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    • 专利摘要:
    Corticosteroids of the formulae wherein: R16 is methyl; and R17 independently is hydrogen, or C2 to Ce linear or branched acyl or R16 and OR17 taken together are the radical (IV) where R3 is hydrogen, C1 to Ce linear or branched alkyl, and R4 is the same or different than R3 as defined above or is C1 to Ce linear or branched alkoxy or R3 and R4 taken together with the carbon atom of said radical is C4 to C9 heterocyclic alkyl having one heterocyclic atom that is oxygen, R21 independently is C, to Ce linear or branched alkyl or C4 to C9 heterocyclic alkyl having one heterocyclic atom that is oxygen; or OR17 and OR21 taken together are the radical (IV) where R3 is defined above and R4 is C1 to Ce linear or branched alkoxy; Y is selected from the group methyl, halomethyl, and the radical -CH2OC(O)R where R is C2 to C6 linear or branched alkyl; Z independently is C1 to C7 linear or branched acyloxy, hydroxy or halo or Z and OR17 taken together are the radical (IV) where R3 and R4 is defined above; are useful as anti-inflammatory agents. Compounds III can be prepared from compounds I through compounds II.
    公开号:SU942601A3
    申请号:SU792747303
    申请日:1979-04-04
    公开日:1982-07-07
    发明作者:Маркс Майкл；Дж. Кертед Денис
    申请人:Синтекс (Ю.С.А.) Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing corticosteroids of the general formula r4 — hydrogen, linear or branched alkyl with 1-6 carbon atoms;
    R 1 I
    r5 ”is hydrogen, linear or branched alkyl with 1-6 carbon atoms, linear or branched alkoxy group with 1-6 carbon atoms, or R ^ CH ^ COR, where OR 6 and 0R ° together form where R 1 -yC = O and Li -CHYZ-,
    R * ^ - methyl;
    R % is hydrogen, linear or branched acyl with 2-6 carbon atoms, or r9-m OR * together - ° h X s'
    -0 Z R 5
    G '
    where r4 is as defined above, a R · '- a linear or branched alkoxy group having 1-4 carbon atoms, Y - is hydrogen, methyl, chloromethyl, bromomethyl or company CHqOC (= O) r1 wherein R 7 - a linear or branched alkyl 2- 6 atomic atoms of carbon, Z - acyloxy group with 1-7 carbon atoms, hydroxyl, halogen, or Z and 0R® together
    where R 4 and R ^ have the indicated meanings, possessing the pharmacological asset „10 KNOWN.
    A known method for producing d-methylene carbonyl compounds is that the carbonyl compound is condensed with formaldehyde in the presence of base 15 ].
    Using the known reaction allows to obtain corticosteroids of the general formula 1 not described in the literature. 20
    The purpose of the invention is a method for producing new pharmacologically active corticosteroids of the general formula I.
    This goal is achieved by the fact that in the method for producing corticosteroid 23 compounds of the general formula 1, namely, that the compound of the general formula
    Ch 7 or 6 i L 30 BUT-C = 0. . JL - OR 3 eleven gF j 1 35 X Fwhere A, R 5 h R fe have the above
    values, 40 is reacted with formaldehyde in the presence of a base and the resulting compound of general formula I, where d and - group CHq == COR ^ isolated or treated with aqueous acid to give compounds of general formula 45 Nij 1 wherein R 1 - SDA, Y - methyl, or with an aqueous solution of chlorine or bromine to give compounds of general formula 1 (wherein R 1 - SDA and Y - chloromethyl or bromomethyl, rye koto- 50 if necessary is reacted with a compound of general formula | RSOOM (III) where I is an alkaline or alkaline earth metal 55, and R * 1 has the indicated meanings for the preparation of compounds of the general formula I, where R 1 is СОУ, and У is a group
    CH ^ OS (= 0) R 7 , where R 7 has the indicated values, which are isolated or treated with sodium borohydride to obtain compounds of the general formula I, where · R 1 ^ is СНУ2, and 2 is hydroxyl, which is isolated or treated with carboxylic acid, by its acid chloride or anhydride to obtain compounds of the general formula 1, where is СНУ2, and 2 is an acyloxy group, or in succession, by sulfonic acid chloride, an alkali or alkaline earth metal halide ^ to obtain compounds of the general formula I, where CHZy, a Z is halogen, or a compound of the general formula 1, where Й ^ - SNU2., 2 and 0R- 'have the meanings indicated, is reacted with trifenilgaloidmetanom-for the preparation of compounds of general formula I, wherein R 1 - SNU2 and 2 - halogen, or a compound of general formula I, wherein R''- SDA and Y is - hydrogen, subjected to interaction with diazomethane at a temperature of from 0 to 25 ° C, for 30 minutes - 48 hours to obtain a compound of General formula 1, where R 1 - SOU, and Y - methyl, followed by isolation of the target products by known methods.
    I
    The reaction of formaldehyde with a compound of general formula II is carried out in a non-reactive polar organic solvent, usually at a temperature of 6O-12O ° C. Preferably, protic solvents are used as a solvent, for example, aqueous methanol, ethanol and the like. Although a variety of basic catalysts can be used to promote the addition of carbonyl reagents to compounds of general formula 11, bases with a low pK value should be avoided since they can cause adverse reactions in other positions of steroid nuclei. Sodium bicarbonate is the most preferred basic catalyst for use in this reaction. When the compounds of formula I are reacted with hypohaloid acids, the corresponding, usually unstable, but capable of releasing 21-hydroxyhalohydrins are formed. Such compounds are also easily dehydrated 'to form the compounds of the invention in which Y is halogenated. Substitution of the 21-a-halogen with an anion of an alkaline or alkaline earth carboxylate in an appropriate solvent gives the 21-a-carboxylic ester.
    When carrying out the hydration reaction, an aqueous solution of an organic 5 solvent containing a 21-methylene compound of the formula I and an acid catalyst are heated at a temperature of 20-120 ° C, preferably at 20-80, °. A variety of acid catalysts can be used to carry out this reaction 10, for example, organic carboxylic acids, such as paratoluenesulfonic acid, acetic acid, and the like. fifteen
    The use of 70% hydrochloric _ formic acid as the organic carboxylic acid. Inorganic mineral acids such as sulfuric acid, hydrochloric acid and the like, preferably dilute sulfuric acid (100 HQSO4 in water) can be used to catalyze the reaction when U is methyl in formula 1. In a reaction using a hypogalo - 25 idic acid optionally add any other catalytic compounds. However, usually a hypogaloid acid or a solution generating hypogaloid acid is used in the presence of a strong mineral acid, such as a 5% sulfuric acid solution.
    20-21-Dion-pregnadienes can be easily converted to compounds of formula 35 in which Y is methyl, halomethyl or the radical —CH ^ OS (= O) R 7 , in which has the previously indicated meanings, and Z is hydroxyl , as a result of selective reduction of the C-21 keto group. Preferably, such reduction is carried out with sodium borohydride in a protic solvent, such as methanol, at 0-20 ° C.
    Corticosteroids of the general formula I <5 are highly effective as topical anti-inflammatory agents. These compounds have little or no systemic activity. Despite the fact that these systemic effects such as adrenal atrophy, mineral corticoids effects and collagen rastrojstva may occur when using large dosages of the compounds of general Formula I for 55 a prolonged period of time, favorable ratio of local and systemic activity of these compounds allows the use of such small dosages that indicated systemic effects are minimized.
    Example 1. 6-alpha, 9 alpha * · difluoro-1 1 beta, 17 alpha, 21-trihydroxy-16 alpha-methyl-21-methylene-preferred-1,4-diene-3,2 0-dion-17 “21- methyl orthoacetate.
    a) a mixture of 6 alpha, 9 alpha-difluoro-1Gbeta, 17 alpha, 21-trihydroxy-16 alpha-methylpregna-1, 4-diene-3,20-dione (1 g) and paratoluenesulfonic acid monohydrate (0.5 g) trimethylorthoacetate (20 ml) and benzene (30 ml) are slowly distilled (90 ° С, bath) in order to azeotropically remove water until, according to thin-layer chromatography, the absence of the starting compound is detected. The reaction mixture is evaporated to dryness, the residue is taken up with benzene and filtered. The resulting substance was isolated by filtration and recrystallized from methanol / methylene chloride to form 6 alpha, alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dione-17, 21-methyl orthoacetate (0.42 g);
    b) the intermediate 17.21 orthoacetate from step (a) (150 mg) is dissolved in a solution of ethanol (10 ml) and aqueous 37% formaldehyde (2.5 ml) and treated with sodium bicarbonate (50 mg) at 80 ° C. for 16 hours in a nitrogen atmosphere. The reaction mixture was poured into ice water and the resulting precipitate was collected and washed with water. The crude product was subjected to preparative thin layer chromatography (2% methanol / chloroform) and a compound was identified that was identified as 21-methylene adduct (75 mg), mp. 218-222 ° C from a mixture of acetone / hexane.
    Replacing trimethyl orthoacetate with triethyl orthopropionate gives 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy-1b-alpha-methyl-21-methylenepregna-1,4-diene-3.2 0-dione-17.21 ethyl orthopropionate, mp 234-237 ° C.
    Replacing orthoacetate (Example 1 a) with 6 alpha, 9 alpha-difluoro-11-beta, 17 alpha, 21-trihydroxy-1b alpha-methylpregna-1, 4-diene-3,20-dion-17; 21 ~ acetonide get 6 alpha, 9 alpha-difluoro-11 beta, 18 alpha, 21-trihydroxy-16 alpha-methyl-21-methylenepreg-1,4-diene-3,20-dion-17,21-acetonide, so pl. 223 “226 ° C (decomp.).
    Example 2.6 alpha-9 alpha-difluoro-11 beta, 16 alpha-17 alpha-21-tetrahydroxy-21-methylene-per-
    - 1, 4-diene-3,20-diene-16.17 ~ acetonide-21-methyl ether.
    Potassium bicarbonate (250 mg) is added to the solution of 6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17. alpha, 1 21-tetrahydroxypregna-1,4-diene · 3,20-dion-16,17 “acetonide- 21-methyl ether (250 mg) in ethanol (20 ml) and formalin (10 ml). The resulting mixture was heated under nitrogen at 90- 1
    100 ° C. for 16 hours, after which part of the co-solvent was removed by evaporation and water was added. The crude product is filtered, dried and purified by preparative · thin layer chromatography, undergoing 2-fold development of 3% methanol in chloroform, 115 mg of the product are obtained, m.p. 235-242 ° C.
    Similarly, using another pregnadiene-21-alkyl 2-ester, 6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17 alpha-21-tetrahydroxy-21-methylene-pregn-1,4-diene-3,20-dione 16.17 "acetonide-21-tetrahydropyran-2-yl ether, mp, 3ι 208-210 ° С, after freezing, mp 280-285 ° C.
    Example 3.6 alpha, 9'alpha-difluoro-11 beta, 17 - alpha-dihydroxy-16 alpha, 21-dimethylpregna-1, 4-diene-z · -3,20,21-trion-17 ~ acetate.
    Solution 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy-
    - 16 alpha-methyl-21-methylenepregna-
    -1, 4-diene-3,20-dion-1b, 21-methylortho- 4 | acetate (example 1) 650 mg in 40 ml of a 50% aqueous solution of acetic acid is heated at 90 ° C for 1 h in a nitrogen atmosphere. After evaporation of the main part of acetic acid, 45 water was added and the mixture was cooled on ice. The resulting solid crude product was collected, washed with water and dried in vacuo. This substance is subjected to preparative thin layer chromatography 50 eluting with a 2.5% methanol-chloroform system. After recrystallization of the substance from acetone-hexane, 370 mg of product is obtained (mp. 300 ° C).
    ss
    Replacing 17,21-orthoacetate with 1b-methyl-17,21-acetonide (Example 2) gives 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha-di hydroxy 16 alpha-21-di-I methylpregna-1,4 -diene-3,20-trion; 189-193 ° C.
    Example 4.6 alpha, 9 alpha-difluoro-11 beta, 16 · alpha, 17 alpha-trihydroxy-21 methylpregnate 1, 4-diene-3,20,21-trion-16,17 “acetonide.
    alpha, 9 alpha-difluoro-11 beta, alpha, 17 alpha, 21-tetrahydroxy-21 methylene-1,4-diene-3, 20-dione-16,17 - acetonide-21-tetrahydropyran-2-yl ether (40 mg ) is dissolved in ethanol (5 ml) and 20 mg of p-toluenesulfonic acid monohydrate is added. After stirring for one hour at room temperature, water was added and ethanol was removed by vacuum distillation. The crude product is filtered off, washed with water and dried in vacuo. The resulting product was purified by preparative thin-layer chromatography (12% acetone in benzene) to obtain 10 mg of pure product (mp. 299 “301 ° C).
    The above compound is also prepared using 6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, alpha, 21-tetrahydroxy-21-methylpregna-1,4-diene-3, 20-dione-16.17 acetonide-21- alkyl or cycloheteroalkyl ethers (example 2).
    Example 5. 2.1a-chloro-6 alpha, 9 alpha-difluoro-11 beta, 17 alpha-dihydroxy 16 alpha-21-dimethylpregna-1,4-diene-3, 20,21-trion-17 acetate.
    A freshly prepared mixture of 5% aqueous sodium hypochlorite (1 ml), tert.-butanol (2 ml) and 1 N. sulfuric acid (2 ml) is added to the solution of 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha-21-trihydroxy-16 alpha-methyl-21-methylenepregna 1, 4-diene-3,20-dion-17,21 methylorthoacetate (125 mg) in tert.-butanol (3 ml). After 10 minutes, water was added and the resulting product was filtered off and dried. After preparative thin layer chromatography (double development in a mixture of 12.5% acetone in benzene), 48 mg of pure 21 a-chloro-6 alpha, 9 alpha-difluoro-11 beta, 17 alpha-dihydroxy-16 alpha, 21 dimethylpregna 1.4 are obtained -diene-Z, 20,21-trion-17 acetate, so pl. 2bO-2b1 ° C.
    Replacing orthoacetate with 16, ^ “acetonide results in 21a-chloro-6 alpha, 9 alpha-11 beta, 16 alpha, 17 alpha-trihydroxy-21-methylpregna-1,4-diene-Z, 20.2 1-trion -16.1 / “acetonide, so pl. 228-233 ° C (decomp.).
    Replacing 17.21-orthoacetate with the 17.21-acetonide of Example 1 yields 21 a-chloro-6 alpha, 9 alpha-difluoro-11 beta, 17 alpha-dihydroxy-1b, 21-dimethylpregna-1,4-diene Z, 20.21 trion, mp 20b-207 ° C.
    Example 6. 21a-bromo-6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, dihydroxy-16 alpha-21 ~ dimethylpregna-
    - 1,4-diene-Z, 20,21-trion-17 “acetate.
    N-bromosuccinimide (239 mg) in tert-butanol (15 ml) and an aqueous solution of 1 N. sulfuric acid (12 ml) is added to the solution of 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trigido-is-si-16-alpha-methyl-21-methylene-pre-
    - 16,4-diene-3,20-dion-17,21-methyl orthoacetate (example 1) in tert, butanol (15 mp). After 10 minutes, water (200 ml) was added and, after cooling, the crude product was filtered off. It is purified by preparative thin-layer chromatography (developing 2% methanol in chloroform twice in medium), after which it is recrystallized from acetone / hexa- 5 san, mp. 232-234 ° C (decomp.).
    Example 721a ~ chloro ~ 6-alpha, 9 alpha-difluoro-11 concrete, 17 alpha, 21-trihydroxy-16 alpha, 21-dimethylpregna-1,4-diene-3,20-dion-17-acetate, 30 epimer B.
    K 21 a-chloro-6 · alpha, 9 alpha-difluoro-11 beta, 17 ~ alpha-dihydroxy-16 alpha, 21-dimethylpregna 1,4-diene-З, 20, 2 1-trion-1 7 ~ acetate ( 155 mg) 35 (Example 6) in a mixture of methylene chloride (2: 1.15 ml) at -20 ° C sodium borohydride (5 mg) in methanol (1 ml) was added, reaction time 30 min. After adding a few drops of acetic acid to break up the excess reagent, the solvents were removed by distillation and the residue was taken up in ethyl acetate. After washing with water and drying the solution, the solvent is removed. The pure compound is obtained by preparative thin layer chromatography (4% methanol in chloroform), mp 242-244 ° C (decomp.).
    Similarly, using 50 3,20,21-trions of examples 4-7, receive the following compounds:
    alpha, 9 alpha-difluoro-11 beta, '17 alpha, 21-trihydroxy-16 alpha-21-dimethylpregn-1,4-diene-3,2O-di-55 he-17 “acetate, epimer B, mp . 23223b ° C, after freezing, mp <2b1-2b7 ° C.
    2601 10
    6-alpha, 9 alpha-difluoro-11 beta-16 alpha, 17 alpha, 21-tetrahydroxy-21-methylpregnan 1,4-diene-3,20-dion-16,17 ~ acetonide, so pl. 234-238 ° C and ’5 6 alpha, 9 alpha-difluoro-11 beta, alpha, 17 alpha, 21-trihydroxy-16,21-dimethylpregna-1,4-diene-3,20dione. Epimer A, mp 214-218 ° C. Epimer B, mp 19b-197 ° C.
    Example 8.6 alpha, 9 alpha-difluoro-11 beta, 17,21a-trihydroxy-16 alpha-21-dimethylpregna-1,4-diene-3,20,21-trion-17,21a-bis-acetate.
    Sodium acetate (250 mg) was added to a solution of 21a-bromo-17 “acetoxy compound of Example 6 (140 mg) in dimethylformamide (10 ml) and the resulting mixture was left overnight at room temperature. After dilution with water, the product is extracted with ethyl acetate, which is then washed with water, dried with sodium sulfate and the solvent removed by vacuum distillation. The pure compound (20 mg) was obtained by thin-layer chromatography of the residue, 3.5% methanol in chloroform was eluted three times, and then recrystallized from acetone-hexane, m.p. 240-242 ° C (decomp.).
    Example 9. 21a-chloro-6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha, 21-dimethylpregna-1,4-diene-3,20-dione-17,21-bisacetate.
    Epimer B. 21a-chloro-6 alpha, 9 alpha-difluoro-1 1 beta, 17 alpha, 21-trihydroxy-16 alpha, 21-dimethylpregn, 1,4-diene-3, 20-dione-17-acetate (130 mg) from Example 7 was dissolved in a mixture of pyridine (4 ml) and acetic anhydride (1 ml). After an hour, ice water was added and the precipitated product was washed and dried. The resulting material was purified by preparative thin layer chromatography (1.5% methanol in chloroform), mp 224-229 ° C.
    Similarly, using the esters described in example 7, receive the following compounds:
    alpha, 9 alpha-difluoro-11 beta, alpha, 21-trihydroxy-16 alpha, 21-dimethylpregna-1,4-diene-3, 20-dione-17,21-bis-acetate. Epimer B, mp 237 “239 ° C, I 6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy-21-methylpregn-1,4-diene-3,20-dione -16.17-acetate-21-acetate. Epimer A, mp 288-293 ° C and epimer B, and 942
    so pl. 193-197 ° C, after freezing, mp 240-242 ° C.
    Example 10. 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21, 21a-tetrahydroxy-1b alpha, 21-dimethylpreGna -! 4-diene-3, 20-dione, 21-methyl-orthoacetate-21a -acetate.
    a) Flumethasone (1 g) is heated with p-toluenesulfonic acid (300 mg) and tri-methyl-acetoacetate (20 ml) in a solution of 1 benzene, as described in example 1, get pure 6 alpha, 9 alpha-di-fluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha-methylpropylamine-1, 4-diene-3, £ 0-dione-17,21-methylorthoacetate in 85% yield.
    b) 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dio | 4-17,21-methyl orthoacetate (820 mg) and 2 sodium bicarbonate (400 mg) in methanol (50 ml) and formalin (50 ml) are heated at 65 ° C for 12 hours. Water is added and most of the methanol is removed. The crude solid product from-2 is filtered and dried. The resulting alpha, 9 alpha-difluoro-11-beta, 17 alpha, 21,21a-trahydroxy ~ 1b alpha, 21-dimethylpregna-1,4-diene-3, 20-dione-17,21-methylorthoacetate is purified by preparative thin layer chromatography (3% methanol in chloroform, double development) and recrystallization from a mixture of acetone / hexane, so pl. 29-3 “296 ° C.
    c) 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21,21a-tetrahydroxy-16 alpha, 21-dimethylpregna-1,4-diene-3, 20-dione-17,21-methyl-orthoacetate (175 mg) is treated for 15 hours with acetic anhydride (1 ml) in pyridine (5 ml). The reaction mixture was poured into water and extracted with ethyl acetate. The extract obtained is dried with sodium sulfate and the solvent is removed by evaporation, the product is obtained by preparative thin layer chromatography in 3% methanol in chloroform, triple manifestation, so pl. 178-184 ° C.
    Example 11. 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha, 21-dimethylpregna-1,4-diene-3,20-dione-17,21-methylorthoacetate (Epimer A).
    Solution 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha, 21-dimethylpregna-1,4-diene-3,20-dione (Epimer A), 190 mg (example 7) and monohydrate para-toluene 601 12 sulfonic acids (40 mg) in trimethyl orthoacetate (10 ml) and benzene (30 ml) are slowly distilled (bath, 75 ° С) to azeotropically distill water until a thin-layer chromatographic analysis shows that the reaction ended. Most of the remaining solvent is then removed by vacuum distillation. Ethyl acetate was added to the residue until и and the solution was washed with dilute sodium bicarbonate and then with water. After drying the solution with sodium sulfate and evaporating to dryness, the crude product is purified by preparative thin-layer chromatography (3% methanol in chloroform), after recrystallization from a mixture of acetone-hexane, 100 mg of the desired product is obtained, m.p. 210-211 ° C.
    > Example 12. 21-chloro-6 alpha, 9 alpha-difluoro-11 beta, 17 alpha-dihydroxy-16 alpha, 21-dimethylpregna-1,4-diene-Z, 20-dione-17 “acetate (Epimer A) .
    A solution of triethyl chloride (400 mg) in methylene chloride (5 ml) is added to 6 alpha, 9 alpha-difluoro-11 beta, 17 alpha, 21-trihydroxy 16 alpha, 21-dimethylpregna-1,4-diene ~ 3,20-dione I -17,21-methyl orthoacetate (Epimer B
    (.110 ml, example 11). After heating at 40 ° C for 1 h, the solvent was removed, the residue was applied to thin-layer chromatography plates, and was developed twice in 2% methanol in chloroform. The obtained purified product is recrystallized from a mixture of acetone / hexane, so pl. 243-246 ° C.
    Similarly using
    The 21-methyl-17,21-orthoester described in Example 12 gives 21-chloro-6 alpha, 9 alpha-difluoro-11 beta ^ 17 alpha-dihydroxy-16 alpha, 21-dimethylpregna-1,4-diene-3 , 20-dion-17 “propionate, so pl. 225-227 ° C. 0
    Example 13 · 21-chloro-6 alpha, alpha-difluoro-11 beta, 16 alpha, alpha-trihydroxy-21-methyl-pregna - 1,4-diene-3,20-dione 16.17 ~ acetonide.
    a) Solution 6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17 alpha: 21-tetrahydroxy-21-methyl-pregna-1,4-diene-3, 20-dione-16,1 / -acetonide (123 mg) in pyridine (3 ml) is treated with methanesulfonyl chloride (0.1 ml) at 0 ° C. After 10 minutes, the reaction mixture was poured into ice water and extracted with chloroform. Chloroform!
    a solution of crude 21-mesyloxy-6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17 alpha-trihydroxy-21-methylpregna-1,4-diene-3,20-dion-16,17-acetonide is washed with ice water, dried with sul - 5 sodium fats and distilled in vacuo to give a solid residue.
    B) Lithium chloride (500 mg) is added to a solution of 21 ~ mesyloxy-6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17 alpha-trihydroxy-21-methylpregna-1,4-diene-3,20-dion- 16.17 ~ acetonide in dimethylformamide (5 ml). After heating for 2 hours at 130 ° C., some dimethylformamide was removed by distillation and the reaction mixture was poured into ice water. The resulting product is filtered, washed with water and dried in vacuo, the resulting C-21 mixture, the epimers are separated by preparative thin layer chromatography (15% acetone in benzene), 44 mg of epimer B. are obtained, mp. 300 ° C. (decomp.) and 47 mg of epimer A, mp. 300 ° C (decomp.).
    Example 14. 6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17 ~ alpha-tri hydroxy-21-methylpregna-1,4-diene-3,20,21-trion-16,17 “acetonide.
    In a 200 ml flask, it is heated at 100 ° C under high vacuum (0.1 mmHg) for 1 h. 470 mg 6 alpha, 9 alpha-difluoro-11 beta, 16 alpha, 17 alpha-three hydroxy-pre -1,4-diene-3,20-dion-21-aldehyde hydrate, the resulting free aldehyde is treated with 100 ml of dry ether at room temperature and 25 ml of a solution of diazomethane in ether obtained from 0.5 g of N-nitroso-M-urea are added . The resulting solution was stirred for two days. The reaction mixture was evaporated to dryness and the residue was recrystallized three times from acetonehexane to give 200 mg of pure product, m.p. 299 “301 ° C.
    权利要求:
    Claims (1)
    [1]
    1. Weigand-Hilgetag. Experimental methods in organic chemistry. M., Himi, 1968, p. 807.
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    CS208494B2|1981-09-15|Method of making the alcylesters of the 4-halogen-3-oxoandrosta-1,4-dien-17 beta-cyrboxyl acid
    US2859212A|1958-11-04|21-aldo steroids
    AP157A|1991-11-15|Novel steroid derivatives.
    US3728337A|1973-04-17|Preparation of 9alpha-fluoro-11-oxo-steroids
    同族专利:
    公开号 | 公开日
    ES479268A1|1979-12-01|
    JPS54132563A|1979-10-15|
    IT7967710D0|1979-04-04|
    GR71692B|1983-06-21|
    NO791142L|1979-10-08|
    ZA791634B|1980-11-26|
    FI791086A|1979-10-06|
    PL214673A1|1979-12-17|
    DK136679A|1979-10-06|
    EP0004765A3|1979-10-31|
    IL56973D0|1979-05-31|
    IT1165656B|1987-04-22|
    ES484101A1|1980-04-16|
    DE2961648D1|1982-02-18|
    PL118660B1|1981-10-31|
    AU4558479A|1979-10-18|
    ES484100A1|1980-04-16|
    EP0004765A2|1979-10-17|
    EP0004765B1|1981-12-30|
    US4181720A|1980-01-01|
    PT69406A|1979-04-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3031375A|1960-01-22|1962-04-24|Pfizer & Co C|17 beta--pregnene derivatives|
    US3093665A|1960-01-22|1963-06-11|Pfizer & Co C|17beta-pyruvoyl-substituted pregnene derivatives|
    US3234095A|1963-06-19|1966-02-08|Pfizer & Co C|21-methyl and 21-hydroxymethyl steroid compounds|
    DD119586A5|1973-12-21|1976-05-05|
    US4011315A|1975-07-07|1977-03-08|Syntex Inc.|21-acetals and mixed acetals of steroidal 21-aldehydes, intermediates and methods of preparation|US5446177A|1984-12-28|1995-08-29|Alcon Laboratories, Inc.|Anti-inflammatory compounds for ophthalmic use|
    ES2120503T3|1990-11-13|1998-11-01|Alcon Lab Inc|ANTI-INFLAMMATORY COMPOUNDS FOR OPHTHALMIC USE.|
    FR2692267B1|1992-06-11|1995-05-19|Roussel Uclaf|New process for the preparation of 20-keto 21alpha-hydroxy steroid compounds and intermediates.|
    AU2002322720B2|2001-07-25|2008-11-13|Raptor Pharmaceutical Inc.|Compositions and methods for modulating blood-brain barrier transport|
    JP2008539047A|2005-04-28|2008-11-13|プロテウスバイオメディカルインコーポレイテッド|Pharma Informatics System|
    WO2008036682A2|2006-09-18|2008-03-27|Raptor Pharmaceutical Inc.|Treatment of liver disorders by administration of receptor-associated protein -conjugates|
    CN104208718B|2009-02-20|2017-12-29|2-Bbb医疗股份有限公司|drug delivery system based on glutathione|
    US20120077778A1|2010-09-29|2012-03-29|Andrea Bourdelais|Ladder-Frame Polyether Conjugates|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/893,631|US4181720A|1978-04-05|1978-04-05|Corticosteroid antiinflammatory agents|
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