CS248728B2 - Production method of the 6alfa methylcorticoid derivatives - Google Patents
Production method of the 6alfa methylcorticoid derivatives Download PDFInfo
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- CS248728B2 CS248728B2 CS8410074A CS1007484A CS248728B2 CS 248728 B2 CS248728 B2 CS 248728B2 CS 8410074 A CS8410074 A CS 8410074A CS 1007484 A CS1007484 A CS 1007484A CS 248728 B2 CS248728 B2 CS 248728B2
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- methyl
- dione
- acetoxy
- trimethylacetoxy
- reaction mixture
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- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 16
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003470 adrenal cortex hormone Substances 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- -1 isobutyryl Chemical group 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KOPMZTKUZCNGFY-UHFFFAOYSA-N 1,1,1-triethoxybutane Chemical compound CCCC(OCC)(OCC)OCC KOPMZTKUZCNGFY-UHFFFAOYSA-N 0.000 description 1
- FGWYWKIOMUZSQF-UHFFFAOYSA-N 1,1,1-triethoxypropane Chemical compound CCOC(CC)(OCC)OCC FGWYWKIOMUZSQF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- BQFPCTXLBRVFJL-UHFFFAOYSA-N triethoxymethylbenzene Chemical compound CCOC(OCC)(OCC)C1=CC=CC=C1 BQFPCTXLBRVFJL-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká způsobu výroby nových derivátů 6a-methylkortikoldu obecného vzorce IThe invention relates to a process for the preparation of novel 6α-methylcorticold derivatives of the general formula I
CH,/' c=oCH 1 / c = o
ve kterém znamená jednoduchou nebo dvojnou vazbu,in which it means a single or double bond,
R znamená acyloxyskupinu s nejvýše 8 atomy uhlíku aR is acyloxy having no more than 8 carbon atoms and
X‘ znamená atom chloru, nebo acyloxyskupinu s nejvýše 8 atomy uhlíku.X ‘represents a chlorine atom or an acyloxy group having at most 8 carbon atoms.
Nové 6a-methylkortikoidy obecného vzorce I mohou jako acyloxyskupiny ve významu symbolu R obsahovat alifatické, cyklo2 alifatické nebo aromatické zbytky, jako jsou napříklald acetylová skupina, propionylová skupina, butyrylová skupina, isobutyrylová skupina, valerylová skupina, 3-methylbutyrylová skupina, trimethylacetylová skupina, hexanoylová skupina nebo benzoylová skupina.The novel 6α-methyl corticoids of the formula I can contain as acyloxy groups in the meaning of R the aliphatic, cycloaliphatic or aromatic radicals such as acetyl, propionyl, butyryl, isobutyryl, valeryl, 3-methylbutyryl, trimoylacetyl, hexaneacetyl, or benzoyl.
Bylo zjištěno, že nové 6a-methylkortikoidy obecného vzorce I, vyrobené způsobem podle vynálezu, mají při lokální aplikaci často významně silnější účinnost než až dosud známé 6a-methylkortikoidy. Tato účinnost je často dokonce ještě významněji silnější, než je účinnost dvojnásobně fluorovaných „ušlechtilých1 kortikoidů, jako je třeba 6a,9a-difluor-ll/3-hydroxy-16a-methyl-21-valeryloxy-l,4-pregnadien-3,20-dion (tj. Nerisona).It has been found that the novel 6α-methyl corticoids of the formula (I) produced by the process according to the invention often have significantly stronger potency when applied topically than the prior art 6α-methyl corticoids. This activity is often even more potent than that of double-fluorinated "noble 1 corticoids" such as 6α, 9α-difluoro-11β-hydroxy-16α-methyl-21-valeryloxy-1,4-pregnadien-3, 20-dione (ie, Nerison).
Při systemické aplikaci jsou tyto 6a-methylkortikoidy překvapivě často slaběji účinné než příslušné dosud známé 6a-methylkortikoidy.Surprisingly, in systemic administration, these 6α-methylcorticoids are often less potent than the corresponding 6α-methylcorticoids known to date.
Nové 6«-methylkortikoidy obecného vzorce I, vyrobené způsobem podle vynálezu, jsou proto vhodné v kombinaci s nosiči obvyklými v galenické farmacii k lokálnímu ošetření kontaktní dermatitidy, ekzémů nejrůznějšího druhu, neurodermatóz, erythrodermie, spálenin, svědění vulvy a řitě, trudoviny růžovité, kožního erythematodu, lu248728 pánky, lišeje plochého červeného a bradavčitého a podobných kožních onemocnění.The novel 6'-methyl corticoids of the formula (I) according to the invention are therefore suitable, in combination with carriers customary in galenical pharmacy, for the topical treatment of contact dermatitis, eczema of various kinds, neurodermatoses, erythrodermia, burns, itchy vulva and anus. erythematodes, lu248728 pans, flat red and warty lichen and similar skin diseases.
Tato speciální léčiva se vyrábějí obvyklým způsobem tím, že se účinné látky s vhodnými přísadami převedou v požadované aplikační formy, jako jsou například roztoky, pleťové vody, masti, krémy nebo náplasti. V takto formulovaných léčivech závisí koncentrace účinné látky na aplikační formě. U pleťových vod a mastí se výhodně používá koncentrace účinné látky v rozmezí 0,001 až 1 %.These special medicaments are manufactured in conventional manner by converting the active ingredients with suitable additives into the desired dosage forms, such as solutions, lotions, ointments, creams or patches. In such formulations, the concentration of active ingredient depends on the dosage form. For lotions and ointments, a concentration of active compound in the range of 0.001 to 1% is preferably used.
Kromě toho se nové sloučeniny, vyrobené způsobem podle vynálezu, popřípadě v kombinaci s obvyklými nosiči a pomocnými látkami, dohře hodí i k výrobě inhalačních prostředků, kterých je možno použít k léčení alergických onemocnění dýchacích cest, jako je například bronchiální asthma nebo zánět nosní sliznice.In addition, the novel compounds produced by the process of the invention, optionally in combination with conventional carriers and excipients, are also useful in the manufacture of inhalants which can be used to treat allergic respiratory diseases such as bronchial asthma or nasal mucositis.
Dále jsou nové kortikoidy vhodné pro aplikaci v podobě tobolek, tablet nebo dražé, které výhodně obsahují 10 až 200 mg účinné látky a užívají se orálně nebo v podobě suspenzí, které s výhodou obsahují 100 až 500 mg účinné látky v jedné dávkovači jednotce a aplikují se rektálně, a též pro léčení alergických onemocnění zažívacího traktu, jako je vředovitá kolitida nebo granulamatózní kolitida.Furthermore, the novel corticoids are suitable for administration in the form of capsules, tablets or dragees, which preferably contain 10 to 200 mg of active ingredient and are used orally or in the form of suspensions, preferably containing 100 to 500 mg of active ingredient per dosage unit and administered. rectally, and also for the treatment of allergic diseases of the gastrointestinal tract, such as ulcerative colitis or granulamatous colitis.
Předmětem vynálezu je způsob výroby derivátů 6a-methylkortikoidů obecného vzorce I, který se provádí tak, že se na dvojnou vazbu A9(11)6a-methylkortikoidu obecného vzorce IV tSUMMARY OF THE INVENTION The present invention provides a process for the preparation of 6α-methyl corticoid derivatives of the formula I, which is carried out by contacting the A 9 (11) 6α-methylcorticoid double bond of the formula IV t
Čh3 (IV) ve kterém , X‘ a R mají výše uvedený význam, aduje kyselina chlorná.CH 3 (IV) wherein, X 'and R are as defined above, adds hypochlorous acid.
Podmínky výroby sloučenin podle vynálezu jsou popsány v některém z německých zveřejňovacích spisů DOS číslo 2 645 104, 2 645 105, 2 340 591, 1 958 549, US patentu č. 3 383 394, jakož i v J. Org. Chem. 38, 4 203 (1973).The conditions for the preparation of the compounds according to the invention are described in one of German Offenlegungsschrift No. 2,645,104, 2,645,105, 2,340,591, 1,958,549, U.S. Pat. No. 3,383,394, and in J. Org. Chem. 38, 4,203 (1973).
Způsob podle vynálezu je blíže objasněn V dále uvedených příkladech:The process according to the invention is illustrated in more detail in the following examples:
Příklad 1Example 1
a) Z roztoku 5,0 g 9a-chlor-ll/3,17a,21-trihydroxy-6a-methyl-l,4-pregnadien-3,20-dionu a 0,5 g pyridiniumtosylátu ve 35 mililitrech dimethylformamidu a 350 ml benzenu se při teplotě 130 QC oddestiluje přes odlučovač vody 150 ml benzenu. K reakčnímu roztoku se za horka pomalu přidá 10 ml triethylesteru kyseliny orthooctové, načež se oddestiluje další množství benzenu a jiné snadné těkavé reakční složky. Pak se přidají 4 ml pyridinu a směs se odpaří za sníženého tlaku do sucha. Izoluje se 9a-chlor-17a,21(ethoxyethylidendioxy )-11(3-hydroxy-6a-methyl-l,4-pregnadien-3,20-dion v podobě oleje.a) From a solution of 5.0 g 9a-chloro-11 / 3,17a, 21-trihydroxy-6a-methyl-1,4-pregnadien-3,20-dione and 0.5 g pyridinium tosylate in 35 ml dimethylformamide and 350 ml benzene at 130 Q C to distill off the water separator 150 ml of benzene. To the reaction solution, 10 ml of triethyl orthoacetic acid ester is slowly added while hot, and a further amount of benzene and other easily volatile reactants are distilled off. Pyridine (4 ml) was added and the mixture was evaporated to dryness under reduced pressure. 9α-Chloro-17α, 21 (ethoxyethylidenedioxy) -11 (3-hydroxy-6α-methyl-1,4-pregnadien-3,20-dione) is isolated as an oil.
bj Surový 9a-chlor-17a,21-(ethoxyethylidendioxy) -11/3-hydr oxy-6a-methyl-l,4-pregnadien-3,20-dion se rozpustí ve 150 ml methanolu a vzniklý roztok se míchá 1 hodinu při teplotě lázně 100 °C se směsí 54 ml 0,1 N kyseliny octové a 6 ml 0,1 M vodného roztoku octanu sodného. Pak se reakční směs zahustí na 1/3 svého objemu, přidá se voda a extrakty esteru kyseliny octové se promyjí do neutrální reakce. Po vysušení a zahuštění se surový produkt přečistí na 500 gramů silikagelu za použití směsí methylenchloridu a 0 až 20 % acetonu jako elučního činidla. Získá se 4,6 g 17a-acetoxy-9a-chlor-ll(5,21-dihydroxy-6a-methyl-l,4-pregnadien-3,20-dionu o teplotě tání 216 až 218 °C.bj Crude 9α-chloro-17α, 21- (ethoxyethylidenedioxy) -11β-hydroxy-6α-methyl-1,4-pregnadien-3,20-dione was dissolved in 150 mL methanol and the resulting solution was stirred for 1 h at bath temperature of 100 ° C with a mixture of 54 ml of 0.1 N acetic acid and 6 ml of 0.1 M aqueous sodium acetate solution. The reaction mixture was then concentrated to 1/3 of its volume, water was added and the acetic acid ester extracts were washed until neutral. After drying and concentration, the crude product is purified on 500 g of silica gel using methylene chloride / 0-20% acetone as eluent. 4.6 g of 17α-acetoxy-9α-chloro-11 (5,21-dihydroxy-6α-methyl-1,4-pregnadien-3,20-dione, m.p. 216-218 ° C) are obtained.
Příklad 2Example 2
a) K roztoku 12,8 g 21-acetoxy-ll(3-hydroxy-6a-methyl-17a-propionyloxy-l,4-pregnadien-3,20-dionu v 65 ml dimethylformamidu a 15 ml pyridinu se při teplotě místnosti přidá 8 ml chloridu kyseliny methansul'fonové a směs se pak míchá 2 hodiny při teplotě lázně 80 °C. Po vysrážení ledovou vodou a obvyklém zpracování se získaný surový produkt přečistí na 800 g silikagelu za použití směsí methylenchloridu a 0 až 8 °/o acetonu jakožto elučního činidla. Získá se 7,0 g 21-acetoxy-6a-methyl-17a-pr opionyloxy-1,4,9 (11 j -pregnatrien-3,20-dionu o teplotě tání 185 až 187 °C.(a) To a solution of 12.8 g of 21-acetoxy-11 (3-hydroxy-6α-methyl-17α-propionyloxy-1,4-pregnadien-3,20-dione in 65 ml of dimethylformamide and 15 ml of pyridine is added at room temperature 8 ml of methanesulfonic acid chloride was then stirred for 2 hours at a bath temperature of 80 DEG C. After precipitation with ice water and usual work-up, the crude product obtained was purified on 800 g of silica gel using methylene chloride / 0-8% acetone as a mixture. There were obtained 7.0 g of 21-acetoxy-6α-methyl-17α-propionyloxy-1,4,9 (11β-prenatriene-3,20-dione, m.p. 185-187 ° C).
bj 2,0 g 21-acetoxy-6a-methyl-17a-propionyloxy-1,4,9 (11 )-pregnatrien-3,20-dionu se rozpustí ve 20 ml dioxanu a ke vzniklému roztoku se přidá 1,8 g N-chlorsukcinimidu. Po přikapání 10 ml 10% kyseliny chloristé se směs míchá 5 hodin při teplotě místnosti. Po vlití reakční směsi na ledovou vodu se směs zpracuje obvyklým postupem. Získaný surový produkt se přečistí na 200 g silikagelu za použití směsí methylenchloridu a 0 až 12 % acetonu jako elučního činidla. Získá se 1,6 g 21-acetoxy-9a-chlor-ll/3-hydroxy-6a-methyl-17a-propionyloxy-l,4-pregnadien-3,20-dionu o teplotě tání 232 až 233 °C.bj Dissolve 2.0 g of 21-acetoxy-6α-methyl-17α-propionyloxy-1,4,9 (11) -pregnatriene-3,20-dione in 20 ml of dioxane and add 1.8 g of N to the resulting solution. -chlorosuccinimide. After dropwise addition of 10 ml of 10% perchloric acid, the mixture was stirred at room temperature for 5 hours. After pouring the reaction mixture onto ice water, the mixture is worked up in the usual manner. The crude product obtained is purified on 200 g of silica gel using methylene chloride / 0-12% acetone as eluent. 1.6 g of 21-acetoxy-9α-chloro-11β-hydroxy-6α-methyl-17α-propionyloxy-1,4-pregnadien-3,20-dione, m.p. 232-233 ° C, are obtained.
Příklad 3Example 3
a) Roztok 2,7 g trlstrifenylfosfin-rhodium-I-chloridu v 75 ml methanolu a 225 ml benzenu se předběžně hydrogenuje 1 hodinu za teploty místnosti. Po přidání 3,0 g 21-acetoxy-6a-methyl-17a-propionyloxy-1,4,9(11 j-pregnatrien-3,20-dionu se znovu hydrogenuje 6,5 hodiny. Po odpaření reakční směsi do sucha se zbytek přečistí na 350 g silikagelu za použití směsí hexanu a 0 až 40 °/o ethylacetátu jako elučního činidla. Získá se 2,5 g 21-acetoxy-6a-methyl-17«-propionyloxy-4,9 (11 j -pregnadien-3,20-dionu o teplotě tání 149 až 151 °C.a) A solution of 2.7 g of tri-triphenylphosphine-rhodium-1-chloride in 75 ml of methanol and 225 ml of benzene was pre-hydrogenated for 1 hour at room temperature. After addition of 3.0 g of 21-acetoxy-6α-methyl-17α-propionyloxy-1,4,9 (11β-pregnatriene-3,20-dione, it is hydrogenated again for 6.5 hours. After evaporation of the reaction mixture to dryness, the residue Purification on 350 g of silica gel using hexane / 0-40% ethyl acetate as eluent gave 2.5 g of 21-acetoxy-6α-methyl-17'-propionyloxy-4,9 (11'-pregnadien-3). 149 DEG -20 DEG C., m.p.
bj Za podmínek příkladu 2bj se 2,0 g 21-acetoxy-6a-methyl-17«-propionyloxy-4,9(ll)-pregnadien-3,20-dionu nechají reagovat s N-chlorsukcinimidem, načež se reakční směs zpracuje a přečistí. Izoluje se 1,05 g 21-acetoxy-9a-chlor-ll/S-hydroxy-6a-methyl-17j3-propionyloxy-4-pregnen-3,20-dionu □ teplotě tání 205 až 206 °C.bj Under the conditions of Example 2bj, 2.0 g of 21-acetoxy-6? -methyl-17? -propionyloxy-4,9 (11) -pregnadien-3,20-dione was treated with N-chlorosuccinimide, after which the reaction mixture was worked up and cleans. 1.05 g of 21-acetoxy-9α-chloro-11β-hydroxy-6α-methyl-17β-propionyloxy-4-pregnene-3,20-dione is isolated, m.p. 205-206 ° C.
Příklad 4 aj 5,0 g 17«,21-dihydroxy-6a-methyl-1,4,9(11 j-pregnatrien-3,20-dionu se nechá reagovat postupem popsaným v příkladu laj s 10 ml triethylesteru kyseliny orthopropionové za vzniku 17a,21-(ethoxypropylidendioxy j -6«-methyl-l,4,9 (11 j -pregnatrien-3,20dionu ve formě oleje.Example 4 and 5.0 g of 17 ', 21-dihydroxy-6α-methyl-1,4,9 (11'-pregnatriene-3,20-dione) were reacted as described in Example 1a with 10 ml of triethyl orthopropionate to give 17a, 21- (ethoxypropylidenedioxy) -6'-methyl-1,4,9 (11'-pregnatriene-3,20-dione as an oil.
bj Surový 17a,21-(ethoxypropylidendioxy) -6a-methyl-l,4,9 (11 j -pregnatrien-3,20-dion se míchá 20 hodin za teploty tlázně 80 CC se směsí 250 ml dimethylformamidu a 5 ml trimethylchlorsilanu. Potom se reakční směs odpaří do sucha a surový produkt se předčistí na 600 g silikagelu za použití směsí methylenchloridu a 0 až 12 % acetonu jako elučního činidla. Výtěžek činíbj The crude 17α, 21- (ethoxypropylidenedioxy) -6α-methyl-1,4,9 (11α-pregnatriene-3,20-dione) was stirred at 80 ° C for 20 hours with a mixture of 250 mL dimethylformamide and 5 mL trimethylchlorosilane. The reaction mixture is then evaporated to dryness and the crude product is pre-purified on 600 g of silica gel using mixtures of methylene chloride and 0 to 12% acetone as the eluent.
3,5 g 21-chlor-6a-methyl-17a-propionyloxy-1,4,9 (11 j-pregnatrien-3,20-dionu.3.5 g of 21-chloro-6α-methyl-17α-propionyloxy-1,4,9 (11β-pregnatriene-3,20-dione).
cj Postupem, obdobným postupu popsanému v příkladu 2b j, se 1,5 g 2Í-chlor-6«methyl-17a-propionyloxy-l,4,9(ll)-pregnatrien-3,20-dionu nechá reagovat s N-chlorsukcinimidem, načež se reakční směs zpracuje a přečistí. Izoluje se 1,32 g 9a,21-dichlor-lld-hydroxy-6a-methyl-17a-propionyloxy-l,4-pregnadien-3,20-dionu o teplotě tání 239 až 241 °C.cj In a similar manner to Example 2b j, 1.5 g of 2'-chloro-6'-methyl-17α-propionyloxy-1,4,9 (11) -pregnatriene-3,20-dione was reacted with N-chlorosuccinimide The reaction mixture is worked up and purified. 1.32 g of 9?, 21-dichloro-11? -Hydroxy-6? -Methyl-17? -Propionyloxy-1,4-pregnadien-3,20-dione, m.p. 239 DEG-241 DEG, is isolated.
Příklad 5Example 5
a) Postupem, obdobným postupu popsanému v příkladu laj, se 2,0 g 17a,21-dihydrox.y-6a-methyl-l,4,9(ll)-pregnatrien-3,20-dionu nechají reagovat s triethylesterem kyseliny orthomáselné za vzniku 17a,21- (ethoxybutylidendioxy j -6a-methyl-1,4,9(11 j-pregnatrien-3,20-dionu ve formě oleje.(a) Following a procedure similar to that described in Example 1a, 2.0 g of 17α, 21-dihydroxy-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione were reacted with triethyl orthobutyrate. to give 17α, 21- (ethoxybutylidenedioxy) -6α-methyl-1,4,9 (11β-pregnatriene-3,20-dione as an oil).
bj Na surový 17a,21-(ethoxybutylidendioxy ) -6a-methyl-l,4,9 (11) -pregnatrien-3,20-dion se za podmínek popsaných v příkladu lb) působí směsí 0,1 N kyseliny octové s 0,1 M roztokem octanu sodného, načež se reakční směs zpracuje a přečistí. Získá se 1,5 g 17a-buíyryloxy-21-hydroxy-6a-methyl-l,4,9(ll)-pregnatrien-3,20-dionu.bj Crude 17α, 21- (ethoxybutylidenedioxy) -6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione is treated with 0.1 N acetic acid with 0.1 N acetic acid under the conditions described in Example 1b). The reaction mixture is worked up and purified. 1.5 g of 17? -Butyryloxy-21-hydroxy-6? -Methyl-1,4,9 (11) -pregnatriene-3,20-dione is obtained.
c) Roztok 1,0 g 17«-butyryloxy-21-hydroxy-6a-methyl-l,4,9 (11) -pr egnatrien-3,20-dionu v 10 ml pyridinu se míchá 1 hodinu při teplotě místnosti s 5,0 ml anhydridu kyseliny octové, načež se reakční směs zpracuje obvyklým postupem. Po překrystalování ze směsi acetonu s hexanem se izoluje 930 mg 21-acetoxy-17a-butyryloxy-6a-methy 1-1,4,9 (11 j -pr egnatrien-3,20-dionu.c) A solution of 1.0 g of 17.beta.-butyryloxy-21-hydroxy-6.alpha.-methyl-1,4,9 (11) -propylnatriene-3,20-dione in 10 ml of pyridine is stirred at room temperature for 5 hours. 1.0 ml of acetic anhydride is then worked up in the usual manner. After recrystallization from a mixture of acetone and hexane, 930 mg of 21-acetoxy-17α-butyryloxy-6α-methyl 1-1,4,9 (11β-propynatriene-3,20-dione) was isolated.
dj Za podmínek, uvedených v příkladu 2b, se nechá 800 mg 21-acetoxy-17a-butyryloxy-6a-methyl-l,4,9(ll)-pregnatrien-3,20-dionu reagovat s N-chlorsukcinimidem, načež se reakční směs zpracuje a přečistí. Výtěžek činí 650 mg 21-acetoxy-17a-butyryloxy-Oa-chlor-ll/i-hydroxy-ea-methyl-l,4-pregnadien-3,20-dionu o teplotě tání 227 až 229 °C.dj Under the conditions described in Example 2b, 800 mg of 21-acetoxy-17α-butyryloxy-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione was reacted with N-chlorosuccinimide, followed by reaction the mixture is worked up and purified. Yield: 650 mg of 21-acetoxy-17.alpha.-butyryloxy-.alpha.-chloro-11H-hydroxy-.alpha.-methyl-1,4-pregnadien-3,20-dione, m.p. 227 DEG-229 DEG.
Příklad 6Example 6
a) K suspenzi 12,2 g jodidu meďného ve 240 ml bezvodého tetrahydrofuranu se při teplotě 0 °C přikape v atmosféře argonu 60 ml 1,6 M roztoku methyllithia. Směs se ještě 15 minut míchá při teplotě 0 °C, načež se nažloutlý roztok ochladí na teplotu —30 °C. Po přikapání roztoku 9,6 g 17a-hydroxy-6a-methyl-21-valeryloxy-l,4,9 (11) -pregnatrien-3,20-dionu se reakční směs míchá 40 minut při teplotě —30 °C, načež se vlije do ledově studeného nasyceného roztoku chloridu amonného a extrahuje ethylacetátem. Organické extrakty se zpracují obvyklým postupem a surový produkt se přečistí na 100 g silikagelu za použití směsí methylenchloridu s 0 až 12 °/o ace,tonu. Výtěžek činí 7,3 g 21-hydroxy-6a-methyl-17a-valeryloxy-l,4,9(ll j-pregnatrien-3,20-dionu.a) To a suspension of 12.2 g of copper (I) iodide in 240 ml of anhydrous tetrahydrofuran at 0 ° C was added dropwise 60 ml of a 1.6 M methyllithium solution under argon. The mixture was stirred at 0 ° C for 15 minutes, then the yellowish solution was cooled to -30 ° C. After dropwise addition of a solution of 9.6 g of 17α-hydroxy-6α-methyl-21-valeryloxy-1,4,9 (11) -pregnatriene-3,20-dione, the reaction mixture was stirred at -30 ° C for 40 min. poured into ice-cold saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts were worked up in the usual manner and the crude product was purified on 100 g of silica gel using methylene chloride mixtures with 0-12% acetone. Yield: 7.3 g of 21-hydroxy-6α-methyl-17α-valeryloxy-1,4,9 (11β-pregnatriene-3,20-dione).
b) Postupem, obdobným postupu popsanému v příkladu 5c), se 5,0 g 21-hydroxy-6a-methyl-17a-valeryloxy-l,4,9(ll j-pregnatrien-3,20-dionu nechá reagovat s anhydridem kyseliny propionové, načež se reakční směs zpracuje a přečistí. Izoluje seb) Following a procedure similar to that described in Example 5c), 5.0 g of 21-hydroxy-6α-methyl-17α-valeryloxy-1,4,9 (11j-pregnatriene-3,20-dione) was reacted with an acid anhydride The reaction mixture is worked up and purified
4,6 g 6«-methyl-21-propionyloxy-17a-valery’oxy-l,4,9(ll j-pregnatrien-3,20-dionu.4.6 g of 6'-methyl-21-propionyloxy-17α-valery'oxy-1,4,9 (11β-pregnatriene-3,20-dione).
cj Za podmínek, uvedených v příkladu 2b j, se 4,0 g 6a-methyl-21-propionyloxy-17a-valeryloxy-l,4,9(ll)-pregnatrien-3,20-dionu nechají reagovat s N-chlorsukcinimidem, načež se reakční směs zpracuje a přečistí. Výtěžek činí 2,6 g 9a-chlor-llfS-hydroxy-6a-methyl-21-propionyloxy-17a-valeryloxy-l,4-pregnadien-3,20-dionu o teplotě tání 257 až 259 °C.cj Under the conditions of Example 2b j, 4.0 g of 6α-methyl-21-propionyloxy-17α-valeryloxy-1,4,9 (11) -pregnatriene-3,20-dione were reacted with N-chlorosuccinimide, The reaction mixture is then worked up and purified. The yield was 2.6 g of 9α-chloro-11β-hydroxy-6α-methyl-21-propionyloxy-17α-valeryloxy-1,4-pregnadien-3,20-dione, m.p. 257-259 ° C.
Příklad 7Example 7
a) Postupem popsaným v příkladu la) se 5,0 g 17/3-21-dihydroxy-6a-methyl-l,4,9(ll)-pregnatrien-3,20-dionu nechá reagovat s 10 ml triethylesteru kyseliny orthobenzoové za vzniku 17a,21-(ethoxybenzylidendioxy) -6a-methyl-l,4,9 (11) -pr egnatrien-3,20dionu, načež se reakční směs zpracuje obvyklým postupem.a) Following the procedure described in Example 1a), 5.0 g of 17 / 3-21-dihydroxy-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione was treated with 10 ml of orthobenzoic acid triethyl ester with formation of 17α, 21- (ethoxybenzylidenedioxy) -6α-methyl-1,4,9 (11) -propenatriene-3,20-dione, after which the reaction mixture is worked up in a conventional manner.
b) Surový 17a,21-(ethoxybenzyliden•oxy ) -6a-methyl-l,4,9 (11) -pregnatrien-3,20-dion se nechá reagovat za podmínek, popsaných v příkladu 4b), s trimethylchlorsilanem a vzniklý reakční produkt se zpracuje a přečistí. Izoluje se 3,2 g 17a-benzyloxy-21-chlor-6a-methyl-l,4,9(ll)-pregnatrien-3,20-dionu.b) The crude 17α, 21- (ethoxybenzylidene-oxy) -6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione is reacted under the conditions described in Example 4b) with trimethylchlorosilane and the reaction mixture formed. the product is worked up and purified. 3.2 g of 17α-benzyloxy-21-chloro-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione are isolated.
c) Postupem, obdobným postupu popsanému v příkladu 2b), se 1,0 g 17a-benzyloxy-21-chlor-6a-methyl-l,4,9 (11) -pregnatrien-3,20-dionu nechá reagovat s N-chlorsukcinimidem, načež se vzniklý produkt zpracuje a přečistí. Výtěžek činí 920 mg 17a-benzoyloxy-9a,21-dichlor-ll,d-hydroxy-Qa-methyl-l,4-pregnadien-3,20-dionu o teplotě tání 230 až 232 °C.c) Following a procedure similar to that described in Example 2b), 1.0 g of 17α-benzyloxy-21-chloro-6α-methyl-1,4,9 (11) -pregnatriene-3,20-dione was reacted with N- with chlorosuccinimide, after which the product is worked up and purified. Yield: 920 mg of 17.alpha.-benzoyloxy-9.alpha., 21-dichloro-11, d-hydroxy-.alpha.-methyl-1,4-pregnadien-3,20-dione, m.p. 230 DEG-232 DEG.
Příklad 8Example 8
a) Roztok 6,5 g 21-acetoxy-17a-hydroxy-6a-methyl-l,4,9(ll)-pregnatrien-3,20-dionu v 80 ml diethylglykoldimethyletheru se míchá 5 hodin při teplotě lázně 80 °C se 20,0 g 4-dimethylaminopyridinu s 20,0 ml anhydridu kyseliny pivalové. Surový produkt, vysrážený vlitím reakční směsi do ledové vody, se zpracuje obvyklým postupem a přečistí na 750 g silikagelu za použití směsí methylenchloridu a 0 až 8 % acetonua) A solution of 6.5 g of 21-acetoxy-17.alpha.-hydroxy-6.alpha.-methyl-1,4,9 (11) -pregnatriene-3,20-dione in 80 ml of diethylglycol dimethyl ether is stirred for 5 hours at a bath temperature of 80 DEG C. 20.0 g of 4-dimethylaminopyridine with 20.0 ml of pivalic anhydride. The crude product, precipitated by pouring the reaction mixture into ice water, is worked up in the usual manner and purified on 750 g of silica gel using mixtures of methylene chloride and 0 to 8% acetone.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823243482 DE3243482A1 (en) | 1982-11-22 | 1982-11-22 | NEW 6 (ALPHA) METHYL CORTICOIDS, THEIR PRODUCTION AND USE |
| CS838675A CS248712B2 (en) | 1982-11-22 | 1983-11-22 | Production method of 6 alfa-methylcorticoids |
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| Publication Number | Publication Date |
|---|---|
| CS248728B2 true CS248728B2 (en) | 1987-02-12 |
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ID=25746602
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS8410073A CS248727B2 (en) | 1982-11-22 | 1984-12-20 | Production method of the 6alfa methylcorticoid derivatives |
| CS8410075A CS248729B2 (en) | 1982-11-22 | 1984-12-20 | Production method of the 6alfa methylcorticoid derivatives |
| CS8410074A CS248728B2 (en) | 1982-11-22 | 1984-12-20 | Production method of the 6alfa methylcorticoid derivatives |
| CS8410076A CS248730B2 (en) | 1982-11-22 | 1984-12-20 | Production method of 6alfa methylcorticoid derivatives |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS8410073A CS248727B2 (en) | 1982-11-22 | 1984-12-20 | Production method of the 6alfa methylcorticoid derivatives |
| CS8410075A CS248729B2 (en) | 1982-11-22 | 1984-12-20 | Production method of the 6alfa methylcorticoid derivatives |
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| Application Number | Title | Priority Date | Filing Date |
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| CS8410076A CS248730B2 (en) | 1982-11-22 | 1984-12-20 | Production method of 6alfa methylcorticoid derivatives |
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| CS (4) | CS248727B2 (en) |
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- 1984-12-20 CS CS8410075A patent/CS248729B2/en unknown
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- 1984-12-20 CS CS8410076A patent/CS248730B2/en unknown
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| CS248729B2 (en) | 1987-02-12 |
| CS248727B2 (en) | 1987-02-12 |
| CS248730B2 (en) | 1987-02-12 |
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