NO840065L - PROCEDURE FOR THE PREPARATION OF 17-ESTERS OF CLOBETASOL - Google Patents
PROCEDURE FOR THE PREPARATION OF 17-ESTERS OF CLOBETASOLInfo
- Publication number
- NO840065L NO840065L NO840065A NO840065A NO840065L NO 840065 L NO840065 L NO 840065L NO 840065 A NO840065 A NO 840065A NO 840065 A NO840065 A NO 840065A NO 840065 L NO840065 L NO 840065L
- Authority
- NO
- Norway
- Prior art keywords
- epoxy
- dione
- diene
- methylpregna
- esters
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 24
- 229960002842 clobetasol Drugs 0.000 title claims description 11
- FCSHDIVRCWTZOX-DVTGEIKXSA-N clobetasol Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O FCSHDIVRCWTZOX-DVTGEIKXSA-N 0.000 title 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 16
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- 229940070710 valerate Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229960004703 clobetasol propionate Drugs 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- 125000003700 epoxy group Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- FGWYWKIOMUZSQF-UHFFFAOYSA-N 1,1,1-triethoxypropane Chemical compound CCOC(CC)(OCC)OCC FGWYWKIOMUZSQF-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- GBDXNHBVYAMODG-DEGNENOVSA-N 16-β methyl epoxide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]23[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]3O2 GBDXNHBVYAMODG-DEGNENOVSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- 150000003945 chlorohydrins Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- -1 steroid epoxides Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- XUXVVQKJULMMKX-UHFFFAOYSA-N 1,1,1-trimethoxypentane Chemical compound CCCCC(OC)(OC)OC XUXVVQKJULMMKX-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- AVGAIPMGSIOHFZ-UHFFFAOYSA-N dichloromethane;2-propan-2-yloxypropane Chemical compound ClCCl.CC(C)OC(C)C AVGAIPMGSIOHFZ-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- BQFPCTXLBRVFJL-UHFFFAOYSA-N triethoxymethylbenzene Chemical compound CCOC(OCC)(OCC)C1=CC=CC=C1 BQFPCTXLBRVFJL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte ved fremstilling av 17-estere av clobetasol. En videre gjen-stand er clobetasol 17-estere erholdt ifølge fremgangsmåten i foreliggende oppfinnelse. Det er kjent fra US-patent nr. 3.721.687 at clobetasol 17-estere kan fremstilles fra 17-estere av betametason via dé tilsvarende 21-alkylsulfonater. Imidlertid forløper reaksjonen langsomt og krever reaksjonstider på 1-3 dager, og utbyttet av oppnådd produkt er dårlig og urent, hvilket nødvendiggjør kromatografi og gjentatt krystallisering for å oppnå den rene form. The present invention relates to a method for the production of 17-esters of clobetasol. A further object is clobetasol 17-esters obtained according to the method of the present invention. It is known from US patent no. 3,721,687 that clobetasol 17-esters can be prepared from 17-esters of betamethasone via the corresponding 21-alkyl sulphonates. However, the reaction proceeds slowly and requires reaction times of 1-3 days, and the yield of product obtained is poor and impure, necessitating chromatography and repeated crystallization to obtain the pure form.
Det er et formål for foreliggende oppfinnelse å tilveie-bringe en enkel og effektiv fremgangsmåte for fremstilling av dlobetasol 17-estere, som ikke medfører lange reaksjonstider og som tilveiebringer produktet i en lett renset form og som er egnet for industriell fremstilling i stor skala. It is an aim of the present invention to provide a simple and effective method for the production of dlobetasol 17-esters, which does not involve long reaction times and which provides the product in an easily purified form and which is suitable for industrial production on a large scale.
Disse formål er oppnådd ved en fremgangsmåte hvor lett til-gjengelige estere av 9beta,llbeta-epoksy-17,21-dihydroksy-16beta-metylpregna-l,4-dien-3,20-dion med formelen I These objects have been achieved by a process where readily available esters of 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione with the formula I
hvor R er en alkylgruppe eller arylgruppe med opptil 6 karbonatomer og R' er hydroksy, behandles med metansulfonylklorid til de tilsvarende 21-mesylatderivater med den generelle formel I, hvor R er som ovenfor definert og R' er mesyloksy, etterfulgt av behandling med litiumklorid where R is an alkyl group or aryl group of up to 6 carbon atoms and R' is hydroxy, treated with methanesulfonyl chloride to the corresponding 21-mesylate derivatives of the general formula I, where R is as defined above and R' is mesyloxy, followed by treatment with lithium chloride
som gir de tilsvarende 21-klorderivater med den generelle formel I, hvor R er som ovenfor angitt og R' er klor, hvilken ved behandling med hydrogenf luorid gir de tilsvar- i which give the corresponding 21-chloro derivatives with the general formula I, where R is as stated above and R' is chlorine, which on treatment with hydrogen fluoride gives the corresponding i
ende 17-estere av clobetasol med formel II, terminal 17-esters of clobetasol of formula II,
hvor R er som ovenfor angitt. where R is as indicated above.
Det vellykkede resultat av reaksjonssekvensen i foreliggende The successful result of the reaction sequence in the present
oppfinnelse er overraskende da den nukleofile substitusjon av en 21-mesyloksygruppe med klor i et substrat inneholdende en 9beta,llbetaepoksygruppe uten at 9beta,llbetaepoksy-gruppen brytes, ikke kunne forutsees av en fagmann. Åpningen av 9beta,llbeta-steroidepoksyder til de tilsvarende klorhydriner ved omsetning med litiumklorid i eddiksyre er kjent fra US-patent nr. 3.652.604. Under oppfinnelsens reaksjonsbetingelser dannes imidlertid ingen påviselige mengder klorhydriner. Faktisk er utbyttene av 21-klor 9beta,llbeta-epoksyforbindelser nesten kvantitative, hvilket er bemerkelsesverdig i betraktning av de lave utbytter som oppnås ved å bruke 9alfa-fluor-llbeta-hydroksyforbindelser i US-patent nr. 3.721.687. invention is surprising as the nucleophilic substitution of a 21-mesyloxy group with chlorine in a substrate containing a 9beta,11betaepoxy group without breaking the 9beta,11betaepoxy group could not be foreseen by a person skilled in the art. The opening of 9beta,11beta steroid epoxides to the corresponding chlorohydrins by reaction with lithium chloride in acetic acid is known from US Patent No. 3,652,604. Under the reaction conditions of the invention, however, no detectable amounts of chlorohydrins are formed. In fact, the yields of 21-chloro 9beta,11beta-epoxy compounds are almost quantitative, which is remarkable in view of the low yields obtained using 9alpha-fluoro-11beta-hydroxy compounds in US Patent No. 3,721,687.
Et ytterligere overraskende trekk ved den nucleofile substitusjon på 9beta,llbeta-epoksyder er hvor lett reaksjonen forløper. I US-patent nr. 3.721.687 utføres en lignende substitusjon på 9alfa-fluor-llbeta-hydroksyforbindelser under betingelser som krever 3 dager ved tilbakeløp og benytter et 2000 % overskudd av litiumklorid. A further surprising feature of the nucleophilic substitution of 9beta,11beta-epoxides is the ease with which the reaction proceeds. In US Patent No. 3,721,687, a similar substitution of 9alpha-fluoro-11beta-hydroxy compounds is carried out under conditions requiring 3 days at reflux and using a 2000% excess of lithium chloride.
Under betingelsene i foreliggende oppfinnelse forløper reaksjonen fullstendig på 1-3 timer ved temperaturer fra Under the conditions of the present invention, the reaction proceeds completely in 1-3 hours at temperatures from
60 til 90°C med bare et lite overskudd litiumklorid.60 to 90°C with only a small excess of lithium chloride.
! En tydelig fordel ved foreliggende oppfinnelse er.at mellom- ! A clear advantage of the present invention is that between
produktene oppnås i en tilstrekkelig ren form ved enkel vandig utfelling (eller total ekstraksjon), slik at rensning av mellomproduktet blir unødvendig. Videre oppnås sluttproduktene i så ren form at de kan bringes til farma-copoeia standard ved enkel krystallisering. Ved å bruke fremgangsmåten fra US-patent nr. 3.721.687 krever mellomproduktet rensning, og sluttproduktet må kromatograferes og krystalliseres flere ganger. Således er fremgangsmåten ifølge foreliggende oppfinnelse mer egnet for industriell fremstilling i stor skala. the products are obtained in a sufficiently pure form by simple aqueous precipitation (or total extraction), so that purification of the intermediate product becomes unnecessary. Furthermore, the end products are obtained in such a pure form that they can be brought to pharmacopoeia standard by simple crystallization. Using the method from US Patent No. 3,721,687, the intermediate product requires purification, and the final product must be chromatographed and crystallized several times. Thus, the method according to the present invention is more suitable for industrial production on a large scale.
Det første trinn i foreliggende oppfinnelse består i dannelse av et 21-mesylatderivat fra den tilsvarende 21-hydroksyforbindelse ved bruk av metansulfonylklorid i pyridin, en kjent reaksjon. Utbyttene i dette trinn er nesten kvantitative. The first step in the present invention consists in the formation of a 21-mesylate derivative from the corresponding 21-hydroxy compound using methanesulfonyl chloride in pyridine, a known reaction. The yields in this step are almost quantitative.
Det andre trinnet av oppfinnelsen består i å substituere 21-mesyloksygruppen med klor. Denne fremgangsmåte utføres The second step of the invention consists in substituting the 21-mesyloxy group with chlorine. This procedure is carried out
i et egnet dipolart apriotisk løsningsmiddel såsom aceton, dimetylformamid, heksametylfosforsyretriamid eller blandinger derav. Søkeren foretrekker å bruke dimetylformamid, da substratene har god løselighet i dette løsningsmiddel, og således muliggjør å utføre reaksjonen i høye konsentrasjoner (16-20 % vekt/volum), en viktig faktor ved industriell fremstilling. in a suitable dipolar apriotic solvent such as acetone, dimethylformamide, hexamethylphosphoric acid triamide or mixtures thereof. The applicant prefers to use dimethylformamide, as the substrates have good solubility in this solvent, thus enabling the reaction to be carried out in high concentrations (16-20% weight/volume), an important factor in industrial production.
I motsetning til dette utføres fremgangsmåten i US-patent nr. 3.721.687 ved én konsentrasjon på mindre enn 1,5 % vekt/volum. In contrast, the method in US Patent No. 3,721,687 is carried out at a concentration of less than 1.5% w/v.
Den foretrukne kloridionkilde er vannfritt litiumklorid, selv om alle forbindelser som er i stand til å avgi kloridioner kan brukes. En fordel ved fremgangsmåten ifølge oppfinnelsen er at bare et lite overskudd av litiumklorid anvendes. Reaksjonen kan utføres ved temperaturer mellom 30° og 120°C, fortrinnsvis. The preferred chloride ion source is anhydrous lithium chloride, although any compound capable of emitting chloride ions may be used. An advantage of the method according to the invention is that only a small excess of lithium chloride is used. The reaction can be carried out at temperatures between 30° and 120°C, preferably.
i i Utbyttene som oppnås i dette trinn er overraskende høye i i The yields obtained in this step are surprisingly high
I IN
(92-96 % av teoretisk). (92-96% of theoretical).
Sluttrinnet i oppfinnelsen består i overføring av 9beta, llbeta-epoksygruppen i det tilsvarende fluorhydrin ved bruk av hydrogenfluorid, en kjent reaksjon. Fluorering kan ut-føres ved vanlige metoder, f.eks. vandig hydrogenfluorid eller blandinger av vandig hydrogenfluorid med tetrahydrofuran, dimetylformamid, urea eller pyridin. Søkeren finner 70 % vandig hydrogenfluorid hensiktsmessig, hvilket gir høye utbytter. The final step in the invention consists in the transfer of the 9beta, 11beta-epoxy group in the corresponding fluorohydrin using hydrogen fluoride, a known reaction. Fluorination can be carried out by usual methods, e.g. aqueous hydrogen fluoride or mixtures of aqueous hydrogen fluoride with tetrahydrofuran, dimethylformamide, urea or pyridine. The applicant finds 70% aqueous hydrogen fluoride appropriate, which gives high yields.
Utgangsmaterialene for foreliggende oppfinnelse, nemlig 9beta,llbeta-epoksy-17,2l-dihydroksy-16beta-metylpregna-1,4-dien-3,20-dion 17-estere er enten kjente eller kan lett fremstilles fra betametasonmellomproduktet 9beta,llbeta-epoksy-17 ,21-dihydroksy-16beta-metylpregna-l,4-dien-3,2 0-dion som er å få i handelen, ved bruk av fremgangsmåten fra US-patent nr. 3.755.302. The starting materials for the present invention, namely 9beta,llbeta-epoxy-17,2l-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione 17-esters are either known or can be easily prepared from the betamethasone intermediate 9beta,llbeta-epoxy -17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione which is commercially available, using the method of US Patent No. 3,755,302.
Uten ytterligere utbrodering antas det at en fagmann vil kunne, ved å bruke foregående beskrivelse, utnytte foreliggende oppfinnelse i fullt omfang. Without further elaboration, it is assumed that a person skilled in the art will be able, by using the preceding description, to utilize the present invention to its full extent.
De følgende foretrukne spesielle utførelsesformer må derfor bare betraktes som illustrerende og ikke begrensende for resten av omfanget på noen måte. The following preferred particular embodiments are therefore to be considered illustrative only and not limiting the rest of the scope in any way.
I de følgende eksempler er alle temperaturer angitt i grader Celsius. In the following examples, all temperatures are given in degrees Celsius.
i in
I IN
Mellomprodukt 1Intermediate 1
Til en suspensjon av 1 kg 93/113-epoksy-17,21-dihydroksy-. 160-metylpregna-l,4-dien-3,20-dion i 2 1 tørt tetrahydro-• furan og 1 liter trietylortopropionat settes en løsning av 10 g par.a-toluensulf onsyre i 1 liter tørt tetrahydrofuran. Blandingen går raskt til løsning og etter 1 time nøytrali-seres den med 100 g natriumacetat og helles i 50 liter vann..Den utfelte 17,21-ortoester oppsamles, vaskes med vann og oppslemmes- i 10 liter metanol. En løsning av 20 ml eddiksyre og 3,2 g natriumacetat i 4 liter vann tilsettes og blandingen oppvarmes under tilbakeløp i 3 timer, konsen-treres til et volum på 4 liter og fortynnes med 10 liter vann. Det utfelte 90,110-epoksy-17,21-dihydroksy-163-metylpregna-1,4-dien-3,20-dion 17-propioriat oppsamles, vaskes godt med vann og tørkes under vakuum. Utbytte: To a suspension of 1 kg of 93/113-epoxy-17,21-dihydroxy-. 160-methylpregna-1,4-diene-3,20-dione in 2 1 of dry tetrahydrofuran and 1 liter of triethylorthopropionate is added to a solution of 10 g of par.α-toluenesulfonic acid in 1 liter of dry tetrahydrofuran. The mixture quickly dissolves and after 1 hour it is neutralized with 100 g of sodium acetate and poured into 50 liters of water. The precipitated 17,21-orthoester is collected, washed with water and suspended in 10 liters of methanol. A solution of 20 ml of acetic acid and 3.2 g of sodium acetate in 4 liters of water is added and the mixture is heated under reflux for 3 hours, concentrated to a volume of 4 liters and diluted with 10 liters of water. The precipitated 90,110-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propiorate is collected, washed well with water and dried under vacuum. Dividend:
1,1 kg.1.1 kg.
En prøve krystallisert fra dietyl.eter har de følgende karakteristika: A sample crystallized from diethyl ether has the following characteristics:
smp.: 150°C under spaltningm.p.: 150°C during decomposition
Ytterligere 17-estere av 93/113-epoksy-17,21-dihydroksy-163-metylpregna-l,4-dien-3,20-dion ble fremstilt ifølge den •ovenfor angitte generelle metode. Ved f.eks. å anvende trietylortobenzoat i stedet for trietylortopropionat oppnås det tilsvarende 17-benzoat med de følgende karakteristika. I.R.v 3500, 1725, 1715 , 1670, 1630, 1610 , 1590, 1280 , Additional 17-esters of 93/113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione were prepared according to the above general method. By e.g. using triethylorthobenzoate instead of triethylorthopropionate, the corresponding 17-benzoate with the following characteristics is obtained. I.R.v 3500, 1725, 1715 , 1670, 1630, 1610 , 1590, 1280 ,
720 cm"1, smp. 144-146°C. 720 cm"1, mp 144-146°C.
Ved å anvende trimetylortovalerat i stedet for trietylortopropionat får man det tilsvarende 17-valerat med de føl-gende karakteristika: I I I By using trimethyl orthovalerate instead of triethyl orthopropionate, the corresponding 17-valerate is obtained with the following characteristics: I I I
I.R.^)^r 3510 , 3460 , 1740 , 1675, 1640, 1615 cm 1.' I.R.^)^r 3510 , 3460 , 1740 , 1675, 1640, 1615 cm 1.'
IT13.XIT13.X
EKSEMPEL 1EXAMPLE 1
Til en løsning av 1 kg 93,113_epoksy-17,2l-dihydroksy-163-metylpregna-1,4-dien-3,20-dion 17-propionat fremstilt under Mellomprodukt 1, i 5 liter tørr pyridin ved 0aC satte man i løpet av 10 minutter 500 ml metansulfonylklorid. Etter 30 minutter ved 0-5°C ble overskuddet av reagens ødelagt med 100 g is og reaksjonsblandingen helt i en godt omrørt blanding av 5,2 liter konsentrert saltsyre og 50 liter vann ved 0°C. Utfellingen av 93/113-epoksy-17,21-dihydroksy-163-mety lpregna-1,4-dien-3,2 0-dion.17-propionat-21-mesylat ble oppsamlet, vasket grundig med vann og tørket under vakuum. Utbytte: 1,18 kg. To a solution of 1 kg of 93,113_epoxy-17,2l-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propionate prepared under Intermediate 1, in 5 liters of dry pyridine at 0aC was added during 10 minutes 500 ml methanesulfonyl chloride. After 30 minutes at 0-5°C, the excess reagent was destroyed with 100 g of ice and the reaction mixture completely in a well-stirred mixture of 5.2 liters of concentrated hydrochloric acid and 50 liters of water at 0°C. The precipitate of 93/113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione.17-propionate-21-mesylate was collected, washed thoroughly with water and dried under vacuum . Yield: 1.18 kg.
En prøve krystallisert fra dietyleter hadde de følgende karakteristika: A sample crystallized from diethyl ether had the following characteristics:
smp. 139,5°Cm.p. 139.5°C
På.lignende måte, men ved å bruke 17-acetatet, 17-butylatet, 17-valeratet eller 17-benzoatet av 93/ 113_epoksy-i17,21-dihydroksy-163-metylpregna-1,4-dien-3,20-dion fikk man de tilsvarende 21-mesylatderivater. In a similar manner, but using the 17-acetate, 17-butylate, 17-valerate or 17-benzoate of 93/113_epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione the corresponding 21-mesylate derivatives were obtained.
Fysikalsk-kjemiske karakteristika for 93/113-epoksy-l7,21-dihydroksy-163-metylpregna-1,4-dien-3,20-dion-17-benzoat 21-mesylat: smp. 194°C. I.R.\)<KBr>: 1740 , 1710 , 1665, 1630 , Physicochemical characteristics of 93/113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione-17-benzoate 21-mesylate: m.p. 194°C. I.R.\)<KBr>: 1740 , 1710 , 1665, 1630 ,
Jr , maxJr., max
1605, 1585, 720 cm . 1605, 1585, 720 cm.
EKSEMPEL 2EXAMPLE 2
Til en løsning av 1,012 kg (2 mol) 93/113-epoksy-17,21-di-hydroksy-163-metylpregna-1,4-dien-3,20-dion 17-propionat ! 21-mesylat (Eksempel 1) i 6,72 liter tørt dimetylformamid To a solution of 1.012 kg (2 mol) 93/113-epoxy-17,21-di-hydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propionate ! 21-mesylate (Example 1) in 6.72 liters of dry dimethylformamide
satte man 106 g (2,5 mol) vannfritt litiumklorid og opp-varmet blandingen under nitrogen i 1,5 timer ved 85-90°C,. avkjølte og helte langsomt i 6 7 liter vann ved 2°C under kraftig røring. Utfellingen av 2l-klor-93,110-epoksy-17-hydroksy-160-metylpregna-l,4-dien-3,20-dion 17-propionat ble oppsamlet, vasket godt med vann og tørket under vakuum. Utbytte: 860 g (96 % av teoretisk). 106 g (2.5 mol) of anhydrous lithium chloride were added and the mixture was heated under nitrogen for 1.5 hours at 85-90°C. cooled and slowly poured into 6 7 liters of water at 2°C with vigorous stirring. The precipitate of 21-chloro-93,110-epoxy-17-hydroxy-160-methylpregna-1,4-diene-3,20-dione 17-propionate was collected, washed well with water and dried under vacuum. Yield: 860 g (96% of theoretical).
En prøve krystallisert fra diklormetylandiisopropyleter hadde de følgende karakteristika: A sample crystallized from dichloromethylene diisopropyl ether had the following characteristics:
smp. 110°C.m.p. 110°C.
På lignende måte, men ved å bruke 17-acetatet, 17-butylatet, 17-valeratet eller 17-benzoatet av 93,113_epoksy-17,21-di-hydroksy-163_m'etylpregna-1, 4-dien-3 , 20-dion 2 1-mesylat, fremstilt i Eksempel 1, fikk man den tilsvarende 17-ester av 21-klor-93,113_epoksy-17-hydroksy-163-metylpregna-1,4-dien-3,20-dion. In a similar manner, but using the 17-acetate, 17-butylate, 17-valerate or 17-benzoate of 93,113_epoxy-17,21-di-hydroxy-163_m'ethylpregna-1,4-diene-3,20-dione 2 1-mesylate, prepared in Example 1, the corresponding 17-ester of 21-chloro-93,113_epoxy-17-hydroxy-163-methylpregna-1,4-diene-3,20-dione was obtained.
Fysikalsk-kjemiske karakteristika for 17-benzoatet av .2l-klor-93,113_epoksy-17-hydroksy-163_metylpregna-1,4-dien-3,20-dion: smp. 202°C. I.R.\><Kbr>: 1740, 1710, 1665, 1630, 1605, 1585, 715 cm . Physicochemical characteristics of the 17-benzoate of .2l-chloro-93,113_epoxy-17-hydroxy-163_methylpregna-1,4-diene-3,20-dione: m.p. 202°C. I.R.\><Kbr>: 1740, 1710, 1665, 1630, 1605, 1585, 715 cm .
EKSEMPEL 3EXAMPLE 3
Til 10 liter 70 % vandig flussyre ved -30°C satte man 1 kg 2l-klor-9 3/113-epoksy-17-hydroksy-163-metylpregna-1,4-. dien-3,20-dion 17-propionat (Eksempel 2). Blandingen ble brakt til -20°C og rørt ved denne temperatur i 2,5 timer, og så.helt langsomt i 100 liter ionefritt vann under røring. Utfellingen av clobetasol 17-propionat ble samlet, vasket grundig med vann til nøytralreaksjon og tørket under vakuum. Utbytte : 1020. g. To 10 liters of 70% aqueous hydrofluoric acid at -30°C was added 1 kg of 2l-chloro-9 3/113-epoxy-17-hydroxy-163-methylpregna-1,4-. diene-3,20-dione 17-propionate (Example 2). The mixture was brought to -20°C and stirred at this temperature for 2.5 hours, and then very slowly in 100 liters of deionized water while stirring. The precipitate of clobetasol 17-propionate was collected, washed thoroughly with water to neutral reaction and dried under vacuum. Dividend : 1020. g.
j Råproduktet som var ca. 80 %-ig var lett å rense til ^>98 %| j The raw product, which was approx. 80%-ig was easy to purify to ^>98%|
I IN
ved krystallisering fra diklormetandiisopropyleter og/eller etanol/vann. Det således erholdte rensede produkt er ident-isk med en autentisk prøve. by crystallization from dichloromethane diisopropyl ether and/or ethanol/water. The purified product thus obtained is identical to an authentic sample.
På lignende måte, med ved å bruke 17-acetatet, 17-butylatet, 17-valeratet eller 17-benzoatet av 2l-klor-93,113-epoksy-17-hydroksy-16(3-mety.lpregna-l, 4-dien-3 , 20-dion fremstilt i eksempel 2 fikk man den tilsvarende 17-ester av clobetasol, hvis fysikalsk-kjemiske egenskaper er som tidligere angitt: Clobetasol 17-valerat: smp. 147°C. I.R.\)KBr : 3330, 1745, 1 max 1730 , 1660, 1610, .1600 ; Similarly, using the 17-acetate, 17-butylate, 17-valerate or 17-benzoate of 21-chloro-93,113-epoxy-17-hydroxy-16(3-methyl-1-pregna-1,4-diene- 3, 20-dione prepared in example 2 gave the corresponding 17-ester of clobetasol, whose physico-chemical properties are as previously indicated: Clobetasol 17-valerate: mp 147° C. I.R.\)KBr: 3330, 1745, 1 max 1730 , 1660, 1610, .1600 ;
Clobetasol 17-benzoat: smp. 183°C. I.R.n) KBr : 3390 , 1740 , Clobetasol 17-benzoate: m.p. 183°C. I.R.n) KBr : 3390 , 1740 ,
max 1710, 1660, 1620, 1600, 1590, 715. max 1710, 1660, 1620, 1600, 1590, 715.
i i<;>i in i<;>i
Claims (12)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20334/83A IT1194178B (en) | 1983-03-29 | 1983-03-29 | PROCESS FOR THE PREPARATION OF 17-ESTERS OF CLOBETASOLO AND COMPOUNDS OBTAINED |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO840065L true NO840065L (en) | 1984-10-01 |
Family
ID=11165811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO840065A NO840065L (en) | 1983-03-29 | 1984-01-09 | PROCEDURE FOR THE PREPARATION OF 17-ESTERS OF CLOBETASOL |
Country Status (10)
| Country | Link |
|---|---|
| JP (2) | JPS59205397A (en) |
| CA (1) | CA1220468A (en) |
| CH (1) | CH661930A5 (en) |
| DK (1) | DK42884A (en) |
| FI (1) | FI840344A (en) |
| IT (1) | IT1194178B (en) |
| NL (1) | NL8400910A (en) |
| NO (1) | NO840065L (en) |
| SE (1) | SE8400145L (en) |
| YU (1) | YU54684A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111944002A (en) * | 2020-07-29 | 2020-11-17 | 河南利华制药有限公司 | Beclomethasone dipropionate intermediate and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727458A (en) * | 2018-05-10 | 2018-11-02 | 浙江仙居仙乐药业有限公司 | A kind of synthetic method of 17- propionic esters |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1253831A (en) * | 1968-01-19 | 1971-11-17 | Glaxo Lab Ltd | 9alpha,21-DIHALOPREGNANE COMPOUNDS |
| JPS51125372A (en) * | 1975-03-31 | 1976-11-01 | Taisho Pharmaceut Co Ltd | Aprocess for preparing pregnane steroid-17-ester-21-halides |
-
1983
- 1983-03-29 IT IT20334/83A patent/IT1194178B/en active
-
1984
- 1984-01-09 NO NO840065A patent/NO840065L/en unknown
- 1984-01-10 CH CH113/84A patent/CH661930A5/en not_active IP Right Cessation
- 1984-01-12 SE SE8400145A patent/SE8400145L/en not_active Application Discontinuation
- 1984-01-19 CA CA000445603A patent/CA1220468A/en not_active Expired
- 1984-01-27 FI FI840344A patent/FI840344A/en not_active Application Discontinuation
- 1984-01-31 JP JP59015956A patent/JPS59205397A/en active Pending
- 1984-01-31 DK DK42884A patent/DK42884A/en not_active Application Discontinuation
- 1984-01-31 JP JP59015957A patent/JPS59205399A/en active Granted
- 1984-03-22 NL NL8400910A patent/NL8400910A/en not_active Application Discontinuation
- 1984-03-28 YU YU00546/84A patent/YU54684A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111944002A (en) * | 2020-07-29 | 2020-11-17 | 河南利华制药有限公司 | Beclomethasone dipropionate intermediate and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DK42884A (en) | 1984-09-30 |
| CH661930A5 (en) | 1987-08-31 |
| JPS59205399A (en) | 1984-11-20 |
| IT1194178B (en) | 1988-09-14 |
| FI840344A0 (en) | 1984-01-27 |
| CA1220468A (en) | 1987-04-14 |
| FI840344A (en) | 1984-09-30 |
| JPS59205397A (en) | 1984-11-20 |
| JPS6228160B2 (en) | 1987-06-18 |
| SE8400145L (en) | 1984-09-30 |
| IT8320334A0 (en) | 1983-03-29 |
| NL8400910A (en) | 1984-10-16 |
| YU54684A (en) | 1986-10-31 |
| DK42884D0 (en) | 1984-01-31 |
| SE8400145D0 (en) | 1984-01-12 |
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