SI8211131A8 - Process for obtaining pyrazine derivatives - Google Patents
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Description
POSTUPAK ZA DOBIJANJE PIRAZINSKIH DERIVATAPROCEDURE FOR OBTAINING PYRAZINE DERIVATIVES
Oblast tehnikeTechnical field
Pronalazak je iz oblasti sinteze organskih jedinjenja. Prema Medjunarodnoj klasifikaciji, oznaka pronalaska je C 07 D 241/24; A 61 K 31/495.The invention relates to the field of synthesis of organic compounds. According to the International Classification, the designation of the invention is C 07 D 241/24; A 61 K 31/495.
Tehnički problemTechnical problem
Pronalaskom je rešen tehnički problem novog postupka za dobijanje pirazin N-oksida koji ima hipolipemičko i hipoglikemičko dejstvo, dok ne pokazuje neželjene sporedne efekte karakteristične za derivate piridina. Postupak je pogodan za industrijsku proizvodnju jer je jednostavniji od postupaka iz ranije nauke i vrši se sa pogodnijim polaznim materijama.The invention solves the technical problem of a new process for the preparation of pyrazine N-oxide, which has a hypolipemic and hypoglycemic effect, while showing no undesirable side effects characteristic of pyridine derivatives. The process is suitable for industrial production because it is simpler than the procedures of earlier science and is done with more suitable starting materials.
Stanje tehnikeThe state of the art
Postupak za dobijanje jedinjenja formule (I),date u daljem tekstu, opisali su Pitrd, Boveri i Grablz u Chem. Ber. 1966, 99, str. 364, Ovaj postupak uključuje reakciju jedinjenja formule:The process for the preparation of the compounds of formula (I) below is described by Pitrd, Boveri and Grablz in Chem. Ber. 1966, 99, p. 364, This process involves the reaction of a compound of the formula:
H.H.
sa kalijum permanganatom, da bi se dobilo jedinjenje formule (I) u kojoj n ima vrednost 0. Ovo jedinjenje se kasnije podvrgava N-oksidaciji.with potassium permanganate to give a compound of formula (I) in which n has a value of 0. This compound is subsequently subjected to N-oxidation.
Dok je ovaj postupak iz ranije nauke možda zadovoljavajudi za laboratorijsku sintezu, u industrijskoj proizvodnji se nije pokazao kao pogodan. Kalijum permanganat je veoma toksičan a stvaranje mangan dioksida kao nuz-proizvoda otežava prečišdavanje i skladištenje proizvoda.While this procedure from the earlier sciences may be satisfactory for laboratory synthesis, it has not proved suitable in industrial production. Potassium permanganate is very toxic and the formation of manganese dioxide as a by-product makes it difficult to purify and store the product.
-la-la
Opis rešenja tehnlčkog problema sa primerIma IzvodjenjaDescription of a solution to a technical problem with an Exemplary Example
Pronalazak se odnosi na postupak za dobijanje jedinjenja formule:The invention relates to a process for preparing a compound of the formula:
(I) u kojoj Rjl predstavlja vodonikov atom ili nizu alkil grupu, R2 predstavlja hidroksilnu grupu, alkoksi grupu sa 1-6 ugljenikovih atoma ili grupu formule -NR^R^, u kojoj R^.i R4 svaki nezavisno predstavljaju vodonik ili alkil grupu sa 1-6 ugljenikovih atoma in je 1 ili 0.(I) in which R 1 represents a hydrogen atom or a lower alkyl group, R 2 represents a hydroxyl group, an alkoxy group of 1-6 carbon atoms or a group of the formula -NR 1 R 2, in which R 1 and R 4 each independently represent hydrogen or an alkyl group of 1-6 carbon atoms in is 1 or 0.
jedinjenja formule (I) se prema sadašnjem pronalasku dobijaju sledečom reakcijom:The compounds of formula (I) according to the present invention are prepared by the following reaction:
(III) kisellna(III) acidic
->->
COOH (I)COOH (I)
Navedena reakcija dicijanopirazina (III).sa kiselinom vrlo iznenadjujuče daje samo jedinjenje formule (I) u kojoj R2 predstavlja hidroksilnu grupu i n je 0. Podesne kiseline su sumporna, metansulfonska, fosforna, trifluorometansulfonska i hlorovodoničnaThe above reaction of dicyanopyrazine (III) .with an acid very surprisingly gives only a compound of formula (I) in which R 2 represents a hydroxyl group and is 0. Suitable acids are sulfur, methanesulfonic, phosphoric, trifluoromethanesulfonic and hydrochloric
I kisellna. Podesan rastvarač je voda, a podesna koncentracija kiseline je od 30 do 50%.And acid. A suitable solvent is water and an appropriate acid concentration is from 30 to 50%.
Dalje faze postupka, koje su opisane u Britanskom patentu 1,361,967, uključuju N-oksidaciju i/ili konverziju OH grupe u alkoksi grupu ili grupu -NR.jR4.Further stages of the process, which are described in British Patent 1,361,967, include N-oxidation and / or conversion of an OH group into an alkoxy group or -NR.jR 4 group.
N-oksidacija jedinjenja formule (I) se poželjno vrši sa nekom perkiselinom, koja može eventualno da se generiše in situ. Konverzija OH grupe u alkoksi grupu vrši se esterifikacijom, na uobičajeni način, a konverzija u -NR^R4 se vrši reakcijom jedinjenja formule (I) u kojoj je -COR2 karboksilna grupa ili njen funkcionalni derivat (na pr. halogenid ili meščviti anhidrid), sa amonijakom ili sa aminom formule HNR^R^.The N-oxidation of the compound of formula (I) is preferably carried out with some peracid, which may eventually be generated in situ. Conversion of the OH group to an alkoxy group is carried out by esterification in the usual manner, and conversion to -NR ^ R 4 is carried out by reaction of a compound of formula (I) in which -COR 2 is a carboxylic group or a functional derivative thereof (e.g., halide or moiety anhydride ), with ammonia or with an amine of the formula HNR ^ R ^.
Dobijanje polaznih dicijanopirazina formule (III) obuhvata kondenzaciju diaminomaleonitrila formule:Preparation of the starting dicyanopyrazine of formula (III) involves the condensation of a diaminomaleonitrile of the formula:
H2NXCN H 2 N X CN
J (11)J ( 11 )
H2N'xJt^'CN sa jedinjenjem opšte formule CHOCORir gde R^ ima značenje kao što je definisano ranije. Kondenzacija se vrši u polarnom rastvaraču, na temperaturi od 35 do 85°C. Kasnija reakcija dobijenog jedinjenja formule (III) sa kiselinom, da bi se dobilo jedinjenje formule (I), takodje se vrši u polarnom rastvaraču i na temperaturi od 35 do 85°C.H 2 N ' xJt ^' CN with the compound of the general formula CHOCOR ir where R ^ has the meaning as previously defined. Condensation is carried out in a polar solvent at a temperature of 35 to 85 ° C. Subsequent reaction of the obtained compound of formula (III) with acid to obtain the compound of formula (I) is also carried out in polar solvent and at a temperature of 35 to 85 ° C.
««
Podesni rastvarač! za kondenzaciju diaminomaleonitrila sa glioksalom ili α-ketoaldehidom su voda, alkohol sa 1-6 ugljenikovih atoma, ili njihove smeše. Kondenzacija se noželjno vrši u pri- ; sustvu neke kiseline.Suitable solvent! for the condensation of diaminomaleonitrile with glyoxal or α-ketoaldehyde are water, an alcohol of 1-6 carbon atoms, or mixtures thereof. Condensation is performed overnight at pri- ; system of some acid.
Neka jedinjenja formule (I) imaju hipolipemičke i hipoglikemičke osobine, dok ne pokazuju neŽeljene sporedne efekte karakteristične za piridinske derivate. Druga jedinjenja formule (I) su intermedijeri za sintezu jedinjenja sa ovakvom aktivnošču.Some compounds of formula (I) have hypolipemic and hypoglycemic properties, while exhibiting no undesirable side effects characteristic of pyridine derivatives. Other compounds of formula (I) are intermediates for the synthesis of compounds with this activity.
Pronalazak je ilustrovan sledečim primerima:The invention is illustrated by the following examples:
pniriER 1pniriER 1
- f j .- f j.
a) Aldohld plrosroždjano kiaolino (170 gj 10¾ raatvor u vodi w/v) dodaja sa ukapavanjam, aa maOonJem 1 na aobnoj tomparaturi, aucpcnziji 100 g diominomalconitrila u amoOi 000 ml voda, S00 ml etanola 1 45 ml alrčatno kiaolino. 'a) Aldohld fumed kiaolino (170 g 10¾ solution in water w / v) was added dropwise, aa maOonJem 1 at aobic temperature, augmentation of 100 g diominomalconitrile in amoOi 000 ml water, S00 ml ethanol 1 45 ml alolino. '
Poalo 20 minuta raatvaranjo Ja komplatnoj temperatura ae popna na 00°C 1 maOanJo ea naatavl daljih 30 minuto· ftaakciona omaCa ao tada ohladi na 0°C i proizvod aa oakupi filtraci! ·After 20 minutes, the complete temperature would go up to 00 ° C for 1 minute and then continue for a further 30 minutes · the cooling medium then cooled to 0 ° C and the product was purchased and the filters were purchased! ·
Jomj poalo iopiranja do noutrolnooti oa vodom i auSonja, dobiva ooJomj poalo iopiring to noutrolnooti oa water and auSonja, gets oo
112 s airovog 2,3-dioiJano-5*motil-pirazino> t.t· 9Q-100°C. PMR (CDCl^) iz THS » 2.0 bata (o, CH3)i 0.05 beta (e, aromatlOnl proton). *112 from air 2,3-dioIano-5 * motil-pyrazino> mp · 9Q-100 ° C. PMR (CDCl?) Of ths "2.0 piston (o, CH 3), and beta 0:05 (s, aromatlOnl proton). *
b) Suspenzijo 10 g airovog 2,3-dioijono*5-motilpirazino dobivona kao Oto Jo oplaono pod o), u 100 ml oumporno kioalino (vodani rast« var. 50t v/v) dr21 so aa maOanjcra 3 Oaoa na tomporoturl 100°C.b) Suspension of 10 g of ayr 2,3-dioionic * 5-motilpyrazine obtained as Oto Jo oploono under o) in 100 ml of ouporescent kioalino (aqueous growth «var. 50t v / v) dr21 so aa maOanjcra 3 Oaoa on tomporoturl 100 ° C.
II
- — .-4- - -.-4 -
Ronkcione omofla so toda geol dodavanjom 100 g smrvljenog loda i ρορησ ee na pH 1 dodavanjcm 270 ml vodonog rootvora natrijumhldrokoida (20% w/v). Vodena faza oo okstrohujo oa motilotilkotonom> ekstrakti aa cpojo i isporu do noutralnooti aa zasičenim rootvorom nntrijum-hlorido.Ronkion omofla with but geol by adding 100 g of crushed lode and ρορησ ee at pH 1 by adding 270 ml of sodium root hydrochloride (20% w / v). The aqueous phase oo is extracted with motilotilcotone> extracts aa cpojo and delivered to the neutral aa by saturated rootwater nntrium chloride.
Ieporavanje raotvarača u vakumu dajo čvrofc oatatak koji kriotaličo iz voda tako da oo dobiva 0 g 5-motil-2-pirozinkorbokoilno kioolino, t.t. 163-167°C. PMR (COClg) iz TMS i 2.0 delta (s, CHg), 0.9, 0.3 dolto (dva o,^aromatični protoni)< 10.0 dolto (o* COOH).Evaporation of the solvents in vacuo gave a solid crystalline crystalline solution from the water such that oo yields 0 g of 5-motil-2-pyrosincorbocoyl kioolino, m.p. Mp 163-167 ° C. PMR (COClg) from TMS and 2.0 delta (s, CHg), 0.9, 0.3 long (two o, ^ aromatic protons) <10.0 long (o * COOH).
PRIMER 2EXAMPLE 2
Rootvor 5-mstil-2-pirozinkarbokeilno kiaolino (9.7.g), -napravljen kao Sto Ja opieano u Primeru 1, u suvom dlokaanu (114 ml) i tributilaminu (17.7 ml) tratira sc oa otilhloroforroijatom (7.5 ml) na 0-5°C. Posla 10 minuta, doda ee dlokocn (100 ml) zasičen ca amonijokom 1 ornoGe so moča 3 časa na aobnoj temperaturi. Olokson oa odostilujo i ootatak se eakupl u zasičenom vodanom rastvoru natrijum-bikarbonata (20 ml·)· Smefla oa fUtruja i proizvod so ioporo sa vodom tako da so dobiva 2-karbomoil-5-motilpirazin (9.2 g), t.t. 204-206°C.The solution of 5-methyl-2-pyrosinecarbokeyl kiaolino (9.7 g), -substituted as Example 1 in dry dlocan (114 ml) and tributylamine (17.7 ml) was triturated with otilchloroforroiate (7.5 ml) at 0-5. ° C. After 10 minutes, add ammonia (100 ml) saturated with ammonia 1 or 3 hours at ambient temperature. The oloxone was separated and the residue was further taken up in saturated aqueous sodium bicarbonate solution (20 ml ·). The browning fluid was evaporated and the product was salted with water to give 2-carbomoyl-5-motilpyrazine (9.2 g), m.p. 204-206 ° C.
Ovo jedinjenja (7 g) as zogrova sa glooijalnom elrčotnom kloolinom (30 ml) 1 35% vodonikperokaidom (20 ml) sa močenjem na 70°C tokom 7 časovo.This compound (7 g) acetic acid with glooial elecochloro chloin (30 ml) is 1 35% hydrogen perocaid (20 ml) with wetting at 70 ° C for 7 hours.
Pošlo hladjonja, proizvod so fiItrujo i ispero oa vodom tako do se dobiva 2-karbomoil-5-mQtilpirazin-4-okeid (5.5 g), t.t· 200-200°C.After cooling, the product was filtered off and washed with water to give 2-carbamoyl-5-methylpyrazine-4-ocean (5.5 g), mp 200-200 ° C.
p-fa.N a v o dp-fa.N a v o d
Prijavilac navodi da je najbolj! njemu poznat način za primenu pronalaska u industriji dat u sledečem primeru:Applicant states that most! a method known to him for the application of the invention to the industry is given in the following example:
a) Aldehid pirogroždjane kiseline (170 g, 10% mas/zapr. rastvor' u vodi) dodaje se ukapavanjem uz mešanje, na sobnoj temperaturi, u suspenziju 100 g diaminomaleonitrila u smeši 800 ml vode, 900 mla) Pyrogenic acid aldehyde (170 g, 10% w / v solution 'in water) was added dropwise with stirring, at room temperature, to a suspension of 100 g diaminomaleonitrile in a mixture of 800 ml water, 900 ml
I etanola i 45 ml sirčetne kiseline. Posle 20 minuta rastvaranje je kompletno. Temperatura se podigne do 80°C i mešanje se nastavi još 30 minuta.And ethanol and 45 ml of acetic acid. After 20 minutes, the dissolution is complete. The temperature was raised to 80 ° C and stirring was continued for another 30 minutes.
II
Reakciona smeša se ohladi do 0°C i proizvod, se sakupi filtriranjem. Nakon lsplranja vodom do neutralnog pH i sušenja, dobija se 112 g sirovog 2,3-dicijano-5-metil-pirazIna, t.t. 98-100°C.The reaction mixture was cooled to 0 ° C and the product was collected by filtration. Purification by water to neutral pH and drying afforded 112 g of crude 2,3-dicyano-5-methyl-pyrazine, m.p. 98-100 ° C.
b) Suspenzija 10 g sirovog 2,3-dicijano-5-metilpirazina u 100 ml 50% vodenog rastvora H2SO4 (zapr/zapr.) meša se na l00°C tokom 3 sata. Reakciona smeša se tada gasi dodavanjem 100 g smrv· ljenog leda i pH se podešava na 1 dodatkom 270 ml 20% vodenog rastvora NaOH (mas/zapr.). Vodena faza se ekstrahuje sa metiletil ketonom, ekstrakti se spoje i isperu do neutralnog pH zasičenim rastvorom NaCl. Uparavanje rastvarača pod vakuumom daje čvrst ostatak koji kristališe iz vode dajuči 8 g 5-metil-2-pirazinkarboksilne kiseline, t.t. 163-167°C.b) A suspension of 10 g of crude 2,3-dicyano-5-methylpyrazine in 100 ml of 50% aqueous solution of H 2 SO 4 (closed / closed) was stirred at 100 ° C for 3 hours. The reaction mixture was then quenched by the addition of 100 g of crushed ice and the pH was adjusted to 1 by the addition of 270 ml of 20% aqueous NaOH (w / v). The aqueous phase was extracted with methylethyl ketone, the extracts were combined and washed to neutral pH with saturated NaCl solution. Evaporation of the solvent in vacuo gave a solid residue which crystallized from water to give 8 g of 5-methyl-2-pyrazinecarboxylic acid, mp 163-167 ° C.
FARMITALIA CARLO ERBA SpAFARMITALIA CARLO ERBA SpA
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8116263 | 1981-05-28 | ||
YU1131/82A YU42766B (en) | 1981-05-28 | 1982-05-27 | Process for obtaining pyrazine derivatives |
Publications (1)
Publication Number | Publication Date |
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SI8211131A8 true SI8211131A8 (en) | 1995-10-31 |
Family
ID=26279610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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SI8211131A SI8211131A8 (en) | 1981-05-28 | 1982-05-27 | Process for obtaining pyrazine derivatives |
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Country | Link |
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HR (1) | HRP921425B1 (en) |
SI (1) | SI8211131A8 (en) |
-
1982
- 1982-05-27 SI SI8211131A patent/SI8211131A8/en unknown
-
1992
- 1992-12-16 HR HRP-1131/8227A patent/HRP921425B1/en not_active IP Right Cessation
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HRP921425B1 (en) | 1996-04-30 |
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