SI21235A - A process for lactonization to produce simvastatin - Google Patents

Abstract

There is disclosed a process for the manufacture of simvastatin of Formula (I) which comprises heating a compound namely an acid or ammonium salt of compound of Formula (II), where Z is H or NH4 in an organic solvent at a temperature of 130 to 140 DEG C.

Description

POSTOPEK LAKTONIZACIJE ZA PROIZVODNJO SIMVASTATINALACTONIZATION PROCEDURE FOR THE PRODUCTION OF SIMVASTATIN

Ta izum se nanaša na postopek laktonizacije za proizvodnjo simvastatina. Lovastatin, simvastatin, pravastatin, atorvastatin in mevastatin so dobro znana učinkovita sredstva proti hiperholesterolemiji, ki delujejo tako, da omejujejo biosintezo holesterola z inhibiranjem encima HMG-CoA reduktaze. Te spojine, splošno znane kot statini, se proizvajajo s postopkom naravnega vrenja ali pa preko pol-sintetičnih in popolnoma sintetičnih sredstev. Dva izmed najbolj priljubljenih spojin v tej terapevtski kategoriji sta simvastatin in atorvastatin. Prvi je eno izmed najpogosteje predpisanih zdravil pri zdravljenju primarne hiperholesterolemije z minimalnimi stranskimi učinki in dobro uveljavljenim profilom varnosti. Uporaba izredno čistega simvastatina je zelo zaželena pri pripravi farmacevtskega izdelka, saj bi se tako izognili kopičenju nečistoč med dolgotrajno uporabo in bi znižali možne stranske učinke med zdravljenjem.The present invention relates to a lactonization process for the production of simvastatin. Lovastatin, simvastatin, pravastatin, atorvastatin and mevastatin are well-known effective anti-hypercholesterolemia agents that act to limit cholesterol biosynthesis by inhibiting the HMG-CoA reductase enzyme. These compounds, commonly known as statins, are produced by the natural fermentation process or by semi-synthetic and fully synthetic agents. Two of the most popular compounds in this therapeutic category are simvastatin and atorvastatin. The first is one of the most commonly prescribed medicines in the treatment of primary hypercholesterolemia with minimal side effects and a well-established safety profile. The use of extremely pure simvastatin is highly desirable in the preparation of a pharmaceutical product, so as to avoid the accumulation of impurities during long-term use and to reduce the potential side effects during treatment.

V večini znanih sintetičnih metod za izdelavo spodaj prikazanega simvastatina (formula I)In most known synthetic methods for the manufacture of the simvastatin shown below (formula I)

formula I je običajna vmesna spojina prav tako spodaj prikazana hidroksi kislinska 10 amonijeva sol (formula II),formula I is a common intermediate also shown below is the hydroxy acid 10 ammonium salt (formula II),

ki se ciklizira, da nastane simvastatin, in tako laktonizacija predstavlja bistven 20 korak sinteze. Zelo pomembno je uporabiti učinkovito metodo za laktonizacijo, ki lahko proizvede simvastatin z izredno čistostjo in dobrim donosom.which cyclizes to produce simvastatin and thus lactonization represents an essential 20 step of synthesis. It is very important to use an effective lactonization method that can produce simvastatin with exceptional purity and good yield.

Postopek, razkrit v patentu US 4,820,850, vključuje segrevanje hidroksi kislinske amonijeve soli v toluenu pri 100°C s pomočjo čistila iz dušika. Izvršitev laktonizacije zahteva 6-8 urni refluks in povzroči nastanek povečanih količin dimere (formula lil).The process disclosed in US patent 4,820,850 involves heating the hydroxy acid ammonium salt in toluene at 100 ° C using a nitrogen cleaner. Performing lactonization requires 6-8 hours of reflux and causes the formation of increased amounts of dimer (lil formula).

To dimerno nečistočo je težko ločiti od želenega laktona celo s ponavljajočo kristalizacijo. Prisotnost dimere znižuje čistost izdelka iz simvastatina.This dimeric impurity is difficult to separate from the desired lactone even by repeated crystallization. The presence of a dimer reduces the purity of the simvastatin product.

Patent US 4,916,239 opisuje drug postopek, pri katerem se je reakcija laktonizacije izvršila z obdelavo hidroksi-kislinske amonijeve soli v mešanici ocetne kisline in vode, in v prisotnosti močnega katalizatorja kisline. Ta postopek zahteva postopno dodajanje vode v večih odmerkih, da učinkuje na kristalizacijo laktoniziranega produkta iz reakcijskega medija, da se ravnotežje premakne na stran laktona in to vodi laktonizacijo do konca. Ta postopek industrijski lestvici ni dostopen zaradi izvajanja odtoka in slabe čistosti simvastatinskega izdelka kljub temu, da naj bi bila vsebnost nastale dimere manjša od 0,2%.U.S. Patent 4,916,239 describes another process in which a lactonization reaction was performed by treating the hydroxy acid ammonium salt in a mixture of acetic acid and water, and in the presence of a strong acid catalyst. This process requires the gradual addition of water in multiple doses to effect the crystallization of the lactonized product from the reaction medium to shift the equilibrium to the lactone side and this leads the lactonization to an end. This process is not accessible to the industrial scale due to the effluent and poor purity of the simvastatin product, even though the dimer content is expected to be less than 0.2%.

Patent US 5,917,058 omogoča izmeničen postopek za laktonizacijo hidroksi kisline ali njene soli z obdelavo z ocetno kislino pri pogojih brez vode.U.S. Patent 5,917,058 permits an alternate process for the lactonization of hydroxy acid or a salt thereof by treatment with acetic acid under conditions without water.

Reakcija mora v osnovi potekati v obdobju 5-7 ur, zahteva se intenzivno spiranje produkta z vodo, da se odstrani ostanke ocetne kisline.The reaction should basically take place over a period of 5-7 hours, and intensive washing of the product with water is required to remove acetic acid residues.

Namen izuma je omogočiti zelo učinkovito metodo za laktonizacijo za proizvodnjo simvastatina z več kot 99% čistostjo in visokim donosom. V WO 99/42601 je naveden primer, pri katerem je bil dosežen simvastatin z več kot ίο 99,5% čistostjo, pri čemer se je izdelek očistil s postopno kristalizacijo iz vodnega acetona in iz etil acetata.The purpose of the invention is to provide a highly effective lactonization method for the production of simvastatin with more than 99% purity and high yield. WO 99/42601 mentions an example in which simvastatin was obtained with a purity of more than 99.5%, the product being purified by gradual crystallization from aqueous acetone and ethyl acetate.

Po izumu je omogočen postopek za laktonizacijo, s katerim se proizvaja simvastatin s formulo I,According to the invention, a lactonization process is provided to produce simvastatin of formula I,

formula I ki obsega segrevanje spojine, in sicer kisline ali amonijeve soli spojine s formulo II,formula I comprising heating a compound, namely, an acid or ammonium salt of a compound of formula II,

HOHO

H,CH, C

COOZ formula II pri čemer je Z H ali NH4 v organskem topilu, izbranem izmed ksilenov, etilbenzena in njihovih mešanic pri temperaturi 130-140°C. Reakcija laktonizacije (segrevanje) poteče v 20-40 minutah. Organsko topilo je po možnosti ksilen in Z je NH₄.COOZ formula II wherein ZH or NH4 is in an organic solvent selected from xylene, ethylbenzene and mixtures thereof at a temperature of 130-140 ° C. The lactonization (warming) reaction proceeds within 20-40 minutes. The organic solvent is preferably xylene and Z is NH ₄ .

V začetnem poskusu je laktonizacija hidroksi kislinske amonijeve soli potekala v toluenu (Vir: Patent US 4,820,850) in je bilo očitno, da je pri tem nastala dimerna nečistoča v deležu 0,6 do 1,0%, reakcija pa je po HPLC trajala od 6 do 8 ur, da je ostalo manj kot 2% nereagiranega začetnega materiala. Nadalje se je raznolikost v rezultatih pojavila v odvisnosti od hitrosti segrevanja in od toka dušikovega čistila. Preiskava drugih v literaturi opisanih postopkov laktonizacije je zaključila, da ciklizacija v toluenu prinaša precej čist simvastatin. Edina slabost je tvorba presežne dimerne nečistoče. Sklepamo, da se ta nečistoča tvori zaradi daljšega trajanja reakcije v toluenu in ni posledica višje reakcijske temperature - 100°C.In the initial experiment, lactonization of the hydroxy acid ammonium salt was carried out in toluene (Source: US Patent 4,820,850), and it was evident that a dimeric impurity of 0.6 to 1.0% was obtained, and the reaction lasted from 6 HPLC. up to 8 hours to leave less than 2% of unreacted starting material. Furthermore, the diversity in the results appeared depending on the rate of warming and the flow of nitrogen cleaner. An investigation of the other lactonization processes described in the literature concluded that cyclization in toluene yields fairly pure simvastatin. The only downside is the formation of excess dimeric impurity. It is concluded that this impurity is formed due to the longer reaction time in toluene and is not due to the higher reaction temperature - 100 ° C.

Izum se nanaša na nov postopek laktoniziranja hidroksi kislinske amonijeve soli v ksilenih pri temperaturi refluksa. Reakcija laktonizacije uspešno poteče v 30 minutah v prisotnosti antioksidanta pri stalnem čiščenju z dušikom. Nivo dimerne nečistoče v reakcijski mešanici pri sedanjih pogojih ciklizacije je omejen na manj kot 0,4% in ga izolacija simvastatinskega laktona iz reakcijske mase še dodatno zniža na manj kot 0,2%, kot priporočajo v Pharma Europa, zvezek 10, št. 3, september 1998. Ta vrsta gladke reakcije in stabilnost izdelka pri visoki temperaturi nista bili predvideni in to opazovanje predstavlja pomemben del izuma.The invention relates to a new method of lactonizing a hydroxy acid ammonium salt in xylene at reflux temperature. The lactonization reaction successfully proceeds within 30 minutes in the presence of an antioxidant under continuous nitrogen purification. The level of dimeric impurity in the reaction mixture under the present cyclization conditions is limited to less than 0.4% and further reduced by isolation of simvastatin lactone from the reaction mass to less than 0.2% as recommended in Pharma Europa, Volume 10, No. 3, September 1998. This type of smooth reaction and the stability of the product at high temperature were not contemplated and this observation is an important part of the invention.

io Količina ksilenov je 20 do 50 volumskih enot na enoto začetnega materiala, vendar je po možnosti 25 volumskih enot dovolj za potek reakcije laktonizacije. Omenjena reakcija lahko poteka v različnih topilih, ki imajo območje vrelišča nad 110°C, kot je etilbenzen. Reakcija poteka pri 110 do 140°C, vendar po možnosti pri 130-140°C. Uporabljeni ksileni ponavadi vsebujejo 98% ortoksilena, preostalo so meta- in para- ksileni. Nadalje se doda antioksidant in skozi reakcijsko maso zavre dušik. Primerni antioksidanti vključujejo butilirani hidroksitoluen in butilirani hidroksianizol.io The amount of xylene is 20 to 50 volume units per unit of starting material, but preferably 25 volume units is sufficient for the lactonization reaction to take place. Said reaction may be carried out in various solvents having a boiling range above 110 ° C, such as ethylbenzene. The reaction is carried out at 110 to 140 ° C, but preferably at 130-140 ° C. The xylenes used usually contain 98% orthoxylene, the remainder being meta- and paraxylene. Further, an antioxidant is added and nitrogen is bubbled through the reaction mass. Suitable antioxidants include butylated hydroxytoluene and butylated hydroxyanisole.

Produkt se izolira z destilacijo ksilenov in kristalizacijo iz cikloheksana, da dobimo simvastatin z več kot 99% čistostjo. Tega se lahko nadalje rekristalizira iz metanola in vode, da se dosledno doseže več kot 99,4% čistost.The product is isolated by xylene distillation and crystallization from cyclohexane to give simvastatin with more than 99% purity. This can be further recrystallized from methanol and water to consistently achieve more than 99.4% purity.

Reakcija laktonizacije ponavadi poteka s segrevanjem amonijeve soli simvastatina v ksilenih pri 135-140°C 30 minut. Vendar pa se je pokazalo, da podaljšano segrevanje v ksilenih da dimero v 0,65% deležu proti 1,2% deležu v toluenu.The lactonization reaction is usually carried out by heating the simvastatin ammonium salt in xylenes at 135-140 ° C for 30 minutes. However, prolonged heating in xylenes has been shown to give a dimer of 0.65% to 1.2% of toluene.

Glavne izvedene prednosti v sedanjih pogojih laktonizacije v primerjavi s prejšnjimi so povišana produktivnost postopka in čistost produkta. Reakcija ponavadi traja 30 minut, kar kaže večjo učinkovitost. Ksileni se v postopku popolnoma obnovijo in reciklirajo, in ne nastane nikakršen vodni iztok.The main advantages achieved under current lactonization conditions compared to the previous ones are the increased process productivity and product purity. The reaction usually takes 30 minutes, which shows greater efficiency. The xylenes are completely recovered and recycled in the process and no water leakage is generated.

Naslednji posebni primeri ilustrirajo postopek po izumu.The following specific examples illustrate the process of the invention.

Primer 1 io PRIPRAVA (1S, 3R, 7S, 8S, 8aR)-3,7-DIMETIL-8-[2-[(2R,4R)-4-HIDROKSI-6OKSO-3,4,5,6- TETRAHIDRO-2H-PIRAN-2-ILJETILJ-1,2,3,7,8,8a-HEKSAHIDRO NAFTALIN-1-IL 2,2- DIMETILBUTANOATAExample 1 io PREPARATION (1S, 3R, 7S, 8S, 8aR) -3,7-DIMETHYL-8- [2 - [(2R, 4R) -4-HYDROXY-6OXO-3,4,5,6-TETRAHYDRO- 2H-PIRAN-2-YETHYL-1,2,3,7,8,8a-HEXAHIDRO NAFTALIN-1-IL 2,2-DIMETHYLBUTANOATE

LaktonizacijaLactonization

Amonijev 7-[1,2,6,7,8,8a(R)-heksahidro-2(S),6(R)-dimetil-8(S)-(2,2dimetilbutiriloksi)-1(S)-naftil]-3(R),5(R)-dihidroksiheptanoat (formula II) (100 g, 0,220 mol) se je hitro dodalo ksilenom (2500 ml) pri 130-135°C, ki so vsebovali tudi butilitani hidroksitoluen (0,05 g) z dušikovo penino. Temperaturo rekacijske mešanice se je vzdrževalo na 135-138°C 30 minut. Nato se je reakcijsko mešanico ohlajalo do 25-30°C in obdelalo z ogljikovimi DCenoantikromi (5 g) 30 minut. Suspenzijo se je filtriralo skozi celit in ostanek spralo s ksileni (2 x 50 ml). Ksilene se je odstranilo pri 60-65°C pod znižanim pritiskom in ostanek raztopilo v cikloheksanu (2000 ml) pri 80-85°C. Raztopino se je počasi ohlajalo z mešanjem do 10-15°C in fiksiralo 1 uro. Produkt se je filtriralo in spralo s cikloheksanom (75 ml) in osušilo v praznem prostoru, da smo dobili simvastatin (83 g, 90%), ki je imel 99,28% čistost HPLC.Ammonium 7- [1,2,6,7,8,8a (R) -hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2,2dimethylbutyryloxy) -1 (S) -naphthyl ] -3 (R), 5 (R) -Dihydroxyheptanoate (formula II) (100 g, 0.220 mol) was rapidly added to xylene (2500 ml) at 130-135 ° C, which also contained butylated hydroxytoluene (0.05 g) with sparkling wine. The temperature of the reaction mixture was maintained at 135-138 ° C for 30 minutes. The reaction mixture was then cooled to 25-30 ° C and treated with carbon DCenoantichromes (5 g) for 30 minutes. The suspension was filtered through celite and the residue was washed with xylene (2 x 50 ml). The xylene was removed at 60-65 ° C under reduced pressure and the residue was dissolved in cyclohexane (2000 ml) at 80-85 ° C. The solution was slowly cooled by stirring to 10-15 ° C and fixed for 1 hour. The product was filtered and washed with cyclohexane (75 ml) and dried in vacuo to give simvastatin (83 g, 90%) having 99.28% HPLC purity.

Kristalizacija iz metanola / vode:Crystallization from methanol / water:

Simvastatin (83 g, 0,198 mol) se je raztopilo v metanolu (830 ml) pri ΙΟΙ 5°C in 1 uro počasi dodajalo vodo DM (830 ml). Produkt v obliki blata se je ohladilo do 3-5°C in se ga 1 uro vzdrževalo na tej temperaturi. Produkt se je potem filtriralo in spralo s hladno mešanico metanola / vode (1:1 v/v, 50 ml) in io osušilo v praznem prostoru pri 50-55°C, da je nastal simvastatin (80 g, 96,4%) s farmacevtsko sprejemljivo 99,55% čistostjo HPLC. Nivo dimere je bil <0,2% (0,18%).Simvastatin (83 g, 0.198 mol) was dissolved in methanol (830 ml) at ΙΟΙ 5 ° C and DM water (830 ml) was added slowly over 1 hour. The sludge product was cooled to 3-5 ° C and maintained at this temperature for 1 hour. The product was then filtered and washed with a cold methanol / water mixture (1: 1 v / v, 50 ml) and io was dried in the blank at 50-55 ° C to give simvastatin (80 g, 96.4%) with a pharmaceutically acceptable 99.55% purity by HPLC. The dimer level was <0.2% (0.18%).

Primer 2Example 2

PRIPRAVA (1S, 3R, 7S, 8S, 8aR)-3,7-DIMETIL-8-[2-[(2R,4R)-4-HIDROKSI-6OKSO-3,4,5,6-TETRAHIDRO-2H-PIRAN-2-IL]ETIL]-1,2,3,7,8,8a-HEKSAHIDRO NAFTALIN-1-IL 2,2-DIMETILBUTANOA TAPREPARATION (1S, 3R, 7S, 8S, 8aR) -3,7-DIMETHYL-8- [2 - [(2R, 4R) -4-HYDROXY-6OXO-3,4,5,6-TETRAHYDRO-2H-PIRANE -2-IL] ETHYL] -1,2,3,7,8,8a-HEXAHIDRO NAFTALIN-1-IL 2,2-DIMETHYLBUTANOA TA

LaktonizacijaLactonization

Amonijev 7-[1,2,6,7,8,8a(R)-heksahidro-2(S),6(R)-dimetil-8(S)-(2,2dimetilbutiriloksi)-1(S)-naftil]-3(R),5(R)-dihidroksiheptanoat (formula II) (5 g, mmol) se je dodalo ksilenom (250 ml) in reakcijsko maso refluksiralo pri 138-140°C s stalnim čiščenjem dušika. Refluks se je nadaljeval 30 minut in reakcijsko maso ohladilo na 25-30°C. HPLC nadzor rekcije je pokazal nereagirano amonijevo sol (1,90%), tvorbo simvastatina (94,8%) in dimere (0,24%). Ksilene se je destiliralo pri 60-65°C pod znižanim pritiskom. Ostanek se je raztopilo pri 80-85°C v cikloheksanu (100 ml) in potem 1 uro ohlajalo doAmmonium 7- [1,2,6,7,8,8a (R) -hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2,2dimethylbutyryloxy) -1 (S) -naphthyl ] -3 (R), 5 (R) -Dihydroxyheptanoate (formula II) (5 g, mmol) was added to xylene (250 ml) and the reaction mass was refluxed at 138-140 ° C with constant nitrogen purification. The reflux was continued for 30 minutes and the reaction mass was cooled to 25-30 ° C. HPLC control of the reaction showed unreacted ammonium salt (1.90%), simvastatin formation (94.8%) and dimers (0.24%). The xylene was distilled at 60-65 ° C under reduced pressure. The residue was dissolved at 80-85 ° C in cyclohexane (100 ml) and then cooled to 1 hour

10-12°C. Produkt se je filtriralo in spralo z ohlajenim cikloheksanom (5 ml) in osušilo v praznem prostoru pri 45-50°C, da je nastalo 4,2 g (91,4%) spojine iz naslova s čistostjo HPLC 98,9% in vsebnostjo dimere 0,15%.10-12 ° C. The product was filtered and washed with chilled cyclohexane (5 ml) and dried at 45-50 ° C in vacuo to give 4.2 g (91.4%) of the title compound with a 98.9% HPLC purity and content dimers 0.15%.

Produkt se je raztopilo v metanolu (42 ml) pri sobni temperaturi in raztopino ohladilo do 5-10°C. Vodo (42 ml) se je 30 minut počasi dodajalo pri 5-10°C. io Tako kristalizirani produkt se je mešalo pri 5-10°C, filtriralo in spralo s hladno mešanico metanola / vode (1:1 v/v, 8 ml). Produkt se je osušilo na konstantno težo v praznem prostoru pri 45-50°C, na je nastal simvastatin (4 g, 95,2%).The product was dissolved in methanol (42 ml) at room temperature and the solution cooled to 5-10 ° C. Water (42 ml) was slowly added at 5-10 ° C for 30 minutes. io The crystallized product was stirred at 5-10 ° C, filtered and washed with a cold methanol / water mixture (1: 1 v / v, 8 ml). The product was dried to constant weight in an empty space at 45-50 ° C to give simvastatin (4 g, 95.2%).

Kromatografska čistost (HPLC) je bila 99,55%, vsebnost dimere pa 0,16%.Chromatographic purity (HPLC) was 99.55% and dimer content 0.16%.

Primer 3Example 3

Hidroksi kislinska amonijeva sol s formulo II, ki se zahteva v laktonizaciji, se pripravi z naslednjim postopkom:The hydroxy acid ammonium salt of formula II required in lactonization is prepared by the following procedure:

KORAK-ISTEP-I

PRIPRA VA N-BENZIL-7-[1,2,6,7,8,8a(R)-HEKSAHIDRO-2(S),6(R)-DlMETIL8(S)-[[2(S)-METILBUTANOIL]OKSI]-1 (S)-NAFTIL]-3(R), 5(R)-DIHIDROKSI HEPTANOJSKEGA KISLINSKEGA AMIDA (LOVASTATIN BENZILAMID)PREPARATION IN N-BENZYL-7- [1,2,6,7,8,8a (R) -HEXAHIDRO-2 (S), 6 (R) -DLMETHYL 8 (S) - [[2 (S) -METHYLBUTANOIL] OXY] -1 (S) -NAFTYL] -3 (R), 5 (R) -Dihydroxy heptanoic acid amide (LOVASTATIN BENZYLAMIDE)

-1010-1010

Mešanico lovastatina (50 g, 0,124 mol) in benzilamina (46,32 g, 0,432 mol) se je zmešalo s toluenom (25 ml) in 1 uro segrevalo do 80°C pod dušikovo atmosfero. Odsotnost lovastatina se je nadzorovalo s HPLC. Presežek benzilamina in toluena se je destiliralo pri 85-90°C pod znižanim pritiskom (55 10 mm Hg). Ostanek se je zmešalo s ksileni (50 ml) in ponovno destiliralo priA mixture of lovastatin (50 g, 0.124 mol) and benzylamine (46.32 g, 0.432 mol) was mixed with toluene (25 ml) and heated to 80 ° C under nitrogen atmosphere for 1 hour. The absence of lovastatin was controlled by HPLC. Excess benzylamine and toluene were distilled at 85-90 ° C under reduced pressure (55 10 mm Hg). The residue was mixed with xylenes (50 ml) and distilled again at

85-90°C pod znižanim pritiskom (5-10 mm Hg), da smo dobili produkt lovastatin benzilamid v obliki svetlo rjave viskozne tekočine. Pridobitev: 67,5 g.85-90 ° C under reduced pressure (5-10 mm Hg) to give the lovastatin benzylamide product as a light brown viscous liquid. Yield: 67.5 g.

KORAK-II io PRIPRAVA N-BENZIL-7-[1,2,6,7,8,8a(R)-HEKSAHIDRO-2(S),6(R)-DIMETIL8(S)-[[2(S)-METILBUTANOIL]OKSI]-1(S)-NAFTIL]-3(R),5(R)-BIS[(tertBUTILDIMETILSILIL)OKSI] HEPTANOJSKEGA KISLINSKEGA AMIDA (DVOJNO ZAŠČITENI LOVASTATIN BENZILAMID)STEP-II and PREPARATION OF N-BENZYL-7- [1,2,6,7,8,8a (R) -HEXAHIDRO-2 (S), 6 (R) -DIMETHYL 8 (S) - [[2 (S) -METHYLBUTANOIL] OXY] -1 (S) -NAFTYL] -3 (R), 5 (R) -BIS [(tertBUTYLDIMETHYLSILYL) OXY] HEPTANOIC ACID AMID (DUALLY PROTECTED LOVASTATIN BENZYLAMIDE)

Raztopino lovastatin benzilamida (63,26 g, 0,124 mol) v N,Ndimetilformamidu (139 ml) se je zmešalo z imidazolom (21 g, 0,309 mol) in ferf-butildimetilsilil kloridom (51,42 g, 0,341 mol) pri 25-30°C pod dušikovo atmosfero. Reakcijsko mešanico se je segrelo do 60-65°C in mešalo 4 ure. HPLC je pokazal popolno pretvorbo lovastatin benzilamida v dvojno zaščiteni derivat.A solution of lovastatin benzylamide (63.26 g, 0.124 mol) in N, Ndimethylformamide (139 ml) was mixed with imidazole (21 g, 0.309 mol) and ferf-butyldimethylsilyl chloride (51.42 g, 0.341 mol) at 25-30 ° C under nitrogen atmosphere. The reaction mixture was warmed to 60-65 ° C and stirred for 4 hours. HPLC showed complete conversion of lovastatin benzylamide into a double protected derivative.

Reakcijsko mešanico seje ohladilo do 10-15°C, dodalo metanol (2,85 ml) in mešalo 30 minut. Potem se je reakcijsko maso zlilo v mešanico cikloheksana (1500 ml) in 5% vodne raztopine natrijevega bikarbonata (750 ml) pri 25-30°CThe reaction mixture was cooled to 10-15 ° C, methanol (2.85 ml) was added and stirred for 30 minutes. The reaction mixture was then poured into a mixture of cyclohexane (1500 ml) and 5% aqueous sodium bicarbonate solution (750 ml) at 25-30 ° C.

-1111 in mešalo 10 minut. Plasti se je ločilo in nato organsko plast spralo s 5% vodno raztopino natrijevega bikarbonata (750 ml) in z demineralizirano vodo (750 ml). Organsko plast se je popolnoma koncentriralo pri 55-60°C pod znižanim pritiskom, da je nastal dvojno zaščiteni lovastatin benzilamid v obliki viskozne tekočine. Pridobitev: 99 g.-1111 and stir for 10 minutes. The layers were separated and then the organic layer was washed with 5% aqueous sodium bicarbonate solution (750 ml) and with demineralized water (750 ml). The organic layer was completely concentrated at 55-60 ° C under reduced pressure to form double protected lovastatin benzylamide in the form of a viscous liquid. Acquisition: 99 g.

KORAK-IIISTEP-III

PRIPRA VA N-BENZIL-7-[1,2,6,7,8,8a(R)-HEKSAHIDRO-2(S), 6(R)-DIMETIL8(S)-[[2(S)-METILBUTANOIL]OKSI]-1(S)-NAFTIL]-3(R),5(R)-BIS[(tert10 BUTILDIMETILSILIL)OKSI] HEPTANOJSKEGA KISLINSKEGA AMIDA (DVOJNO ZAŠČITENI SIMVASTATIN BENZILAMID)PREPARATION IN N-BENZYL-7- [1,2,6,7,8,8a (R) -HEXAHIDRO-2 (S), 6 (R) -DIMETHYL 8 (S) - [[2 (S) -METHYLBUTANOIL] OXY] -1 (S) -NAFTYL] -3 (R), 5 (R) -BIS [(tert10 BUTYDIMETHYLSILY) OXY] HEPTANIC ACID AMID (DUALLY PROTECTED SIMVASTATIN BENZYLAMIDE)

Raztopino pirolidina (25,1 g, 0,353 mol) v tetrahidrofuranu (150 ml) se je 30 minut počasi dodajalo raztopini n-butillitija v heksanih (13,5%, 224 ml, 0,321 mol) pri -25°C do -20°C. Reakcijsko mešanico se je mešalo še naslednjih 30 minut pri -25°C do -20°C. Potem se je reakcijsko mešanico razredčilo s tetrahidrofuranom (450 ml) in ohladilo do -50°C. Nato se je 10 minut dodajalo raztopino dvojno zaščitenega lovastatin benzilamida iz koraka-ll (91,4 g, 0,123 ml) v tetrahidrofuranu (450 ml), in pri tem vzdrževalo temperaturo pod -40°C.A solution of pyrrolidine (25.1 g, 0.353 mol) in tetrahydrofuran (150 ml) was slowly added over 30 minutes to a solution of n-butyllithium in hexanes (13.5%, 224 ml, 0.321 mol) at -25 ° C to -20 ° C. The reaction mixture was stirred for a further 30 minutes at -25 ° C to -20 ° C. The reaction mixture was then diluted with tetrahydrofuran (450 ml) and cooled to -50 ° C. A solution of the double-protected lovastatin benzylamide from step-11 (91.4 g, 0.123 ml) in tetrahydrofuran (450 ml) was then added over 10 minutes, maintaining the temperature below -40 ° C.

Reakcijsko mešanico se je mešalo 2 uri pri -30°C do -35°C. Metil jodid (28,06 g, 0,197 ml) se je dodalo v enem kosu (eksotermna reakcija, temperatura je narasla na -16°C) in reakcijsko mešanico mešalo 1,5 ure pri -30°C. Potek reakcije se je nadzorovalo s HPLC (začetni material < 0,1%). TemperaturoThe reaction mixture was stirred for 2 hours at -30 ° C to -35 ° C. Methyl iodide (28.06 g, 0.197 ml) was added in one piece (exothermic reaction, temperature increased to -16 ° C) and stirred for 1.5 hours at -30 ° C. The reaction was monitored by HPLC (starting material <0.1%). Temperature

-1212 reakcijske mešanice se je nato rahlo zvišalo na -10°C in mešalo 30 minut. Reakcijo se je nato prekinilo z dodatkom vode (550 ml) in vsebino mešalo 10 minut pri 10°C. Plasti se je ločilo in organsko plast spralo z 1N vodno raztopino klorovodikove kisline (550 ml) pri 10°C. Organsko plast se je delno koncentriralo pri 40-45°C pod znižanim pritiskom, da smo dobili produkt v grobem, dvojno zaščiteni simvastatin benzilamid, v obliki rjave tekočine, ki se je kot tak uporabil v naslednjem koraku.The -1212 of the reaction mixture was then slightly raised to -10 ° C and stirred for 30 minutes. The reaction was then quenched by the addition of water (550 ml) and the contents stirred for 10 minutes at 10 ° C. The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid (550 ml) at 10 ° C. The organic layer was partially concentrated at 40-45 ° C under reduced pressure to give the product in a coarse, double-protected simvastatin benzylamide, in the form of a brown liquid, which was used as such in the next step.

KORAK-IV ίο PRIPRAVA AMONIJEVEGA 7-[1,2,6,7,8,8a(R)-HEKSAHIDRO-2(S),6(R)DIMETIL-8(S)-[[2(S)-DIMETILBUTANOIL]OKSI-1(S)-NAFTIL]-3(R),5(R)~ DIHIDROKSIHEPTANOATA (SIMVASTATIN AMONIJEVA SOL)STEP-IV ίο PREPARATION OF AMMONIUM 7- [1,2,6,7,8,8a (R) -HEXAHIDRO-2 (S), 6 (R) DIMETHYL-8 (S) - [[2 (S) -DIMETHYLBUTANOIL ] OXY-1 (S) -NAFTYL] -3 (R), 5 (R) ~ DIHYDROXYHEPTANOATE (SIMVASTATIN AMMONIUM SOL)

Zgoraj omenjeno koncentrirano maso se je raztopilo v metanolu (750 ml) priThe above concentrated mass was dissolved in methanol (750 ml) at

25-30°C in dodalo metansulfonsko kislino (2,22 g, 0,023 mol). Reakcijsko mešanico se je 3 ure mešalo pri 30-32°C. Dodalo se je vodno raztopino natrijevega hidroksida (2N, 375 ml) in reakcijsko mešanico segrelo na 78°C. Mešanico tetrahidrofurana in metanola (675 ml) se je destiliralo in za tem preostalo reakcijsko mešanico 3 ure refluksiralo pri 78-79°C.25-30 ° C and methanesulfonic acid (2.22 g, 0.023 mol) was added. The reaction mixture was stirred at 30-32 ° C for 3 hours. An aqueous solution of sodium hydroxide (2N, 375 ml) was added and the reaction mixture was heated to 78 ° C. The mixture of tetrahydrofuran and methanol (675 ml) was distilled off and the resulting reaction mixture was refluxed at 78-79 ° C for 3 hours.

Nato se je reakcijsko mešanico ohladilo do 60°C in topila odstranilo v praznem prostoru. Ostanek se je razredčilo z vodo (25 ml) in ohladilo na 10°C. pH raztopine se je uravnalo na 7,0 z dodatkom 3N klorovodikove kisline (265 ml). Dodalo se je etil acetat (800 ml) in pH nadalje znižalo na 5,0 s 3N vodnoThe reaction mixture was then cooled to 60 ° C and the solvents were removed in the blank. The residue was diluted with water (25 ml) and cooled to 10 ° C. The pH of the solution was adjusted to 7.0 by the addition of 3N hydrochloric acid (265 ml). Ethyl acetate (800 ml) was added and the pH further lowered to 5.0 with 3N aq

-1313 raztopino klorovodikove kisline. Po 10 minutnem mešanju pri 15°C seje plasti ločilo in vodno plast izločilo z etil acetatom (125 ml). Sestavljene organske plasti se je razredčilo z metanolom (250 ml) in segrelo na 25-30°C. Mešanico vodne raztopine amonijaka (-25%) in metanola (1:3 v/v, 83 ml) se je 30 minut počasi dodajalo pri 25-30°C, med tem časom pa je produkt sedimentiral. Sedimentirani produkt se je 30 minut mešalo pri 25-30°C in 1 uro ohlajalo do 10°C. Produkt se je filtriralo in spralo z mešanico metanola in etil acetata (1:3 v/v, 50 ml) pri 10°C. Produkt se je končno osušilo pod znižanim pritiskom pri 40-45°C. Pridobitev: 40 g. (HPLC čistost > 99%).-1313 hydrochloric acid solution. After stirring at 15 ° C for 10 minutes, the layers were separated and the aqueous layer was separated with ethyl acetate (125 ml). The combined organic layers were diluted with methanol (250 ml) and heated to 25-30 ° C. A mixture of aqueous ammonia solution (-25%) and methanol (1: 3 v / v, 83 ml) was slowly added at 25-30 ° C for 30 minutes, during which time the product sedimented. The sedimented product was stirred at 25-30 ° C for 30 minutes and cooled to 10 ° C for 1 hour. The product was filtered and washed with a mixture of methanol and ethyl acetate (1: 3 v / v, 50 ml) at 10 ° C. The product was finally dried under reduced pressure at 40-45 ° C. Acquisition: 40 g. (HPLC purity> 99%).

Claims (3)

1. Postopek za laktonizacijo za proizvodnjo simvastatina s formulo I, ki obsega segrevanje spojine, in sicer kisline ali amonijeve soli spojine s formulo 11, formula II pri čemer je Z H ali NH₄ v organskem topilu pri temperaturi 130-140°C.A method for lactonization for the production of simvastatin of formula I, comprising heating a compound, namely, an acid or ammonium salt of a compound of formula 11, formula II wherein ZH or NH _{4 is} in an organic solvent at a temperature of 130-140 ° C. -1515-1515 2. Postopek po zahtevku I, pri čemer reakcija laktonizacije (segrevanje) poteče v 20-40 minutah.The process of claim I, wherein the lactonization (heating) reaction proceeds within 20-40 minutes. 3. Postopek po zahtevku I, pri čemer je organsko topilo ksilen in Z NH₄.The process of claim I, wherein the organic solvent is xylene and Z is NH ₄ .