylmethylenecycloheptan-1--one-/E~-oxime is filtared o~fO
Yield: 2003 g /94.3 ~/0/. Mop~ 67 C
~xample 7 20 g /0.1 mola/ o~ 2~/E~-phe~ylmeth~lenecycloheptan-l--o~, 7.65 g /0~11 mole~/ of hydro~ylamine h~drochloride, 90 cm3 o~ ethanol, 10 cm3 o~ water and 9.24 g /0.11 mole3/ o~
sodium hydroge~ carbo~ate are boiled for 3 hours, under s~xr ~ .
Then 80 g of cru3hed ice are added to t~e reaction mi~ture, a~d th~ 2-JE/-~he~ylmethylenecgcloheptan-l-o~-/E/-o~ime ~e-parated in ~orm of white Gry~q-tals i~ fil~ered off and dri2d~
YieldO 20.2 g /93.8 C,~o/- M.p.: 67 C
Analy~is: C14H17~0 /215~29J
~ , ~... . .
Calculated: C: 78.1 ~7.96 ,0 N: 6.5 -~0 Found: C: 78.23 ~ioH: 7.72 ~ ~: 6.53 ~0
water. ~hen 10.94 g /0.056 mole~/ o~ po-t~s~ium carbo~ate are added, under ~tirri~g. After boiling the mixture ~or a few - ~o hour~ the reactio~ te~minate~ he~ t~e mixture i~ cooled ~2~
to about 50 C~ 100 g of cru3hed ice are added, the cry~tal~
are fil-tered off and dxied4 Yield: 18.48 g /a7.5 ~io/ of white cry~tal~ cont~i~in~ at lea~t 95 ~o of 2~E/ phenylmethyle~ecycloheptan-l~one-/EI-o~ime.
M.p.: 67 C
An~ly`~i~ C14~17~ /215~29/
~alculat~d: C: 78~ 7096 v/0 ~: 6,5 ~
~ound: C: 77.91 ,~ H: 7,8 ~0 ~: 6.47 ~0 ExamPle 6 20 g J0.1 mole~ of 2-/~/ phenylm~thylQnecycloheptan-l-o~e ~nd 7.65 g /0.11 mole~/ of hydro~yl ~m; ne hydrochloride ~re heated to boiling in 100 c~3 of etha~ol, under vigorous stirring, and a solution of 6.17 g /0.11 mole3/ of pota~ium hydroxide in loo cm3 of water i~ dropped to the reactio~ mix-ture~ The~ it i9 allowed to react for hal~ an hour, ~lowly cooledl and the separated 2-/E/-phenylmethylenecycloheptan-1--one-/E~-oxime is filtared o~fO
Yield: 2003 g /94.3 ~/0/. Mop~ 67 C
~xample 7 20 g /0.1 mola/ o~ 2~/E~-phe~ylmeth~lenecycloheptan-l--o~, 7.65 g /0~11 mole~/ of hydro~ylamine h~drochloride, 90 cm3 o~ ethanol, 10 cm3 o~ water and 9.24 g /0.11 mole3/ o~
sodium hydroge~ carbo~ate are boiled for 3 hours, under s~xr ~ .
Then 80 g of cru3hed ice are added to t~e reaction mi~ture, a~d th~ 2-JE/-~he~ylmethylenecgcloheptan-l-o~-/E/-o~ime ~e-parated in ~orm of white Gry~q-tals i~ fil~ered off and dri2d~
YieldO 20.2 g /93.8 C,~o/- M.p.: 67 C
Analy~is: C14H17~0 /215~29J
~ , ~... . .
Calculated: C: 78.1 ~7.96 ,0 N: 6.5 -~0 Found: C: 78.23 ~ioH: 7.72 ~ ~: 6.53 ~0
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 2-[E]-phenylmethylene-cycloheptan-1-one-[E]-oxime of the formula [I]
[I]
substantially free of other isomers by reacting 2-[E]-phenylmethyl-enecycloheptan-1-one of the formula [II]
[II]
with hydroxylamine obtained "in situ" from a hydroxylamine salt in the presence of a base, characterized by carrying out the reaction in water, in a completely water-miscible lower aliphatic alcohol or in a mixture of water and a completely water-miscible lower aliphatic alcohol and subsequently, if necessary adjusting the alcohol content of the reaction medium to 40 - 60%.
[I]
substantially free of other isomers by reacting 2-[E]-phenylmethyl-enecycloheptan-1-one of the formula [II]
[II]
with hydroxylamine obtained "in situ" from a hydroxylamine salt in the presence of a base, characterized by carrying out the reaction in water, in a completely water-miscible lower aliphatic alcohol or in a mixture of water and a completely water-miscible lower aliphatic alcohol and subsequently, if necessary adjusting the alcohol content of the reaction medium to 40 - 60%.
2. A process as claimed in claim 1 wherein the 2-[E]-phenyl-methylenecycloheptan-1-one-[E]-oxime is isolated from the reaction medium.
3. A process as claimed in claim 1, wherein the reaction is carried out in a C1-3 straight-chained or branched alcohol.
4. A process as claimed in claim 3, wherein the alcohol is ethanol.
5. A process as claimed in claim 1, wherein the reaction is carried out in a mixture of an alcohol and water.
6. A process as claimed in claim 5, wherein the reaction medium is a /50-98/:/2-50/ mixture of an alcohol and water.
7. A process as claimed in claim 1, 2 or 3 wherein the alcohol content of the reaction medium is adjusted to 40-60%, by adding water or ice or a mixture of water and ice or an aliphat-ic, with water unrestrictedly miscible alcohol.
8. A process as claimed in claim 4, 5 or 6 wherein the alcohol content of the reaction medium is adjusted to 40-60%, by adding water or ice or a mixture of water and ice or an aliphat-ic, with water unrestrictedly miscible alcohol.
9. A process as claimed in claim 1, 2 or 3 wherein the alcohol content of the reaction medium is adjusted to 50% by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol.
10. A process as claimed in claim 4, 5 or 6 wherein the alcohol content of the reaction medium is adjusted to 50% by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol.
11. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out at a temperature between 20°C and 90°C.
12. A process as claimed in claim 4, 5 or 6 wherein the reaction is carried out at a temperature between 20°C and 90°C.
13. A process as claimed in claim 1, 2 or 3 wherein the alcohol content of the reaction medium is adjusted to 40-60%, by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol and the reaction is carried out at a temperature between 20° and 90°C.
14. A process as claimed in claim 4, 5 or 6 wherein the alcohol content of the reaction medium is adjusted to 40-60%, by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol and the reaction is carried out at a temperature between 20° and 90°C.
15. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out at a temperature between 75°C and 85°C.
16. A process as claimed in claim 4, 5 or 6 wherein the reaction is carried out at a temperature between 75°C and 85°C.
17. A process as claimed in claim 1, 2 or 3 wherein the alcohol content of the reaction medium is adjusted to 40-60%, by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol and the reaction is carried out at a temperature between 75°C and 85°C.
18. A process as claimed in claim 4, 5 or 6 wherein the alcohol content of the reaction medium is adjusted to 40-60%, by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol and the reaction is carried out at a temperature between 75°C and 85°C.
19. A process as claimed in claim 1, 2 or 3 wherein the alcohol content of the reaction medium is adjusted to 50% by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol and the reaction is carried out at a temperature between 75°C and 85°C.
20. A process as claimed in claim 4, 5 or 6 wherein the alcohol content of the reaction medium is adjusted to 50% by adding water or ice or a mixture of water and ice or an aliphatic, with water unrestrictedly miscible alcohol and the reaction is carried out at a temperature between 75°C and 85°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU82997A HU185518B (en) | 1982-04-01 | 1982-04-01 | Process for preparing 2-/e/-phenyl-methylene-cycloheptan-1-one-/e/-oxime |
| HU997/82 | 1982-04-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1210027A true CA1210027A (en) | 1986-08-19 |
Family
ID=10952372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000425105A Expired CA1210027A (en) | 1982-04-01 | 1983-03-31 | Process for the preparation of 2-/e/phenyl- methylenecycloheptan-1-one-/e/-oxime |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS58208262A (en) |
| AT (1) | AT384423B (en) |
| BE (1) | BE896279A (en) |
| CA (1) | CA1210027A (en) |
| CH (1) | CH656121B (en) |
| DD (1) | DD209619A5 (en) |
| DE (1) | DE3311895A1 (en) |
| DK (1) | DK148783A (en) |
| ES (1) | ES8405366A1 (en) |
| FI (1) | FI831087L (en) |
| FR (1) | FR2524464B1 (en) |
| GB (1) | GB2117773B (en) |
| HU (1) | HU185518B (en) |
| IL (1) | IL68079A (en) |
| IT (1) | IT1194184B (en) |
| NL (1) | NL8301175A (en) |
| SE (1) | SE8301817L (en) |
| YU (1) | YU77683A (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4083978A (en) * | 1976-01-27 | 1978-04-11 | Egyt Gyogyszervegyeszeti Gyar | Oxime ethers |
-
1982
- 1982-04-01 HU HU82997A patent/HU185518B/en not_active IP Right Cessation
-
1983
- 1983-03-07 IL IL68079A patent/IL68079A/en unknown
- 1983-03-28 BE BE1/10748A patent/BE896279A/en not_active IP Right Cessation
- 1983-03-29 ES ES521096A patent/ES8405366A1/en not_active Expired
- 1983-03-30 DK DK148783A patent/DK148783A/en not_active IP Right Cessation
- 1983-03-30 SE SE8301817A patent/SE8301817L/en not_active Application Discontinuation
- 1983-03-30 FI FI831087A patent/FI831087L/en not_active Application Discontinuation
- 1983-03-31 FR FR8305314A patent/FR2524464B1/en not_active Expired
- 1983-03-31 GB GB08308956A patent/GB2117773B/en not_active Expired
- 1983-03-31 CH CH179183A patent/CH656121B/de unknown
- 1983-03-31 CA CA000425105A patent/CA1210027A/en not_active Expired
- 1983-03-31 JP JP58056809A patent/JPS58208262A/en active Pending
- 1983-03-31 DE DE19833311895 patent/DE3311895A1/en not_active Withdrawn
- 1983-04-01 AT AT0116983A patent/AT384423B/en not_active IP Right Cessation
- 1983-04-01 IT IT20428/83A patent/IT1194184B/en active
- 1983-04-01 NL NL8301175A patent/NL8301175A/en not_active Application Discontinuation
- 1983-04-01 YU YU00776/83A patent/YU77683A/en unknown
- 1983-04-04 DD DD83249465A patent/DD209619A5/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2524464A1 (en) | 1983-10-07 |
| IT8320428A1 (en) | 1984-10-01 |
| SE8301817L (en) | 1983-10-02 |
| ATA116983A (en) | 1987-04-15 |
| IT1194184B (en) | 1988-09-14 |
| ES521096A0 (en) | 1984-06-01 |
| GB2117773B (en) | 1985-08-29 |
| HU185518B (en) | 1985-02-28 |
| BE896279A (en) | 1983-09-28 |
| FR2524464B1 (en) | 1986-05-30 |
| CH656121B (en) | 1986-06-13 |
| IL68079A0 (en) | 1983-06-15 |
| NL8301175A (en) | 1983-11-01 |
| IL68079A (en) | 1986-10-31 |
| GB8308956D0 (en) | 1983-05-11 |
| AT384423B (en) | 1987-11-10 |
| DK148783A (en) | 1983-10-02 |
| JPS58208262A (en) | 1983-12-03 |
| FI831087L (en) | 1983-10-02 |
| SE8301817D0 (en) | 1983-03-30 |
| DD209619A5 (en) | 1984-05-16 |
| DE3311895A1 (en) | 1983-10-06 |
| DK148783D0 (en) | 1983-03-30 |
| IT8320428A0 (en) | 1983-04-01 |
| FI831087A0 (en) | 1983-03-30 |
| GB2117773A (en) | 1983-10-19 |
| ES8405366A1 (en) | 1984-06-01 |
| YU77683A (en) | 1985-12-31 |
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