TW200400825A - Process for the production of 7 α-methyl steroids - Google Patents

Abstract

This invention relates to a process for the production of 7 α-methyl steroids of general formula I, starting from compounds of general formula II, which are reacted in an aprotic solvent in the presence of 1-30 mol% of a copper compound CuYnLm with 1-3 molar equivalents of CH3MgX, then with a strong acid. The process according to the invention is distinguished in that 7 α-methyl steroids are obtained in good yields as well as high chemical purity and high diastereomer purities. The process is distinguished in that less waste accumulates with considerably higher throughput. The process according to the invention can therefore be suitable for the production of 7 α-methyl steroids on the industrial scale.

Description

200400825 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to a method for manufacturing a 7α-methyl steroid. The method of the present invention provides base steroids' in good yields as well as high chemical purity and high diastereomeric purity, thus allowing the production of & methyl steroids on an industrial scale. [Prior art] Androgens, especially testosterone ', are used to treat male menopause and for the development of male sexual organs and male contraception. In addition, some of these hormones have the same function as L to promote muscle growth (E. Nieschlag, H. Behre, Andr〇l〇gle_Grundlagen und Klimk der repr〇duk heart) GesundheU des Marines [Andrology_ Human Reproductive Health Principles And clinical research] "Springer Verlag, Berlin 2000). Regarding the indications for steroid hormone replacement therapy, the use of 7α-methyl-19-neosteroidone (πβ-light-based-7α-fluorestradiol-4-en-3-one) has been proposed. With a high binding affinity, the compound has, on the one hand, a higher biological effect than testosterone (JA Campbeii et al., Steroids 1963, 1, 3 17-3 24). On the other hand, 'the difference of this compound lies in metabolic stability' This putative metabolic stability is attributed to the steric effect of 7α-methyl (WO 99/138 12, WO 99/1 3883, US 5,342,834; K. Sundaram et al. Human 'International Journal of Andrology, 2000, 23 (Supplement 2), 13-15; DE Cummings et al.' Journal of Clinical Endocrinology and Metabolism 1998, 83, 4212-4219). Those skilled in the art know that in most of the synthesis of 7α-methyl steroids, the introduction of 7α-methyl is by 1,6-addition (S. Woodward, Chemical Society Review 2000, 2 9, 3 9 3 -4 0 1) Organometallic compounds to estra-4,6-difluoren-3 -one derivatives. 84453 200400825 As described in US 4,000,273, 7α-methyl-19-neurosterone production method, 17β-acetamidine Oxy-4,6-estradien-3-one is reacted with at least 3 equivalents of lithium dimethyl copperate (Me2CuLi) [also manufactured via reaction of a T group with steel.] Then, after acid post-treatment, A 4'5 was isomerized to a △ 3,4 double bond, and the 17-acetamidine group was saponified. After crystallization, the yield of 7α-methyl-1 9-nesterone was only 36% (Example 4 of US 4,000,273). The disadvantages of this method are low chemical yield, low space-time yield, high excess of reactants, and high amount of copper salts (high stoichiometric amount). This has led to additional problems in removing copper from active ingredients and environmental factors related to waste water disposal. According to the method described in US 3,341,5 57, 6-dehydrotestosterone (4,6_estradien-3_one) is reacted with an excess of at least 5 equivalents of fluorenyl_magnesium in the presence of a steel salt. The amidine compound was then reacted with pyridine / acetic anhydride and purified twice by chromatography. This method yields about 34% (85 mole equivalents of CH3MgBr) of β-ethoxyl-7α-methyl-19-neosteroid. As for life's inevitable & ^ ^

The method described in 34i, 557 is used in a similar manner for other steroids 4 84353 200400825 dien-3-one (J. A. Campbell et al., Journal of the American Chemical Society 959, 81, 4069-4074). In the reaction of 3-keto-17α-preg-4,6-diene-21,17-fluorene, after purification by chromatography and recrystallization, only 22% of the corresponding 7α-methyl compound (NW Atwater Et al., Journal of Chemistry [% 丨,%, 3 077-3 083). In other respects, it is described in the literature that copper-catalyzed reaction of steroid 4,6_dien-3-one with alkyl functional magnesium can only obtain 7α-alkyl compounds with poor yield (j. R. Grunwell Et al., Steroids 976, 2 and 759 771, GC Buzby et al., Journal of Medicinal Chemistry 1966, 9, 782-784; NP van Vliet et al., Ree .. Trav Chim (Totally 1986, 105, 1 U_U5). As for 7α-fluorenylsteroid, only 40% yield was obtained according to this method (M. E. Wolff et al., Journal of Medicinal Chemistry, 1970, 13, 531-534). Due to the low yield, low space / time yield and large excess of reactants, Xianli cannot use any of the methods available to those skilled in the art to economically and reasonably affect the mounting, making it 7α_ on an industrial scale. Methyl steroids. [Summary of the Invention] Therefore, the object of the present invention is to find an improved method for synthesizing 7α-methyl steroids. 'This method requires a reduction in the number of reactants and can provide as high as possible'; π-direction production speed without chromatography Purification is 'at the same time economical and resentful' and is therefore suitable for manufacturing on an industrial scale. These objects can be achieved by the present invention. The present invention relates to a method for manufacturing a general formula I 7α_methyl steroid, S43S3

200400825 where R1 (3 represents hydrogen or methyl, R113 represents hydrogen,

Rnb represents hydrogen, hydroxyl, fluorine, or -OC (0) R19, or Rllb together with Rlla represents an oxygen atom, R19 represents CVCu-alkyl, R13 represents hydrogen, methyl, or ethyl, 1117; 1 represents hydrogen, and R17b represents Hydrogen, hydroxyl, R19, -OR19, -〇 (CO) R19 or R17b together with R17a represents an oxygen atom, or R17b also represents an -OM 'group, where M represents -SiRiR ^ R3, R1, R2, R3 each Representing R19, -OR19, benzyl, aryl, or 0aryl, respectively, the method includes the following steps: a) using a compound of formula II 84353-10-200400825

among them

R1Q represents hydrogen or fluorenyl,

Rna means hydrogen,

Rllb represents hydrogen, hydroxyl, fluorine or -0C (0) R19, or Rllb together with Rlla represents an oxygen atom, R19 represents CVCu-alkyl, R13 represents hydrogen, fluorenyl or ethyl, and 11173 represents hydrogen,

R17b represents hydrogen, hydroxyl, R19, -OR19, -〇 (CO) R19 or R17b together with R17a represents an oxygen atom, or R17b also represents an -OM group, where M represents -QR ^ R ^ R3 or -QR ^ R2 , Q represents boron, Ming or Zhen, R1, R2 'and R3 respectively represent R19, -OR19, benzyl, aryl or aryl, and react with 1-3 mole equivalents of CH3MgX in an aprotic solvent (if X Represents 84353 Π 200400825 chlorine, bromine, and Qi), or reacts with 0.5-3 molar equivalents of CH3MgX (if χ represents methyl), and the II reaction is performed in the presence of i -30 molar% copper compound CuYnLm, where γ is an inorganic anion Or organic anions, L is a ligand, η is 1 or 2, m is 0 or a natural integer, b) adding a strong acid to the reaction mixture and additional stirring, c) separation and purification. The Ci-C ^ -alkyl group of the R19 group may be, for example, an unbranched alkyl group such as an alkyl group, an ethyl 'n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group Group, n-decyl, n-alkyl, or n-dodecyl; or branched alkyl groups such as copropyl, isobutyl, second butyl, third butyl, isopentyl, neopentyl, 2- Fluorenylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,2,3-trifluorenyl Butyl, or 2,3,3-trimethylbutyl. The aryl groups of the R1, R—, and R3 groups may be, for example, phenyl, fluorenyl, tolyl, xylyl, biphenyl, pyridyl, and corresponding substituted aryl groups. The -QR ^ W or -QW gene of the OM group can be a trimethylsilyl group, a third butyldimethylsilyl group, a methyldiphenylsilyl group, a dimethylphenylsilyl group, and a triethyl group. Silyl, triisopropylsilyl, diphenylboryl, diethoxyboryl, triethoxyboryl, trimethoxyboryl, di (di-butoxy) Mingyuan Group, triisopropoxymethyl group, triethoxy 84535 2000040825 aluminyl group or trimethoxyaluminum alkyl group.酉 4 Ruan is for example compounds: water, dialkyl ethers such as diethyl ether, tetrahydrofuran, dialkyl sulfides such as dimethylsulfide, diethylsulfide or diisopropylsulfide · benzene; Palmar or non-palmophane or diphosphanes such as triphenylphosphanes, [U1-biphenyl] -2,2, -diylphosphonium (dibenzylphosphanes). The inorganic anion may be a t anion, a t anion, a -bromide anion, a Hong anion, or a cyanide anion. The organic anion is, for example, trifluoromethyl phosphate or acetate. CuYnLm is, for example, copper halides such as copper fluoride (π), copper chloride gadolinium, gasified copper gadolinium, copper desert (1), copper bromide gadolinium-dimethyl complex, bromine Copper (II) or copper iodide (1), copper cyanide (1), copper trifluoromethanesulfonate (1), copper trifluorofluorinate (π), or copper acetate (Η). The acid is, for example, an inorganic acid such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, or hydroiodic acid; or an organic I such as difluoromethanedicarboxylic acid, moxadicarboxylic acid, or p-toluenesulfonic acid. Preferably, sulfuric acid is used in step b). The method of the present invention is particularly suitable for compounds of the general formula II, in which RI 0 and R11 a represent hydrogen, R represents methyl, Rnb represents hydrogen or fluorine, represents OC (〇) R, R represents hydrogen or R17a & R17b collectively represent— An oxygen atom or R] 7b represents -OM to react to form a compound of general formula I. Embodiments of the method according to the present invention, such as tetrahydrofuran (ΤΗρ), 2-methyltetrahydrofuran or methyl-tertiary butyl ether (MTBE), are suitable as aprotic solvents. A preferred solvent is tetrahydrofuran. The amount of solvent (i.e., dilution) is suitably from .50 to 25 times the amount of the steroid of the general formula II of the starting material. The difference of the method of the present invention is that excellent results can also be obtained by using 3 to 10 times the solvent in the range of low dilution factor 84353 -13-200400825. The reaction is carried out at a temperature of -40 C to 0 C. The preferred temperature is at _35.匚 to -1 5 ° C. 1.0-1.8 mol equivalent CH ^ MgX is preferably used in the presence of 5 to 25 mol% copper compound. If Han ... represents a hydroxyl group, or & claw and Hanyu collectively represent an oxygen atom, it is preferable to use 2-2.8 equivalents of CH3MgX. If methyl, use instead! _3 Mol equivalent CH3MgX, half of the amount (CH3) 2Mg can also be used. A particularly preferred reaction is performed using 1'2- 丨 .35 molar equivalents of fluorenylmagnesium chloride in the presence of 10 to 20 mol% copper (I) chloride. Particularly good dilution ranges from 4 to 6 times the volume of the steroid solvent, and particularly good temperature ranges. If necessary, additional steps can be performed between method steps _ and 0 to remove protective groups that are selectively present in the product, such as _c (〇) r19 or. The fluorenyl c (0) Rl9 is removed by alkalization using a strong base in an alcoholic solvent to obtain the corresponding η- or 17- via a methyl or methyl group. To achieve this plutonium, it is preferred to use uranium hydroxide or potassium hydroxide in methanol, ethanol or isopropanol. All protection groups μ required to represent ㈣-based RiRV can be removed in accordance with standard methods known in the literature (eg, Tw · Youyou, pg M.WutsJ Machine Synthesis Protection Group, 2nd Edition, Yolun Power & Sons, New York 1991 year). In addition, an optional additional step between method steps b) and c), that is, the general formula "dagger compound (where H is commonly represented by an oxygen atom) can react with a suitable reducing agent to generate a corresponding 17β pin derivative. For this project For use, preferably 84353 -14-200400825 use a compound hydride such as sodium borohydride, lithium borohydride, potassium borohydride zinc borohydride, sodium diethoxyborohydride, trimethoxyborohydride, -a ^ ] Second tributoxy)-lithium aluminum hydride, lithium triisopropoxy aluminum hydride, triethoxy aluminum gasification bell, and lithium trioxo aluminum hydride. The product is preferably purified by crystallization from a suitable solvent. The solvent is, for example, methyl acetate, ethyl acetate, isopropyl acetate, MTBE, ethyl, _r ~ mono (propyl) ether, THF, hexane, heptane, acetone, dichloromethane, toluene Formic acid or ethanol. Use ethyl acetate or MTBE to achieve particularly good results. Crystallization is carried out at a reflux temperature of -40 ° C but preferably at a temperature of _2 (rc to 40 r.) Known when commonly used 17α-methyl_19-neosteroid test method, pollution will be caused Crystals, thereby reducing the yield of 7 steroids and steroids. According to the method of the present invention, the formation of by-products is also minimized. This condition results in the excellent crystallization properties of the reaction products, so the crystallization yield is increased. Strong acid interrupts the ongoing addition reaction, 6_ addition reaction, and continuous stirring for a period of time at a pH value less than 1 after the addition reaction is completed can ensure this result. In most cases, 10-60 minutes is sufficient additional mixing Time. The difference between the methods of the present invention is that 7α-methyl steroids can be obtained in good yields and with high chemical purity and high diastereomeric purity. The difference in this method is that there is a significantly higher yield by eliminating less wasteful accumulation. Therefore, the method of the present invention is suitable for manufacturing 7α-fluorenyl steroids on an industrial scale, and is particularly suitable for manufacturing 7α-methyl-19-neurosteroid, 17β-ethoxy_7α-methyl-19-neurosteroid, 7α -Methyl testosterone '17β-acetoxy-7α-methyltestosterone, 11β_fluoro-7 (1-methylest-4-en-3,17-dione, 10_fluoro_173_hydroxy_7. 1_methylestrone 84353 200400825 • 4-associated 3-keto 7α-methylandrostene_3_ene_3 , 11, 17-difluorene, Ι7β-kidney_7α, 18- —methylwei-4-fine-3-isotop-3-one, Πβ-[(third butyldiene-3-one, And 17β-[(Third-7α-fluorenylest-4-en-3-one. 170-Ethyloxy-7001, 18-difluorenyl estra-4_fluorenylsulfonyl) oxygen Group] _7α-methylestradiol 4-butyldimethylsilyl) oxy] _ 1 丨 β_fluoro [Embodiment] Synthetic starting materials according to general formula II t can be cooked from the corresponding steroids in a manner known to those skilled in the art 4-ene-3-one production, such as conversion to associated acetic acid acetate, followed by bromination and dehydrobromination (see j. Fried et al., Chemical Organic Reactions of Steroids, Vanox Strong Charge (乂 & 11 ^ 〇valence & 11 (1) ^ 1111〇1 (1), London 1972). Another possible discrimination is the dehydrogenation of the steroid 4_en_3_one (see, for example, E. J. Agnello et al., Journal of the American Chemical Society 1960, 82, 4293-4299). Compounds of general formula II in which Rm represents a -OM group can be obtained by a) compounds of general formula II in which R17b represents a radical (_〇H) reacted with a hydride type H-QR RR reactant, or with a chloride type Reactant ci_qr1r2r3 or Cl-QR R reaction (for example, see τ · w. Greene, PG · M · Wuts, Organic Synthesis Protecting Group '2nd Edition, John Willy & Sons, New York 丨 99 years, or FA Carey, RJ Sundberg, Organische Chemie [Organic Chemistry], VCH, Weihai 1995); b) compounds of the general formula II in which the oxygen atom and the hydride type reactant H-QR1 R / R3 react together (for example, see f. A. Carey, RJ Sundberg, Organic Chemistry). If there is a desired 'protecting group, it can be cleaved according to methods known to those skilled in the art (τ. 84353 -16- 200400825 W · Gfeene, p. G. M. Wuts' organic synthetic protecting group). Operating instructions for the production of fluorenyl steroids (AV 1): 140 ml of 3M methyl magnesium hydride in THF (42 mol) was added dropwise to 0.32 molton in 3-4 hours at 30 C under a nitrogen atmosphere. A solution of a compound of formula [VII] and 57 g (0.058 mol) of copper chloride in 500 ml of THF. Then add 3 2 liters of 50 volume ° / within 20 minutes. Sulfuric acid and stirred for another 30 minutes. The mixture was diluted with 250 ¾ liters of water and stirred for another 30 minutes. The organic phase was separated and absorbed three times with each 300 liters of aqueous chlorinated ammonia solution. The solvent was removed by vacuum distillation. The product is then selectively purified by filtration through silica gel, and then crystallized from a suitable solvent. If they collectively represent an oxygen atom, the compound of the general formula 丨〗 reacts with a double amount of fluorenyl magnesium chloride. If the product of the 1,6-addition to the hydrazone-C (0) R19 is saponified, the reaction solution is further processed as follows. The solution was concentrated to approximately 400 ml via vacuum evaporation. 100 ml of a 10% methanolic potassium hydroxide solution was added to the solution 'and stirred under nitrogen for 3-4 hours. Then, 60 ml of a 10% citric acid solution was added to set the pH to 6, and the solvent was removed by vacuum distillation. The residue was taken up in 1600 ml of MTBE, and the organic phase was washed with 400 ml of water. The product was crystallized by removing the solvent by vacuum distillation and cooling to room temperature. The crystals were dissolved in 800-6200 ml of MTBE at 50-6 CTC, removed by vacuum distillation to a residual volume of about 150-250 ml, and cooled to room temperature to crystallize the product. Example 1 7α-methyl-1 9-neurosterone (1 7β-fluorenyl-7α-methylest-4-ene-3-isopyridine) 84353 -17- 200400825 according to AV 1 ′ from 100 g of Ι7β- Ethyloxy-4,6-estradiol_3_one (ο]) mol) produced 56 grams of 7α-methyl-19-neosteroid (0.20 mol). Yield: 62% HPLC (100% purity): 99.1% HRMS: calculated 288.2089; found 288.2088 Example 2 7α-methyltestosterone (17β_hydroxy_7α_methyl_androst_4_ene_3_ Ketone) According to AV 1 ', 50 g of 7α-methyltestosterone (0.17 mol) was produced from 100 g of 17β-ethoxy-4,6-androstadien-3-one (0.30 mol). Yield: 57% HPLC (100% purity): 98,6% HRMS: calculated 302.2247; found 302.2245 Example 3 17β-hydroxy-7α, 18-dimethylest-4-en-3-one Similar to AV 1 'from 100 grams of 17β-ethoxyl-18-fluorenyl_4,6_estadienone (0.30 mol) 53 g of 17β-hydroxy-7α, 18-dimethylestradiol-4_ Dilute _3_ ketones (0.18 moles). Yield: 60% HPLC (100% purity): 98.8% HRMS: calculated 302.2247; found 302.2246 Example 4 11β-Fluoro-7 α-methylest-4--4--3,17-dione similar to AV 1 64 g of 11 β-fluoro-7α-formaldehyde were obtained from 100 g of β-fluoroestradiol-4,6-diene-3,17-dione (0.35 moles) using a double amount of methyl magnesium chloride. Gestrel 84353 > 18- 200400825 -4-ene-3,17-dione (0.21 mole). Yield: 60% 1 ^ 1 ^ (100% purity): 98.5% HRMS: calculated 304.1 838; found 304.1838 Example 5 7 a-'f 基 雄 -4- 联 -3,11,17-三 17 同Similar to AV 1, 58 grams of 7α-methylandrosine-3 were obtained from 100 grams of hepta-androstaene-3,11,17-trione (0.34 moles) using a double amount of methyl magnesium chloride. 11,17-trione (0.19 mole). Yield: 56% HPLC (100 ° /. Purity): 99.0% HRMS: Calculated 300.1725; Found 300.1724 Example 6 17β-[(Third-butyldifluorenylsilyl) oxy] _7α_methylestradiol Keto-3_ ketone is similar to AV 1, from 20 g of 17β-[(third butyldimethylsilyl) oxy] _ estra-4,6-diene-3-one (0.052 moles) to obtain 15 G of 17β _ [(Third-Butyldimethylsupryl) oxy] -7α-methylest-4--4-one · 3-one (0.037 mole). Yield: 71% ^ 1 ~ 1 ^ (100% purity): 96.5 / HRMS: Calculated value 402.2954; Found 402.2950 The reaction product was then dissolved in 300 ml of propionol, mixed with 200 ml of 20% sulfuric acid , And stirred at room temperature for 48 hours. The reaction solution was extracted with MTBE, and the product was crystallized from MTBE (Reference Example 1). Yield: 85% 84353 * 19- 200400825 HPLC (100% purity): 97.6% Compounds of general formula II in which R17b represents an OM group Production instructions (AV 2) 4 8 0 ml tri-tert-butoxy A solution of IS hydrogenated in THF was added dropwise to a solution or suspension of 0.32 Mol compound of general formula II (where R17a & R17b represents an oxygen atom) in 500 ml of THF. The addition was performed at 0 ° C under a nitrogen atmosphere, at Stir at 0 ° C for 30 minutes. The reaction solution was then further reacted according to AV 1. Example 7 11β-fluoro-17β-hydroxy-7α-methylest-4-en-3-one is similar to 类似 ¥ 2, and 100 g of 110-fluoroestrone-4,6-difluorene-3, 7-diketone (0.35 Molar) obtained 59 g of 11β-fluoro-17β-hydroxy-7α-methylestra-4-one-3-one (0.19 Molar). Yield: 54% [^ 1 ^ (100% purity): 97.3 ° /. HRMS: calculated 306.1995; found 306.1990. 84353 20-

Claims (1)

200400825 Scope of patent application: 1. A method for manufacturing general formula I 7α-fluorenyl steroids ’ among them r1q represents hydrogen or fluorenyl, and & represents hydrogen, Rllb represents hydrogen, hydroxyl, fluorine, or -〇C (0) R19, or R " b together with the ruler represents an oxygen atom, R19 represents C1-C12-morpho 'R13 represents hydrogen, methyl or ethyl, 1117 & represents hydrogen, R17b represents hydrogen, hydroxyl, R19, -OR19, -〇 (CO) R19 or R17b together with 1117 £ 1 represents an oxygen atom, or R17b also represents the -OM1 group, where M 'represents -SiRiR ^ R3, R1, R2 And R3 respectively represent ij as R19, -OR19, fluorenyl, aryl, or aryl, and the method includes the following steps: a) using a compound of general formula 84353 200400825 where R1G represents hydrogen or methyl, R11 & represents hydrogen, Rllb represents hydrogen, hydroxyl, fluorine or -OC (0) R1Q, or Rllb together with 11113 represents an oxygen atom, R19 represents Ci-Cu-alkyl, and R13 represents Hydrogen, methyl or ethyl, Ri7a represents hydrogen, R17b represents hydrogen, hydroxyl, R19, -OR19, -〇 (CO) R19 or R17b together with 1117; 1 represents an oxygen atom, or R17b also represents -OM group, Wherein M represents -QR ^ W or -QWR2, Q represents deletion, chain or stone, R1, R2, R3 are separately > j represents R19, -OR19, fluorenyl, aryl or 0 aryl, which is inert to protons Reaction with 1-3 molar equivalents of CH3MgX in solvent (if X represents chlorine, bromine, iodine), or with 0.5-3 molar equivalents (: 113) ^ § 乂 (if again methyl), 84353 2004 ° 0825 This reaction is calculated in the presence of i-30 mole% copper compound CuYnLm, where # Y is a canonical anion or organic anion, L is a ligand, η is 1 or 2, m is 0 or a natural integer , B) adding strong acid to the reaction mixture and additional stirring 'c) separation and purification. For example, the method of applying for the scope of the patent No. 1 acid 0 is characterized by step b) using sulfur 3 · jealousy to avoid any of the scope of T a profit-seeking method 'wherein in the general formula ^, rule 10 and Rlla represent hydrogen' Ri3 represents a methyl group, Rllb represents argon or fluorine, _, -0C (0) R19, Han ... Tables, Wind, and & collectively indicate an oxygen atom 'or R represents -0M. 4. The method according to any one of the foregoing claims, wherein the general formula is defined as -AlR ^ W. 5. A method as described in any one of Hemi's patent applications, in which an additional step is performed between step D) and c). 6. The method according to item 5 of the patent application, wherein the additional step is the cleavage of donkey-C (0) R19 through the use of an isocyanate as described in Example 1. 7. Ruo Shen: The method of patent target No. 6 in which sodium hydroxide or potassium hydroxide is used as a test in methanol ethanol or isopropanol. 8. If the method of applying for a patent encloses item 5, wherein the additional step is ^, the basis 9. For the method of claim 5, the additional step is to make a compound of the formula j S4353 (where R17a spots "17b formation" also means an oxygen atom) reacts with a reducing agent to fight the 17β-hydroxy derivative. 1 10. The compound reactant as described in item 9 of the patent scope. 11. It is carried out as described in the aforementioned patent application. 〃, sufficient method, wherein the purification system is described in terms of any of the patent scope of the application, and the amount of trimethyl magnesium halide is between 5 and 25, · Mainly. 8 moles when used. 'Earth 25 旲 ° /. In the presence of copper compound CuYnLni 13. As mentioned in the aforementioned patent application, any of the terms-the amount of methylmagnesium chloride is 1Q Qianmo,' ". To 丨 35 Eardang 14. As stated before ... Wu Er / ° Copper chloride is used in the presence. Mum. a & the method of any-item, wherein the solvent is tetrahydrofuran 1 5. The method of applying patents to the -1 method as described above, it is visualized 16. :: = Please refer to the method of any of the scope of the item 'where the The reaction is carried out in the case of a solvent = three-fold dilution with respect to the steroid used. . The method of applying any one of the patent scopes of Kou Zemei, in which mol Mordan = based magnesium chloride is in the presence of 10 to 20 mol% copper chloride, in tetrahydropfran, at -3. 5 Τ '$ -1 ς. <-> = · e,. Λ,, " C reaction temperature, and 4 to 6-fold dilution with the solvent volume relative to the steroid used. The method of item 1 in the u.mr range, wherein in the general formula 11, π represents an aryl group or R and ^ together represent an oxygen atom. 19. The method according to item 18 of the patent application, wherein 2.2,8 mole equivalents of methyl magnesium chloride are used. 84353 200400825 20_ The method according to any one of the aforementioned patent applications, which method is used to produce a compound selected from the group consisting of: 7α-methyl-19-negotosterone, 17β-acetoxy-7α -Methyl-19-neosteroid, 7α-methyltestosterone, 17β-acetoxy-7α-methyltestosterone, 11β-fluoro-7α-methylestradiol-3,17-dione, 11β -Fluoro-17β-hydroxy-7α-fluorenylest-4-en-3-one, 7α-methylandrostene-3,1 丨, 17-trione, 17β-hydroxy-7α, 18-dimethylest-4-en-3-one, 17β-acetoxy-7α, 18-dimethylest-4-en-3-one, 17β-[(third butyldimethylsilyl) oxy] -7α-methylest-4-en-3-one, 17β- [ (Third-butyldimethylsilyl) oxy] -11β-fluoro-7α-fluorenylestren-4-one-3-one. 84353 200400825 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the representative symbols of the components in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: S4353