SI9700202A - Process for manufacturing simvastatin from lovastatin or mevinolinic acid - Google Patents
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POSTOPEK IZDELAVE SIMVASTATINA IZ LOVASTATINAPROCEDURE FOR THE PRODUCTION OF SIMVASTATIN FROM LOVASTATIN
ALI MEVINOLINSKE KISLINEBUT MEVINOLINIC ACIDS
Povezava s sorodno prijavoLink to related application
Ta patentna prijava je povezana s patentno prijavo P-9700203, ki ima naslov Ključne vmesne spojine pri izdelavi simvastatina in je bila vložena skupaj s predmetno prijavo.This patent application is related to patent application P-9700203, which is entitled Key Intermediates in the manufacture of simvastatin and was filed with the present application.
Ozadje izumaBACKGROUND OF THE INVENTION
Spojine s strukturno formulo I, ki je prikazana spodaj so zelo aktivni antihiperholesterolemni agensi, ki delujejo tako, da omejijo biosintezo holesterola s pomočjo inhibicije encima HMG-CoA reduktaze.The compounds of the structural formula I shown below are highly active antihypercholesterolemic agents that act to limit cholesterol biosynthesis by inhibiting the HMG-CoA reductase enzyme.
Spojine s strukturno formulo I obsegajo naravne fermentcijske produkte mevinolina (strukturna formula la, kjer je R=CH3, prikazana v ZDA patentu št. 4,231,938, ki je poznana pod imenom lovastatin), kompaktin (strukturna formula Ib, kjer je R=H, prikazana v ZDA patentu št. 3,983,140), ter skupino njihovih pol-sintetičnih in povsem sintetičnih analogov, ki imajo vsi naravno 2-metilbutiratno stransko verigo.Compounds of structural formula I comprise the natural fermentation products of mevinolin (structural formula Ia, where R = CH3, disclosed in U.S. Patent No. 4,231,938, known as lovastatin), compactin (structural formula Ib, where R = H, shown U.S. Patent No. 3,983,140), and a group of their semi-synthetic and fully synthetic analogues, all of which have a naturally occurring 2-methylbutyrate side chain.
Spojine s strukturno formulo II, ki je prikazana spodaj imajo 2,2-dimetilbutiratno stransko verigo (t.j. simvastatin, struktura Ila, kjer je R=CH3) so znani kot bolj aktivni inhibitorji HMG-CoA reduktaze kakor njihovi 2-metilbutiratni analogi, ter imajo tako večjo uporabno vrednost pri zdravljenju ateroskleroze, hiperlipemije, familialne hiperholesterolemije, ter podobnih motenj.The compounds of structural formula II shown below have a 2,2-dimethylbutyrate side chain (i.e., simvastatin, an Ila structure where R = CH 3) are known to be more active HMG-CoA reductase inhibitors than their 2-methylbutyrate analogs, and have thus, greater utility in the treatment of atherosclerosis, hyperlipemia, familial hypercholesterolemia, and similar disorders.
Nedavna tržna predstavitev simvastatina (Ila), močnejšega inhibitorja HMG-CoA reduktaze kot lovastatin -(la) , je povzročil potrebo po bolj učinkovitem postopku, ki bi bil ekonomsko bolj učinkovit in okolju prijaznejši od v stroki poznanih.The recent market launch of simvastatin (Ila), a more potent HMG-CoA reductase inhibitor than lovastatin - (1a), has led to the need for a more efficient process that is more cost effective and more environmentally friendly than those known in the art.
Spojine s strukturno formulo II (t.j. simvastatin), z 2,2dimetilbutiratno stransko verigo, ter postopki za njihovo pridobivanje, so bili že razkriti v ZDA patentu št. 4,444,784 ter EPO objavljeni patentni, prijavi s številko 33538. Postopek prikazan v omenjenih dokumentih vključuje štiri ločene kemijske korake:Compounds of structural formula II (i.e., simvastatin), with a 2,2-dimethylbutyrate side chain, and processes for their preparation have already been disclosed in U.S. Pat. No. 4,444,784 and EPO published Patent Application No. 33538. The process disclosed in said documents involves four separate chemical steps:
1. de-esterifikacija 2-metilbutiratne stranske verige;1. de-esterification of the 2-methylbutyrate side chain;
2. zaščita 4-hidroksi skupine piranonskega obroča;2. protection of the 4-hydroxy group of the pyranone ring;
3. re-esterifikacija stranske verige, da bi tako oblikovali želj eni 2,2-dimetilbutirat; ter3. re-esterification of the side chain to form the desired 2,2-dimethylbutyrate; ter
4. deprotekcija 4-hidroksi skupine.4. Deprotection of the 4-hydroxy group.
Ta pot je počasna, in daje slabe donose.This route is slow, yielding poor returns.
Simvastatin je bil pripravljen tudi z α-alkilacijo esterskega dela, kakor je bilo že opisano v ZDA patentu št. 4,582,915 in 4,820,850.Simvastatin was also prepared by α-alkylation of the ester moiety as previously described in U.S. Pat. No. 4,582,915 and 4,820,850.
ZDA patent št.4,582,915 (1986) prikazuje neposredno metilacijo naravne 2-(S)-metilbutiriloksi stranske verige mevinolina v enem samem kemijskm koraku z uporabo kovinskega alkilnega amida in metilnega halida, da bi tako pridobili simvastatin.U.S. Patent No. 4,582,915 (1986) discloses direct methylation of the natural 2- (S) -methylbutyryloxy side chain of mevinolin in a single chemical step using a metal alkyl amide and methyl halide to obtain simvastatin.
Ta postopek pa ima slabo pretvorno razmerje C-metilacijskega koraka. Dodatno, pa mnoge stranske reakcije potekajo zaradi metilacije na drugih mestih molekule. C-metilacijsko pretvorno razmerje se lahko izboljša do neke mere z drugim ali tretjim polnjenjem amidne baze in metilnega halida. Tudi pri tem pa so skupni donosi zelo skromni. Prav tako pa je tudi čistost tako pridobljenega simvastatina skoraj na meji, ki je še dovoljena za uporabo kot produkt za nego zdravja ljudi.This process, however, has a poor conversion ratio of the C-methylation step. In addition, many side reactions occur due to methylation at other sites of the molecule. The C-methylation conversion ratio can be improved to some extent by the second or third charge of the amide base and methyl halide. Even with this, the overall returns are very modest. Likewise, the purity of the simvastatin thus obtained is almost at the limit still permitted for use as a human health care product.
ZDA patent št. 4,820,850 (1989) prikazuje postopek, kjer se visoka konverzijska C-metilacija 2-(S)-metilbutiriloksi stranske verige mevinolina zgodi z enim samim polnjenjem amidne baze in alkilnega halida. Postopek opisan v tem patentu zajema šest korakov in ni ekonomičen, saj vključuje zaščito in deprotekcijo dveh hidroksilnih skupin vmesne spojine lovastatin butilamida z uporabo dragega sililatnega sredstva, tertbutildimetilsilil klorida.U.S. Pat. No. 4,820,850 (1989) illustrates a process where high conversion C-methylation of the 2- (S) -methylbutyryloxy side chain of mevinoline occurs with a single charge of an amide base and an alkyl halide. The process described in this patent covers six steps and is not economical as it involves the protection and deprotection of two hydroxyl groups of the lovastatin butylamide intermediate using the expensive silylate, tertbutyldimethylsilyl chloride.
Povzetek izumaSummary of the Invention
Ta izum zagotavlja nov postopek in nove vmesne spojine za pripravo simvastatina (Ha). Novi postopek se lahko opiše z naslednjo reakcijsko shemo:The present invention provides a new process and novel intermediates for the preparation of simvastatin (Ha). The new process can be described by the following reaction scheme:
(a) R3 = Buti( <b) Rj ~-<] (a) R3 = Buti!(a) R 3 = Butti (< b ) Rj ~ - <] (a) R3 = Butti!
(b) R3= -<](b) R 3 = - <]
llalla
VV
Glavne lastnosti tega izuma so:The main features of the present invention are:
a)Simvastatin se lahko pripravi iz soli mevinolinske kisline, ki nam služi kot začetni material in ga uporabimo namesto lovastatinaa) Simvastatin can be prepared from a salt of mevinolinic acid, which is used as a starting material and used instead of lovastatin
b) Simvastatin pripravimo v postopku s štirimi koraki, ki pa ne vključujejo zaščite in deprotekcije dveh hidroksilnih skupin odprtega piranonskega obroča. Zatorej metode, ki so bile opisane doslej v predhodnih postopkih potrebujejo zaščito in deprotekcijo hidroksi skupin kot bistvene korake za pripravljanje simvastatina.b) Simvastatin is prepared in a four-step process, but does not involve the protection and deprotection of two hydroxyl groups of the open pyranone ring. Therefore, the methods described so far in the preceding procedures require the protection and deprotection of hydroxy groups as essential steps for the preparation of simvastatin.
c) V prednostni izvedbi tega izuma se nova vmesna spojina lovastatin ciklopropil amid (Illb) pripravi iz začetnega materiala (lovastatin ali oblika soli mevinolinske kisline). Ta nova vmesna spojina se nato pretvori v drugo novo vmesno spojino (IVb).c) In a preferred embodiment of the present invention, a new lovastatin cyclopropyl amide intermediate (Illb) is prepared from starting material (lovastatin or a form of mevinolic acid). This new intermediate is then converted to another new intermediate (IVb).
Simvastatin, pripravljen z novim postopkom ima nekatere prednosti pri komercialni izdelavi. Čistost in donos simvastatina s pomočjo tega postopka sta velika, ob manjši porabi reagentov, časa, dela, in manjših stroških, dogaja pa se v manj korakih.Simvastatin prepared by the new process has some advantages in commercial manufacture. The purity and yield of simvastatin by this process are high, with less reagent consumption, time, labor, and lower costs, but in fewer steps.
Podroben opis izumaDETAILED DESCRIPTION OF THE INVENTION
Začetni material za način po predmetnem izumu je lovastatin (la) ali mevinolinska kislina (Ic), s tem da je slednja odprta obročasta oblika lovastatina. Mevinolinska kislina je izdelana s fermentacijo Aspergillus terreus (glej ZDA patent št.The starting material for the method of the present invention is lovastatin (Ia) or mevinolinic acid (Ic), the latter being an open ring form of lovastatin. Mevinolic acid is made by fermentation of Aspergillus terreus (see U.S. Pat.
4,231,938). Lovastatin (la) ali sol iz mevinolinske kisline (Ic), bo tipično uporabljena kakor začetni material. Izraz mevinolinska kislina, če ni naznačeno drugače, vključuje primerne oblike njenih soli; dovoljena je katerakoli sol, ki se ne meša z drugimi reagenti ali pogoji, ki so uporabljeni za izvedbo predmetnega izuma. Uporabijo se lahko na primer tudi soli alkalijskih kovin, kot sta Na in K, ali pa prednostno tudi oblike amonijeve soli.No. 4,231,938). Lovastatin (1a) or a salt of mevinolinic acid (Ic) will typically be used as starting material. The term mevinolic acid, unless otherwise indicated, includes suitable forms of its salts; any salt which is not miscible with the other reagents or conditions used to carry out the present invention is permitted. For example, alkali metal salts such as Na and K may also be used, or preferably ammonium salt forms.
Lovastatin pridobimo iz mevinolinske kisline z laktonizacijo, ki jo opravimo z metodami, ki so v tej stroki že znane, nato pa jo izoliramo s tehnikami· kristalizacije, ki povzročajo izgubo materiala. Pri tem pride do okoli 20% izgube materiala, do katere pride ob pretvorbi naravne mevinolinske kisline v lovastatin. Eden izmed ciljev tega izuma je tudi odprava te izgube pri čemer za začetni material, namesto mevinolinske kisline raje uporabimo lovastatin.Lovastatin is obtained from mevinolinic acid by lactonization, which is performed by methods already known in the art, and then isolated by crystallization techniques that cause loss of material. This results in about 20% of the loss of material that results from the conversion of natural mevinolic acid to lovastatin. One of the objects of the present invention is also the elimination of this loss by using lovastatin instead of mevinolinic acid as starting material.
Glede na ta novi postopek po predmetnem izumu, se simvastatin (Ha) pripravi z reakcijo med lovastatinom (la) ali mevinolinsko kislino (Ic), prednostno v obliki amonijeve soli, z n-alkilaminom ali cikloalkilaminom s formulo R3-NH2, kjer je R3 enak C3-C6. Prednostno je amin R3-NH2 n-butilamin, vmesna spojina, ki se oblikuje pa je lovastatin n-butilamid (lila). Ciklični amid, vmesna spojina, lila ali Illb, ki smo ga tako pripravili raztopimo v suhem tetrahidrofuranu (THF) ter ga dodamo v raztopino amida alkalijskih kovin, t.j. litijev pirolidid v THF pri temperaturi od okoli -35°C pa do -40°C. Litijev pirolidid se generira in situ z reakcijo n-BuLi s pirolidinom v THF. Raztopino vmesnega amida lila ali Illb in in situ generirano baza pustimo 1 uro stati pri -35°C do -40°C, nato pa z enim samim polnjenjem dodamo osušeni alkilni halid, prednostno metilni jodid (2 do 3.5 mol. ekvivalentov). Vsebino nato 1 uro mešamo pri -30°C, jo segrejemo na -10°C, ter jo pri tej temperaturi pustimo stati še 20 minut. Nato reakcijski mešanici dodamo vodo, sloje pa medsebojno ločimo. THF sloj speremo z mineralno kislino, najbolje klorovodikovo kislino, nato pa jo koncentriramo do oljne mase, ki vsebuje vmesno spojino IVa ali IVb.According to this new process of the present invention, simvastatin (Ha) is prepared by reaction between lovastatin (Ia) or mevinolinic acid (Ic), preferably in the form of an ammonium salt, with n-alkylamine or cycloalkylamine of formula R3-NH2, where R3 equal to C3-C6. Preferably, the amine R3-NH2 is n-butylamine, and the intermediate to be formed is lovastatin n-butylamide (lilac). The cyclic amide, intermediate, lilac or Illb thus prepared is dissolved in dry tetrahydrofuran (THF) and added to a solution of an alkali metal amide, i.e. lithium pyrrolidide in THF at a temperature from about -35 ° C to -40 ° C. Lithium pyrrolidide is generated in situ by the reaction of n-BuLi with pyrrolidine in THF. The solution of the lilac or Illb intermediate amide in in situ generated base was allowed to stand at -35 ° C to -40 ° C for 1 hour, and then the dried alkyl halide, preferably methyl iodide (2 to 3.5 molar equivalents), was added with a single charge. The contents were then stirred at -30 ° C for 1 hour, heated to -10 ° C and allowed to stand for 20 minutes at this temperature. Water was then added to the reaction mixture and the layers separated. The THF layer is washed with a mineral acid, preferably hydrochloric acid, and then concentrated to an oil containing IVa or IVb.
V raztopino vmesne spojine IVa ali IVb v metanolu brez purifikacije dodamo 2.0 N NaOH, nakar vse skupaj 2 do 6 ur refluksiramo pri temperaturi od 80°C do 81°C, prednostno pa le 2 uri. Mešanico nato ohladimo do 50°C, metanol pa odstranimo pri zmanjšanem tlaku, nakar ga razredčimo z vodo. Mešanico nato okisamo pri okoli 10°C s pozornim dodajanjem 2.0 N HC1, s tem da vzdržujemo pH 6, nato pa izvedemo še ekstrakcijo z etil acetatom med tem, ko jo nadalje okisamo do pH 4. Etil acetatni sloj nato ločimo, hidrolizirani produkt pa odpercipitiramo, kot kristalni material v obliki amonijeve soli (V) s počasno adicijo metanolnega amonijevega hidroksida v trajanju 30 minut pri okoli 22°-25°C, čemur sledi hlajenje na 5°C.To the solution of intermediate IVa or IVb in methanol without purification was added 2.0 N NaOH, then refluxed for a total of 2 to 6 hours at a temperature of 80 ° C to 81 ° C, preferably only 2 hours. The mixture was then cooled to 50 ° C and the methanol was removed under reduced pressure and then diluted with water. The mixture was then acidified at about 10 ° C by carefully adding 2.0 N HCl while maintaining the pH of 6, followed by extraction with ethyl acetate while further acidifying to pH 4. The ethyl acetate layer was then separated and the hydrolyzed product separated. is precipitated as a crystalline material in the form of ammonium salt (V) by slow addition of methanolic ammonium hydroxide for 30 minutes at about 22 ° -25 ° C, followed by cooling to 5 ° C.
Amonijevo sol (V) nato ponovno laktoniziramo s segrevanjem v ogljikovodikovemu topilu, kot je toluen. Mešanico nato suspendiramo v toluenu, segrejemo in mešamo pri okoli 100°110°C v trajanju 2 do 10 ur, najbolje pa pri okoli 105°C v trajanju 5 ur, ob hitrem prehodu dušikovega plina. Mešanico nato ohladimo do okoli 35°C, obdelamo z ogljikom, filtriramo, nato pa filtrat pri znižanem tlaku koncentriramo pri temperaturi kopeli okoli 60°C na eno desetino prvotne prostornine. Lakton kristaliziramo iz ogljikovodikovega topila, kakršen je cikloheksan, da bi tako pridobili simvastatin (Ha) visoke čistosti.The ammonium salt (V) is then lactonized again by heating in a hydrocarbon solvent such as toluene. The mixture is then suspended in toluene, heated and stirred at about 100 ° 110 ° C for 2 to 10 hours, preferably at about 105 ° C for 5 hours, with a rapid transition of nitrogen gas. The mixture was then cooled to about 35 ° C, treated with carbon, filtered, and then the filtrate was concentrated under reduced pressure at a bath temperature of about 60 ° C to one-tenth of the original volume. Lactone was crystallized from a hydrocarbon solvent such as cyclohexane to obtain high purity simvastatin (Ha).
V najbolj prednostni izvedbi novega postopka po predmetnem izumu se mevinolinska kislina (Ic) v obliki amonijeve soli uporabi kot začetni material nato pa jo pretvorimo v lovastatin ciklopropilamid (Illb). Mevinolinsko kislino suspendiramo v toluenu in jo 5-6 ur refluksiramo pri cca. 1000-110°C, prednostno pa pri cca. 105°-107°C. Dobljeno raztopino koncentriramo na eno desetino njene prvotne prostornine z destilacijo toluena pri znižanem tlaku pri temperaturi kopeli cca. 50°-55°C. Pri 30°C dodamo ciklopropilamin, mešanico ponovno grejemo 4-5 ur na cca. 40°50°C. Toluen in nezreagirani ciklopropilamin pri znižanem tlaku odstranimo z destilacijo, da bi tako dobili lovastatin ciklopropilamid (Illb) v kvantitativnem donosu. Tako pridobljeni ciklični amid se v nadaljnjem koraku C-metilacije uporabi kot tak, brez predhodne purifikacije, na podoben način, kot je bilo opisano zgoraj brez zaščite dihidroksi sistema, da dobimo simvastatin (Ha) .In the most preferred embodiment of the new process of the present invention, mevinolic acid (Ic) in the form of an ammonium salt is used as starting material and then converted to lovastatin cyclopropylamide (Illb). The mevinolinic acid is suspended in toluene and refluxed for 5-6 hours at approx. 100 0 -110 ° C, preferably at ca. 105 ° -107 ° C. The resulting solution is concentrated to one-tenth of its original volume by distillation of toluene under reduced pressure at a bath temperature of approx. 50 ° -55 ° C. At 30 ° C, cyclopropylamine was added and the mixture was heated again for approx. 4-5 hours. 40 ° 50 ° C. Toluene and unreacted cyclopropylamine under reduced pressure are removed by distillation to obtain lovastatin cyclopropylamide (Illb) in quantitative yield. The cyclic amide thus obtained is used as such without further purification in a further step of C-methylation in a similar manner as described above without the protection of the dihydroxy system to give simvastatin (Ha).
Nasednji primeri nadalje ilustrirajo ta izum:The following examples further illustrate the present invention:
Primer 1Example 1
Pripravljanje simvastatina (Ha) iz amonijeve soli mevinolinske kisline (Ib) z uporabo ciklopropilaminaPreparation of simvastatin (Ha) from the ammonium salt of mevinolinic acid (Ib) using cyclopropylamine
Korak-1: amid N-Ciklopropil-7-(1, 2, 6, 7, 8, 8a (R)heksahidro-2(S), 6(R)-dimetil-8 (S)-((2(S)metilbutanoil)oksi)-1(S)-naftil)-3 (R) , 5(R)dihidroksiheptanojske kisline (Illb)Step-1: N-Cyclopropyl-7- (1, 2, 6, 7, 8, 8a (R) hexahydro-2 (S) amide, 6 (R) -dimethyl-8 (S) - ((2 (S ) methylbutanoyl) oxy) -1 (S) -naphthyl) -3 (R), 5 (R) dihydroxyheptanoic acid (Illb)
Amonijeva sol mevinolinske kisline (Ic) (12.5 g, 0.296 molov) smo suspendirali v toluenu (400 ml). Mešanico smo segreli in mešali pri 105-107°C ob hitrem prehodu dušikovega plina v trajanju 5 ur. Temperaturo smo nato spustili na 60°C, nakar smo oddestilirali približno 350 ml toluena. Pri 30°C smo nato dodali ciklopropilamin (12 ml, 0.172 molov), nakar smo raztopino spet mešali pri 40-45°C v trajanju 4 ur. Toluen smo nato počasi odstranili pri znižanem tlaku in pri temperaturi kopeli 55°C, da bi tako dobili naslovno spojino v gumijasti obliki. HPLC čistost = 99.63%; 'H NMR (CDC13, 300 Mhz): σ 0.495 (m, 2H), σ 0.50 (m, 2H), σ 0.86 (m, 6H), σ 1.08 (m, 6H), σ 2.3 (d, 2H), σ 2.6 (m, IH), σ 3.7 (m, IH), σ 4.18 (m, IH), σ 5.4 (m, IH), σ 5.5 (bt, J=3.0Hz, IH), σ 5.7 (dd, J=6.1, 9.5 Hz, IH), σ 5.9 (d, J=9.6 Hz·, IH), σ 6.2 (bt, J=5.3 Hz, IH) ; IR(CHC13) : Xmax 3500-3300 (b), 3000, 1740, 1660, 1530, 1450, 1210, 860, 760 cm'1.The ammonium salt of mevinolinic acid (Ic) (12.5 g, 0.296 mol) was suspended in toluene (400 ml). The mixture was heated and stirred at 105-107 ° C with a rapid transition of nitrogen gas for 5 hours. The temperature was then lowered to 60 ° C, then distilled off about 350 ml of toluene. Cyclopropylamine (12 ml, 0.172 mol) was then added at 30 ° C and the solution was again stirred at 40-45 ° C for 4 hours. The toluene was then slowly removed under reduced pressure and at a bath temperature of 55 ° C to give the title compound as a gum. HPLC purity = 99.63%; 1 H NMR (CDCl 3 , 300 Mhz): σ 0.495 (m, 2H), σ 0.50 (m, 2H), σ 0.86 (m, 6H), σ 1.08 (m, 6H), σ 2.3 (d, 2H) , σ 2.6 (m, 1H), σ 3.7 (m, 1H), σ 4.18 (m, 1H), σ 5.4 (m, 1H), σ 5.5 (bt, J = 3.0Hz, 1H), σ 5.7 (dd , J = 6.1, 9.5 Hz, 1H), σ 5.9 (d, J = 9.6 Hz ·, 1H), σ 6.2 (bt, J = 5.3 Hz, 1H); IR (CHC1 3 ): Xmax 3500-3300 (b), 3000, 1740, 1660, 1530, 1450, 1210, 860, 760 cm -1 .
To gumo smo nato uporabili neposredno v naslednjem koraku, brez prečiščevanja.This rubber was then used directly in the next step, without purification.
Korak-2: amid N-Ciklopropil-7-(1, 2, 6, 7, 8, 8a (R)heksahidro-2 (S), 6(R)-dimetil-8(S)-((2,2-dimetilbutanoil)oksi)-1(S)-naftil-3(R), 5(R)-dihidroksiheptanojske kisline (Ivb)Step-2: N-Cyclopropyl-7- (1, 2, 6, 7, 8, 8a (R) hexahydro-2 (S) amide, 6 (R) -dimethyl-8 (S) - ((2,2 -Dimethylbutanoyl) oxy) -1 (S) -naphthyl-3 (R), 5 (R) -dihydroxyheptanoic acid (Ivb)
Pirolodin (13.5 ml, 0.163 molov) v THF (50 ml) smo ohladili na -45°C, nato pa smo dodali n-butil litijev heksan (1.6 M,Pyrrolodine (13.5 ml, 0.163 mol) in THF (50 ml) was cooled to -45 ° C, then n-butyl lithium hexane (1.6 M,
100 ml, 0.163 molov) pod dušikom v taki količini, da smo vzdrževali temperaturo od -20°C do -15°C. Mešanico smo nato mešali pri -20°C do -25°C v 'trajanju 40 minut po končani adici j i.,100 ml, 0.163 moles) under nitrogen in such a quantity that the temperature was maintained from -20 ° C to -15 ° C. The mixture was then stirred at -20 ° C to -25 ° C for 40 minutes after the addition was complete.
Raztopina spojine Hib v THF (300 ml) smo pripravili, kakor je bilo že opisano zgoraj, nato pa smo jo po cevki počasi dodajali, tako da smo vzdrževali temperaturo pod -35°C tokom celotnega postopka adicije. Raztopino smo nato pustili stati pri -35°C do -40°C v trajanju 1 ure. Na situ osušeni metilni jodid (4.82 ml, 0.077 molov) smo dodali v enem samem koraku. Belkasto motno raztopino, ki smo jo tako pridobili smo mešali 1 uro pri -35°C, nato segreli na -10°C ter pustili stati 20 minut. Doddali smo destilirano vodo (105 ml), vsebino pa smo nato močno mešali 5 minut. Sloje smo nato medsebojno ločili, nakar smo zgornji THF sloj obdelali z IN HC1 (105 ml). THF sloj smo skoncentrirali pri reduciranem tlaku do prostornine 40 ml, da bi tako pridobili naslovno spojino Ivb, kjer je bil R3 ciklopropil.A solution of the Hib compound in THF (300 ml) was prepared as described above and then slowly added to the tube, maintaining the temperature below -35 ° C throughout the addition process. The solution was then allowed to stand at -35 ° C to -40 ° C for 1 hour. Methyl iodide-dried (4.82 ml, 0.077 mol) was added in a single step. The whitish opaque solution thus obtained was stirred for 1 hour at -35 ° C, then warmed to -10 ° C and allowed to stand for 20 minutes. Distilled water (105 ml) was added and the contents were then stirred vigorously for 5 minutes. The layers were then separated from each other, after which the upper THF layer was treated with IN HCl (105 ml). The THF layer was concentrated under reduced pressure to a volume of 40 ml to give the title compound Ivb, where R3 was cyclopropyl.
Korak-3: 6(R)-(2-(8(S)-(2,2-dimetilbutiriloksi)-2(S), 6(R)dimetil-1, 2, 6, 7, 8, 8a(R)-heksahidro-1(S)-naftil) etil)4(R)-hidroksi-3, 4, 5, 6-tetrahidro-2H-piran-2-on (Ila) (Simvastatin)Step-3: 6 (R) - (2- (8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (R) dimethyl-1, 2, 6, 7, 8, 8a (R ) -hexahydro-1 (S) -naphthyl) ethyl) 4 (R) -hydroxy-3,4,4,6-tetrahydro-2H-pyran-2-one (Ila) (Simvastatin)
Koncentrirani raztopini iz predhodnega koraka, ki je vsebovala spojino IVb smo dodali vodno raztopino NaOH (2N, 25 ml) ter MeOH (175 ml). Mešanica smo· pri 80°-81°C dve uri refluksirali. Mešanico smo nato ohladili na 50°C, maksimalno količino MeOH pa smo nato postrgali pri zmanjšanem tlaku, nato pa smo jo še razredčili z vodo (90 ml). Raztopino smo nato okisali pri temperaturi 10°C s previdnim dodajanjem 2N Hcl (pH 6).To a concentrated solution of the previous step containing compound IVb was added an aqueous solution of NaOH (2N, 25 ml) and MeOH (175 ml). The mixture was refluxed at 80 ° -81 ° C for two hours. The mixture was then cooled to 50 ° C, the maximum amount of MeOH was then scraped under reduced pressure and then further diluted with water (90 ml). The solution was then acidified at 10 ° C with the careful addition of 2N Hcl (pH 6).
Mešanici smo dodali še etilni acetat (200 ml), nato pa smo vse skupaj močno agitirali med nadaljnjim okisanjem na pH 4. Sloj etil acetata smo nato ločili od vodnega sloja. Raztopino NH4OH in MeOH (1:1, 10 ml) smo počasi dodajali v času več kot 30 minut pri 22°-25°C. Percipitate smo nato mešali pri 25°C v trajanju 1.5 ure, nato pa smo vse skupaj ohladili na 5°C ter pri tej temperaturi mešali še 30 minut. Filtraciji je sledilo spiranje s hladnim etilnim acetatom (25 ml) ter sušenje v vakuumu pri 35°C, s čimer smo dobili amonijevo sol (V) .Ethyl acetate (200 ml) was added to the mixture and then strongly agitated during further acidification to pH 4. The ethyl acetate layer was then separated from the aqueous layer. A solution of NH 4 OH and MeOH (1: 1, 10 ml) was slowly added over 22 minutes at 22 ° -25 ° C. The precipitates were then stirred at 25 ° C for 1.5 hours, then cooled to 5 ° C and stirred at this temperature for another 30 minutes. The filtration was followed by washing with cold ethyl acetate (25 ml) and drying in vacuo at 35 ° C to give the ammonium salt (V).
Surovo amonijevo sol (V) iz'predhodnega koraka (lOg, 0.022 molov) smo suspendirali v toluenu (350 ml). Mešanico smo nato segreli in mešali pri 105°C ob hitrem prehodu dušikovega plina v trajanju 5 ur. Raztopino smo nato ohladili do 35°C, nakar smo dodali aktivirano oglje (0.5 g), mešali smo še 0.35 ure, nato pa filtrirali skozi posteljo diatomejske zemlje blagovne znamke Celite. Filtrat smo koncentrirali v vakuumu do prostornine 40 ml pri 60°C temperature kopeli. Nato smo dodali cikloheksan (125 ml), raztopina smo ponovno refluksirali 15 minut, hladili 1 uro na 25°C, ter nato nadalje ohladili do 10°12°C 30 minut. Percipitate smo nato pri 10°-12°C mešali 30 minut, jih filtrirali in nato sprali s hladnim cikloheksanom (50 ml), jih osušili v vakuumu pri 35°C, in tako dobili bel kristalni produkt (Ha), ki smo ga nato nadalje kristalizirali iz absolutnega etanola, da smo dobili naslovno spojino z >99% čistostjo.The crude ammonium salt (V) from the previous step (10g, 0.022 moles) was suspended in toluene (350 ml). The mixture was then heated and stirred at 105 ° C with a rapid transition of nitrogen gas for 5 hours. The solution was then cooled to 35 ° C, then activated charcoal (0.5 g) was added, stirred for 0.35 hours, and then filtered through a bed of Celite brand diatomaceous earth. The filtrate was concentrated in vacuo to a volume of 40 ml at 60 ° C bath temperature. Cyclohexane (125 ml) was then added, the solution refluxed for 15 minutes, cooled to 25 ° C for 1 hour, and then cooled to 10 ° 12 ° C for 30 minutes. The precipitates were then stirred at 10 ° C-12 ° C for 30 minutes, filtered and then washed with cold cyclohexane (50 ml), dried in vacuo at 35 ° C to give a white crystalline product (Ha), which was then further crystallized from absolute ethanol to give the title compound with> 99% purity.
Primer IIExample II
Priprava Simvastatina (Iia) iz lovastatina (la) z uporabo ciklopropilamina.Preparation of Simvastatin (Iia) from lovastatin (Ia) using cyclopropylamine.
Korak-1: amid N-Ciklopropil-7-(1, 2, 6, 7, 8, 8a(R)heksahidro-2(S), 6(R)-dimetil-8)S)-(2(S)-metilbutanoil)oksi)1(S)-naftil)-3(R), 5(R)-dihidroksiheptanojske kisline (Illb) Lovastatin (la) (12.5 g, 0.03 mol) smo suspendirali v ciklopropilamin (13 ml, 0.174 mol) pri 25°C. Mešanico smo nato počasi segreli do 40-45°C, nato pa mešali pri tej temperaturi 5 ur. Presežek amina smo pustili izhlapeti pri znižanem tlaku pri temperaturi kopeli40°C, da smo dobili naslovno spojino v gumijasti obliki. To gumo smo nato uporabili v naslednjem koraku neposredno, brez prečiščevanja.Step-1: N-Cyclopropyl-7- (1, 2, 6, 7, 8, 8a (R) hexahydro-2 (S), 6 (R) -dimethyl-8) amide amide) - (2 (S) -methylbutanoyl) oxy) 1 (S) -naphthyl) -3 (R), 5 (R) -dihydroxyheptanoic acid (Illb) Lovastatin (1a) (12.5 g, 0.03 mol) was suspended in cyclopropylamine (13 ml, 0.174 mol) at 25 ° C. The mixture was then slowly warmed to 40-45 ° C and then stirred at this temperature for 5 hours. The excess amine was allowed to evaporate under reduced pressure at a bath temperature of 40 ° C to give the title compound as a gum. This rubber was then used in the next step directly, without purification.
Koraka 2-3: Spojino (Illb), pridobljeno iz predhodnega koraka smo pretvorili v simvastatin (Ha) s pomočjo istega postopka, kot je opisana za primer I.Step 2-3: The compound (Illb) obtained from the previous step was converted to simvastatin (Ha) by the same procedure as described for Example I.
Primera III in IVExamples III and IV
Priprava simvastatina (Ha) iz lovastatina (la) in amonijeve soli mevinolinske kisline (Ic) z uporabo n-butilaminaPreparation of simvastatin (Ha) from lovastatin (Ia) and the ammonium salt of mevinolinic acid (Ic) using n-butylamine
Simvastatin (Ha) smo pripravili iz lovastatina (la) in amonijeve soli mevinolinske kisline (Ic), ki sta nam služila kot začetna materiala tako, da smo sledili istim zaporednim korakom, ki so bili že opisani v primerih I in II s tem, da smo substituirali ekvimolarne količine n-butilamina namesto ciklopropilamina.Simvastatin (Ha) was prepared from lovastatin (Ia) and the ammonium salt of mevinolinic acid (Ic), which served as starting materials by following the same sequential steps already described in Examples I and II, in that we substituted equimolar amounts of n-butylamine instead of cyclopropylamine.
Čeprav je bil ta izum opisan s pozivanjem na določene upodobitve, pa so omenjene upodobitve namenjene le ilustraciji. V stroki izkušenim, bodo takoj očitne tudi številne druge alternativne upodobitve, ki so še vedno v obsegu tega izuma.Although the present invention has been described by reference to certain drawings, the foregoing drawings are for illustration purposes only. Many other alternative embodiments which are still within the scope of the present invention will be readily apparent to those skilled in the art.
zafor
19, Nehru Plače, New Del19, Nehru Wages, New Del
RANBAXY LABORATORIRANBAXY LABORATORS
Zastopnik: JaRepresentative: Yes
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