NO122880B - - Google Patents
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- Publication number
- NO122880B NO122880B NO16479066A NO16479066A NO122880B NO 122880 B NO122880 B NO 122880B NO 16479066 A NO16479066 A NO 16479066A NO 16479066 A NO16479066 A NO 16479066A NO 122880 B NO122880 B NO 122880B
- Authority
- NO
- Norway
- Prior art keywords
- general formula
- diaryl
- phenyl
- carbon atoms
- dioxopyrazolidines
- Prior art date
Links
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 150000002902 organometallic compounds Chemical class 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000002641 lithium Chemical group 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- XDPKQGKEOCYMQC-UHFFFAOYSA-N 1,2-diphenylpyrazolidine-3,5-dione Chemical compound O=C1CC(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 XDPKQGKEOCYMQC-UHFFFAOYSA-N 0.000 description 1
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical class COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000007011 Robinson annulation reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007278 cyanoethylation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
- C07D231/32—Oxygen atoms
- C07D231/36—Oxygen atoms with hydrocarbon radicals, substituted by hetero atoms, attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Epoxy Compounds (AREA)
Description
Framgangsmåte ved fremstilling av 1,2-diaryl-3,5-dioxopyrazolidiner. Procedure for the preparation of 1,2-diaryl-3,5-dioxopyrazolidines.
Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av 1,2-diaryl-3,5-dioxopyrazolidiner med den generelle formel I: The present invention relates to a new process for the production of 1,2-diaryl-3,5-dioxopyrazolidines with the general formula I:
hvor R er rettkjedet eller forgrenet alkyl med 1-5 carbonatomer, fenyl eller benzyl, og Ar-^og Ar^ er fenyl som eventuelt er substi-tuert med en eller to alkoxygrupper med 1-5 carbonatomer eller med ett eller to halogenatomer. where R is straight-chain or branched alkyl with 1-5 carbon atoms, phenyl or benzyl, and Ar-^ and Ar^ are phenyl which is optionally substituted with one or two alkoxy groups with 1-5 carbon atoms or with one or two halogen atoms.
Av forbindelsene med den generelle formel I er noen av be-tydning som legemidler med betennelseshemmende virksomhet, eksempel- vis fremfor alt det kjente 1,2-difenyX-3,5-dioxo-^-f y-oxobutyl]-pyrazolidin, som man f.eks. kan fremstille ved hydrolyse av ^-klor-crotyl-1,2-difenyl-3,5-dioxopyrazolidin eller ved kondensering av methylvinylketon med 1,2-difenyl-3,5-dioxopyrazolidin. Disse veier tjener "bare til fremstilling av det nevnte derivat og kan ikke an-vendes til generell fremstilling av andre forbindelser hvor gruppen R er forskjellig fra methyl. Slike derivater er tilgjengelige ved Mannich-Robinson-syntese, f.eks. ved omsetning av kvartære salter av Mannich-baser fremstilt av tilsvarende ketoner med 1,2-disub-stituerte 3j 5-dioxopyrazolidiner. Of the compounds with the general formula I, some are of importance as drugs with anti-inflammatory activity, for example, above all the known 1,2-diphenyX-3,5-dioxo-^-f y-oxobutyl]-pyrazolidine, which e.g. can be prepared by hydrolysis of ^-chloro-crotyl-1,2-diphenyl-3,5-dioxopyrazolidine or by condensation of methyl vinyl ketone with 1,2-diphenyl-3,5-dioxopyrazolidine. These routes serve "only for the preparation of the aforementioned derivative and cannot be used for the general preparation of other compounds where the group R is different from methyl. Such derivatives are available by Mannich-Robinson synthesis, e.g. by reaction of quaternary salts of Mannich bases prepared from corresponding ketones with 1,2-disubstituted 3j 5-dioxopyrazolidines.
Det har nu vist seg at man kan fremstille 1,2-diaryl-3,5-dioxopyrazolidiner av den generelle formel I på en ny, teknisk godt anvendelig måte ifblge foreliggende oppfinnelse. Prinsippet ved foreliggende fremgangsmåte ligger deri at man forst omsetter 1,2-diaryl-3,5_(iioxopyrazolidinderivater av den generelle formel II: hvor Ar^og Ar 2 er som ovenfor angitt, med organometalliske forbindelser av den generelle formel III: It has now been shown that 1,2-diaryl-3,5-dioxopyrazolidines of the general formula I can be prepared in a new, technically applicable way according to the present invention. The principle of the present method is that one first reacts 1,2-diaryl-3,5_(iioxopyrazolidine derivatives of the general formula II: where Ar^ and Ar 2 are as indicated above, with organometallic compounds of the general formula III:
hvor R er som ovenfor angitt, og M er en Mg-halogengruppe eller et lithiumatom, hvoretter det dannede mellomprodukt spaltes med vann. where R is as stated above, and M is a Mg halogen group or a lithium atom, after which the intermediate product formed is cleaved with water.
Denne reaksjon er ny og har ikke tidligere vært beskrevet i kjemien for 3?5-dioxopyrazolidinderivater. Den lette tilgjengelig-het av forbindelsene av den generelle formel III også,i teknisk målestokk muliggjor erholdelsen av en lang rekke av 1,2-diaryl-3,5-dioxopyrazolidiner av den generelle formel I med de forskjel-ligste R-grupper. Den lette fremstilling av de onskede produkter lettes også av de reaksjonsdyktige utgangsforbindelser med den generelle formel II som er tilgjengelige ved cyanethylering av 1,2-diaryl-3, 5-d.ioxopyrazolidiner. This reaction is new and has not previously been described in the chemistry of 3?5-dioxopyrazolidine derivatives. The easy availability of the compounds of the general formula III also, on a technical scale, makes it possible to obtain a wide range of 1,2-diaryl-3,5-dioxopyrazolidines of the general formula I with the most different R groups. The easy preparation of the desired products is also facilitated by the reactive starting compounds of the general formula II which are available by cyanoethylation of 1,2-diaryl-3,5-d-ioxopyrazolidines.
Reaksjonen av forbindelser med den generelle formel II med organometalliske forbindelser av den generelle formel III lar seg gjennomfore i vannfrie organiske opplosningsmidler, som i ether, hydrocarboner, spesielt aromatiske, eller i blandinger derav. Det dannede mellomprodukt overfores tilslutt i sluttproduktet ved spalt-ning av reaksjonsblandingen med vann, med en vandig ammoniumklorid-eller saltsyreopplosning. The reaction of compounds of the general formula II with organometallic compounds of the general formula III can be carried out in anhydrous organic solvents, such as in ether, hydrocarbons, especially aromatic ones, or in mixtures thereof. The intermediate product formed is finally transferred into the final product by cleavage of the reaction mixture with water, with an aqueous ammonium chloride or hydrochloric acid solution.
De efterfolgende eksempler vil belyse oppfinnelsen nærmere. The following examples will illustrate the invention in more detail.
Eksempel 1 Example 1
Til en opplosning av 6,1 g 1,2-dif enyl-3, 5-dioxo-M--( p-cyan-ethyl)-pyrazolidin i 50 ml benzen dryppes under omroring og avkjbl-ing en opplosning av fenylmagnesiumbromid i 50 ml ether, fremstilt av 2,5 g magnesium. Efter tilsetning av hele mengden av Grignard-reagenset omrores i ytterligere 12 timer. Derefter spaltes reaksjonsblandingen med 500 ml vann, det utskilte bunnfall skilles av og vaskes omhyggelig med vann. Fra filtratet fraskilles det organiske skikt og det vandige skikt filtreres med avfarvende kull. Filtratet syres med saltsyre, det utskilte produkt avsuges og vaskes med vann. Ved krystallisasjon fra n-propanol fåes 1,2-difenyl-3,5-dioxo-V-((3-benzoylethyl)-pyrazolidin med et smeltepunkt på 172 - 17h°C. A solution of phenylmagnesium bromide in 50 ml of ether, prepared from 2.5 g of magnesium. After adding the entire amount of the Grignard reagent, stir for a further 12 hours. The reaction mixture is then split with 500 ml of water, the separated precipitate is separated off and washed carefully with water. The organic layer is separated from the filtrate and the aqueous layer is filtered with decolorizing charcoal. The filtrate is acidified with hydrochloric acid, the separated product is suctioned off and washed with water. Crystallization from n-propanol gives 1,2-diphenyl-3,5-dioxo-V-((3-benzoylethyl)-pyrazolidine with a melting point of 172 - 17h°C.
Eksempel 2 Example 2
Til en opplosning av 6,1 g 1,2-dif enyl-3, 5-dioxo-1+-((3-cyan-ethyl)-pyrazolidin i 50 ml benzen tildryppes en opplosning av methylmagnesiumjodid i 50 ml ether fremstilt fra 2,9 g magnesium. Efter 12 timers omroring opparbeides reaksjonsblandingen som i eksempel 1. Efter rensning over natriumsaltet fåes 1,2-difenyl-3,5-dioxo-^-f Y-oxobutyl)-pyrazolidin med et smeltepunkt 125 - 127°C. A solution of methylmagnesium iodide in 50 ml of ether prepared from 2 .9 g of magnesium. After stirring for 12 hours, the reaction mixture is worked up as in example 1. After purification over the sodium salt, 1,2-diphenyl-3,5-dioxo-(((Y-oxobutyl)-pyrazolidine is obtained with a melting point of 125 - 127°C) .
Eksempel Example
Til en opplosning av 6,1 g 1,2-dif enyl-3, 5-dioxo-^f-( p-cyan-ethyl)-pyrazolidin i 50 ml benzen tildryppes under omroring en opplosning av fenyllithium i 50 ml ether, fremstilt fra 15 g brombenzen og en ekvivalent mengde lithium. Efter 3 timers omroring opparbeides reaksjonsblandingen som i eksempel 1. Der fåes et produkt som er identisk med det som er fremstilt i eksempel 1, smeltepunkt 172-17^°C. A solution of phenyllithium in 50 ml of ether, prepared from 15 g of bromobenzene and an equivalent amount of lithium. After stirring for 3 hours, the reaction mixture is worked up as in example 1. A product is obtained which is identical to that prepared in example 1, melting point 172-17°C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS580665 | 1965-09-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO122880B true NO122880B (en) | 1971-08-30 |
Family
ID=5403639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO16479066A NO122880B (en) | 1965-09-24 | 1966-09-20 |
Country Status (11)
| Country | Link |
|---|---|
| AT (1) | AT258897B (en) |
| BE (1) | BE687146A (en) |
| CH (1) | CH461512A (en) |
| DE (1) | DE1620408A1 (en) |
| DK (1) | DK114483B (en) |
| ES (1) | ES331533A1 (en) |
| FI (1) | FI46508C (en) |
| GB (1) | GB1098160A (en) |
| NL (1) | NL6613352A (en) |
| NO (1) | NO122880B (en) |
| SE (1) | SE314377B (en) |
-
1966
- 1966-09-20 NO NO16479066A patent/NO122880B/no unknown
- 1966-09-20 CH CH1352666A patent/CH461512A/en unknown
- 1966-09-20 BE BE687146D patent/BE687146A/xx unknown
- 1966-09-21 AT AT886566A patent/AT258897B/en active
- 1966-09-21 NL NL6613352A patent/NL6613352A/xx unknown
- 1966-09-21 FI FI247666A patent/FI46508C/en active
- 1966-09-22 DE DE19661620408 patent/DE1620408A1/en active Pending
- 1966-09-22 SE SE1277066A patent/SE314377B/xx unknown
- 1966-09-23 GB GB4244666A patent/GB1098160A/en not_active Expired
- 1966-09-23 ES ES0331533A patent/ES331533A1/en not_active Expired
- 1966-09-26 DK DK499266A patent/DK114483B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES331533A1 (en) | 1967-10-01 |
| BE687146A (en) | 1967-03-01 |
| DK114483B (en) | 1969-07-07 |
| SE314377B (en) | 1969-09-08 |
| AT258897B (en) | 1967-12-11 |
| CH461512A (en) | 1968-08-31 |
| NL6613352A (en) | 1967-03-28 |
| FI46508C (en) | 1973-04-10 |
| GB1098160A (en) | 1968-01-10 |
| DE1620408A1 (en) | 1970-05-14 |
| FI46508B (en) | 1973-01-02 |
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