TWI248443B - Processes for preparation of 9,11-epoxy steroids and intermediates useful therein - Google Patents

Abstract

Multiple novel reaction schemes, novel process steps and novel intermediates are provided for the synthesis of epoxymexrenone and other compounds of formula I, wherein: -A-A- represents the group -CHR4-CHR5- or -CR4=CR5-, R3, R4 and R5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, aryloxy; R1 represents an alpha-oriented lower alkoxycarbonyl or hydroxyalkyl radical; -B-B- represents the group -CHR6-CHR7- or an alpha- or beta-oriented group: where R6 and R7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R8 and R9 together comprise a carbocyclic or heterocyclic ring structure, or R8 or R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring.

Description

1248443 A7 Β7 V. INSTRUCTIONS (I) BACKGROUND OF THE INVENTION The novel method for preparing 9,1 epoxy steroid compounds in April, 疋 氧 oxy oxet series and the like can be used for the preparation of new steroid compounds. Intermediate, Li for preparing this new class of intermediates In particular, the present invention relates to a novel and advantageous method for preparing methyl hydrogen 9,1 L epoxy-l^hydroxy-3-ketogestrel-7 (21_ Dicarboxylic acid, plant _ 酉曰 (also known as eplerenone or epoxymexrenone). A process for the preparation of a 20-spirooxane series of compounds, described in U.S. Patent No. 4,55, 332, the compound produced by the method of the '32 patent. , with the following formula: Open oxygen ring E: (Please read the back of the note before you fill out this page) Clothing ·, 11

IA wherein -AA- represents -CH2-CH2- or -CH=CH-; R1 represents a lower alkoxycarbonyl or hydroxycarbonyl group of a-position; -Β-Β- represents -CH2-CH2- or π- or yS- In the direction of the group, the cadres of the second squadron

"CH

〆•CH CH — CH2 — CH- Completion R6 and R7 are hydrogen; X represents two hydrogen atoms or keto groups.-4- This paper size applies to China National Standard (rNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 V. INSTRUCTIONS (2) γ1 and γ2 together represent oxygen bridge-Ο-, or Υ1 represents a hydroxyl group, and γ2 represents a hydroxyl group, a low-carbon alkoxy group, or a lower-carbon alkoxy group if χ represents Η2; A salt of this compound wherein X represents a ketone and Υ2 represents a hydroxy group, i.e., a comparable 17; 5-hydroxy-21-carboxylic acid. U.S. Patent No. 4,5,59,3,32 describes a process for the preparation of epoxy mebresone of the formula Ia and related compounds. With regard to the novel and expanded clinical utility of epoxigenone, the need to improve this and other comparable steroids has been created. OBJECT OF THE INVENTION The object of the present invention is to propose an improved process for the preparation of epoxidized meclirenone, other bismuth-oxanes, and other steroids having a common structural character. In particular objects of the present invention include: an improved method for producing a product of the formula IA and other related compounds at a high yield; the method is proposed to involve a small number of separation steps; the method is proposed, which can reasonably capitalize and facilitate conversion It is carried out under the operation of the fee. The present invention relates to a series of synthetic procedures for epoxigenone; it can be used to prepare an intermediate of oxime-mecrarone; and the synthesis of this novel intermediate. The synthetic procedure for the new pain is detailed in the description of the preferred embodiment. The novel intermediates of the present invention are as follows. Compound of formula I V, equivalent to the following structure: (Please read the notes on the back and fill in this page) Clothing.

(210x 297 mm) 1248443 A7 B7 V. Inventive Note (3) wherein -AA- represents -CHR4-CHR5- or -CR4=CR5-; R3, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, and low Carboalkyl, lower alkoxy, alkyl, alkoxyalkyl, carbonyl, cyano and aryloxy; R1 represents α-azimuth lower alkoxycarbonyl or hydroxyalkyl; R2 is 11 α - The leaving group can be separated to produce a double bond between 9 and 11 carbon atoms; -Β-Β- represents a group of -CHR6-CHR7 or 0-azimuth: (Please read the notes on the back first) Fill in this page again) 'CH-

/ •CH -CH —— CH«

III. The third member of the Ministry of Economic Affairs, the Ministry of Economic Affairs, and the Ministry of Health and Economics, 3, including R6 and R7, independently selected from the group consisting of hydrogen, halogen, lower alkoxy, fluorenyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl , alkyl, alkoxycarbonyl, enzymatic oxyalkyl, cyano and aryloxy; and R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, _, lower alkoxy, aryl-per-burning oxygen An alkyl group, a thiol group, a pyridyl group, a pyrithion group, a decyloxy group, a cyano group and an aryloxy group, or R8 and R9_ including a carbocyclic or heterocyclic ring structure or R8 or R9 plus R6 or R7 A carbocyclic or heterocyclic ring structure is included and fused to a pentacyclic D ring. The compound of the formula IVA corresponds to the formula IV' wherein R8 and R9 together with the ring carbon to which they are attached form the following structure:

〇{ 1 7) mn( CH2) 2 - C - X

XXXIV 6 - This paper is sized to use Chinese National Standard ((, NS ) Λ 4 size (210X 297 mm) ---- 1248443 A7 B7

V. INSTRUCTIONS (4) wherein X, Y1, Y2 and c(17) are as defined above. The compound of formula IVB corresponds to formula IV, wherein R8 and R9 together form the structure of formula XXXIII:

XXXIII Formula IVC, IVD and IVE compounds, respectively, corresponding to Formula IV, IVAi IVB, wherein -AA- and -B-B_ are -CH2-CH2-, R3 is hydrogen, and r1 is an oxycarbonyl group, preferably A Oxycarbonyl. The compound of the formula IV can be prepared by reacting a low-temperature deuteration or a brewing agent, or a compound generating agent, with a compound corresponding to the range of the formulae ~. The compound of formula V corresponds to the following structure: ϋι.1 ^ϋϋ ·Β1_ϋϋ ϋϋ ϋ I (please read the notes on the back and fill out this page)

V wherein -Α-Α·, -B_B-, R1, R3, R8 and R9 are as defined by the formula I v . The compound of the formula V A corresponds to the formula v, wherein R8 and R9 together with the carbon consumption thereof form the following structure: a ring "C(1 7) mn(CH2)

XXXIV where X, Y1, γ2 and C(17) are as defined above

1248443 A7 _____B7 V. INSTRUCTIONS (5) The compound of formula VB is equivalent to formula V, wherein R8 and R9 form a χχχπι structure: 〇 cr

XXXIII VC, VD and VE compounds, respectively, are equivalent to formula V, VA or VB, wherein -A_A• and -BB- are each -CH2-CH2-, R3 is hydrogen, and Ri is a calcined carboxyl group, preferably A Oxycarbonyl. Compounds of the formula V can be prepared by reacting an alkali metal alkoxide with a compound of the formula VI. The compound of formula VI is equivalent to the following structure: ----------- (Please read the notes on the back and fill out this page)

through? ? ^* Ministry of Standards and Regulations J-Consumer At works for the printing of f where -A-A-, -B-B, R3, R8 and R9 are as defined in the formula ιν. The compound of formula VIA corresponds to formula VI wherein the inverse 8 and 9 plus the ring carbon with which it is attached form the following structure:

7) mii( CH2) 2 - C - X χχχιν -8 - >, paper scale applicable to China National Standard (CNS) Λ 4 specification (210X297 mm) i 1248443 a7 A7 B7 V. Invention description (6) where X, Γ1, Y2 and C(17) are as defined above. The compound of the formula VIB corresponds to the formula VI' wherein R8 and R9 together form the structure of the following formula XXXIII:

XXXIII Formula VIC, VID and VIE compounds correspond to Formula VI, VIA or VIB, respectively, wherein -A-A- and -B-B- are each 'and R3 is chloro. Compounds of formula VI, VIA, VIB and VIC are prepared by hydrolysis of a compound corresponding to formula VII, VIIA, VIIB or VIIC, respectively. The compound of formula VII is equivalent to the following structure: (Please read the notes on the back and fill out this page).

VII

, 1T 椋 中 中 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - The compound of the formula VIIA is equivalent to the formula νπ, wherein R8 and R9 are added to it, ΧΧΧΐν -9 - the paper size 4 is 7 (10) M specification (2lQx 297 public Chu 1244843 A7 B7 5, invention description ( Wherein X, Y1, Y2 and C(17) are as defined above. The compound of formula VIIB corresponds to formula VII, wherein R8 and R9 together form the structure of formula XXXIII:

XXXIII Formula VIIC, VIID and VIIE compounds, respectively, correspond to Formula VII, VIIA, or VIIB, wherein -A-A- and each are _CH2-CH2-, and R3 is oxime. Compounds of the formula VII can be prepared by cyclizing a compound of the formula VIII. The compound of formula VIII corresponds to the following structure: (Please read the notes on the back and then fill out this page)

VIII 订 中 中 中 标准 贽 贽 贽 贽 贽 贽 贽 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 - - - - - - - - - - - - - - - - - - - - - - The compound of the formula VIIIA corresponds to the formula VIII, wherein R8 and R9 together with the ring carbon of which they are formed form the following structure: ', C(1 7> mu(CH2) wherein X, Y1, γ2 and C(17) are as described above Definition -10- The paper scale applies to the Chinese national standard bee to 'Yangshuo six materials see (a) Chuan / tearing PCT) xxxiv 1248443 A7 B7 V. Description of the invention (Formula VIIIB compound is equivalent to Formula VIII, where R8 & R9 together XXXIII structure:

XXXIII The compounds of the formulae VIIIC, VIIID and VIIIE correspond to the formula νπι , VIIIA, or VIIIB, respectively, wherein -A-B- and -B_b_ are each _CH2_CH2, and R3 is hydrogen. The compound in the range of the formula νπι can be prepared by oxidation of a host containing a ruthenium compound of the formula XXX as follows. The fermentation can be carried out by introducing a 1-hydroxy group into the α-azimuth substrate. The compound of formula I X is equivalent to the structure of the formula:

IX (Please read the note on the back and then fill out this page) Clothing. Μ 中 中 员工 员工 Employees of the Bureau of the Department of the consumption of the Zhu Chushe printed f where - Α - Α -, - Β - Β -, R3, R8 and R9 Formula I ν is defined by Formula V. As defined, and R1 is a compound of the formula 相当于 IX, wherein R8 and R9 plus the ring carbon adhered thereto form the following structure: , ^C(1 7) iiiii(CH2) 2 -

XXXIV -11 This paper scale applies to China National Standard (rNS) A4 specification (2l〇x297 mm) 1248443 A7 B7 V. Inventive Note (9) where X, Y1, Y2 and c(17) are as defined above. The compound of formula IXB corresponds to formula IX wherein R8 and R9 plus the ring carbon adhered thereto form the structure of formula XXXIII:

XXXIII Formula IXC, LCD and IXE compounds, respectively, correspond to Formula 1x, ixa or IXB, wherein -A-A- and -B-B- are each -CH2-CH2-, and R3 is hydrogen. Compounds within the scope of Formula IX can be prepared by biological transformation of equivalent compounds within the scope of Formula X. The compound of formula XIV is equivalent to the following structure: (Please read the notes on the back and fill out this page)

, 1T

XIV wherein -A-A-, -B-B, R3, R8 and R9 are as defined in formula IV. The compound of the formula XIVA corresponds to the formula XIV, wherein R8 and R9 together with the ring carbon to which they are attached form the following structure: , , C(1 7>丨丨丨"(CH2>

XXXIV 12- This paper scale applies to China National Standard (CNS) Λ4 specification (21 OX 297 mm) 1248443 A7 B7 V. Description of invention (10) where X, Y1, Y2 and c(17) are as defined above. The compound of formula XIVB corresponds to formula XIV wherein R8 and R9 together with the ring carbon to which they are attached form the structure of formula XXXIII:

XXXIII Formula XIVC, XIVD and XIVE compounds' correspond to the formula χιν, XIVA or XIVB, respectively, wherein -A, A- and _B-B- are each _CH2-CH2-, and R3 is hydrogen. Compounds of the formula XIV can be prepared by hydrolysis of equivalent compounds in the range of formula XV. The compound of formula XV is equivalent to the following structure: (Please read the notes on the back and fill out this page)

, 1T

XV Ρ. wherein _A-A·, -B_B, R3, R8 and R9 are as defined in the formula IV. The compound of formula XVA is equivalent to formula XV, wherein R8 and R9 plus the ring carbon with which it is attached form the following structure ^C(1 7 ) !MH( CH2) -13 - The paper scale of Zhangzhou China national standard _ ( NS ) Λ 4 size (210X 297 mm)

XXXIV 1248443 A7 B7 V. INSTRUCTIONS (ir where X, Y1, Y2 and C(17) are as defined above. The compound of formula XVB corresponds to the formula χν, wherein R8 and R9 together with the ring carbon attached thereto form formula XXXIII Structure: 〇

The XVC, XVD and XVE compounds of the formula XXXIII correspond to the formula XV, XVA or XVB, respectively, wherein -A-A· and ·Β·Β_ are each -CH2-CH2·, and R3 is hydrogen. Compounds of the formula XV can be prepared by cyanation of comparable compounds within the scope of formula XVI. The compound of formula XXI is equivalent to the following structure: (Please read the notes on the back and fill out this page)

, 1T, '?/ ΓΊ 中 中 中 中 中 Employees’ consumption

XXI wherein -A-A-, -B-B, R3, R8 and R9 are as defined in formula IV. The compound of formula XXIA corresponds to formula XXI wherein R8 and R9 plus the attached ring carbon form the following structure:

rV I C( 1 7 ) nm( CHj) a · c 14- This paper scale applies to Chinese national standards ((, NS ) Λ 4 specifications (210x 297 mm)

XXXIV 1248443 A7 B7 V. INSTRUCTIONS (12) wherein X, Y1, Y2 and c(17) are as defined above. The compound of formula XXIB corresponds to formula XXI wherein R8 and R9 together form the structure of formula XXXIII:

XXXIII Formula XXIC, XXID and XXIE compounds correspond to formula XXI, XXIA or XXIB, wherein -A-A- and -B-B- are each -CH2-CH2-, and R3 is hydrogen. Compounds of the formula XXI can be prepared by hydrolysis of compounds equivalent within the scope of formula XXII. The compound of formula XXII is equivalent to the following structure: ----------0 at -- (Read the first note on the back and fill in this page)

Wherein -A-A-,, R3, R8&R9 are as defined in the formula [V].

XXII ^1. The compound of the formula XXIIA corresponds to the formula XXII, wherein R8&R9 plus the ring carbon adhered thereto form the following structure: 1 7) um(CH-) 2 -

XXXIV -15- This paper scale applies to Chinese national standard (d) Λ4 specification (21〇'χ 297 mm) 1248443 A7B7 V. Invention description (13) where X, Y1, Y2 and C(17) are as defined above . The compound of formula XXIIB corresponds to formula XXII, wherein R8 and R9 together form the structure of formula XXXIII:

XXXIII Formula XXIIC, XXIID and XXIIE compounds, respectively, correspond to Formula XXII, XXIIA or XXIIB, wherein -A-A- and -B-B- are each -CH2-CH2-, and R3 is hydrogen. Compounds of the formula XXII can be prepared by cyanation of a compound of the formula XXIII. The compound of formula XXIII corresponds to the following structure:

XXIII (Please read the precautions on the back and fill out this page.) The Department of Economics and the Department of the Ministry of Justice is the second member of the company. -A-A·, -B-B, R3, R8 and R9 are as defined in Formula I V. The compound of the formula XXIIIA corresponds to the formula XXIII, wherein R8 and R9 together with the ring carbon adhered thereto form the following structure: 7) mu(CHj)

XXXIV 16 This paper scale is stated in Chinese National Standard Rate (CNS) Λ4 Specification (210X 297 mm) 1248443 A7 B7 V. Description of Invention (14) where X, Y1, Y2 and C(17) are as defined above. The compound of formula XXIIIB corresponds to formula XXIII, wherein R8 and R9 together form the structure of formula XXXIII:

XXXIII The compounds of the formula XXIIIC, XXIIID and XXIIIE correspond to the formula XXIII, XXIIIA, or XXIIIB, respectively, wherein -A-A- and -B-B- are each -CH2-CH2., and R3 is hydrogen. Compounds of the formula XXIII can be prepared by oxidation of a compound of formula XXIV, as described below. The compound of formula XXVI has the following structure:

XXVI wherein -A-A-, -B-B, R3, R8 and R9 are as defined in formula IV. Pressed by the Department of Biscribing, J'-Consumer Cooperatives (please read the note on the back and fill out this page). The compound of formula XXVIA is equivalent to formula XXVI, where -AA· and -BB- are each -CH2- CH2-, and R3 is hydrogen. Compounds of the formula XXVI can be prepared by oxidation of a compound of the formula XXVII. The compound of formula XXV is equivalent to the following structure·· 17- This paper scale applies to China National Standard (CNS) Λ4 specification (210X 297 mm)

TJ 248443 A7 B7 V. Description of invention (15)

NH.

XXV where _A-A_, -B_B, R3, R8 and R9 are as defined in formula IV. The compound of formula XXVA corresponds to formula XXV wherein -A-A- and -Β.Β- are each -CH2-CH2- and R3 is hydrogen. Compounds of the formula XXV can be prepared by cyanation of a compound of the formula XXVI. The compound of formula 104 is equivalent to the following structure:

(Please read the notes on the back and fill out this page.) 104 Printed by the Department of Standards and Staff Consumer Cooperatives of the Department of Drips, where -AA-, -BB- and R3 are as defined in Formula IV, and 1^ is CVC4 alkyl . The compound of formula 104A corresponds to formula 104 wherein each of -A-Ay and -B-B- is CH2-CH2- and R3 is hydrogen. Compounds within the scope of Formula 104 can be prepared by thermal decomposition of a compound of Formula 103. -18- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 B7 V. Description of invention (16) The compound of formula 103 is equivalent to the following structure:

alkyl. The compound of formula 103A corresponds to formula 103, wherein each is _CH2-CH2-, and ... is hydrogen. The compound in the range of Formula 1〇3 can be prepared by reacting a compound of the formula ι〇2 with a dialkyl malonate in the presence of a base such as an alkali metal alkoxide. The compound of formula 102 corresponds to the following structure:

(Please read the notes on the back and fill out this page)

1T wherein -A-A-, -B-B-, R3 and R11 are as defined in formula 104. The compound of formula 102A corresponds to formula 102, wherein -A_A-&_b_b_ is each _cH2_CH2., and R3 is hydrogen. The compound in the range of the formula 1〇2 can be produced by reacting a compound of the formula ι〇1 with a trialkylsulfonium compound in the presence of a base. -19- This paper size is applicable to China National Standard (CNS) Λ4 specification (210Χ297 mm) 1248443 A7 B7

V. INSTRUCTION DESCRIPTION (17) The compound of the formula 10 1 corresponds to the following structure: 101 wherein - A-A-, -B-B-, R3 and R11 are as defined in the formula 104. The compound of formula 101A corresponds to formula 101 wherein -A-A- and -B-B- are each _CH2-CH2- and R3 is hydrogen. Compounds within the scope of formula 101 can be prepared by reacting 11-hydroxyandrostene-3,17-dione or other compound of formula XXXVI with a trialkyl orthoformate in the presence of an acid. The compound of formula X L is equivalent to the following formula:

XL (please read the note on the back and then fill out this page). The Department of Economics and Consumers of the Department of Economics and Statistics of the Ministry of Economic Affairs, Zhu Zhushe, f. -E-E- is selected from the following \1; c = c-

XLIII

XLIV -20- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 V. Invention description (18) R21 OR24\["

XLV OR24 R21 Xc—C—

XLVI (please read the notes on the back and fill out this page) and the Ministry of Economic Affairs is responsible for the decision of the Ministry of Economic Affairs, T consumption, Zhu Zhushe, f XLVII R21, R22 and R23 are independently selected from the following including hydrogen, alkyl, self, and nitrate. And cyano-R24 are selected from the group consisting of hydrogen and lower alkyl; R8G and substituents independently selected from ketones and which may form R8 and R9 (as defined above, reference formula 1); and -AA-, -BB- and R3 are as defined in formula IV. The compound of formula XLA corresponds to formula XL wherein R21, r22 & r23 are independently selected from the group consisting of hydrogen, _ and a lower carbon group. The compound of formula XLB corresponds to XLA' wherein - corresponding to formula XLIII, XLIV, XLV or XLVII. The compound of the formula XLC corresponds to the formula Xlb, wherein .E-E- corresponds to the formula XLV. The compound of formula XLD corresponds to sXLB, wherein _E_E- corresponds to formula XLVII. The compound of the formula XLE corresponds to the formula XL wherein R8G and the ring carbon atom to which the adhesion is attached includes a ketone group or: -21 - the paper size fine wipes® fresh material (Fns) λ4 size (mx297 mm) - ' ----— ^1. 1248443 A7 B7 V. INSTRUCTIONS (19 7) nm( CH2) , - C - X where X, Y1, Y2 and C(17) are as defined above, or

XXXIV

XXXIII The formula XLIE compound corresponds to XL, wherein R8G and R9G together form a ketone. The XLF, XLG, XLH, XLJ, XLM and XLN compounds are equivalent to Formula XL, XLA, XLB, XLC, XLD and XLE, respectively, wherein -A-A-, -B-B- and R3 are as defined above. Formula XLI compound is equivalent to the following formula

Xu

XLI (Read the first note on the back and fill out this page)

, 1T where -E-E- is selected from the following: Employees of the Ministry of Economic Affairs and the Ministry of Economic Affairs and Consumers eliminate frAt Zhusheyin f R21 P22 \1 I ό c-

XLI II \l 〇R< .22

XLV -22- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 B7 V. Invention description (20) OR \1

XLVI and

Dr*1

XLVII R is a CVC4 alkyl group, or a Ru〇- group together form a fluorene-oxime-oxyalkylene bridge; R, R22 and R23 are independently selected from the group consisting of hydrogen, alkyl, halo, nitro, and cyano, and r24 is selected from hydrogen. And a lower alkyl group; R8〇 and r9〇 are independently selected from a keto group, and may constitute a substituent of r8 and R9; and, _B-B_ and R3 are as defined in the formula Jv. The compound of the formula XLIA is equivalent to the formula XLI, wherein R22 and R23 are independently selected from the group consisting of hydrogen, hydrazine, and lower alkyl. The compound of the formula XLIB corresponds to the formula XLIA, wherein -E-E_ corresponds to the formula XLIII 'XLIV, XLV or XLVII. The compound of formula XLIC corresponds to formula XLI, wherein R8G and R9G plus the ring carbon atom to which it is attached include g homo group or:

| ; 1 7> imi( CH 山· C _ X

XXXIV^衣-- (Please read the back of the note before you fill out this page) Order-^1. After the drip department of the 泱桴 局 J Jr. 贽 贽 竹 竹 社 社 其中 其中 X X X, Y1, Y2 and C (17 ) as defined above. The XLID compound of the formula corresponds to the formula XLI, wherein the substituent XXXIV corresponds to the structure XXXIII: '

XXXIII -23 'This paper scale applies to the Chinese national standard frNS. Λ4 specification (210X 297 mm) 1248443 A7 B7 V. INSTRUCTION DESCRIPTION (21) The compound of the formula XLIE is equivalent to the formula XL, wherein R8G and R9G together form a ketone group. The formulas XLIF, XLIG, XLIH, XLIJ, XLIM and XLIN compounds correspond to the formulas XLI, XLIA, XLIB, XLIC, XLID and XLIE, respectively, wherein -A-A-, -B-B- and R3 are as defined above. Compounds of the formula XLI can be prepared by hydrolysis of a compound of the formula X L, as defined below. The compound of formula XLII is equivalent to the following formula:

(Please read the notes on the back and fill out this page)

XLII where -E-E- is selected from the following:

XLIII

XLIV 经 中 中 中 β , , , , τ τ τ τ 印象 印象 l l l l l l l l l l

OR24 R \l I c-c

-twenty four-

XLV

XLVI

XLVII This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 __________B7 V. Description of invention (22) R21, R22 and R23 are independently selected from the group consisting of hydrogen, alkyl, nitro, and cyanide. R24 is selected from the group consisting of hydrogen and lower alkyl; R8G and R9G are independently selected from ketones, and one may constitute a substituent of R8 and R9; and -AA-, -BB- and R3 are as defined in formula IV. The compound of formula XLIIA corresponds to formula XLII wherein R21, R22 and R23 are independently selected from the group consisting of hydrogen, i and lower alkyl. The compound of formula XIIIB is equivalent to formula XLIIA wherein -E-E- corresponds to formula XLIII, XLIV, XLV or XLVII. The compound of the formula XLIIC corresponds to the formula XLII, wherein R8G and R9G plus the ring carbon atom to which it is attached include a keto group or: Y2 γ1, 丨'

C( 1 7) mn( CH.) - · C - X

/ , XXXIV where X, Y1, Y2 and C(17) are as defined above. The compound of the formula XLIID is equivalent to the formula XLII, wherein the substituent XXXIV is equivalent to the structure XXXIII: the secondary standard board member of the Ministry of Consumer Affairs

(Please read the notes on the back and fill out this page)

The compound of formula XXXIII is equivalent to the formula XLII, wherein R8G and R9G together form a ketone group. The formulas XLIIF, XLIIG, XXLII, XLIIJ, XLIIM, and XLIIN are equivalent to Formula XLII, XLIIA, XXLIB, XLIIC, XLIID and XLIIE', wherein -A_A- and -B-B- are -CH2-CH2.' and R3 is a mouse. In the formula -25- This paper scale applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm)

1248443 A7 B7 V. INSTRUCTIONS (23) Compounds within the scope of XLII can be prepared by deprotection of a compound of the formula XLI. The compound of the formula XLIX corresponds to the following structure:

XLIX wherein -E-E- is as defined in formula XL, and -A-A-, -B-B-, R1, R3, R8 and R9 are as defined in formula IV. The compound of the formula XLIXA is equivalent to the formula XLIX, wherein R8 and R9 together with the ring barrier adhered thereto form the following structure: (Please read the note on the back and then fill out this page) Order, C (1 7> um(CH2)

XXXIV where X, Y1, Y2 and C(17) are as defined above. The compound of the formula XLIXB is equivalent to the formula XLIX, wherein R8 and R9 together form a compound of the formula XXXIII: 〇XXXII working XLIXC, XLIXD, XLIXE compound, respectively equivalent to the formula XLIX, 26- The paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) ^1. Department of Standards and Regulations of the Ministry of Economic Affairs, Department of TCM, Tsenghua Hezhu Private Printing, 1244843 A7 B7 V. Description of Invention (24) XLIXA or XLIXB compounds, of which -A-A_ and -Β_Β· Is -CH2-CH2-, R3 is hydrogen and R1 is an alkoxycarbonyl group, preferably a methoxycarbonyl group. Compounds of the formula XLIX can be prepared by reacting an alcoholic or aqueous solvent with a compound of formula VI in the presence of a suitable base. The compound of formula A203 corresponds to the following structure:

OR18 [A203] where -E-E- is selected from the following including 322 Μ"·

XLIII 24 (Read the first note on the back and fill out this page)

OR , 22 by the Department of Standards in the Department of Drops

XLV OR24 R2\l ι c-c-

XLVI and C&R21

XLVI I -27- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 A7 ___ B7 V. Invention description (25) · R18 is selected from the following including Ci-C# Tiger base; R21, R22 and R23 is independently selected from the group consisting of hydrogen, alkyl, _, nitro and cyano; R24 is selected from hydrogen and lower alkyl; and -AA-, -BB- and R3 are as defined in formula IV. The compound of formula A203A corresponds to formula A203 wherein R21, R22 and R23 are independently selected from the group consisting of hydrogen, halo and lower alkyl. The compound of formula A203B corresponds to formula A203A wherein -E-E- corresponds to formula XLIII, XLIV, XLV or XLVII. The compounds of the formulae A203C, A203D and A203E correspond to the formulae A203, A203A and A203B, respectively, wherein -A-A- and -B-B- are each -CH2_CH2., and R3 is hydrogen. Compounds within the scope of formula A203 can be prepared by reduction of a compound of formula A202, as defined below. The compound of formula A204 is equivalent to the following structure: -- (Please read the notes on the back and fill out this page)

, 1T

It is a CVC4 alkyl group, and -E-E·, -A-A-, -B-B- and R3 are as defined in Eq. 203. The compound of formula A204A corresponds to formula A204 wherein R21, R22 and R23 are independently selected from the group consisting of hydrogen, and lower alkyl. The compound of formula A204B corresponds to formula A204A, wherein -E-E- corresponds to formula XLIII, XLIV, XLV or XLVII. -28- This paper scale applies to Chinese national standards ((, NS ) Λ 4 specifications (210X 297 mm) 1248443 A7 B7 V. Invention description (26) The formulas A204C, A204D, and A204E are equivalent to the formula A204, A204A, and A204B 'wherein Α·Α· and -BB- are each -CH2-CH2-' and R3 is hydrogen. The compound in the range of formula Α204 can be prepared by hydrolysis of a compound equivalent to Α2 03. The compound of formula 205 corresponds to the following structure. : -- (Read the first note on the back and then fill out this page) The full-time secondary 摞 β β β 消费 消费 消费 消费 消费 消费 消费 消费 其中 其中 其中 其中 其中 其中 其中 where R20 is (^ to C4 alkyl, and -Ε-Ε-, R19 , -Α-Α-,·Β_Β- and R3 are as defined in formula 204. The compound of formula 205 is equivalent to formula 205, wherein R21, R22 and R23 are independently selected from the group consisting of hydrogen, i and lower alkyl. Corresponding to formula A205A, wherein -EE- corresponds to formula XLIII, XLIV, XLV or XLVI formula A205C, A205D, and A205E compounds respectively correspond to formulas A205, A205A and A205B, wherein -AA- and _BB- are each -CH2 -CH2-, and R3 is hydrogen. Compounds within the scope of formula A205 can be equivalent compounds of formula A204 Prepared by reacting with an alkanol and an acid. The compound of formula A206 is equivalent to the following structure: , , 11 Ρ.

-29- This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 27

V. DESCRIPTION OF THE INVENTION [A206] wherein R19, R20, -E-E-, -A-A-, -B-B- and R3 are as defined in Equation 205. The compound of formula A206A corresponds to formula A206 wherein R21, R22 and R23 are independently selected from the group consisting of hydrogen, halo and lower alkyl. The compound of formula A206B corresponds to formula A206A, wherein -EE- corresponds to formula XLIII, XLIV, XLV or XLVII° formula A206C, and the compounds A206D and A206E correspond to formulas A206, A206A and A206B 'where -AA- and 'and _B_B- Each is -CH2-CH2-' and R3 is hydrogen. Compounds within the scope of formula A206 can be prepared by reacting a comparable compound within the scope of the compound of formula A205 with a trialkyl oximation i. The compound of formula A207 is equivalent to the following structure: -- (Please read the notes on the back and fill out this page)

, 1T Μ部中决#准局β〈,τ消贽合竹私印f 〇

CO,R2* [A207] -30 This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 B7 V. Description of invention (28) where 25 is CVC4 alkyl and -E-E_, R19, R20, -AA-, -Β·Β_ and R3 are as defined in the formula 205. The compound of the formula 207 is equivalent to the formula 207, wherein R21, R22 and R23 are independently selected from the group consisting of hydrogen, i and a lower alkyl group. The compound of the formula A207B corresponds to the formula A207A, wherein -EE- corresponds to the formula XLIII, XLIV, XLV or XLVI, and the compounds A207D and A207E correspond to the formulas A207, A207A and A207B, respectively, wherein -AA- and -Β·Β- Each is -CH2_CH2- and R3 is hydrogen. The compound of formula A207 can be prepared by reacting a compound of formula A206 with a dialkyl malonate. The compound of formula A208 corresponds to the following structure:

π 08 [Α208] 3⁄43⁄4•部中决# rate bureau beijing consumption and bamboo $print (please read the note on the back and fill out this page) where -Ε-Ε-, R80 and R90 are as defined in XLII ;-Α-Α-, -Β-Β- and R3 are as defined in formula 104; and R19, R20, -Α-Α-, -Β-Β-, R3 are as defined in formula 205. The compound of formula 208 is equivalent to formula 208 wherein R2 and R22 are independently selected from the group consisting of hydrogen and a lower carbon group. The compound of formula A208B is equivalent to formula A208A, wherein -EE- is equivalent to formula -31 - the paper scale is applicable to Chinese national standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 B7 5. Invention description (29) XLIII, XLIV, XLV Or XLVII. The compounds of formula A208C correspond to formula A208, respectively, wherein R8G and R9G plus the ring carbon to which they are attached comprise a ketone or:

17) mn( CHf) , - C - X

XXXIV (Please read the note on the back and fill out this page) where X, Y1, Y2 and C(17) are as defined above.

The compound of formula 208D corresponds to formula 208C wherein substituent XXXIV corresponds to structure XXXIII 〇

XXXIII The compounds of formula A208E, A208F, A208G, A208H and A208J are equivalent to formula A208, A208A, A208B, A208C and A208D, respectively, wherein -A-A- and -B-B- are each -CH2-CH2-, and R3 is hydrogen. Compounds within the scope of formula A208 can be prepared by thermal decomposition of a compound of formula A207. The compound of formula A209 is equivalent to the following structure: Printed by the Ministry of Standards and Staff of the Ministry of Standards

0H

[A209] 32- The paper size applies to the Chinese national standard _((^^) 八4 specification (210'乂297 mm) 1248443 A7 B7 V. Invention description (30) where R80 and R90 are as defined in the formula XLI, And -E_E- and -AA-, ·Β-Β-, and R3 is as defined in formula 205. The formula 209 Α compound corresponds to the formula 209, wherein R21 and R22 are independently selected from the group consisting of hydrogen, hydrazine, and a low carbon alkyl group. Α209Β The compound corresponds to the formula Α209Α, wherein -Ε·Ε_ corresponds to the formula XLIII, XLIV, XLV or XLVII. The compound of the formula A209C corresponds to the formula Α209Β, wherein -Ε-Ε- corresponds to the formula XLIV. The compound of the formula A209D corresponds to the formula Α208 , wherein R8G and R9G plus the ring carbon adhered thereto comprise a ketone group or: Y*

Γ1, I -CM 7) Mm(CHf)i - C - X χχχϊν where X, Υ1, Υ2 and C(17) are as defined above.

The compound of the formula 209E corresponds to the formula A209D, wherein the substituent XXXIV corresponds to the structure XXXIII, the second member of the pouring section, and the τ 贽 贽 竹 社 印 印 f

(Please read the notes on the back and fill out this page again)

XXXIII The formula A209F, A209G, A209H, A209J, A209L and A209M are respectively equivalent to the formulas A209, A209A, A209B, A209C, A209D and A209E, wherein -AA- and -Β·Β- are each _CH2-CH2·, and R3 It is hydrogen. The compound in the range of formula A209 can be hydrolyzed by the equivalent compound of formula A208-33- This paper scale is applicable to China National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 Μ Β7 V. Inventive Note (31 Preparation by Function. Formula A2 1 〇 compound is equivalent to the following structure

.00 [A210] wherein r80 and R90 are as defined in formula XLI, and the substituents -A-A-, -B-B- and R3 are as defined in formula IV. The compound of formula A210A corresponds to formula A210 wherein R80 and R90 plus the ring carbon to which it is attached comprise a keto group or:

:c( 1 7) MMI( CHf) 2 - C - X

XXXIV

Wherein X, Y1, Y2 and c(17) are as defined above. The compound of the formula 210B corresponds to the formula A210A in which the substituent XXXIV is equivalent to the structure XXXIII (please read the notes on the back and fill out this page)

, 1T by the Ministry of Defence in the Ministry of the standard ^ ^ ^ 贽 贽 贽 $ $ $ $ 〇 〇 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 210 210 210 210 210 210 34- The paper size is applicable to the Chinese national standard ((, NS) Λ4 specification (210X 297 mm) 1248443 V. Inventive Note (32 A7 B7 keto group. The formula A210D, A210E, A210F and A210G compounds are equivalent to the formula A210 'A210A respectively ' A210B and A210c, wherein each of them is _ 2 CH 2 and R 疋 hydrogen. Compounds in the range of formula 210 can be prepared by epoxidation of a compound of formula 209, wherein -EE- is di-CH-. Type: 〇

[Α211] wherein - Α-Α- '-Β-Βη each R3 is as defined above. The compound of formula 211 corresponds to formula 211, wherein R80 and R90 together contain a keto group or: :C(1 7> mn(CH2)f

XXXIV (Please read the note on the back and fill out this page.) Μ 中 中 τ τ 4- 4- 4- 4- 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 . The compound of formula A211B corresponds to formula A211A wherein substituent XXXIV corresponds to structure XXXIII: ' 〇

XXXIII -35- This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 ___ _______ B7 V. Description of invention (% f~ ~~ ~ ~ Formula A211C compound is equivalent to formula A210A, where R80 And R9〇 together form a ketone group. The compounds of the formula A211D, A211E, A211F and A211G correspond to the formulas A211, A211A, A211B and A211C, respectively, wherein each is -CH^CH2·, and R3 is hydrogen. The compound may be prepared by oxidation of a compound of the formula A210 or during the epoxidation of a compound of the formula A2, wherein -e-e_ is > = CH_. The compound of the formula 211 may be in the following manner Conversion to a compound of formula I. The compound of formula L corresponds to the following structure: ------- - 1#! (Please read the notes on the back and fill out this page again.

Order

L wherein R 疋C1-(^4 alkyl group' and AA-, -B-B_, Rl, r2, r3, uldent 8 and R9 are as defined above. The compound of formula LA corresponds to formula L, wherein R8 and R9 are added The carbon atoms with which it is attached include XXXIV wherein X, γ1 and Y2 are as defined above.

Formula LB compound is equivalent to formula L, wherein R8 and R9 are equivalent to sXXXIII -36-% MM part of the middle 摞 局 局 J J JT-消贽告竹社印繁

This paper scale applies to Chinese national standards ("CNS) (210X 297/>f) 1248443 A7 V. Invention description (disaster)

ΜΜ 部 部 部 部 J J J J J J J J J J J J J J LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC And R3 is hydrogen. It is apparent from the disclosure of the specific reaction schemes shown below that these compounds are extremely useful in the specific reaction scheme. The compounds of the present invention can be used as intermediates for methacrylone and other steroids. Other topics and features are obvious, and some are indicated below. 1 is a schematic flow diagram of the biotransformation of a canrenone or a canrenone derivative into a comparable 11 alpha-hydroxy compound; Figure 2 is a biotransformation of a ketone and a carbitol derivative / 11 alpha - A schematic flow diagram of a preferred method of hydroxylation. Figure 3 is a schematic flow chart of a particularly good method for biotransformation/u-hydroxylation of ketones and ketones derivatives. Figure 4 shows the particle size distribution of ketones prepared by the method of Figure 2; The small distribution of the particles of the ketone in the transformed fermentation tank according to the method of Fig. 3 is shown. The equivalent reference characteristic shows a considerable part of the whole figure. The specific width of the silk __example 曰i according to the invention For preparing epoxy meclorone and other equivalent formula I

-- (Please read the notes on the back and fill out this page again)

, 1T I I- I- - I - 1248443 V. Description of the invention 35 A7 B7 compounds, various novel process procedures have been proposed

Wherein AA- represents -CHR4_chr5 or _CR4 = CR5_ group; R' R4 and R5 are independently selected from the group consisting of hydrogen, halogen, light base, low-blocking alkyl group, lower alkoxy group, hydroxyalkyl group, alkoxy group Alkyl, hydroxycarbonyl, cyano and aryloxy; R1 represents a-position of lower alkoxycarbonyl or hydroxyalkyl; and represents -CilR6-CHR7_ or azimuthal group: f« read the back of the matter顼Refill this page} Order 'CH-

/ •CH

_CH — CHS

-CH

IU 潆 中 中 负 负 J J J J J 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中a hydroxycarbonyl group, an alkyl group, an alkoxycarbonyl group, an anthracenyl group, a cyano group and an aryloxy group; and υ R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, aryl, aryl , alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxy oxyalkyl, cyano and aryloxy, or R8 and R9 together contain an anthracene ring, a ring structure, or R8 or R9 plus R6 or R7 contains a carbocyclic or heterocyclic ring, a hetero, a, σ Fu, and 38- the paper ruler (four) 彳, __ (Τ^^(2Κ)Χ297 mm) %». I- -1- · 1248443 Μ -------------- Β7 V. Description of invention (36) Condensed to a five-ring D ring. Further, as indicated, the organic group is referred to in the present disclosure as a low carbon, and contains up to 7, and preferably 1 to 4 carbon atoms. The lower alkoxycarbonyl group is preferably derived from an alkyl group having from 丨 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and butyl Particularly preferred are methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl. The lower alkoxy group is preferably derived from one of the above fluorenyl-alkylene groups, especially from the first--C4 alkyl group; more preferably, it is a methoxy group. The lower alkane group is preferably derived from a linear alkyl group having 7 carbon atoms of i soil; more preferably, it is a methyl group and an ethyl group. The methylene bridge is preferably 0-azimuth at the 15,16-position. A preferred class of compounds which can be produced according to the process of the present invention are the 2 〇-spirooxane compounds described in U.S. Patent No. 4,559,332, which is equivalent to the compound of the formula IA: - (Please read the back note and fill out this page) )

Ψ Ψ 中 中 中 J J J J J J J J J J J J J J J J J J J J J J J J J J J J J J · or α - or 々 - orientation of the group IIIA C Η ^ C Η - ΙΙΙΑ -39- This paper scale applies to the Chinese national standard rate ((Which) eight 4 specifications (210^<297 mm) 1248443 A7 1 ~~-~! ———- B 7 V. Invention Description (37) — ~~--~————~~

R1 represents "a lower alkoxycarbonyl or hydroxycarbonyl group; X represents two hydrogen atoms, a keto group or =s; Y1 and Y2 together represent an oxygen bridge-〇-, or Υ1 represents a hydroxyl group, and:: a hydroxyl group, The lower alkoxy group, or the lower alkane group if χ represents Η2, is preferably a 20-spirooxane produced by the novel process of the invention, wherein Yk Y2 represents a compound of formula I of oxygen bridge-Ο. Preferably, the compound of formula I is one wherein χ represents a ketone group. In the compound of the formula, wherein X represents a ketone group, the most preferred one is... plus Υ2 represents an oxygen bridge, -0-. The 17-hydroxyl-21-carboxylic acid may also be in the form of its salt. Among the metals and ammonium salts, such as alkali metal and alkaline earth metal salts, such as sodium, calcium, magnesium, and preferably potassium salts, may be considered. And derived from ammonia or suitable, preferably physiologically compatible with the ammonium salt of an organic nitrogen base. The alkali can be considered not only an amine, such as a lower alkylamine (such as triethylamine), a hydroxyl group - Lower alkylamines (eg 2-(E-ethylamine) bis(2-hydroxyethyl)-amine or 叁(2-hydroxyethyl)-amine), cycloalkylamines (eg dicyclohexylamine) ) or 芊a base amine (such as decylamine and hydrazine, hydrazine-dimercaptoethylenediamine), and a nitrogen-containing heterocyclic compound such as an aromatic compound (such as pyridine or quinoxaline) or a heterocyclic ring having at least partial saturation (such as Ν-ethylhexahydropyridine, morphine, hexahydropyrrolidine, or hydrazine, hydrazine, _dimethylhexahydropyrrolidine). Also included in the preferred compounds are also the bases of the formula I oxime compounds. a metal salt, especially a potassium salt, wherein R1 represents an alkoxycarbonyl group, X represents a ketone group, and γΐ and γ2 -40- are applicable to the Chinese National Standard Rate (CNS) Λ4 specification 7^1 〇χ 297 public Chu) Department of the Ministry of Standards and Regulations, τ 贽 贽 竹 社 社 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 As follows: 9α, 11 a - 乳乳基-7 α-methoxy-based -20-spiroxo-4-conazole, 3,21-dione, 9α, 11--5-oxime-7-milk谈基-20-Insectoxy-4-consin-3,21-dione, 9", 11-Han-5-Alkoxy-7-H-isopropyloxy- 20-spiro-oxy-4-return-_3 21-dione, and 1,2-dehydrogenated analogs of each compound; 9",11"-epoxy-6",7"- Methyl-20-spiroox-4-indole-3,21-dione, 9α,11α-epoxy-6 point, 7/?-methylene-20-spiroox-4-indole-3,21 Diketone, 9α, 11α-epoxy-6 cold, 7/?; 15々,16/?-bismethylene-2〇_spiro-4-ene-3,21-dione, and these 1,2-Dehydrogen analogs of each compound; 9α,11 epoxy-7 α-methoxycarbonyl-17/?-hydroxy-3-keto-pregnant -4-4-distributed _ 2 1 - oxic acid , 9",11"-epoxy-7<^-ethoxycarbonyl-17;5-#-form-3-one-pregnant-4-fine- 21-rebel, 9α,11 epoxy- 7α-Isopropoxycarbonyl-17/?-hydroxy-3-keto-pregnant-4-lean '-21-decanoic acid, 9α,11 epoxy- 17/?-hydroxymethylene-3-keto -pregn-4-ene-21-carboxylic acid, 9,α,11 epoxy--17-hydroxy-6/?,7/?-methylene-3-keto-pregnant_4-ene-21- Carboxylic acid, -41 - This paper size is applicable to China National Standard #(CNS) Λ4 specification (210X297 mm) IT (please read the back note and fill out this page) A7 1248443 B7 — V. Invention description (39) Ring Oxyl-17/?-hydroxy-60,7 rou; 15y5,16/?-bismethylene-3-methyl-pregn-4-ene_21_skin acid, and the alkali metal salts of these acids, especially Salt or ammonium, and the equivalent 1,2-dehydrogen analog of each of the mentioned carboxylic acids or their salts; 9 no, 11α-epoxy-15 yS, 16 Θ-methylene-3,21 -Diketo-20-spirooxy-4-ene-7α-carboxylic acid methyl ester, ethyl ester and isopropyl ester, 9 π, 11 ^ epoxy-1 5 /?, 1 6 /?-methylene -3,21-diketo-20-spirooxy-1,4-diene-7?-carboxylic acid methyl ester, ethyl ester and isopropyl ester, 9 from, 11"-epoxy-3-keto- Methyl 20-spirooxy-4-ene-7-carboxylate, ethyl ester and isopropyl ester, 9π, 11α-epoxy-6/?, 6/5-methylene-20-spiroox-4-晞-3·ketone, 9α,11α-epoxy-6y5,7y5 ; 15 lux, 16 々-bismethylene-20-spiro-oxy-4 -conazole-3, fluorene, 9π, 11 epoxy group, 17/? ·Hydroxy-17α(3-hydroxy-propyl)-3-keto-androst-4-ene-7-carboxylate, ethyl ester and isopropyl ester, 9", 11<^-ring Oxy,17;5-light-based-17〇/-(3-light propyl)-6-pan, 7(^-methylene-androst-4-indole-3-one, 9 from, 11 α-ring Oxy, 17 lb-hydroxy-17 α -(3-hydroxypropyl)-6y5,7/? methylene-androst-4-en-3-one, 9^,11^-epoxy, 170- Hydroxy-17-pan-(3-hydroxypropyl)-6/?, 7 cold; 15/?, 16/?- Methylene-androst-4-en-3-one, including 17α-(3·acetoxypropyl) and Πα-(3-formoxypropyl) analogs of the above maletane compound, and male-4 -Allene-3-one and 20-spiro-4-en-3-one series All of the above compounds _ -42- 呆 纸 纸 纸 _ _ fcNS ) Λ 4 specifications (210X ^ 97 mm) - '- - IT (please read the notes on the back and fill out this page) 1248443 A7 —*— ---—一-__Β7 V. Invention Test (4() ) ' " — --~^ Dehydrogenation analogs. The chemical formulas of the compounds of the formula I and the formula A and the analogues having the same characteristic structure are derived according to the current name: Y1 plus Y2 represents a compound of _〇·, derived from 20-spirooxane a compound of j A, wherein χ represents a keto group and Υ1 plus Υ2 represents a derivative derived from 2〇_spirooxane-21-one; and a compound in which υ1 and γ2 each represent a hydroxy group and χ represents a ketone group, from η / ?-hydroxy-17α-pregnene_21_carboxylic acid; and γ1&γ2 each represents a hydroxyl group, and X represents two hydrogen atoms derived from _hydroxy- 17 "-(3-hydroxypropyl)-androstane. The cyclic and open-chain versions, respectively, refer to lactones and 17 lb-hydroxy-21-carboxylic acids and their salts, which are highly related to each other, and the latter can only be regarded as the hydrated version of the former, so above and below It is to be understood that, unless otherwise indicated, the end products of the formula I and the starting materials and intermediates of the similar structures are all present together in the examples. In accordance with the invention, in order to achieve high yields and Prepared formula compounds at reasonable cost, many separate process flows have been suggested. Preparation of a series of intermediates. Many of these intermediates are novel compounds, and the preparation of these intermediates is a novel method. The flow j is 1 (from the ketone or related matter, the full part of the decision) #埤局β-τ消费告竹社印 ¥ A preferred procedure for the preparation of a compound of formula I may advantageously start from a kerafluone equivalent to formula XIII or a related starting material (or alternatively, the process may begin with Androstenedione or related starting material)

-43- ---------0II (Please read the notes on the back and fill out this page) ^9!

XIII public i a)---

1248443 Α7 _____ Β7 V. Description of invention (;) ~~~ --- where: represents -CHR4-CHR5· or -CR4=CR5-; R3, R4 and R6 are independently selected from the group consisting of hydrogen, south, hydroxyl, low carbon Alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; i-IB- represents a -CHR6-CHR7 or a- or 々-oriented group:

Rex R7

CH--CH CH CH^

III wherein R6 and R7 are independently selected from the group consisting of hydrogen, lower alkoxy, fluorenyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, decyloxy, cyano and Aryloxy; and R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, fluorenyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, oxo 1 methoxy oxane a group, a cyano group and an aryloxy group, or r8 and R9 together contain a keto group = 'ring or heterocyclic ring structure, or R8 and R9 plus R6 and R7 contain a carbocyclic ring or a ring structure and are fused to a penta ring D ring. Using the biotransformation process of the type illustrated in Figures 1 and 2, the q-square cadmium 1 hydroxy group is introduced into the compound of the formula XIII, and the compound νΙΠ compound can be produced.

VIII This paper scale applies to China National Standard Rate (CNS) Λ4 Specifications (210X297 mm) ---------0! (Read the first note on the back and fill out this page.) Order 1244843 A7 B7 V. Invention Description (42) wherein -AA-, -BB-, R3, R8 and R9 are as defined in formula XIII. Preferably, the compound of formula XIII has the following structure

, Cch2]t~( XII ΙΑ and 1 1 f hydroxy product has the following structure

CCH2]y

VIIIA in each of the examples -AA- stands for -CH2-CH2- or -CH=CH-; -BB- stands for -CH2-CH2- or or Lu-oriented group: Order (please read the notes on the back and fill in On this page) J. 贽 贽 贽 私 私 . . . . . C C C C C C C C C C C C C C C C C C C C C C C C C

IIIA R3 is hydrogen, lower alkyl or lower alkoxy X represents two hydrogen atoms, keto group or =S; Y1 and Y2 represent oxygen bridge-〇-, or 45- this paper size is suitable for China Standard (CNS) Λ4 size (210X 297 mm) 1248443 A7 ____________ B7 V. Inventive Note (43) Y1 stands for hydroxyl group, and (please read the back of the note before you fill in this page) Y2 represents hydroxy, lower alkoxy Or if X represents H2, there are also alkyl alkoxy groups; and salts of the compounds, wherein X represents a ketone group and Y2 represents a hydroxyl group. Preferably, a compound of formula VIIIA is produced in the reaction, corresponding to a compound of formula VIIIA, wherein -AA- and -B-B_ are each -CH2-CH2-; R3 is chloro; Y1'Y2 and X are as defined in formula XIIIA And R8 and R9 together form a 20-spirooxane structure:

Preferred organisms that can be used in this hydroxylation step are Aspergillus oryzae NRRL 405, Aspergillus oryzae ATCC 18500, Aspergillus niger ATCC 16888 and ATCC 26693, Aspergillus nidulans ATCC 1 1267, Rhizopus oryzae ATCC 11145, Rhizopus oryzae ATCC 6227b, Streptomyces faecalis ATCC 10745, Bacillus megaterium ATCC 14945, Pseudomonas clostridium ATCC 13262, and P. pinkus ATCC 12543. Other preferred organisms include Fusarium oxysporum ATCC 11171 and Rhizopus arrhizus ATCC 1 1 1459. Other organisms that can exhibit activity in this reaction include: Blue Color plowshare [ATCC 6647, A. grisea ATCC 22752, M. vaginalis ATCC 6476, Aspergillus oryzae ATCC 1030, Aspergillus fumigatus ATCC 26934, Beauveria bassiana ATCC 7159 and ATCC 13144, Phytophthora sinensis IMI 038560 , Li Chi shell ATCC 14767, snail shell ATCC 10195, also known as A. sphaeroides ATCC 16718, short thorns, silver worm, ATCC 8688a, -46- i paper scale for Chinese national ginseng (() NS): Λ 4 Specification (2ΙΌΆ97 mm) 1248443 A7 ^ B7 V. Inventive Note (44) T. sphaeroides ATCC 3655, elegant C. sinensis ATCC 9245, Curvularia sp. ATCC 22921, Curvularia sp. ATCC 12017, E. coli ATCC 1011, Wetococcus pyogenes ATCC 12722, O. oxysporum ATCC 22822, Chrysosporium parasitic ATCC IMI 109891, Mortierella aurantia ATCC 42613, Rhodococcus sp. ATCC 4605, Trichophyton rubrum ATCC 1207A, Fusarium oxysporum ATCC 9095 , Nocardia coralis ATCC 19070, Paecilomyces ATCC 46569, exhibition of ACC 24550, Pithomyces atro-olivaceus IFO 6651, Pithomyces cvnodontis ATCC 26150, P. oxysporum ATCC 1223 1, S. erythraea ATCC 1 1635, Xanthos sp. ATCC 13378, Stachvlidium bicolor ATCC 12672, water-absorbing chain Mold _g_ATCC 27438, Streptomyces faecalis ATCC 25489, T. oxysporum ATCC 18192, Thamnostvlum piriforme ATCC 8992, Clostridium sp. ATCC 13 807 and Cocoa falciparum ATCC 12474 〇 expected to show 11 a - chemification Additional organisms that are active include: Phytochemistry (1996), 42 (2), 411-415, J. Biotechnol (1995), 42 (2), 145-150, Tieghemella orchidis (Khim.-Farm.Zh. (1986), 20 (7), 871-876), Tieghemella is printed by the J.-Consumer Cooperative of the Department of Standards and Regulations of the Ministry of Consumer Affairs (read the first note on the back and fill out this page) ) hvalospora (Khim.-Farm.Zh. (1986), 20 (7), 871-876), singular KActa Microbiol. Pol., Ser. B. (1973), 5 (2), 103-110), Aspergillus oryzae (Acta Microbiol· Pol·, Ser. B. (1973), 5 (2), 103-110), Gramineae spp. (Acta Microbiol. Pol· Ser. B. (1973), 5 (2), 103-110), Verticillium sp. (Acta Microbiol. Pol., Ser. B. (1973), 5 (2), 103-110), and black Rhizopus (J. Steroid Biochem. (1987), 28 (2), 197-201). -47- The paper size is applicable to China National Standard (CNS) Λ4 specification (210X 297 mm). The Ministry of Economic Affairs will determine the squad of the Ministry of Economic Affairs-T-消贽合竹社印 f 1248443 A7 ~_____ Β7 V. Invention Description (45 The oxime _ hydroxy derivative of androstenedione and meglione can be prepared according to the biotransformation methods shown in Examples 2A and 19B, respectively. The inventors have similarly sighed that the compound of formula viii, wherein the C11 hydroxy-hydroxyl substituent replaces the equivalent hydroxy isomer of the cU hydroxy substituent, can also be prepared by a similar biotransformation process, wherein the use can be carried out 11 /?- A hydroxylated microorganism, more than one microorganism as disclosed herein. Formula XIII Kenridone or other hydroxylation of the substrate from the preparation to the scale of the fermentation of the 'preparation of the cell inoculum can be prepared in the sub-test fermentation system, which contains a seed fermentation tank, or more than two seed fermenters series. A spore suspension of the stock solution is introduced into the first seed fermenter, and a solution for the growth of the cells is added. If the amount of inoculum required for the desired or production exceeds that produced in the first seed fermenter, the inoculum volume can be gradually and geometrically expanded by the remaining fermentation tanks in the seed fermenting line. Preferably, the inoculum produced in the seed fermentation system has sufficient amount and viable cells to achieve rapid stimulation of the reaction in the fermenter (compared to a relatively short batch cycle), and high Production of fermentation tank activity. Regardless of the number of passenger vessels in the seed fermenting tank, the second and subsequent seed fermenting tanks preferably have a full size, so that the dilution levels can be the same in each step of the row. The initial dilution of the inoculum in each seed fermenter can be approximately the same dilution factor as in the fermenter. The ketone or other formula XIII is filled into the fermentation tank, and the inoculum and nutrient solution are added, and the hydroxylation reaction is carried out therein. { The spore suspension of the seed acid fermentation system is derived from the j bottle of the suspension of the Benin liquid spore suspension, which is taken from many vials that constitute the cell bank of the operating reservoir, and the ____ - 48 - this ^- — -------- Stupid ------, 玎 ------ (Please read the notes on the back and fill out this page) 1248443 A7 V. Inventions (46) - ~~---- Wait until the use of Benin in cold-beam conditions. The operating reservoir cell bank is derived from the mother cell bank, which is prepared in the following manner. Spores from appropriate sources, such as ATCC First suspended in an aqueous medium, such as a saline solution, a nutrient solution or a surfactant solution (such as a nonionic surfactant, such as Dinger 2, a concentration of about 0.1% by weight), and suspended The liquid is distributed on the culture tray, each tray having a solid nutrient mixture, usually based on a non-hydrolyzable polysaccharide, such as agar, in which the spores can proliferate. The solid nutrient mixture preferably contains about 0.5% and about 5% by weight. Between the glucose, about 5 〇 and about 5% by weight of the nitrogen source, such as protein gland, 〇〇 5% and about 5% 5% by weight of the phosphorus source Such as ammonium phosphate or an alkali metal salt, such as dipotassium hydrogen phosphate, about 0.25% and about 2.5% by weight of yeast extract or lysate (or other source of amino acids, such as meat extract or brain Infusion), about 1% and about 2% by weight of agar or other non-hydrolyzable polysaccharide. The solid nutritional mixture may further contain about 〇·1% and about 5% by weight of the malt. The pH of the solid nutrient mixture is preferably between about 5 Torr and about 7 _0, adjusted as desired with an alkali metal hydroxide or orthophosphoric acid. Useful solid growth media are as follows: 1. Solid medium #1 : 1% glucose, 0.25% yeast extract, 0.3% Κ2ΗΡ04, and 2% agar (Bacto); pH 値 adjusted to 6·5 with 20% NaOH 2. Solid medium # 1 : 2 % protein gland (Bacto), 1% yeast extract (Bacto), 2% glucose', and 2% agar (Bacto); pH 调 adjusted to 5 with 10% H3PO4. 3. Solid medium #3: 0.1% protein gland (Bacto), 2% wheat Bud Extract-49- Urine paper scale applies to China National Standard Rate ([NS) Λ4 specification (210X 297 mm)

1248443 In the middle of the full division, the squad of the squadron 1 贽 贽 贽 私 私 A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A 4»Liquid medium: 5% black rope molasses, 〇_5% grain impregnation solution, 0.25% glucose, 0.25% NaCl and 0.5% KH2P04, pH adjusted to 5.8. 5 · Difco Mycological agar (low pH 値), based on further requirements for the mother stock, the number of agar plates used to develop the mother reservoir cell bank, but usually about 5 to about 3 disks. After a suitable growth period, such as 7 to 10 days, scrape the dish, usually saline or buffer solution, in the presence of an aqueous solvent to recover the spores, and the resulting mother stock suspension is divided into several vials, such as 1 soared in the h5 soaring vial. For the preparation of the operating liquid spore suspension for use in research or production of fermentation operations, more than one second generation of mother stock vial contents can be distributed and grown on agar plates in the same manner as the above-described mother stock suspension suspension . When it is intended to perform routine operations, up to 1 to 400 trays can be used to produce a second generation operating reservoir. Each tray is scraped and placed in a different operating reservoir vial, each vial typically containing an inoculum produced in milliliters. For long-term storage, the mother stock suspension and the inoculum produced by the second generation may be removed from the vapor space of the cryopreservation vessel containing liquid nitrogen or other cold bundle liquid. In the process illustrated in Figure 1, an aqueous growth medium is prepared which comprises a nitrogen source such as protein Yuedong, a yeast derivative or its equivalent, glucose, and a phosphorus source such as phthalate. The microbes are cultured in this medium of the seed fermentation series. A preferred microorganism is Aspergillus oryzae nrrl 4〇5 (atcc 185〇〇). The seed produced in this way is then introduced into the production acid fermentation tank, and the paper scale is applicable to the Chinese national standard (rNS) Λ4 rule ^ (please read the notes on the back and fill out this page)

-50- The Ministry of the Ministry of Economic Affairs and the Ministry of the People's Republic of China, J. Consumers' Bamboo "Printing 1248443 kl -"1—B 7 V. Invention Description (48) The quality of the formula XIII. The fermented gravy is stirred and ventilated for a sufficient period of time to react to the full extent of the desire. The medium for the seed fermenter preferably contains an aqueous mixture comprising: about 0.5% and about 5% by weight of glucose, about 0.05% and about 5% by weight of a nitrogen source, such as a protein gland, About 5% and about 0.5% by weight of the phosphorus source, such as ammonium phosphate or alkali metal salt, such as monobasic ammonium phosphate or dipotassium hydrogen phosphate, about 0.25% and about 2.5% by weight of the yeast solution Cell products or extracts (or other sources of amino acids, such as vinasse), about 1% and about 2 °/. Soil fat or other non-hydrolyzable polysaccharides by weight. A particularly preferred seed growth base contains about 0.05% and about 5% by weight of the nitrogen source, such as protein glands, about 0.25% and about 2.5% by weight of the auto-dissolved yeast or yeast extract, about ο. 〗 〖% and about 5% by weight of glucose, and about 〇〇5. / () and about 5. 5 () / () by weight between the phosphorus source, such as a basic ammonium phosphate. A particularly economical process is provided by the use of another preferred seed medium containing about 〇5〇/. And about 5% by weight of the grain impregnation solution, about 0.25% and about 2.5% of the auto-dissolved yeast or yeast extract, about 5% and about 5% by weight of the glucose and about 0.05 % and about 0.5% by weight of one of the basic ammonium phosphates. Grain Leaching Liquids, peptides, carbohydrates, organic acids, vitamins, metal ions, trace substances and phosphates are particularly economical sources. An impregnation solution from other grains can be used instead of or in addition to the grain impregnation. The pH of the medium can be adjusted to range between about 5 Torr and about 7. Torr by the addition of an alkali metal hydroxide or orthophosphoric acid. When the grain infusion is used as a nitrogen and carbon source, the pH is preferably adjusted to between about 6.2 and about 6.8. The medium containing the protein gland and glucose is preferably adjusted to between about 5.4 and about 6.2. Growth medium that can be used in seed fermentation _ -51 - National standard, ^TX4 Specification one---- (Please read the note on the back and fill out this page) Order t 1248443 A7 B7 V. Description of invention ( 49 medium [1 2 /〇-protein gland ' 2 % yeast autolysate (or yeast / month) and 2% glucose; pH 调 adjusted to 5.8 2 with 20% NaOH · medium # 2 3% autumn > Crush, 15% yeast extract, 3% 3% ammonium citrate, and 3% glucose; pH 调 adjusted to 6.5 with 20% NaOH. Microbial spores are introduced from the vial into the medium, usually per ml of suspension Contains about H), spores. The optimum production force of seed production is understood to be reduced to a sub-population density of less than about ΗΓ per ml in the growth medium at the beginning of the seed culture. Preferably, the stalk is cultured in the seed fermentation system until the compact hyphal volume (PMV) in the seed fermentation tank is at least about 鸠, preferably from about 35% to about 45%. Since the circulation in the seed fermenting vessel (or any of the many vessels containing the seed acid yeast) depends on the initial concentration in the vessel, it is desirable to propose two or three seed fermentation stages to speed up the overall process. However, it is better to avoid using more than three seed-growing tanks in the series, because if the seed fermenting passes through too many stages, the activity will be impaired. The seed culture fermentation is carried out under agitation and at about 23° to about 37X: preferably about 24. And about 28. Between. The culture from the seed fermentation system is introduced into a fermentation tank and a growth medium is added. In a specific embodiment of the present invention, the unsterilized ketone or other formula XIII is used as a reaction medium, and the substrate is added in a growth medium of 10% to 30% by weight. In the production of acid fermentation tank. In order to increase the surface area available for the 1 1 α-hydroxylation reaction, the 52- paper scale applies to the Chinese National Standard (CNS) Λ4 specification (2ω'χ297 mm) (please read the notes on the back and fill out this page) ) - Ding Wei 1248443 A7 B7 V. Description of the invention (The size of the particles of the formula XIII can be reduced, that is, the substrate is passed through the micronizer on the line before being introduced into the fermentation tank. The sterile nutrient feed stock containing glucose And a yeast derivative, such as an autonomously soluble yeast (amino acid blend according to different sources such as distiller's grains), is also introduced separately. The medium contains an aqueous mixture, including about 5% and about 5% by weight. Between glucose, about 0.05% and about 5% by weight of the nitrogen source, such as protein glands, about 0.05% and about 0.5% by weight of the phosphorus source, such as ammonium phosphate or alkali metal salts such as dipotassium hydrogen phosphate , about 0.25% and about 2.5% by weight of yeast lysate or extract (or other amino acid source, such as vinasse), 1% and about 2% by weight of agar or other non-hydrolyzable polysaccharide The excellent production growth medium has about 0.05% and about 5〇/❻. According to the re-calculated nitrogen source, such as protein Yuedong, about 25% and about 2.5% by weight, the self-dissolving yeast or yeast extract, about 5% and about 5% by weight of glucose And about 5% and about 5% by weight of the source, such as - test ammonium sulphate. Another preferred production medium contains about 0.5% and about 5 〇 / 〇 by weight The grain impregnation solution, about 25% and about 2.5% of the self-priming yeast or yeast extract, about 0.5% and about 5% by weight, glucose 1, 々〇.〇 5% and about 5% by weight, one of the accredited methods of riding ammonium sulphate to produce acid yeast, i 养 之 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値 Η値Zhusheyin f: Type: Shi: For the protein gland 'glucose-based medium and grain dip>, the same medium has the same preferred range. Useful biotransformation growth medium is shown below: #1 H protein gland, 2% yeast autonomous lysate (or yeast / sputum) and 2. / 〇 glucose; pH 调 adjusted to 5.8 with 20% NaOH. 53 (210X297 mm 1244843 A7 B7 V. Description of invention (51 Full house摞准局贝_τ消费合竹社印繁culture#2 : 1% protein gland, 1% yeast autonomous lysate (or yeast / X霄)' and 2% glucose; pH 値 adjusted to 20% Na〇H 5.8. 5% 5% protein gland, 〇.5% yeast autolysate (or yeast 'same), and 0.5% glucose; pH 値 adjusted to 5.8 with 2 〇〇 / 〇 NaOH. 3% grain immersion, H5% yeast extract, 3% 3% monobasic ammonium phosphate, and 3% glucose; pH 调 adjusted to 6.5 with 2% NaOH. 2·55% of the herbicide dipping solution, 1.275% yeast extract, 0.255%-basic ammonium phosphate, and 3% glucose; pH 値 was adjusted to 6.5 with 20% NaOH. 2.1% grain impregnation solution, 5% yeast extract, 〇-alkali ammonium phosphate, and 3% glucose; pH 调 adjusted to 6.5 with 20% N a Ο 。. The non-sterile Kenfurone and the sterile nutrient solution are continuously added to the production fermentation tank, and are about 5 to about 20, preferably about 丨〇 to about 15, in the cycle of each production batch, preferably substantially It is added in the same number of copies. The beneficial mode is as follows: the substrate is first introduced in an amount sufficient to develop a concentration between about 1% and about 3% by weight, preferably between about 0% and about 2% by weight, and is fermented with seeds. The gravy is carried out before inoculation, and it is convenient to take it every 8 to 24 hours on a regular basis, and add to the cumulative ratio between about 1% and about 8% by weight. If additional doses are added every 8 hours, the total amount will be slightly lower (eg 0.25% to 2.5% by weight). The amount of double shells added only on a mother-day basis. In the latter case, the tired-54-冢 paper size is used.) Λ4 size (2^297 mm) '-----_3. Medium #3: 4. Medium #4: 5. Medium #5: 6 .Culture #6 : (Please read the notes on the back and fill out this page)

, 1T

• I 1248443 A7 B7 52 V. INSTRUCTIONS (The amount of ketopurone added should be in the range of 2% to about 8% by weight. The supplemental nutrient mixture added to the fermentation reaction is preferably a concentrate. Such as about 40% and about 60% by weight of sterile glucose, and about 16% and two 32% by weight of sterile yeast extract or other sterile source of yeast derivatives (or other sources of amino acids) a mixture of antibiotics can be added to the fermented gravy regularly to control the growth of the desired organism. The antibiotics can be doxorubicin, tetracycline and head hug. Cefalexin will not adversely affect growth and biotransformation. Preferably, the concentration of the added mashed broth is between about 0.0004% and about 0.002%, based on the total amount of gravy, including 〇2% and about 〇6〇/. The difference between ketomycin sulfate, about 0.0002% and about 0006·0006% tetracycline hydrochloride and / or about 0 · 0 01% and about 〇 · 〇〇 3 % In the first place, the total amount of gravy is subject to the total amount of gravy. 0 - 16 hours or so. Therefore, each part of the XIII substrate and the camp solution is usually added every 2 to 1 hour, preferably every 4 to 6 hours. The anti-foaming agent can also be beneficially introduced into the seed fermentation system, and In the production of the fermentation tank. Preferably, in the process of Figure 1, the inoculum is from about 0.5% to about 7%, preferably from about 1% to about 2% by volume (based on the total mixture in the fermentation tank) Adding to the fermentation tank, and maintaining the glucose concentration between about 0.01% and about 1.0%, preferably between about 0.025% and about 0.5%, and preferably about 0.05% and about 0.25% by weight. It is preferred to add about 0.05% to about 0.25% on a regular basis, which is preferably based on the total batch. The temperature range of the acid fermentation can be conveniently controlled between about 20 ° and about 37 ,. Good about 2 4 °C to about 28 °C, but hopefully at -55- this paper scale Chengzhou China National Standard (CNS) Λ 4 specifications (210X 297 mm) (that is, read the back of the note before you Fill in this page) C·

, 1T 1248443 决 中 中 β 〈 〈 〈 〈 〈 〈 〈 〈 〈 〈 A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A (The increase is to maintain the tightness of the _ body and (ΡΜV) below about 60%, preferably below about 5%, and to prevent the viscosity of the acid mash to interfere with satisfactory mixing. If the growth of the biological mass rises out of the liquid surface, the material remaining in the biological mass can be discharged outside the reaction zone and cannot be applied to the chemical reaction. In terms of productivity, it is desirable to reach a range of 30-50%. The PMV is preferably between 35% and 45% in the first 24 hours of the fermentation reaction, but the subsequent conditions are preferably to control further growth within the above limits. The pH of the fermentation medium is controlled between about 5 Torr and about 6.5, preferably between about 5.2 and about 58, and the fermentation tank is agitated at a rate of between about 400 and about 800 rpm. And about 1 · 0 vvm to achieve a dissolved oxygen level of at least 1% saturation in the batch, and maintain the pressure in the head space of the fermentation tank between about atmospheric and about 1 bar, and preferably Near the specification of about 7 bar. The agitation rate can also be increased as needed to maintain the minimum dissolved oxygen level. Beneficially, the dissolved oxygen is maintained at about ίο%. In fact, up to about 50% can promote the conversion of the substrate. The pH range is maintained at 5_5 ± 0.2, which is also most suitable for biotransformation. If necessary, a common anti-foaming agent can be added to control foaming. After the addition, the reaction is preferably continued until the ratio of the molar concentration of the product of formula VIII to the remaining unreacted χιπ receptor is at least about 9: 1. This can be achieved after 8 cycles of Μ6〇h batch. Transformation: It has been found that high conversion is related to the initial nutrient level being lower than the initial filling level, and that by controlling the gas demand rate and the mobilization rate, it is possible to avoid the spillage of liquid gravy. In the process of Figure i, The nutrient level is consumed and maintained at no more than about 60%, preferably about 50% of the initial filling level; and in the figure: and) ____ _ 56 - the paper size is 2 ίο X 297 mm y • loaded --- ---1T------· (Read the first note on the back and then fill out this page.) Μ 中 中 中 中 舄 - - - - - 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 --- B 7 V. Description of the invention (Μ) <In the process, the nutrient level is reduced and maintained at no more than about 8〇%, preferably about The initial filling level of 70%. The aeration rate is preferably not more than iv whip, preferably in the range of about 〇5Vvm, and the stirring rate is preferably not more than 6〇〇卬^^. A particularly good method for preparing the compound of formula viii is shown in Fig. 2. Description. For the compound along the 1]; compound (such as ketone), the preferred microorganism for hydroxylation is tortuous «NRRL 405 (ATCC 18500) 〇, preferably containing about 0.5% and about 5% by weight </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Ammonium phosphate. However, other production growth media described herein can also be used. Seed culture methods Basically, as in the method of Figure 1, any of the seed fermentation bases described herein are utilized. In the growth medium, the unmicronized keneride or other formula is prepared by mixing the shell 5# liquid 'in the mixer, preferably at about 丨 and about 3 by weight. Go on. Preferably, the sterile preparation may include sterilization or pasteurization of the suspension after mixing. At the beginning of the batch, the entire amount of aseptic suspension required for the production batch is introduced into the fermentation tank or continuously added during the full period. The sample is reduced in particle size by wet milling in a connected shear pump. This pump can transfer the slurry to the production fermentation tank, thus eliminating the need to use a non-wired micronizer. When the pasteurization method is used instead of the sterilization method, the degree of aggregation is not significant, but the use of the cut fruit provides positive control of the particle size. Sterile growth medium and glucose solution are introduced into the production acid fermentation tank in substantially the same manner as described above. All components introduced into the fermenter are sterilized prior to introduction, so no antibiotics are required. Preferably, in the method of operation of Figure 2, the inoculum is applied to the Chinese national standard at a ratio of about 0.5% and about 7% -57- of this paper size ((^5丁八四规格(2]0'乂297 mm) (Please read the notes on the back and fill out this page)

1248443 The squad of the squad in the Ministry of Manchuria-T-Chan 贽 竹 社 印 印 A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A Between °C and about 37 °C, the pH is controlled between about 4.4 and about 6.5, preferably between about 5.3 and 5.5. If ammonia gas can be introduced, Ammonium hydroxide water>Liquid solution, aqueous alkali metal hydroxide solution, or orthophosphoric acid. As shown in Figure 1, the temperature is better adjusted to control the growth of the biological mass, so that the PMV does not exceed 55-60%. The initial glucose filling amount is preferably between about 1% and about 4% by weight, preferably 2.5% to 3.5% by weight, but it is better to reduce it to about 1.0% by weight in the fermentation. Count below. The supplemental glucose is periodically added at a ratio of about 0.2% and about 丨·〇, based on the total batch load, to maintain the glucose concentration in the fermentation zone at about 〇.1% and about 1.5 〇 / 〇 by weight, preferably between about 0.25% and about 0.5% by weight. Depending on the desired nitrogen and phosphorus source, it can be added together with glucose. However, since the entire load of the ketone is completed at the beginning of the batch cycle, the nutrient containing nitrogen and phosphorus, the necessary lacquer addition can be introduced at the same time, so that only the glucose solution is replenished in the middle of the reaction. The rate and nature of the agitation is significantly variable. Moderately vigorous mixing can promote the transfer of the mass between the solid substrate and the aqueous phase. However, low shear blades should be used to avoid degradation of microbial mycelial tissue. The optimum agitation rate varies from 200 to 800 Γρηι, depending on the viscosity of the broth of the culture broth, and the mixing conditions affected by the vessel, the conditioning plate and the vane structure. In general, a preferred agitation rate is in the range of 350-600 rpm. Better agitation of the vanes provides axial down pumping to aid in the good mixing of the fermented biota. Preferably, the batch is aerated at a rate of between about 0.3 and about 1.0 vvm, preferably from 0.4 to v8 vvm, and the pressure in the head space of the fermentation tank is preferably between about 0.5 and about L0 bar. Temperature, agitation, ventilation and anti-_____58- The paper size is applicable ^-- (please read the note on the back and fill in this page), 1Τ f 1248443 V. Invention description ( 56 A7 B7 sign better control In order to maintain the dissolved oxygen in the biotransformation in at least about ι〇% of the joint. The total batch cycle is usually between about (10) and about 1. Although,;,: Figure 2 to the operating principle is essentially the entire Kenry Early ketone loading: The introduction is correct. It should be understood that the growth of the mashed gravy can be carried out in the whole group of ketones. Some parts of the ketone can also be added later in the batch. In general, at least about 75% of the sterile ketones should be introduced into the transfer fermentation tank within 48 hours of the start of the fermentation. Furthermore, it is hoped that at least about 25% can be introduced at the beginning of the fermentation. The weight of the gram of ketone, or at least within 24 hours, to promote the production of biotransformation enzymes. * In a further preferred method as illustrated in Figure 3, the entire batch load and nutrient solution before the inoculum is introduced Sterilization in the production system _ container. The nutrient solution used, and the difference between them, | the above and Figure 2 The method is the same. In the specific example of the present invention, the shearing action of the '(4) wheel will disintegrate the agglomerate, which is easily formed under sterilization. It is found that if the average particle size of the Kennedy is less than about 300 Micro, and at least 75% by weight of the particles are less than 240 micron, then the reaction can proceed satisfactorily. Use suitable vanes, such as disc turbid wheel vanes, with a range of 200-800 degrees, at least about 400 The tip speed of sec/sec is found to provide a rate of cut that is sufficient to maintain the particle size characteristics, and it is estimated that agglomeration will occur easily in sterilization in the fermenter. The remainder of the operation of Figure 3 is basically The same is true of Figure 2. The methods of Figures 2 and 3 provide many advantages over the method of the drawing. A particular advantage is the use of low cost nutrients such as grain impregnation, but further advantages are understood to be necessary to eliminate antibiotics. , simplify the addition steps, and the -59- f paper scale applies to the Chinese National Standard (CNS) Λ 4 specifications (210X297 mm) (please read the notes on the back and then fill out this page) -= 口1 S- f Secondary standard position消贽合竹杉印象1248443 Μ ^__________ Β7 _ V. Description of invention (57) The carbaryl ketone or other formula XIII can be batch sterilized. Another special advantage is that a simple glucose solution can be used in the reaction cycle. Instead of a complex nutrient solution to supplement. In the method described in Figures 1 to 3, the product of formula VIII is a crystalline solid which can be separated from the reaction broth by filtration or separated by low speed centrifugation. The product can be extracted from the whole reaction broth by an organic solvent. The product of the formula VIII is recovered by solvent extraction. For maximum recovery, the liquid filtrate and the biological mass of the filtrate or the centrifuge block are treated with an extraction solvent, but usually the product is $ 95% combined with biological mass. Typically, hydrocarbons, esters, chlorinated hydrocarbons and ketone solvents can be used for the extraction. Ethyl acetate is preferred as the solvent. Other typical suitable solvents include toluene and methyl isobutyl ketone. For extraction from the liquid phase, it is convenient to use a solvent volume approximately the same as that of the reaction solution. In order to recover the product from the biological agglomerate, the former may be suspended in a solvent, preferably in an amount greater than the initial loading of the substrate, such as 5 to 100 ml of solvent to the initial loading per gram of ketone, and generated The suspension is preferably refluxed for about 20 to several hours to ensure that the product can be transferred from the pockets and pores of the biological mass to the solvent phase. Thereafter, the biological mass is removed by filtration or centrifugation, and the filter block is preferably washed with fresh solvent and deionized water. The aqueous and solvent washes are remixed and phase separated. The product of formula VIII is recovered from the solution by crystallization. To maximize yield, the mycelial tissue is contacted once with fresh solvent. After settling, the aqueous phase is completely separated and the product is recovered from the solvent phase. Preferably, the solvent is removed under hollowing until crystallization begins, after which the concentrated extract is cooled to about 〇 C to about 20 ° C, preferably about 1 Torr. To about 1 5 °C 'the time for the crystal to sink and grow, usually about $ to about 1 2 small•60- ® (cm) (210X 297^1 &quot;) --- (read the back first) Note: Please fill out this page)

, 1T f 1248443 A7 B7 by the Ministry of Consumers in the Huanzheng Bureau of Bei Er Xiao Qi He Zhushe f f, invention description (缒). The method of Figure 2, and especially Figure 3, is a particularly preferred method. These methods operate at low viscosities and are susceptible to tight control of process variables such as enthalpy, temperature and dissolved oxygen. Furthermore, the formula can be easily preserved without resorting to antibiotics. The biotransformation process is exothermic, so heat should be removed, using a packaged acid fermentation tank or a cooling coil in the fermentation tank. Alternatively, the reaction broth can be circulated via a heat exchanger on the outside. The dissolved oxygen is preferably maintained at a level of at least about 5%, preferably at least about 1% by volume, sufficient to provide the energy required for the reaction' and to ensure conversion of glucose to c〇2 and H2〇, which may be introduced via air. Rate regulation within the reaction tank to reflect the detection of oxygen potential in the gravy. Preferably, the pH is controlled between about 4.5 and about 6.5. In various different processes for the 11-hydroxylation of the formula XIII, the production force is limited to the transfer of solids to the agglomerates of the aqueous phase, or to the phase interface at which it is known to react. As noted above, the production force is not significantly limited by the mass transfer of the mass of the substrate, which is reduced to less than about 3 micrometers, and at least 75% of the particles are less than 240 micrometers by weight. . However, the production forces in these methods can be further enhanced in a number of specific examples, in which the ketones in an organic solvent or other equivalent formulas are filled into the fermentation tank. According to one option, the substance is dissolved in a water incompatible solvent and mixed with the aqueous growth medium inoculum and the surfactant. Useful water incompatible solvents include, for example, DMF, DMSO, (6-(: 12 fatty acids, CfCu n-alkanes, vegetable oils, sorbitans, and interfacially active aqueous solutions. This load can be stirred to produce an emulsion reaction system) , it has the extension of the boundary -61 - I paper size suitable for China mrnTCcm) A4*m (210x297^1) &quot;&quot; a c please read the back of the note before you fill out this page) 衣衣·订f 1248443 ^, Ministry of Standards and Regulations Bureau _ τ consumption Hezhu private printing wood A7 -------------- B7 1 _ — ------ V, invention description (59) The region allows the mass of the mass to be transferred from the organic liquid phase to the reaction site. First, the choice is to first dissolve the substrate in a water compatible solvent such as acetone, methyl ethyl ketone, methanol, ethanol, or glycerin, and its concentration will be substantially greater than its solubility in water. By preparing the initial shell solution at a higher temperature, the solubility can be increased by further increasing the double mass of the liquid mixture pattern introduced into the reaction tank, and finally, the load of the reaction tank can be enhanced. The warm shell/liquid mixture is filled into the fermentation tank together with the relatively cold aqueous material containing the growth medium and the inoculum. Precipitation of the substrate occurs when the substrate is mixed with an aqueous medium. However, under fairly supersaturated and moderately agitated conditions, the nucleation will exceed the growth of the crystal and will form extremely fine particles with a ruthenium surface area. The surface area of the crucible promotes the transfer of liquid and solid interstitial masses. However, in the presence of a water-compatible solvent, the equilibrium concentration of the acceptor in the aqueous liquid phase also increases, thereby promoting the productivity. While microorganisms are not necessarily resistant to high organic solvent concentrations in the aqueous phase, it may be beneficial to use, for example, from about 3% to about 5% by weight of ethanol. A third option is to dissolve the substrate in an aqueous cyclodextrin solution. It can be noted that I cyclodextrin includes hydroxypropyl-lu-cyclodextrin and methyl j-cyclodextrin. The molar concentration of the cyclodextrin may range from about 1:5 to about 1:15, preferably from about 1:8 to about 1:1. Substance: The cyclodextrin mixture can be further aseptically added to the biotransformation reaction tank. 11 I-hydroxynorrenone and other products of the 11 I hydroxylation process (formula VIII and vmA) are novel compounds which can be isolated by filtering the reaction medium and extracting the biological mass collected on the filter medium. Traditional organic solvents such as ethyl acetate, acetone, toluene, chlorinated hydrocarbons and methyl butyl ketone-------- clothing (please read the notes on the back and fill out this page) , 1Τ f • i- - I -1 - I i 1- I..... - - · -62- 1248443 A7 B7 60 V. INSTRUCTIONS (Similar to extraction. The product of formula VIII can be regenerated from the same The compound of the formula VIII is re-cracked. The compound of the formula VIII is prepared as an intermediate to prepare a compound of the formula I, and in particular has a comparable valence in the formula IA. Preferably, the compound of the formula VIII corresponds to the formula VIIIA, wherein -AA- and _BB - is -CH2-CH2-, R3 is hydrogen, low-carbon alkyl or low-carbon alkoxy, and R8 and R9 together form a 20-spirooxane ring: XXXI workers according to the method of Scheme 1, the compound of formula VIII in the base Reaction with a cyanide ion source to produce an enamine compound of formula VII (please read the back note before refilling this page)

VII

, 1T f M in the full part of the standard bureau, τ 贽 贽 竹 竹

Wherein -A-A-, -B-B-, R3, R8 and R9 are as defined above, wherein, in the formula VIIIA, the product is a phase of the formula VIIA

VII a 63- 1248443 A7 B7 Five invention descriptions 61 The Ministry of Economic Affairs and the Ministry of Standards and Regulations of the Ministry of Economic Affairs and the Ministry of Standards and Regulations II, --A-A-, -BB-, R3, γΐ&amp; γ2, and χ as defined in the formula χπΐΑ . Preferably, R3 is hydrogen. The cyanidation of the π -3⁄4 basal symmetry can be judged by its cyanide ion source, such as ketoximeonitrile, preferably acetone sterol, and the metal salt is present and tested, preferably Licl , the reaction proceeds. Alternatively, cyanidation can be achieved in the presence of an acid using an alkali metal cyanide under a typical alkanolonitrile. In the ketoxime method, the reaction is carried out in a solution, preferably using an aprotic polar solvent such as dimethylformamide or dimethyl sulfoxide. The formation of the enamine requires at least 2 moles of cyanide ion source per mole of carbon, and a slight excess of the cyanide source is preferred. The base is preferably a nitrogen-containing base such as a dialkylamine, a trialkylamine, an alkanolamine, pyridine or the like. However, an inorganic base such as an alkali metal carbonate or an alkali metal hydroxide can also be used. Preferably, the acceptor of the formula vm is first present in a ratio between about 20 and about 50% by weight, and is present in a ratio between _5 and 2 g i per equivalent of beryllium. The temperature of the reaction is not critical, but operation at higher temperatures enhances the production force. Therefore, when triethylamine is used as a base, the reaction can be advantageously carried out at a temperature of from about 80 °C to about 90 °C. At this temperature, the reaction can be carried out to completion in about 5 to about 20 hours. When diisopropylethylamine is used as a base and the reaction is carried out at 10 ° C, the reaction can be completed at 8 hours. At the end of the reaction period, the solvent is removed under a hollow, and the residual oil is dissolved in water, and neutralized to pH 7 with a dilute acid, preferably hydrochloric acid. The product precipitated from this solution, then washed with distilled water and air dried. The released HCN can be scrubbed with an inert gas and then quenched in an alkaline solution. The desired precipitate is absorbed in a gas or other suitable solvent and then extracted with a concentrated acid such as HCl. The extract is added to the machine test, and the father is good at checking the metal oxide, neutralizing to pH 7, and cooling -64 - ^ paper size is appropriate 7 (CNS) Λ 4 specifications (mm) clothing 1T--- ---- (Please read the back of the note before you fill out this page) 1248443

The precipitate formed by the range of the stalks is washed and dried, and then recrystallized from a suitable solvent, such as acetone, to produce a product of the formula VII, which is suitable for use in the method of the 淖 中 中 J J J J Social printing is complicated - steps. Alternatively, the reaction can be carried out in an aqueous solvent system containing a water-soluble organic solvent such as decyl alcohol or in a two-phase system containing water and an organic/exciting agent such as ethyl acetate. In this variant, the recovery of the product can be carried out by diluting the reaction solution with water, followed by extraction of the product with an organic solvent, such as methylene chloride or chloroform, followed by extraction from the organic extract with concentrated mineral acid, such as HCl. See U.S. Patent No. 3,200,113. According to a further variant, the reaction can be carried out in a water-compatible solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or monomethyl sulphate, after which the reaction product solution Dilute with water and make it acceptable, such as adding alkali metal carbonate, and then cooling to hydrazine. To the end. Oh, then let the product sink. Preferably, the system is quenched with an alkali metal hypoacid salt or other reagent which is effective in preventing cyanide spillage. After filtration and washing with water, the precipitated product is suitable for the next step in the process. According to still further variations, the enamine product of formula VII can be reacted with an excess of metal cyanide, preferably NaCN, in the presence of a proton source, in the presence of a proton source, which contains an aprotic water phase. A polar solvent such as dimethylformamide or dimethylacetamide. Proton source The fork is good mineral acid or C! - C 5 is acid, sulfuric acid is a good one. Exceptionally, when the cyanide reagent is a commercialized LiCN/DMF, no additional proton source is required. Source of cyanide ion, such as alkali metal salt, added to the reactor -65 - This paper scale applies to China's national standard ((, NS) Λ 4 specification (210X 297 mm) (Read the first note on the back) Please refill this page) f 1248443 A7 B7 Description of invention (63 is better between each equivalent of about 2.05 and about 5 moles of equivalent weight. The other proton sources of salty inorganic acid can promote HCN over 4, 5 and 6, 7 double bonds: force, and preferably in a molar ratio of at least molar molars per mole equivalent. However, the reaction system should be kept alkaline by maintaining a metal excess of the metal amide present. Preferably, it is carried out at a temperature of at least about 75, usually from 60 C to 100 C, for from about 1 to about 8 hours, preferably from about 15 to about 3 hours. At the end of the reaction period, the reaction mixture is cooled, preferably to about At room temperature, the product guanamine is precipitated by the acidification reaction mixture, and then mixed with cold water, and the acidification is close to the 17-lactone, which is commonly used in ammoniation. The chain is opened under alkaline conditions. The reaction mixture can be acidized with the same acid. The acid is present in the reaction, preferably the sulfuric acid water is preferably a novel compound of the formula VII at a ratio of about 10 and about 50 mole equivalents per mole of product, and In the middle of the preparation of the compound, there is a substantial price, especially in the formula IA. Preferably, the VII compound corresponds to the formula VIIA, wherein -AA- and -BB- are -CH2-CH2 R3 is hydrogen, low Carbosilane or lower alkoxy, and r8 and R9 together form a 2 〇 oxygen ring: Additive-spiral (please read the back note first, then fill out this page), 11 f Bureau member X consumption Hezhushe printed

〇II

XXXIII The preferred compound of formula VII is 5'R(5'α),7'-20'-aminohexadecyl-11,-trans-base-10' alpha,13' alpha-dimethyl-3',5 , Diketopyl snail [furan-2 (3 Η), 17, α -66- This paper scale applies to China National Standard Rate (CNS) Λ4 specification (210X 297 mm) 1248443 淖 中 中 消费 消费 消费 消费 消费 消费告竹社印繁

〇 A7 ____________ B7 V. INSTRUCTIONS (64) (5Ή)-[7,4] Methylene [4H]cyclopenta[a]phenanthrene-5,-carbonitrile. In the conversion of a compound of formula VIII to an enamine of formula VII, a 7-cyano derivative of a compound of formula VIII is observable via crude product chromatography. It has been hypothesized that 7-cyano compounds are intermediates in the conversion process. It is further hypothesized that the 7-cyano intermediate itself will react to form a second intermediate, a 5,7-dicyano derivative of the compound of formula VIII, which can be re-reacted to form an oxime ester. See, for example, 'R. Christiansen et al., The Reaction of Steroidal 4, 6-Dien-3-0nes With Cyanide, Steroids, Vol. 1, June 1963, which is incorporated herein by reference. These novel compounds are also useful in the use of chromatographic labels and synthetic intermediates. In a preferred embodiment of this step of the overall Scheme 1 synthesis method, these intermediates are 7 α-cyano-11 11 ,17-dihydroxy-3-keto-17 α-pregn-4-ene-21-dicarboxylic acid , r-lactone, and 5/?, 7-sodium-dicyano-11", 17-dihydroxy-3-keto-17-pregnane _21_ diacid, plant_lactone. The next step of the synthesis, the enamine hydrolysis of formula VII produces a diketone compound of formula

VI wherein -A-A-,, R3, R8&amp;R9 are as defined in the formula χιπ. Any ^-67- The paper size ϋί W towel Guanxu # ( Gs ) Λ 4 specifications (21GX297 public shame) ~------ -------------- Order --- ---^— (Please read the notes on the back and fill in this page) 1248443 A7 B7 65 V. Invention Description (Organic or inorganic acid aqueous solution can be used for hydrolysis. Hydrochloric acid is preferred. To strengthen production capacity, Preferably, a water-compatible organic solvent such as dimethylacetamide or a lower alkanol is used as a latent solvent. Preferably, dimethylacetamide is used as a solvent, and the ratio of the acid is present per equivalent of the formula. At least one equivalent. In an aqueous system, the enamine acceptor VII can be substantially converted into the same formula of the formula VI in about 5 hours and at about 80 ° C. Operating at higher temperatures can increase production. Force, but the temperature is not critical. Choose the right temperature based on the solvent system and the volatility of the acid.

Preferably, the indoleamine of formula VII is equivalent to the formula VIIA^-- (please read the notes on the back and fill out this page)

c-X

VIIA, 11 by the Ministry of the Ministry of the Ministry of the Ministry of Standards and Bureaus

And the diketone product is equivalent to the formula VIA

VIA This paper scale applies to China National Standard Rate (rNS) Λ4 Specification (210X 297 mm) 1248443 A7 B7 V. Invention Description (66 Where -AA-, -BB-, R3, γΐ and Υ2 and χ are each as χιΠΑ Preferably, R3 is hydrogen. At the end of the reaction, the solution is cooled to about 〇 to 25. 〇 to crystallize the product. The crystals of the product can be recrystallized from a suitable solvent, such as isopropanol or methanol, to produce a suitable method. The product of formula VI in the next step; however, recrystallization is generally not necessary. The product of formula VI is a novel compound which has a considerable valence in the middle of the preparation of the compound of formula I, especially the compound of formula I. The compound of formula VI corresponds to formula VIA wherein -A_A-, and -BB- are CHy, R3 is hydrogen, lower alkyl or lower alkoxy, and R8&amp;R9 together form a 20-spirooxane ring:

〇IJ

XXXIII (Please read the precautions on the back and then fill out this page j Λ衣. The book is destroyed by the Ministry of Justice, and the J-eco-cooperative is the best. The compound of formula VI is 4'S (4丨α), 7丨-hexadecahydro-1 - sulphate - hydroxy - 10 丨, 13' 々 - dimethyl - 3', 5, 2 〇丨 · triketo snail [furan_2 (3 Η), 17 'cold · [4 , 7] methylene [7Η]cyclopenta[a]phenanthrene-5, anthracene (2, anthracene)-nitrile. In a particularly preferred embodiment of the invention, the product enamine of formula VII is produced from a compound of formula VIII, in a manner As described above, and converted in situ to the diketone of formula VI. In this embodiment of the invention, the formula νπι is reacted with an excess of the alkali metal cyanide in an aqueous solvent containing a proton source, or as needed The sterol nitrile in the presence of a base and Licl, as described above. However, if the reaction mixture is not cooled, acidified, and water is added in portions to cause precipitation of the enamine, it is better to avoid the substantial Cooling. Water and acid, compared with -69 paper size 4; species _:;f(10)(CNS) A4^m (210X297^* 1248443 ΑΊ ___Β7 5, invention description (67)-'~~ One~~- good is no An acid such as sulfuric acid may be added to the mixture at the end of the cyanidation reaction. The proportion of the added beer is sufficient to neutralize the excess alkali metal cyanide, and usually an acid of at least i molar concentration is introduced per type of VIII acceptor. Preferably, each amount is between about 2 and about 5 mole equivalents. However, the temperature is maintained high enough: and the dilution is sufficient to avoid considerable precipitation, and the hydrolysis of the enamine to the diketone can be in the liquid phase. Therefore, the process can be carried out under the least interference and high productivity. The hydrolysis is preferably carried out at a temperature of at least 8 Torr, preferably from about 90 C to about 1 Torr. It is preferably from about 2 to about 5 hours, preferably from about 2 to about 5 hours. The reaction mixture is then cooled, preferably between about 1 and about 5 C. 'Beneficially in an ice bath from about $ to about 1 Torr, it can sink. The product of the formula VI is a ketone. The solid product can be recovered, such as by filtration, and the impurities are reduced by washing with water. In the next step of the synthesis of Scheme 1, the diketone compound of formula VI is reacted with a metal alkoxide via a carbonyl group and The ketone bridge between the 4 and 7 positions is opened by the dissociation of the 4 _ carbon bond 7 in position "- the azimuth alkoxycarbonyl substituent, and erasing 5 -. On the cyanide carbon is equivalent to the product of this reaction the hydroxy ester compound of formula V

Where -A_A-, -B_B_,, R8&amp;R9 are as defined in the formula χιπ, and 1 is -70- The paper size is _ (CNS) Λ4 size (210 X 297 mm) clothing -- (阅读Read the notes on the back and fill out this page.) Ding-&quot; f 淖 中 中 员工 员工 员工 Employees Employees Zhu Zhushe f f 1248443 A7 B7 Five inventions description ( 68 lower alkoxycarbonyl or hydroxycarbonyl. The metal alkoxide in the reaction corresponds to the formula r1gom, wherein ]V[is an alkali metal, and the r1Gcm is an alkoxy substituent of the group. When the metal alkoxide is potassium methoxide or sodium methoxide, the reaction The yield is most satisfactory, but other lower alkoxides can also be used. Potassium alkoxide is particularly preferred. Phenol salts, other aromatic oxides, and aryl sulfides can also be used. The reaction can be present in the alcohol. It is conveniently carried out, that is, an alcohol equivalent to the formula R 0M, wherein R 10 is as defined above. Other conventional solvents can also be used. The carrier is good at about 2% and about 2% by weight. The proportion is calculated, preferably at least about 6% by weight. Preferably, Rl〇〇M is about 〇5 and, 'spoon 4 moles (per Mo The ratio between the mass spectrometers exists, preferably between about! and about 2 moles, and more preferably about 1.6 moles per mole. The temperature is not harsh, but the temperature is lower than the temperature. The production time can be increased. The reaction time is usually about 4 and 'force 24 hours, preferably 疋 4 to 16 hours. Conveniently, the reaction is carried out at atmospheric reflux temperature depending on the solvent used. The time required is affected by the addition of alkoxide to the alkoxide in the reaction mixture, and the manner in which the alkoxide is added. Alkoxide: added in one portion or in multiple additions, or continuously added. When adding multiple times, it is better to about 1-6 equivalents of potassium methoxide in two steps plus the staff of the Ministry of Standards and Bureau of the Ministry of Standards and the Department of Consumers of the Department of Health and the Department of Health (the first reading of the back of the note and then fill out this page) In the two-step addition, the equivalent amount of potassium methoxide is first added to the reaction mixture, and then 6 equivalents of potassium methoxide is added in 90 minutes. The addition of the two steps can shorten the time required to reach equilibrium, compared with Adding 6.6 equivalents of potassium methoxide in a single time. It is more beneficial to produce hydroxy esters at low concentrations of diketones. The reaction is better at higher dilution ratios, such as up to 4 〇:1 for use with steel sheets - 71 paper metrics 5ii? 7CNSM4 size 1244843 V. Description of the invention (69 A7 B7 It is found that the use of potassium methoxide instead of sodium sulphide should be known to the force of the people's ^, because the dilution factor in the range of about 1 usually makes the reverse cyanide The degree of chemistry is minimized, wherein potassium methoxide is tested according to the invention, and the chemical or physical method of self-reaction is carried out in the fourth step; the removal of by-product cyanide ions in the belt can inhibit the reverse cyanidation reaction. . Thus, in a further embodiment of the present invention, the diketo oxime metal alkoxide reaction can be carried out in the presence of a cyanide ion precipitating agent such as σ to form a salt of the non-cyanide compound. Such salts include, for example, zinc iodide, iron sulphate, or any sulphate or other salt of substantially soil or transition metal which is more soluble than cyanide of phase #. If the proportion of Qihua is within one equivalent of each equivalent of diketone, the yield of the reaction can be observed compared to the process without alkali metallization; the texture is increased. Even if the cyanide ion is removed by using a precipitating agent, it is still preferable to carry out the reaction at a relatively high dilution ratio, but the molar concentration ratio of the diketone solvent in the use of the precipitant is compared with that in the absence of the agent. The former can be significantly reduced. The recovery of the hydroxy ester of the formula V can be carried out according to either the extraction or non-extraction step described below. ^ The hydroxy ester can also be removed from the reaction mixture after the synthesis by controlling the equilibrium of the reaction. Removal by the base ester can be carried out stepwise or continuously by a method such as filtration. Removal of the hydroxyester can be used to control the equilibrium, either separately or in combination with the chemical or physical removal of cyanide from the reaction mixture. The heating of the resulting filtrate can drive the reaction balance. 72 The paper size is applicable to the Chinese National Standard ((NS) Λ4 specification (210Χ 297 mm, please kj read the back note and fill in the page. _T消贽合作社印 f 1248443 A7 B7 V. Description of the invention (70 copies of the standard dioxin consumption co-operatives have left the conversion of the VI diketone to the hydroxy ester of the formula V. The conversion of the diketone of the formula VI to the formula V In the ester, a small amount of 5-cyanohydroxy ester is visible in the crude product, usually less than about 5% by weight. It is hypothesized that the 5-cyanohydroxy ester is between the formula II ketone and the formula hydroxy ester. A balanced intermediate. Further hypothesis states that this equilibrium intermediate is formed from a diketone, protonated at the 5,7-keto and enoate via a methoxide, and from a by-product from a benzyl ester. The cyanide ion is added to the 3-keto-indenyl 4,5 functional group of the hydroxy ester. In addition, the 5-cyano-7-acid and the 17-alkoxide of the hydroxy ester of the formula V can be chromatographed via crude product. Observed. There is a hypothesis that 5 _ cyano hydroxy ester intermediates Reacts with by-product cyanide ions (existed as a result of de-cyanation, which is introduced into the ruthenium 4,5 double bond) to produce 5-cyano-7-acid. It is hypothesized that the action of cyanide ions can be dealkylated. 5 _ cyano hydroxy ester 7 _ ester group, resulting in 5-cyano-7-acid and equivalent alkyl nitrile. Further hypothesis indicates that the transition intermediate 17_alkoxide acts on the per-ester by methoxide The 17-spirolactone is formed (or the intermediate described above can be converted to each base). The 17-alkoxide, once treated with an acid, can be readily converted to a hydroxy ester. Thereafter, it is typically not found in the product matrix. 5-Cyanosyl ester, 5-cyano-7-acid, and 17-alkoxide are novel compounds which can be used as chromatographic labels and serve as intermediates in the preparation of hydroxyesters. This step is isolated from the crude product synthesized in Scheme 1. Alternatively, it can be directly synthesized for use as a label or intermediate. 5 _Cyanohydroxy ester can be separated from the diketone solution of formula VI with a base such as an alkane. An oxide or an amine, which is synthesized by reaction, and then the precipitate formed is separated. The prepared paper ruler is prepared. Degree_巾_(四)神---------^^衣—(Please read the notes on the back and fill out this page), 11 f -73- [248443 A7 B7 V. Inventions 71 Good Is -cyano-11 α-17-dihydroxy-3-keto-17 α-pregnane-7π,21_dicarboxylic acid 7-methyl ester, lactone. 5-cyano-7-rebel acid can be obtained by formula VI The diketone is directly synthesized by reacting with a weak aqueous solution such as sodium acetate or sodium hydrogencarbonate, and the resulting precipitate is separated. The compound prepared is preferably 5-lu-cyano-11α, 17-dihydroxy- 3-keto-17-pregnane _7 α, 2 di dicarboxylic acid, r - lactone. The 17-alkoxide can be directly synthesized from a solution of a hydroxy ester of the formula V with an alkoxide to form a mixture of 17-alkoxide and equivalent hydroxyester. The compound to be prepared is preferably 11α,17-diriyl-fluorenyl-17 α-pregnane-4-zil-7 α,21-dicarboxylic acid dimethyl ester, plant-lactone.

Preferably, the ketone of formula VI is equivalent to the formula VIA (please read the notes on the back and fill out this page)

The Ministry of Economic Affairs and the Ministry of Standards

And the hydroxyester product corresponds to the formula V A

VIA

VA This paper scale applies to China's national standard net (rNS) from the specification (210Χ297 mm). The Department of Standards and Regulations of the Ministry of Economic Affairs - Gongxiao Yihe Private Print f 1248443 - A7 — .. — . 7 V. Description of invention (72 ) — — ~ a — — where _AA· ' , R 3 , γ ΐ and Υ 2 and X are each defined as in the formula ′ and R, 1 is as defined in the formula V. Preferably, R3 is hydrogen. The product of formula V is a novel compound which has a substantial valence in the preparation of the hydrazine compound, especially on the formula. Preferably, the compound of the formula ν corresponds to the formula VA 'where _Α_Α_ and each 『Ch2-CH2_, R3 is hydrogen, a lower alkoxy group or a lower alkoxy group, and R8 and R9 together form a 2〇-spirooxane Alkane ring:

Preferably, the compound of formula V is ιΐα, ΐ7α-dimethyl-3-S with pregnancy-4-晞_7α, 21-di-light acid, and lactone. The compound of the formula V can be isolated by filtration or acidification of the reaction solution, for example, by using an inorganic acid such as HCl or sulfuric acid, cooling to ambient temperature, and extracting the product, such as dichloromethane or ethyl acetate, with an organic solvent. The extract was washed with an aqueous alkaline washing solution, dried and filtered, and then the solvent was removed. Further, the reaction solution containing the product of the formula V is further quenched with a concentrated acid. The product solution was concentrated and cooled to about hydrazine. Between 25 ° C and product solids were isolated by filtration. In a preferred embodiment, methanol and HCN are removed by distillation after summing up the reaction period. A mineral acid such as hydrochloric acid or sulfuric acid is added prior to distillation and water is added. The mineral acid is added in a single step or added multiple times or continuously. In a preferred embodiment, the mineral acid is continuously added over a period of from about 10 to about 40 minutes, preferably from about 15 to about 30 minutes. Alternatively, the water can be added to the stationary bottom multiple times or continuously in a single step. In the preferred embodiment, the Chinese National Standard (rNS) Λ4 specification (210X297 mm) is applied to the water-75-sheet scale. ------IT------^- (Read first Precautions on the back side Fill in this page} ^淖部中决标准局员二消贽合竹社印来1248443 A7 •~________Β7 V. Invention description (73) Yes, the concentrated reaction mixture is cooled from the reflux temperature. The mixture is cooled to a temperature of from about 5,0 ° C to about 7 Ο X: preferably from about 6 〇t to about 7 Torr, more preferably about 65 ° C, and water is added. The period is from about 5 minutes to about 3 hours, and preferably from about 6 minutes to about 9 minutes, while the temperature is maintained at about a fixed temperature. When the water continues to be added, the product of formula V can be crystallized from the standstill and once crystallized. After addition to the mixture, the diluted reaction mixture is maintained at about the same temperature for about 1 hour and then cooled to about 1 5 for about 4 to about 5 hours. The mixture is maintained at about 1 5 X: 2 hours. Maintaining a long time at 15 C can increase the yield of cyano ester in the mixture. This recovery mode can be used without extraction. High quality crystalline product is provided under operation. According to another preferred recovery mode of the product of formula V, after the reaction period is summarized, methanol and HCN are removed by distillation, and water and acid are added before or during distillation. Water may be added before distillation. Simplify the operation, but gradually add it in the distillation to keep the volume of the stationary state substantially fixed. When the distillation is carried out, the product of the formula V can be crystallized out from the static state. This recovery mode can be used in the absence of extraction operation. Crystalline product of quality. According to a further variation, the reaction solution containing the product of formula V can be quenched by acid, such as HCl, after which the solvent is removed by distillation. The residual HCN can also be removed from the reaction product. Solvent removal. It has been found that it is necessary to extract and purify the compound of formula V by multiple solvent extraction, wherein the compound of formula V is used as an intermediate in the preparation of epoxigenone, as described above. In fact, this extraction can often be completely omitted. The product is purified by solvent extraction, and it is desirable to wash the solvent with the salt water and the alkaline lotion. However, when the extraction of the solvent is omitted, the brine and the alkaline lotion are also omitted. Slight extraction and lotion can be significantly increased _ _ 76 _ only see the grid (210X297 Gongqiao - -- ---------------1T------Φ - (Read first Note on the back side of this page) 1248443 By the Ministry of the Ministry of Defense, the standard of the Bureau of the Department of X, Xingzhu, the impression of the company, 7 Β 7 5, invention description (74) Forced production capacity, without sacrificing yield or product quality, It is also possible to dispense with the need for a desiccant, such as sodium sulphate, to dry the wash. The crude 11 I hydroxy-7 I alkoxycarbonyl product is again absorbed in a solvent and used in a reaction step below the process, which converts the U-hydroxy group into &quot;The leaving of the position, by the production of the compound of formula IV:

Wherein -AA- ' R3 ' -BB-, R8 and R9 are as defined in the formula R, Ri is as defined in the formula V, and R 2 is a lower aryl aryloxy group, which is alkoxy, oxime Base or halide. Preferably, 11 is esterified from a -hydroxy group by reaction with a lower alkylsulfonium halide, a mercapto halide or an anhydride, which is added to a solution containing the intermediate product of formula V. Lower grade acid fibers such as vinegar liver and tris-acid fiber, such as trifluoroacetic acid, can be used to prepare suitable decyloxy leaving groups. It is preferred to use a lower alkyl sulfonium sulfonate. Alternatively, the 1 1 α _ group can be converted to a halide, i.e., via a suitable reagent such as sulfinyl bromide, sulfilifolium based gas, thioindole based gas or grass turmeric gas. Other reagents which form the 1 1 ^ -sulfonate include toluenesulfonium chloride, benzenesulfonate and trifluoromethanesulfonic anhydride. The reaction is carried out in a solvent containing a hydrogen halide scavenger such as triethylamine or pyridine. It is also possible to use an inorganic base such as potassium carbonate or sodium carbonate. The initial concentration of the hydroxyester of the formula V is preferably between about 5% and about 50% by weight. The esterification agent is preferably present in a slight excess. -77, Paper scale applies to China National Standard (CNS) M specification (210χ297 mm) --------------IT------ (Please read the notes on the back first) Fill in this page) 1248443 A7

B7 V. Inventive Note (75) A solvent which is particularly suitable for the reaction of methylene chloride, but other solvents such as di-ethane, pyridine, chloroform, 'methyl ethyl ketone', dimethyl sulfonate, methyl Butyl ketone, acetone, other ketones, esters, acetonitrile, toluene and tetrahydrofuran. The reaction temperature is mainly controlled by the volatility of the solvent. When methylene chloride is used, the reaction temperature is preferably between about -1 〇 ° C and about 10 °. Preferably, the hydroxyester of formula V is equivalent to the formula v A

And the product is equivalent to Formula IVA

IVA ---------0^ ! (Read the first note on the back and then fill out this page) Book I f The Ministry of Justice and the Ministry of Justice SX Consumer Co., Ltd. Printed in it -Α·Α-, -BB-,3,γΐ,γ2 and χ are each as defined in the formula χπΐΑ, R1 is lower alkoxycarbonyl or hydroxycarbonyl, and R2 is as defined in formula IV. Preferably, R3 is hydrogen. The product of formula I V is a novel compound which has a substantial valence in the middle of the preparation of the compound of formula I, and especially the preparation of formula I. Preferably, the formula IVa-78- the paper size is _: material (rNS) ^^ΤΤΪ0Χ 297 mm) 1248443 kl B7 five invention description (76 compound is equivalent to the formula VA, where _Α_Α· and r: is hydrogen , a carbon or alkyl alkoxy group, and ... and 乂9 together constitute a 2 〇 _ _ _ _ _ _

0II

XXXIII 淖 中 中 中 τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ 最好 最好 最好 最好 最好, 21-dicarboxylate, r-lactone. When a methoxyoxypeptidyl group is desired, the compound of formula IV is preferably 17-hydroxy-3-yl-keto-Ua_(2,2,2-j fluoro-1-ketoethoxy)_17α-pregn-4-ene-7-α , 21_dicarboxylic acid 7-methyl ester ', '-lactone; or 11α-(ethyloxy)_17-hydroxy-3-enketone-17"_pregnant_4_ene_α,21- Resin acid 7-methyl sputum, corpse - internal purpose. If desired, the formula IV chemical can be separated by solvent removal. Better and should be washed first with water washing solution, such as 〇·5- 2Ν Na〇H, followed by pickling, such as 0.5-2N HC1. After removing the reaction solvent, the product crystallizes, such as dimer methane absorption product, and another solvent such as diethyl ether, which can reduce the solubility of #IV product. To precipitate in a crystalline form. In the recovery of the product of formula iv, or to prepare a reaction solution to convert the intermediate of formula Iv to the intermediate of formula 11, as described further below, all extraction knives/wash steps are exempt When the solution is replaced by an ion exchange resin to remove acid and basic impurities, the solution is first treated with an anion exchange resin and then treated with a cation exchange resin. In addition, the reaction solution can be thought first Treatment with an adsorbent such as basic alumina or basic silica, then washed with dilute acid. This -79- LAI paper size / species _ braking rotation (mm (Read precautions and then fill the back side of this page)

1 248443 V. INSTRUCTIONS (77 A7 B7 alkaline vermiculite or alkaline alumina is usually mixed with the reaction solution in a ratio of between about 5 and about 50 grams per kilogram of product, preferably between about 15 and about 2 grams. The ion exchange resin or the inorganic adsorbent is used, and the treatment can be carried out by simply removing the resin or inorganic adsorbent at ambient temperature and stirring to remove the resin or inorganic adsorbent by filtration. In another and more preferred embodiment of the present invention, the product of the formula IV is removed and the main solution is recovered; the concentrated solution is recovered in a crude form. The concentrated solution can be directly used in the following steps of the process, which removes u ^ The base is removed from the compound of formula Iv, which is the ester of formula jj: -- (Read the first note on the back and fill out this page)

II 订 中 中 消费 消费 消费 消费 消费 其中 其中 其中 其中 其中 其中 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - For the purposes of this reaction, the R2 substituent of the compound of formula IV can be any leaving group which is effective for the production of double bonds between 9- and 1-carbon. Preferably, the leaving group is a lower sulfomethoxy or decyl substituent which is removed by reaction with an acid and an alkali metal salt. A mineral acid can be used, but a low-sulphur acid is preferred. Advantageously, the reagent in the reaction further comprises an alkanoic acid metal salt. It is particularly preferred that the leaving group contains a continuous oxygen and the reaction contains formic acid or acetic acid and an alkali metal salt of these acids or another lower alkanoic acid. When the thiol group is removed and the reagent is removed, the reagent is acetic acid and sodium acetate or formic acid and formic acid 80-4, and the ''zamp scale field is used in the Chinese national standard rate ((, NS) Λ specification (2 public 1244843) A7

, 刈 刈 刈 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 If there is free water in the removal of the leaving group, the quality, such as specifically refers to 7,9-lactone. Y into j

--------— (Please read the note on the back and fill out this page again) q,,,,,1 is used to remove water in formic acid. Therefore, the free energy in the reaction mixture before the reaction should be maintained. At less than about 0.5%, preferably about %1% by weight, this Fischer is determined by analysis of water, based on the total reaction solution. Although the mixture is dried as far as practicable, it should be understood that 〇·3 % by weight of water, with satisfactory results. Preferably, the reaction load mixture contains 纟4% and about 50% by weight of the formula Ιν is in the alkanoic acid. 〇/〇 and about 20% by weight of the alkali metal salt of the acid. When adjusted with acetic anhydride, its proportion is better than about 5 moles per mole of acid and about 2 moles It has been found that the by-product 7, lactone and 彳n, l2• chain oxime in the reaction mixture is quite low, wherein the elimination reagent contains a combination of trifluoroacetic acid, trifluoroacetic anhydride and potassium acetate, and the reagent can be The leaving group is eliminated and an enester (9, alkene) is formed.

•I I - 1 1 I- I I I · I 'δι- 1248443 A7

Please read the note and fill out this page.

1248443 A7 B7 V. DESCRIPTION OF THE INVENTION (Although impurities are not observed in the crude product solution, the ketone of the hydroxyester of the formula V is prepared by oxidation of the η-hydroxyl group of the corresponding hydroxy ester with a suitable oxidizing agent such as Jones reagent. The 11-ketone prepared is preferably 17-hydroxy-3,11-dione- 17 α-pregn-4-ene-7 α,21-dicarboxylic acid 7·methyl ester, lactone. The 11-mer of the compound of the formula IV can be used to remove the olefinic vinegar of the production worker, which can be heated by a solution of the formula IV in an organic solvent such as DMSO, DMF or DMA. Further according to the invention, the formula IV The compound can be reacted first with an alkenyl alkanoate such as isopropenyl acetate in the presence of an acid such as toluenesulfonic acid or an anhydrous mineral acid such as sulfuric acid to form a 3- oxime ester of the compound of formula IV: (please read the back first) Note on this page)

IV(Z) it MM·Ministry of the Ministry of Health and Industry, the consumption of the employees of the company. In addition, the 3-enol ester can be formed by treating the compound of the formula i v with an acid anhydride and a base such as acetic anhydride and sodium acetate. Further variations include the treatment of a compound of formula IV with an anthrone in the presence of an acid to yield a compound of formula IV. The intermediate of formula IV (Z) is then reacted with an alkali metal formate or acetate in the presence of formic acid or acetic acid to produce a Δ9,10 enol acetate of formula IV (Y): -83- This paper scale applies to China Standard rate (C, NS) Λ 4 specifications (210X297 public Chu) 1248443 A7 V. Invention description ( 81

IV(Y) It can be converted into an π-enyl ester in an organic solvent, preferably an alcohol such as methanol, i.e., thermal decomposition of the enol acetate, or its reaction with an alkali metal alkoxide. = The dereaction is highly selective for the ester of formula II, more than nu-alkenes and 7,9-lactone, and this selectivity is preserved in the conversion of sterol acetate to the ketene. Preferably, the quality of the formula IV is equivalent to the formula IVA (please read the notes on the back and then fill out this page) #订

In the IVA f department, the ruling party member τ, the consumer 竹竹社印来

And the ester product corresponds to Formula IIA

CCH2d; .Ux

IIA -84 - This paper scale applies to China's national standard ((, NS) Λ 4 specifications (210X 297 mm). The Ministry of Economic Affairs, Ministry of Finance and Industry, J-Consumer, Zhu Zhushe, printed 1244843 A7 ~___________________ B7 V. Description of invention (82)&quot;&quot;~~' &quot; ~1~-- f in H,·Β-β-, R3, Y1 and Y2 and X are each as defined in the formula XIIIA, and R1 is as defined in the formula V Preferably, R3 is hydrogen. If the celebrity seeks, the compound of formula 11 can be isolated by removal of the solvent, the solid product is absorbed in cold water, and then extracted with an organic solvent such as ethyl acetate. After a palatable washing and drying step Thereafter, the product is recovered by removal of the extraction solvent. The wine is redissolved in a solvent suitable for conversion to the product of formula I. Alternatively, the separation of the vinegar can be carried out by adding water to the concentrated product solution, and then filtering the solid product. The 7,9-lactone is removed. The conversion of the product of the formula π to the formula -8 can be carried out in the manner described in U.S. Patent No. 4,559,332, which is incorporated herein by reference in its entirety, or preferably Novel reaction of indoleamine promoter. In another embodiment of the invention, The hydroxy ester of V can be converted to the olefinic vinegar of the formula 11 without separating the intermediate of the formula IV. In this method, the hydrazine vinegar is absorbed by an organic solvent, such as dichloromethane; and a hydrating agent is added to the solution, such as Methane sulfonium chloride, or a reagent such as sulfonium chloride. The mixture is agitated, and when halogenation is involved, an HC1 eliminator such as imidazole may be added. This reaction is highly exothermic and should therefore be controlled under complete cooling. The rate is carried out. Once the test is added, the resulting mixture is warmed to a moderate temperature, such as about 〇. 〇 to the chamber 'or slightly 冋' and then reacted for about 1 to about 4 hours. Once the reaction is complete, the solvent is vaporized, preferably. Under high hollow conditions (eg 24, 'to 28, mercury), about -1 ° ° C to about +15 ° C, preferably about 0 ° to about 5 ° C, to concentrate the solution and remove excess The base is redissolved in an organic solvent, preferably a solvent such as a gas to be converted into an enester. The preparation of the leaving group elimination reagent is preferably an organic acid, an organic acid salt and a dry- 85- $ Paper Scale China National Standard (CNS) A4ft^ ( 210X 297^1 ) ' --- ---------3⁄4II (Read first on the back) Please fill out this page again)

, 1T f 1248443 A7 _______B7 V. Description of the invention (骀) ^ Desiccant, preferably formic acid, alkali metal formate and acetic anhydride, mixed in a dry reaction. The addition of vinegar liver is exothermic and will cause the release of C ,, so the rate of addition should be controlled. To promote the removal of water, the temperature of this reaction is preferably maintained at about 6 Torr. Up to about 90 ° C, preferably about 6 5 . Up to about 7 5 °C. This reagent is then added to the product solution of the compound of formula IV to effect elimination. After about 4 to about 8 hours, the reaction is preferably heated to a temperature of at least about 85 ° C, but preferably no more than about 95 ° C until all volatile sites are removed and then the reaction is complete for a period of time, usually About 1 to about 4 hours. The reaction mixture is cooled&apos; and after recovery by standard extraction techniques, the oxime ester can be recovered as desired by evaporation of the solvent. It has further been found that the enester of formula 11 can be recovered from the reaction solution by another method; it does not require an extraction step after the elimination reaction, thereby saving cost, improving yield and/or increasing productivity. In this process, the oxime ester product was precipitated by diluting the reaction mixture with water after removal of the product. The product was then separated by filtration. No extraction is required. According to a further variant of the conversion of the hydroxy ester of the formula V to the hydrazine of the formula II without the need to isolate the compound of formula IV, the hydroxyl group of the hydroxy ester of the formula V is replaced by hydrazine and the olefinic ester of the formula 11 is thermally dehydrogenated in situ. Formed by the action. The replacement of the hydroxyl group can be achieved by reaction with thiopurine, preferably thiopurine, in the presence of a cold in the presence of a hydrogen halide scavenger, such as imidazole. The hydroxy ester is dissolved in a solvent such as tetrahydrofuran and cooled to about 0 to about -7 Torr. The sulfonium halide is added and the reaction mixture is warmed to a moderate temperature, such as room temperature, for a period of time sufficient to complete the elimination reaction, usually from about 1 to about 4 hours. The process of this specific example not only combines the two steps into one, but also omits the following use: self-chemical reaction -86- The paper scale applies to the Chinese National Standard Rate (CNS) Μ specification (21〇&gt;&lt;297 public) - ----------- (Please read the notes on the back and fill out this page)

, 1T f 1248443 A7 — B7 V. Description of the invention (铋) —~' ------- ‘Valley, acid (for example, acetic acid); and desiccant (such as acetic anhydride or sodium sulfate). In addition, the conditions are reversed and the by-product C 〇 is avoided, which is the result of using acetic acid as a desiccant. J-Chan 贽 贽 Μ Μ ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ----

• I, according to the specific example of this &amp; Ming Tejia, the diketone compound of the formula v can be converted into the epoxy group of the formula I or other compounds without separating the purification of the t-form. . According to this preferred process, the reaction solution containing the base vinegar is quenched with a strong acid solution, cooled to ambient temperature, and extracted with a suitable extractant. Advantageously, an inorganic brine solution, such as about 10% by weight aqueous salt solution, is added to the reaction mixture prior to extraction. The extract was washed and dried by azeotropic distillation to remove the ketone to remove the methanol solvent remaining in the reaction. And the resulting concentrated liquid containing about 5% and about 50% by weight of the compound of formula V, and then contacted with a deuterated or alkylsulfonating agent in a cold to form a sulfonic acid or dicarboxylic acid. Acid ester. After the alkyl sulfonation or carboxylation reaction is complete; the reaction solution is passed through an acid and subsequent alkaline exchange resin column to remove basic and acidic impurities. After each passage, the column is washed with a suitable solvent, such as dichloromethane, to recover residual sulfonic acid or dicarboxylate therefrom. The mixed falling liquid and the washing stream are mixed and reduced, preferably under a hollow, to produce a concentrated solution containing the sulfonate or dicarboxylic acid ester of formula IV. The concentrated solution is then contacted with a drying reagent which contains a substrate which removes the nucleus ester leaving group and eliminates hydrogen to form a 9,11 double bond. Preferably, the reagent for removing the leaving group comprises the above formic acid/alkali metal formate/acetic anhydride drying reagent solution. Once the reaction is complete, the reaction mixture is allowed to cool and then moved down to remove the formic acid and/or other volatile components. The residue is cooled to ambient temperature and subjected to a suitable wash step %' to dry to yield a concentrated solution containing the formula 11®. This Agreement is intended to be used in China's national standard ((, NS ) Λ 4 specifications (210X297^) - ------- -. 1248443 A7 B7 85 V. Description of invention (8 The method described, or the method of U.S. Patent No. 4,559,332, is incorporated into an epoxy meclorone or other compound of formula I. In a particularly preferred embodiment of the invention, the solvent is removed from the reaction solution under a hollowing, and the product of formula IV It is partitioned between water and a suitable organic solvent such as ethyl acetate. The aqueous layer is then extracted back with an organic solvent, and the extract is washed with an alkali solution, preferably an alkali metal solution containing an alkali metal dentate. Concentration, preferably under venting, produces a product of the formula 再, which is then taken up in an organic solvent, such as dichloromethane, and further reacted as described in the F3 32 patent to produce the product of formula I. When tri- 13⁄4 acetonitrile When used in the epoxidation reaction, it is found that the choice of solvent is very important, and the solvent is preferred, and methylene chloride is preferred. Solvents such as dichloroethane and chlorobenzene can obtain a reasonably satisfactory yield. However, the yield is more preferably in the dichloromethane reaction medium. Solvents such as acetonitrile and ethyl acetate generally have poor &lt;yield yields, while reactions in solvents such as methanol or water/tetrahydrofuran have few desirable products. ~a Further according to the present invention, it has been found that triacetamide is used. Non-tri-acetonitrile is an epoxide activator for epoxidation, and it should be understood that there are many improvements in the synthesis of epoxigen. According to a particularly preferred process, epoxidation proceeds with the treatment of formula IIA with hydrogen peroxide. Preferably, the reaction is carried out in the presence of trisamplylamine and a suitable buffering material. Preferably, the reaction is carried out at a pH ranging from about 3 to about 7, more preferably from about 5 to about 7. However, it is preferred that these considerations are preferred. There is still a successful reaction outside the range of ^^. It contains a buffer solvent containing dipotassium hydrogen phosphate and/or contains potassium dihydrogen phosphate and potassium dihydrogen phosphate in a relative ratio of about 1:4 and about 2:1. Good about 2:3 range _ -88- this 297 mm]-------- --------- clothing - (please read the notes on the back and fill out this page), 11 f 1248443 A7 V. Description of the invention (86 - liquid % Han 'V < results. Borate buffer can also be used", but conversion is usually slower In the case of a mixture of bis(2,4,2,2, kh2p〇4), the combination of the pH of the combination and the pH of the above range is shown in the above range. Or a buffer solution which can be transmitted to at least the right portion of the buffer solution is composed of a test core (four), which is more efficiently used as a catalyst for the homogenization of the ion, and is involved in the accelerator containing the accelerator. In the formation of an ion "adduct or complex, its production is then necessary for the whole epoxidation reaction mechanism. Therefore, the quantitative requirement for the two-test scalar salt (preferably from a Κ2ΗΡ〇4) It may be only a low catalytic concentration f. Typically, the tongue, κ 2 ΗΡ〇 4 is preferably present in a ratio of at least about 1 equivalent, such as between about 0.1 and about 0.3 equivalents per equivalent of the substrate. The reaction is carried out in a suitable solvent, preferably methylene chloride, but other self-chemical solvents such as chlorobenzene or dichloroethene may also be used. Toluene and mixtures of toluene and acetonitrile were also found to have satisfactory results. Without being bound to a particular theory, it is hypothesized that the reaction is most efficient in the two (four) wipes, where the hydroperoxide intermediate is formed and distributed to the low water organic phase and can be combined with the organic phase. Receptive reaction. Therefore, the preferred solvent is low in water. Another solvent, such as acetonitrile, promotes efficient recovery from toluene. In the conversion of Formula II to the product of Formula I, toluene provides the advantage of the process because the substrate can be freely dissolved in toluene without product. Thus, in the reaction, when the conversion reaches a range of 40-50%, the product can be precipitated, and a three-phase mixture is produced, whereby the product can be conveniently separated by filtration. In the horse of the reserve site, the paper size is 1Ι/1Ϊ®_: material (rNS) 21GX 297

1248443

λ I Μ Μ 屮 负 J J J J - - - - A A A A A A A A A A A A A A A A A A A A A A A A A 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 THF/water has not been proven to be as effective as solvating solvents or toluene. Although triclosan is a highly preferred reagent, other triethylamines such as trifluoroacetamide and chlorodifluoroacetamide can also be used. It is also possible to use trimethyl decylamine, and other compounds having an exo-, alkenyl or block moiety between the electron-absorbing tris-methyl and the carbonyl of the guanamine (or other electron-absorbing groups) The electron absorption is transferred to the group of the indole carbonyl group). Heptaflubutylamine can also be used, but few good results. In general, the peroxide activator can be equivalent to the formula: R ° C (0) NH 2 wherein R ° is its electron absorption intensity (measured by the d constant) at least, and the same as the monomethyl group . The t subgas base is preferably directly adhered to the indole carbonyl group for maximum effectiveness. Preferably, the peroxide activator is equivalent to the formula: 〇, Ρ 11 ΝΗ. wherein Rp is a group which can transfer the electron absorption of the electron absorbing group to the guanamine carbonyl group, and is preferably selected from an aryl group. , an alkynyl group, and a (CX4X5) n- moiety; X1, X2, X3, X4 and Χ5 are independently selected from the group consisting of _, hydrogen, alkyl, _alkyl and cyano and cyanoalkyl; and η is 〇 , 1 or 2; the restriction is that when η is 0, then at least one of X1, X2 and Χ3 is _, and when rp is - 90- This paper scale applies to Chinese national monument ( ΓΝ§ ) Λ 4 specification (210x297 mm) )

1248443 A7 V. Description of invention (88) The Consumers Department of the Ministry of Consumer Affairs and the Government of the People's Republic of China (CXX3)n and η is 1 or 2, then at least one of ^ and 5 is _. 告^, Χ2'Χ 'X4 or X5 任-, when it is not quotient, it is preferably _alkyl,: a good-percent haloalkyl group. Particularly preferred activators include therein. It is 〇, and χΐ, χ, χ 3: Less is the heart or Where ^ is ^ coffee to ... is (4), ^^ less 疋 Χ, Χ and χ 5 the other is halogen or perhaloalkyl, and χ 1, χ 2 χ 3 is \ or full tooth burning base. χ 1, X2, X3 Preferably, each of X4 and X5 is C1 or F: preferably Cl, however, mixed halides are also suitable, such as perchloroalkyl or perbrominated groups and combinations thereof, with the restriction being directly attached to the decylamine group. ^ Carbon is replaced by at least one self-base. The peroxide activator is preferably present in an amount of at least about 1 equivalent, preferably about 2 equivalents per equivalent of the initially present acceptor. At least a moderate excess is added to the reaction, and &amp; is gradually added as the epoxidation reaction proceeds. Although the reaction consumes only 2 equivalents of peroxygen per mole of the substrate, hydrogen is compared to the substrate and initially In the activator, peroxydichloro is preferably added in substantially excess form. It is not intended to limit the invention to a particular theory, and the reaction mechanism involves the formation of an activator and a peroxide anion adduct, and The formation of this reaction is reversible, and the balance is beneficial for the reverse reaction, so in order to drive the reaction in the forward direction, the hydrogen peroxide must be added in more than the initial amount. The temperature is not strictly limited, and q is carried out efficiently in the range of from about 0 C to about 〇. The optimum temperature depends on the choice of solvent. In general, the preferred temperature is between about 2 〇 and about: C, but at some In some solvents, such as toluene, the reaction can be advantageously carried out in the range of from about 6 Torr to about 7 ° C. At about 25 Torr, the reaction is usually below -5 hours, usually from about 3 to about 6 hours. If necessary, please read the back δδ at the end of the reaction cycle and then fill in the page to rectify the requirements. 3 0 10 -91 This paper scale is suitable for the Chinese national standard bee ((, NS ) Λ 4 specifications (210X297 mm) 1248443 Α7 Β7 89 invention description (can add extra The activator and hydrogen peroxide are used to achieve complete conversion of the substrate. At the end of the reaction cycle, the aqueous phase is removed, and the organic reaction solution is preferably washed to remove water-soluble impurities, and then the product can be recovered by solvent removal. Before removing the solvent, the reaction solution should be washed with moderate to moderate alkali, such as sodium carbonate. Preferably, the reaction mixture is washed successively with a mild reduction solution such as sodium sulfite in water (e.g., about 3% by weight). a solution; a solution such as NaOH or KOH (preferably about 5 Ν); an acid solution such as Hcl (preferably about 1 N); and finally a water or saline neutral detergent, preferably saturated brine' To minimize product loss. An additional solvent such as an organic solvent, preferably ethanol, may be advantageously added before removal of the reaction solvent, such that the product may be recovered by crystallization after removal of the more volatile reaction solvent by distillation. It will be appreciated that the novel epoxidation process utilizing trichloroacetamide or other novel peroxide activators is more useful than the various processes for preparing epoxigenone and can be used in the formation of epoxides. It can cross the various olefinic double bonds that accept the reaction in the liquid phase. The reaction is particularly effective for unsaturated compounds in which the alkene is tetrasubstituted and triple substituted, i.e.,

RaRb〇CReRd and RaRbc = CRCH, wherein ^ to represent a substituent other than hydrogen. When the acceptor is a cyclic compound and has a triple-substituted double bond, or the cyclic or broadcast compound has a tetra-substituted double bond, the reaction can be most rapidly and completely ordered. Exemplary receptors for epoxidation reactions include Λ9,11-kenrexone, and the following receptors: ______________ 92 - This paper size is applicable---- 1 heart "((,奶)/\4 specifications (21 (^ 297 mm) Order ~~ (Read the first note on the back and fill out this page again) 1248443 A7 V. Description of invention (90) 〇 0

0

〇

0 0

In the case that the compound contains other double bonds and the alkene carbon is monosubstituted or monosubstituted, the selective epoxidation of the double bond of the tooth is particularly late I- -- : -..... 1_1| II ·ϋϋ _ - I-..... (Read the first note on the back and fill in this page)

Other non-limiting examples of general epoxidation reactions include the following stringent oxidation reactions: I -93- This paper scale is suitable for the Chinese National Monument (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 V. Description of invention ( 91.)

(Please read the precautions on the back and fill out this page.) After the squad, the squad of the squad, nJ.

It will be further appreciated that the reaction can be used to facilitate epoxidation of the mono- or even di-substituted double bonds, such as 11,12-alkenes in various steroid substrates. However, because it can epoxidize higher-substituted double bonds differentially, such as -94- This paper scale is suitable for the Chinese National Standard Ping (rNS) Λ4 specification (21〇Χ 297 mm) Λ, invention description (9,11 - Alkene, also highly selective in various reaction schemes in the epoxidation step, 'The process of the invention is particularly effective here for the improved method for achieving high yields and yields. Foot preparation is particularly beneficial

IB --------0^-- (Read the first note on the back and fill out this page) epoxidation:

0

, 1T and preparation: ; and

1C This paper scale applies to the Chinese national standard _ ( rNS ) Λ 4 specifications (210X297 mm) 1248443 V. Description of the invention (9~3~) epoxidation:

The process of the present invention has been shown to have a number of advantages in which trichloroacetamide replaces trichloroethane as an oxygen transfer reagent for the epoxidation reaction. The trichloroacetamide reagent system sub-pliers lacks the chain 晞 with low affinity, such as no, Lu-unsaturated 酉 similar. For example, a non-conjugated chain containing a type 2 double bond can be selectively epoxidized. In addition, in complex receptors such as steroids, disubstituted and trisubstituted chains can be distinguished by reaction. Therefore, good selectivity was observed in the oxidation of the compounds of the isomeric ruthenium, 9,11 and ruthenium,11,12. In this case, 9,11 epoxide can be formed, and the isomer containing Δ_11,12 double bond is less reactive. Therefore, the reaction yield, product profile and final purity can be substantially enhanced in comparison with the reaction using tri-acetonitrile. It has further been found that excessive oxygen production can be observed when trihaloacetonitrile is used, and is minimized in the case of trichloroacetamide, making epoxidation safer. Further, contrary to the reaction promoted by trichloroacetonitrile, the dioxetamine reaction exhibits the least exothermic effect and thus contributes to the control of the heat profile of the reaction. It can be observed that the agitation effect is minimized and the performance of the reactor is relatively uniform, which is a further advantage over the trichloroacetonitrile process. The reaction is more easily expanded than the reaction promoted by tri-acetonitrile. The separation and purification of the product is very simple. There is no use of meta-peroxybenzoic acid or -96 - paper size Λ1 + Guanjia (('NS) X4 size (21 〇X 297 mm~) ' --- ί I I-- - ; ------I - n (Please read the notes on the back and fill in this page) Book 1244843, invention description (94) Other carbonyl used in the past acid (peroxide promotion difficulty / = y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 〗 〖Compound: 4) Formula (10) brewing novel 11α,...·epoxide, such as lactyl-mi-based·3·_ base. Heart_pregnant_4_晞_7α, 2ι_ ester, 7-lactone; (2) Novel octa-ester of the formula II (3) epoxide, such as ", 5 π π ι ΐ - - - - - - _ _ _ _ _ _ _ _ _ _ _ _ 孕 孕 孕 孕 孕 孕 孕r · lactone; (3) formula (10) vinegar novel 12-ketone, such as 17_transcarbyl, 3,12_di__17 heart pregnancy 4,9 (11)-diene_7α,21_dicarboxylic acid 7 _Methyl ester, plant_lactone; (4) Formula II 晞 vinegar novel μ di dihydroxy, such as &amp; ^ μ, 17_ trihydroxy (5) Formula I Novel i2-hydroxyl analogs of I enoesters, such as ΐ2α, ι7_dihydroxyketone -17^pregna-4,9(11)-dioxa-7,21-dicarboxylic acid 7-methyl^,~l-ester And (6) a novel 7-acid of the compound of formula I, such as 9, Ua_epoxy 17-hydroxy"yl-17-pregn-4-ene-7", 7-methyl ester of 21-dicarboxylate, , _ vinegar 1; These compounds have a utilization valence in the synthesis of the compound and the chromatographic label in the preparation of the compound. In particular, the epoxy methremin. 11 olefin ester of the formula II α, 12α-ring The oxide is assumed to be formed from the impurities produced in the previous step, wherein the compound of formula 1 is converted to the cyclic group: 9 acid 3-endone / or hydrazine --------0^---- --, 玎 ------ (Please read the notes on the back and fill out this page) -97- The paper size of the Suichuan China National Monument (CNS) eight 4 specifications (210X 297 mm) 1248443 Α7 Β7 95 V. Inventive Note (酉曰. This impurity is chromatographed and is produced by the Δ 1 ester together in a ratio of about 90:10 (Λ9, “enyl ester: Δπ, 丨2 conjugated ester), however this ratio may vary. In the conversion of the formula π enester to the compound of formula, △, 11: oxidation of oxime ester The UH2 core epoxide is formed. The 4,5:9,11-diepoxide of the formula I ester can be separated by chromatography. It is hypothesized that it is derived from the excessive epoxidation of the ruthenium. The product was observed at a level of about 5% by weight or less, although the amount may vary. The 12-ketone of the formula II vinegar can be separated by chromatography. It has a hypothesis that points out the propyl oxidation effect of the association. It is usually below about 5% by weight in the crude product (the level is observed 'however this amount can vary. When trichloroacetonitrile is used as the hydrogen peroxide activator, the 12-ketone is measured in the crude product. The level is higher than that when the dioxetamine is used as the activator. The 9, n-dihydroxyl group can be separated by chromatography. It is usually about 5 〇 / 在 in the crude product. The following levels have been observed, however this amount can vary. There is a hypothesis that it is derived from the hydrolysis of the oxime epoxide. The oxime of the formula II is separated by a cleavable layer, which is usually present in the crude product. 5% by weight is observed below, but this amount can be quantified. There is a hypothesis that it is derived from the elimination of the u,12_epoxide via the base. In addition, the prepared formula I is disclosed accordingly. Compounds can be further +dithered to produce metabolites with improved properties, derivatives, and two: solubility and absorbency) to aid in the administration and/or disintegration of epoxigen. 6_# base of the compound of formula 1 (such as di-based epoxy... ke-17α-pregnant n7a 21 m ^ 匕 clothing based on -3 - copper, 21--杈鲛7-methyl vinegar, Γ _ vinegar) is novel fPlease read the notes on the back and then fill in this page. j.

96 1248443 A7 B7 V. INSTRUCTIONS (Compounds, which are known to be possible metabolites in the art. Several base metabolites can be prepared, equivalent ethyl enol ethers (eg, 9, 丨丨"-epoxy- Ethoxy-7-hydroxy-17 α-pregn-4-ene-7 α,21-dicarboxylic acid 7-decyl ester, r _ lactone. The ethyl enol ether of the compound of formula I can be shown in Weia and l M.

Prepared by the procedure of Hofmann (L Med Chem 1977, 1304), which is incorporated herein by reference. The ethylenol ether is then reacted with meta-chloroperbenzoic acid to form a comparable 6-protecting group for the compound of formula I. Further hypothesis states that epoxigenone monocarboxylates, particularly potassium and sodium monocarboxylates, are a suitable variant for facilitating administration of a compound to an individual, wherein the individual has Take a lysone antagonist. It is possible to selectively open the spironolactone of the compound of formula 1 under mild alkaline conditions, but it is possible to hydrolyze the c-substituted group to produce a comparable 17 wide knee... ♦ propionic acid) analog. These open-chain analogs are more polar than their corresponding counterparts and have a shorter residence time when analyzed by reverse phase HPLC. Acidic conditions usually cause regeneration of the lactone ring. Under stricter conditions, the vinegar in the screw is opened and the C7 is hydrolyzed to form a by-product of the phase, ie, the formula! Compound 17/?m (3_propionic acid)_7_acid^ Some of the citric acid when compared with the reverse phase muscle c, there are more than the carboxylic acid (4) lag time conditions (such as treatment with dilute acid, such as w Chlorochlorohydrazine) is regenerated into a retinol ring. /, the invention of the novel method of enthalpy deuteration, in the summary of the flow core synthesis step i useful. In the special process as follows: in the special (in the case - in the overall example), the overall process, the paper size 13⁄4 with the Chinese national standard bee --------- order c please read the back of the note and then fill out This page) -99- 1248443 A7 B7 V. Description of invention (97)

(Please read the notes on the back and fill out this page.) Process 2 The second novel reaction process (Scheme 2) of the present invention begins with Kenridone or other equivalents of Formula XIII. Standard (rNS) Λ4 specification (210X297 mm) 1248443 A7 B7 V. Description of invention (98)

XIII wherein -A_A-, -B-B-, R3, R8 and R9 are as defined in formula XII. In the first step of the process, the acceptor of formula XIII is converted to the product of formula XII.

NH· Clothes -- (Please read the notes on the back and fill out this page)

, 1T

XII #1

This is carried out using a cyanidation reaction scheme which is substantially the same as described in the conversion of formula VIII to the intermediate of formula VII. Preferably, the formula XIII is equivalent to the formula XIIIA

c-X

XIIIA

And the enamine product is equivalent to the formula XIIA-101 - This paper scale applies to the Chinese national standard ((,NS) Λ4 specification (210X297 mm) 1248443 A7 B7

V. Description of the invention (99)

XIIA wherein -A-A-, -B-B-, R3, γ1 and γ2 and X are each as defined in the formula XIIIA. Preferably, R3 is hydrogen. In the second step of the process 2, the enamine of the formula can be hydrolyzed to form the diketone product of the formula XI. (Note: Please read the back of the note and fill out this page)

XI wherein -A-A-, -B-B-, R3, R8 and R9 are as defined in formula XIII, using the same reaction scheme as described for the conversion of formula VIII to the intermediate of formula VII. Preferably, the formula XII is equivalent to the formula XIIA, -102- The paper scale applies to the Chinese national standard _(rNS) Λ4 specification (210x297 mm) 1248443 A7 B7 V. Invention description (100

XIIA and diketone products are equivalent to ΧΙΑ

ΧΙΑ (Read the first note on the back and fill out this page), 11 The Ministry of Economic Affairs, the sub-standards, the member of the Ministry of Economic Affairs, and the 竹 贽 贽 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中And X are each as defined in the formula. Preferably, R3 is hydrogen. Further in accordance with Reaction Scheme 2, the ketone of formula XI is reacted with an alkali metal alkoxide to form a melixone or other product corresponding to formula X:

X This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 101 Description of the invention (where -AA-, -BB-, R3, R8 and R9 are each defined in formula XIII, and R1 As defined in Formula V, using the compound of formula v I to be converted to the same formula v

Reaction process. Preferably, the formula X I is equivalent to the formula χι A

•cmx ΧΙΑ

And the intermediate product is equivalent to the formula ----A ---------- IIII (^ read the back of the note and then fill out this page) 屮 if: the standard office

1_ CCh2]j-C 2)

XA wherein -A-A-, -B-B-, R3, Y1 and Y2 and X are each as defined in the formula XIIIA' and R1 is as defined in the formula V. Preferably, R3 is hydrogen. Mesretonone and other compounds of the formula 再9 ^ -hydroxylation, using the novel biotransformation process to produce the product of formula I X

Order f Paper size - ϋϋϋίϋ ) Λ 4 specifications (210X297 mm)

IX 1248443 A7 ____________B7 V. Description of invention (1〇2) The sub-standards of the pouring section, the second consumption, and the consumption of the bamboo company, f (please read the notes on the back and fill out this page). -AA-,-BB-, R3, R8 and R9 are as defined in formula XIII, and R1 is as defined in formula V. Among the organisms available for this hydroxylation step are: Nocardia conicruria ATCC 31548, Nocaria aurentia ATCC 12674, Corynespora cassiicola (mountain peas), ATCC 16718, Streptomvces hydroscopicus ATCC 27438, Mortierella isabellina ATCC 42613, Beauvria bassianaf Beauveria bassiana ATCC 7519, Penicillum purpurogenum ATCC 46581, Hvpomyces chrysospermus IMO 109891, Thamnostvlum piri forme ATCC 8992, Cunninghamella blakesleeana ATCC 8688a, Cunninghamella echinulataf, ATCC 3655, Cunninghamella elegans ATCC 9245, Trichothecium roseum ATCC 12543, Epicoccum humicola ATCC 12722, Saccharopolyspora eythrae ATCC 1 1635, Beauvria Bassiana (Bacillus fungi) ATCC 13 144, Arthrobacter simplexf), Bacterium cyclooxvdans ATCC 12673, Cvlindrocarpon radicicola ATCC 11011, Nocardia aurentia ATCC 12674, Norcardia restrictus ATCC 14887, Pseudo Monas testosteroni pillone pseudo-fishing carp ATCC 11996, Rhodococcus egui ATCC 21329, Mycobacterium fortuitum NRRL B8 119, and Rhodococcus rhodochrousf erythropolis ATCC 191 50. The manner in which the reaction proceeds is substantially related to that described in Figures 1 and 2. The process of Figure 1 is particularly good. The growth medium for biotransformation preferably contains about 0.05% and about 5% of the available nitrogen by weight; about 5% and about 5% by weight of the grape-105- China National Standard (CNS) A4 Specification (210X297 mm) After the Ministry of the Ministry of the Ministry of Defense, the MJ-Drinking and Bamboo Shirt Printing F 1248443 A7 Γ------___________Β7 V. Invention Description (1〇3) ~ --*--- Sugar; about (Κ25% and about 2.5% by weight of yeast derivatives; and about 5% and about 〇.5% by weight (4). Excellent growth medium includes The following: Daphnia powder: about 0.5% and about 3% by weight of glucose; about %1% and about η by weight of soy flour; about 0.05% and about 〇·5% by weight of alkali a metal halide; about 0.05% and about 5% by weight of a yeast derivative, such as an autonomously dissolved yeast or yeast extract; about 5% and about 5% by weight of the phosphate, Such as Κ2ΗΡ04, ρΗ=7; protein gland-yeast immersion _ glucose: about 2% and about 2% by weight of the protein gland; about 0.05% and about 0.5% by weight of the yeast extract; and About 2% and about 5% by weight of glucose ;

Mueller-Hinton: about 10% and about 4〇〇/. Beef extract by weight; about 0.35% and about 8.75% by weight of tyrosine; about 15% and about 7%.7% by weight of starch. Bacteria can grow on soy flour or protein gland nutrients, while actinomycetes and normal bacteria can be used in soy flour (plus 5% to 1% by weight of lean acid salt such as nail-stained steel) for living organisms Transformed) or in Mueller-Hinton gravy. The production of 11 lux of hydroxy meclirenone from merickone by fermentation was discussed in Example 19B. A similar biotransformation process can be employed to prepare other starting materials and intermediates. Example 19A discloses the biotransformation of androstenedione to 11-hydroxy androstene. Example 19C reveals mesreone to 11^-hydroxymexrein g, Δmecroreone, 6 yS-hydroxy meclirone, 12 Θ-hydroxy meclirone, and 9 α-hydroxy meclirenone Biotransformation. Example 19D reveals the biotransformation of kenridone to ruthenium 9,11-rendrone. -106- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) 0^------1Τ------^― (Please read the notes on the back and fill out this page) 1248443 A7 B7 V. INSTRUCTIONS (1〇4) The product of formula IX is a novel compound, and can be isolated by filtration, washed with a suitable organic solvent, such as ethyl acetate, and then self-known from the same or similar solvent. re-crystallize. It is quite expensive in the middle of the compound of the formula I, and especially in the middle. The preferred compound is equivalent to the formula, wherein _Α_ A-, -Β-Β- is -CHrCH,-, R3 county ^ 'lower alkyl or lower alkoxy, and R8 and R9 - constitutes a 20-spirooxane ring: 〇

II

XXXIII In the next step of the synthesis of Scheme 2, the hydrazine product is reacted with a dehydrating agent (a suitable dehydrating agent such as PhSOC1 or ClS〇3H is known to the artisan) to produce a compound of formula II--------- 3⁄4-I (Please read the note on the back and fill out this page)

II f wherein -A-A-, -B_B_, R3, R8 and R9 are as defined in formula XIII, and R1 is as defined in formula V. Preferably, the formula IX is equivalent to the formula ΙχΑ

ΙΧΑ This paper scale applies to China National Standard (CNS) Λ4 specification (210Χ 297 mm) 1248443 A7 by the Ministry of Consumer Affairs, the Standards Bureau S<, T consumption

Order 1248443 A7 B7 Description of invention (106

L«CI. OMF, EljN. Acetone cyanohydrin 05· C. β-15 h Kenrifone

Ester

Cl3C-C(0)NH2, H2〇j, CH2Ci2. 10· C, 24 h

V &quot;COOCHj

PhSOCl, Of CISO.

11-/? Keimereone (Please read the note on the back and fill out this page) Ethyl Methreone Process 3 In this case, the synthesis begins with the equivalent of Equation XX.

XX -109- This paper size is applicable to China National Standard Rate (CNS) Λ4 Specification (210X 297 mm) 1248443 A7 B7 V. Invention Description (107) where -AA- and R3 are as defined in Formula XIII, ·Β-Β _ As defined in the formula ηι, except that R6 and R7 are not fused to the ring moiety of the anthracene ring at the 16,17 position, and R26 is a lower alkyl group, preferably a methyl group. Preferably, R3 is hydrogen. The reaction of the formula X with the decyl halide produces an epoxide equivalent to the formula:

XIX where _Α-Α-, -Β-Β-, R3, R8&amp;R26 are as defined in the formula. Preferably, R3 is hydrogen. In a step below the synthesis scheme 3, the intermediate of the formula XIX is converted into a further intermediate of the formula XVIII-- (Read the first note on the back and then fill in the page) - Order the Ministry of Economics消贽合:^社印来〇

CO,Et

XVIII wherein -A-A-'-B-B- and R3 are as defined in formula XX. Preferably, it is chlorine. In this step, the compound of formula XIX is converted to the intermediate of formula XVIII and reacted with NaCH(COOEt) 2 in the presence of a solvent. -110 This paper scale applies to China National Standard Rate (CNS) Λ4 gauge (210X 297 mm) 1248443 A7 B7 __ V. Description of invention (108) The compound of formula XVIII is exposed to heat, water and halides can produce equivalent Decarboxylation intermediate of formula XVII〇

XVII wherein -A-A-, -B-B- and R3 are as defined in formula XX. Preferably, R3 is hydrogen. The conversion of the compound of the formula XX to the compound of the formula XVII is substantially equivalent to that described in U.S. Patent Nos. 3,897,417, 3,413,288 and 3,300,489, the disclosures of which are incorporated herein by reference. The conditions for introduction of the reagents, mechanism and 17-spirolactone are basically the same, although the quality is different. The reaction of the χνπ intermediate with the hydrogenation reagent can generate a further intermediate of the formula XVI -------- in the form of -I (please read the notes on the back and fill out this page)

, 1T, the sub-standard rate of the full division, the _τ·消贽合竹社 impression 〇

XVI where -Α-Α-, -Β-Β- and R3 are as defined in formula XX. Preferably, R3 is hydrogen. Useful dehydrogenating reagents include di-dicyanophenyl hydrazine (DDQ) and gas hydrazine (2,3,5,6-tetrachloro-p-benzoquinone). In addition, dehydrogenation is applied to the 6-position-111 - paper scale for the Chinese national standard (CNS) Λ 4 specifications (210X 297 mm 1244843 Α 7 -------- -------- ---~一— Β7 V. Invention Description~~ On the carbon, the hydration reaction can also be achieved. The XVI intermediate can be converted into the enamine of the formula XVB\HjC〇j.

X (Read the first note on the back and fill out this page) Clothing. Where -A-A-, -B-B- and R3 are as defined in Equation XX. Preferably, r3 is hydrogen. Conversion by cyanidation, in a substantially basic manner, is converted to the guanamine of formula VII as described above for the vnii oxime-hydroxyl compound. Typically, the cyanide ion source can be an alkali metal cyanide. The base is preferably pyrrolidine and/or tetramethylguanidine. A methanol solvent can also be used. The product of formula XVB is a novel compound which can be separated by chromatography. These and other novel compounds of formula XV are used as intermediates to prepare compounds of the formula, especially those of formula I A. The structure of the compound χν compound phase

• 112 PCT) This paper scale is based on the Chinese National Standard (rNS) Λ4 specification (2l0x297 public 1244843 A7 B7 5. Inventive Note (110 where -AA-, -BB-, R3, as defined in χπι. in Formula XV) And the preferred compound of the formula XVB, -a_A4_BBkH2_ch2, and R3 is hydrogen. According to the above-mentioned hydrolysis of the diketone compound of the formula VI, the enamine of the formula 可νΒ can be converted into the diketone oxime of the formula XIVB.

〇 XIVB. (Read the first note on the back and then fill out this page) -L# The sub-standard rate of the Ministry of Warfare is divided into two parts: -A-A-, and R3 as defined in Equation XX. Preferably, R3 is hydrogen. A particularly preferred compound for the synthesis of epoxidized meclirone is the formula χιν, which is also in the range of formula XIVB as defined below. The product of formula XIVB is a novel compound which can be isolated from the sink. These other novel compounds of the formula XIV are highly intermediate in the preparation of the compounds of the formula I, especially the formula I A. The compound of the formula XIV corresponds to the following structure and

, 1T t 〇

XIV This paper scale applies to China National Standard (CNS) Λ4 specification (210x297 mm) 1248443 V. Invention description (川A7 B7 ------^ where -AA- ' -B-,p 3 8 〇R,R And R9 is as defined in formula XIII. XIV and XIVB are optimized to be one of the formulas. -AA- and -BB- are -CIVCH, R3 is hydrogen. L2-, and compound of formula XIVB Huai_half π #, ν can be converted into a compound of the formula XXXI, which is converted into a basic formula of a vinegar of the formula V by using a diketone of the formula: ..., in which it is necessary to separate the intermediate ΧΧΧΙ U U.

XXXI -------- Participate in II (please read the notes on the back and then fill out this page) and then further convert to the product of formula XXXII

XXXII

, 1T f? /^部中中#准局G(JM/n费合竹$印多中中_Α-Α-, _Β-Β· and R3 are as defined in Equation XX, and R1 is as defined by the formula. R3 is hydrogen. Preferably, the compound of the formula XXXI is of the formula HA. The compound of the formula XXXI is converted to the compound of the formula XXXII, as described in U.S. Patent No. 4,559,332, or the method described above. Preferably, the compound of the formula XIV is 4,S(4'a),7'n,2,,3,,4,4,,5,5,,6,, -114 This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) ) 1248443 A7 B7 V. INSTRUCTIONS (112) 7, 8, 8, 10', 12, 13, 13, 14', 15', 16-'Hex Hydrogen-10々-, 13,,? Methyl-3,5,20,trione snail [furan-2(31^),17'々_[4,7]methylene[17:«]_cyclopenta[3]phenanthrene]5, nitrile; And the compound of the formula XV is 5' (5'〇〇57'/?-20'-amino-1', 2', 3', 4, 5, 6!, 7\8\101, 12, 13' ,14',15,16,,tetradecyl _10'",13,"_dimethyl-3-s5-dione snail [furan-2(3Η), 17' π (5Ή)-[ 7,4] Methylene [4H]-cyclopenta [a]phenanthrene]-5f-nitrile. In the specific example The overall process of Process 3 is as follows:

weO (Please read the back of the note first and then fill out this page)

Heating NaC I 〇ms〇

Eliminate 1V A H in the Ministry of Printing

Epoxy Meikere I with - 115 This paper scale is suitable for China National Standard (CNS) Λ 4 specifications (210X 297 mm). (113) ----- Process 4 The first three steps of Process 4 and the same process of Process 3 are the same as the preparation of the intermediate XVII intermediate by the compound corresponding to the formula 。. Thereafter, the intermediate of formula XVII is epoxidized using the method of U.S. Patent No. 4,559,332 to form a compound of formula XXIV.

Xxiv where and R3 are as defined in equation xxt. However, in a particularly preferred embodiment of the present invention, the χνπ accepting oxidizing agent using a guanamine-type peroxide activator, preferably trimethylacetamide, is epoxidized through a 9, u-double bond. The process for converting the olefin of the formula π to the product of the formula according to the above Scheme 1. The reagent conditions and characteristics used in this reaction are essentially as described for the conversion of the ester of formula 11# to oxymoxime. A particularly preferred formula of the formula XXIXMb is wherein A_A- and -B-B- are as defined in formula XIII, and R3 is hydrogen. It has been found that the epoxidation of the formula XVII can also be achieved in excellent yields, and peracids such as meta-p-peroxybenzoic acid can be utilized. However, the trichloroacetamide reagent provides excellent results in reducing the formation of oxidation by-products in Villager. The latter by-product can be removed, but this is required from the solvent? Titration in (e.g., ethyl acetate) followed by crystallization from another solvent, such as di-methane. Dehydrogenation of the epoxy compound to produce a double bond between 6 _ and 7 _ carbon, with -116- the paper size of the 13⁄4 fiscal "Fresh (&amp;S) Λ 4 specification (21GX 297 mm) -- --- Clothing 1T------- (Please read the note on the back and then fill out this page) 1248443 A7 __________ B7 V. Description of invention (m) Dehydrogenation (oxidation) agent reaction, such as ddq or chloranil, Or using a bromination/dehydrobromination (or other halogenation/dehydrohalogenation) sequence to produce another novel intermediate of the formula

The Μ 中 中 _ _ _ _ _ _ 贽 贽 XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX Particularly preferred compounds of formula XXIII are those wherein -Α-Α- and -Β-Β are as defined in formula XIII and R3 is hydrogen. Although direct oxidation is effective for the formation of the product of formula XXIII, the yield is usually very low. Therefore, the oxidation is preferably carried out in two steps, first halogenating the formula XXIV to the C-6 position in the mass, and then hydrohalogenating to the 6,7-olefin. The halogenation is preferably achieved by a hydrazine-halogen organic reagent such as ν-bromoarene. The chemistry is carried out in a suitable solvent, such as acetonitrile, and is present in the presence of a dentate promoter such as guanidinated peroxygen. The reaction is about 5 〇. (: to be effective in the range of about 100 ° C, preferably at atmospheric reflux temperature, and in a solvent such as four-gasified carbon 'acetonitrile or a mixture thereof. However, it takes 4 to 1 hour to complete the reaction. The solvent is subjected to vaporization, and the residue is absorbed by a solvent in which the water is not mixed, such as ethyl acetate. The resulting solution is sequentially diluted with a base (such as an alkali metal hydrogencarbonate) and water, or preferably saturated. The brine is washed to reduce the loss of the product, after which the solvent is vaporized, and the residue is based on another -117- paper scale (CNS) Λ4 specification (210X 297^^) -------- -0^-- (Read the first note on the back and fill out this page), 1Τ f 1248443 A7 B7 5. Inventive Note (彳15) Solvent absorption (such as dimethylformamide), which is suitable for dehydrogenation Adding a suitable degassing agent such as 1,4 _di-p-bicyclo[2 2 2 ]octane (DABCO) to the solution, and adding an alkali metal halide such as UBr, solution heating To a suitable reaction temperature, such as 60. (: to 8 〇 1, and the reaction can continue for several hours, usually 4-15 hours, to complete dehydrobromination. Additional dehydrobromination reagent may be added as needed in the reaction cycle to recover the reaction. The product of formula XXIII is recovered, and the product is precipitated by adding water, which is then separated by filtration, preferably with an additional portion of water. Preferably, the product is recrystallizable from dimethylformamide. The product of formula XXIII, such as 9,11· epoxy ketone, is a novel compound which can be isolated by extraction/crystallization. The compound of formula I is prepared, and in particular has a substantial valence in formula IA. For example, it can be used as a compound for the preparation of a compound of formula X X111. x A compound of formula VII, a compound of formula XXIII and cyanide, is prepared by substantially the above-described process. The compound ion reacts to produce a novel #enamine compound corresponding to SXXII, and the latex (precautions for reading the back side and then fill in the page)

, 1T by the Ministry of Consumer Affairs, the Bureau of Standards and Bureaus, τ 贽 贽 竹 社

XXII f where -Β-Β-, R3, R8 and R9 are as defined in the formula ΧΧ. Especially good -118-

This paper ruler money money home ΓΓΝ 5) Λ 4 ^ ( 21 ^ ^ ¥ T 1248443 A7 V, invention description (116

The hydrazine compound is wherein Α-Α-, -B_b_ is as defined by the formula xm, and RS is hydrogen. The product of formula XXII is a novel compound which can be isolated by precipitation and filtration. In the preparation of the intermediate compound, and especially in the formula, it has a substantial price. In the most preferred compound, _a_a_ and 4_1 are '_CH2-CH2-, and R3 is hydrogen. Using the above-mentioned process of the compound of the formula VI, the epoxy olefin amine of the formula can be converted into the novel epoxy diketone compound of the formula XXI----^^^ (Read the first note on the back) Please fill in this page again; &gt;

ο

MM 'Ministry of the Ministry of Standards, T-consumer, Zhu Zhushe, ¥

XXI where -Α-Α-,, R3, R^R9 are as defined in the formula χπι. In the most preferred compound of formula XXI, -Α_Α- and each Β· are -CH2_CH2_, and 3 is hydrogen. The product of formula XXI is a novel compound which can be isolated by precipitation and filtration. It is used as an intermediate to prepare a compound of formula I, especially formula I A, which has a substantial valence. Particularly preferred compounds of the formula XXHb are those in which Α_Α_ and ·B_B• are as defined in the formula. In the most preferred compound of formula XXI, -A-A- and -B-B- are -CHrCHr, and r3 is hydrogen. -119- This paper size 4 is used with a towel _ ( &amp; S ) Λ 4 size (21GX 297 mm) ' 1248443 A7 --------- _________ V. Description of invention (117) Self-style! The preparation of a diketone compound for the preparation of a v-based vinegar compound, and the epoxidized epoxy diketone compound can be converted into a compound of the formula χχχπ

XXXII wherein -α-α-, -Β-β_ and R3 are as defined in the formula, and R1 is as defined by the formula ν in the sub-standard section of the T. The conversion of the ketone of the formula V to the hydroxy ester of the formula VI can also form a 5_々-cyano-7-ester intermediate during the conversion of the formula XXI epoxydione to the formula XXXII. The 5·々-cyano-7_ester intermediate in the second series can be isolated by treatment with an equivalent diketone in an alcohol such as methanol and in the presence of a base such as triethylamine. Preferably, the intermediate is prepared by refluxing a mixture of a diketone and an alcohol, such as methanol, wherein each moledione contains from about 0.1 to about 2 equivalents of triethylamine for about 4 to about 10 hours. The product was isolated in pure form, i.e., the mixture was cooled to about 25 and filtered. The isolated intermediate can be converted to a compound of formula XXXII, such as an alkali metal alkoxide, in a solvent, preferably an alcohol such as methanol. The use of alkoxides in alcohols allows the development of equilibrium mixtures which are similar to those formed by treatment of the equivalent formula XXI diketone under the same conditions. Further, a 7-oxime ester of a compound of the formula XXXII (e.g., 9,11α-epoxy-17-hydroxy-3-keto-17α-pregnant 4_晞_7 cold, 21-dicarboxylic acid 7-methyl ester , r _ intrinsic 已) has been observed in the crude product chromatography of the final step of the Process 4 process. -120- The paper size ii / il towel country _ ¥ standard _ ( ^ NS ) Λ 4 specifications (210X 297 mm) ' - ^ clothing -- (please read the back of the note before filling this page}, v $ t 1248443 A7 V. INSTRUCTIONS (B7 118 + burned oxides and / or cyanide in the liquid can react and convert 7 ^ _ ester into 7 ^ vinegar and the epi-isomeric mixture of 7y5-acetone epimer. The pure 7 oxime can be separated from the mixture of epimers by selective crystallization. Preferably, the compound of formula XXI is 4,8 (4,"), 7, -9, 11 epoxide hexahydro _ 10^-13'/?·Dimethyl_3',5,20f-trione snail [furan_2(3H),17,y5-[4,7] methylene [17H]-cyclopenta[a]菲_5'-nitrile; formula: 是: the compound is 5, R (5, a), 7, p -20 '-amino-9, 11 /? _ epoxy hexahydro-1 〇 ', 13 ,_Dimethyl_3,,5-dione snail [唉喃-2(3H), 17'a(5'H)-[7,4]methylene [4H]cyclopenta[a]phenanthrene-5 , - nitrile; and the compound of formula XXIII is 9,11 α -epoxy_17 ^hydroxy-3-ketone - 4,6-diene 21-carboxylic acid, plant-lactone. In a particularly preferred embodiment The overall process of Process 4 is as follows: I ϋ I Order ~~ (Please read the back of the note first) The item will be filled out again.) The Department of Economic Affairs and the Ministry of Economic Affairs and the Ministry of Economic Affairs, J-Chan, and the Bamboo; ^Print f -121 - This paper scale applies to the Chinese National Standard Rate (CNS) Λ4 Specification (210x297 mm) 1248443 A7 B7 , invention description (119)

Epoxy Mere Rexone (Read the first note on the back and fill out this page) The Manchurian Standards Board Member - T-Consumer Hezhu Society Print Process 5 Process 5 begins with the equivalent of XXIX R3

XXIX -122- This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 V. Inventive Note (120) where -A-A-, -B-B- and R3 are as defined in Equation XX. The following microorganisms can perform 9 π-hydroxylation of compounds of formula XXXV (such as androstenedione)

(Please read the notes on the back and fill out this page)

XXXV wherein -Α-Α-, -Β·Β· and R3 are as defined in formula XIII, forming a compound of formula XXIX under conditions similar to those described in Example 19:

Aspergillus niger ATCC 16888 and 26693, Corynespora cassiicola ATCC 16718, Curvularia clavata ATCC 22921, Mycobacterium fortuitus NRRL B8119, Nocardia canis ATCC 3 1548, Minoculus ATCC

1223 1, Aspergillus oryzae ATCC 2833, T. oxysporum ATCC, -~~~~. 18192, and Thamnostylum piriforme ATCC 8992 〇 equivalent to the conversion of the formula XXIX to the product of formula XXVIII The standard clerk of the squadron

XXVIII is reacted with a trimethyl orthoformate wherein -A-A_, -B-B- and R3 are as defined in formula XX. After the compound of formula XXVIII is formed, it is subjected to the formula XX to 123. The paper scale is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm). 1248443 A7 B7 V. Description of the invention (Ί21) The conversion method of the formula XVII, These compounds can be converted to compounds of formula XXVII. The compound of formula XXVII has the following structure:

XXVII wherein -A-A-, -B-B- and R3 are as defined in formula XX, and Rx is either a common hydroxy protecting group. In addition, the C9 α-hydroxy group can be protected in the synthetic scheme from the previous step, if the protective step is necessary, that is, the C9 hydroxyl group of the compound of the formula XXVIII or the C 9 hydroxyl group of the compound of the formula XXIX can have a common hydroxyl protecting group. Protect either. Using the process described for the compound of formula XVI above, the compound of formula XXVII can be oxidized to form a novel compound of formula XXVI ---------^ winter-- (please read the notes on the back and fill out this page)

, 1T by the Ministry of the Ministry of Standards, the second member of the standard

XXVI where -Α-Α·, -Β-Β- and R3 are as defined in formula XX. Particularly preferred compounds of the formula XXIX, XXVIII, XXVII and XXVI are those wherein Α_Α- and -Β-Β are as defined in formula XIII, and R3 is hydrogen. -124- This paper size applies to Chinese National Standard (CNS) Λ4 specification (21〇X297 mm) t 1248443 ΑΊ ~~- ________Β7 V. Description of invention (122) The product of formula XXVI is a novel compound which can be precipitated/filtered Separation. It is of intermediate interest in the preparation of Formula I, and in particular Formula IA. A particularly preferred compound of formula XXVI is wherein -Α-Α· and _B-heart are as defined in formula XIII, and r3 is hydrogen. In the preferred compound of formula XXVI, _A_A- and -B-B- are -CH2_CH2., and R3 is hydrogen. The novel intermediate of formula νν can be converted to the novel hydroxy enamine intermediate of formula XXV using the method defined by the above cyanation of the compound of formula VIII.

XXV wherein -Α-Α-, -Β-Β- and R3 are as defined in formula XX. The XX 贽 贽 贽 竹 社 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ It is used as an intermediate to prepare a hydrazine compound, and especially a hydrazine, having a substantial valence. A particularly preferred compound of formula XXV is as defined in formula XIII, and R3 is hydrogen. In the most preferred formula χχνι compound, -Α-Α- and _Β·Β- are -CHrCHr, and R3 is hydrogen. The 9-hydroxyl enamine intermediate of the formula χχν can be converted to the diketone compound of the formula XIVB by the above conditions for the preparation of the formula V I diketone compound. Note that in this example, the reaction can effectively carry out the hydrolysis of the enamine structure at the same time and 9, u_bit-125- the paper size is suitable / 丨 standard) Λ 4 specifications (other - secret) 1248443 A7 B7 V. Description of the invention (123) Dehydration introduces two conditions of 9,11-double bond. The compound of formula XIV is then converted to the compound of formula XXXI, followed by the compound of formula XIII, using the same procedure as described above in Scheme 3. Preferably, the compound of formula XIV is 4's (4'a), 7, l', 2', 3, 4, 4, 5, 5, 6, 6, 7, 8, 10, 12, ,13,14',15,16,-hexadecahydro-100-,13,dimethyl-3,5,20'-trione snail [furan·2(3Η), 17'/ -[4,7]methylene [ΠΗ]_cyclopenta[a]phenanthrene] 5'-nitrile; the formula χχν compound is 5'11(5'"),7,;5_20,-aminohexadecane -9|0-hydroxy-1〇'^13'"-dimethyl-3',5-dione snail [furan-2(311)17, α(5Ή)-[7,4]methylene [ 4H]-cyclopentane|&gt;phenanthrene-5'-nitrile; formula χχνι compound is 9α,17α-dihydroxy-3-keto-pregn-4,6-diene-21-carboxylic acid, r-endo vinegar; Further, the compound of the formula XX VII is 9α,17 α-dilight-3-one-pregnant-4-indole-21-rebel, r-inner. In a particularly specific example, the overall process of Process 5 is as follows: ^^ 参 订 ------ ^ - (Please read the notes on the back and then fill out this page) Department of the Ministry of Finance, τ 贽 贽 竹 126 126-126- This paper scale applies China National Rate (CNS) Λ 4 specifications (210X 297 mm) 1248443 V. Invention description (124) A7 B7

CMeO〇3CH

Me〇

D DO four thin

NbOCH3&lt;CHjOH. reflux

COOCH, C, 3CCN. H2〇2 (CH?Cl i〇

Cooch3 Epoxy Meikerui - (Please read the note on the back and fill out this page), 1Τ Process 6 f In the anger of the Ministry of the Ministry of Defence, J. Provides the preparation of epoxy meclorone and other equivalents! The compound method begins with male or female XXXV compound 11 α or 11々-hydroxylation 0

XXXV This paper scale is applicable to China National Standard (CNS) Λ4 specification (21GX 297 mm) 1248443 Α7 Β7 V. Invention description (125) where - , -BB- and R3 are equivalent to the formula ΧΧΧγΙ as defined in formula XIII Intermediate or its equivalent 11 /?-hydroxyisomer

The Ministry of Finance and Economy, the second time, the rate of the bureau, the second consumer, such as the printing of water (please read the notes on the back and fill out this page)

Wherein -Α-Α-, -Β-Β· and R3 are as defined in formula XIII. In addition to the choice of substrate, the 11 α -hydroxylation process is as described in Scheme 1 above. The following microorganisms can perform 11 α-hydroxylation of androstenedione or other compounds of formula XXXV: Absidia glaucaf, ATCC 22752, Aspergillus f-lavipesf, Aspergillus, 1030, Aspergillus fumigatus Qu Xue) ATCC 10254, Aspergillus fumigatus (ATCC 26934, Aspergillus ochraceusi) NRRL 405 (ATCC 18500), Aspergillus nigerr (ATCC 1 1394), Aspergillus nidulans (Aspergillus nidulans) ATCC 1 1267, Beauveria bassiana ATCC 7159, Fusarium oxysporumf, ATCC 7601, Fusarium oxysporum cepaei, ATCC 11171, Fusarium lini, ATCC IFO 7156, Gibberella fujikor, ATCC 14842, Hypomyces Chvrsospermusi 跑 窬 ) ) ) IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR Ervthraeaf Saccharomyces cerevisiae ATCC -128- paper scale ί Use Chinese national standard () Λ 4 specification (210X 297 mm) 1248443 A7 __*_____ B7 __ V. Invention description (126 ) &quot;635, Thamnostvlum piriforme ATCC 8992, RJiizopus M, yzae (Rheumella) ATCC 11145, Rhizopus Stoloniferf Rhizopus oryzae) ATCC 6227b, and Trichothecium roseumf pink stipitis) ATCC 12519 and ATCC 8685 ° or less microorganisms can perform 11 Θ-synonymization of androstenedione or other compound of formula XXX··

Aspergillus fumigatusf Aspergillus fumigatus ATCC 26934, Aspergillus ATCC 16888 and ACTT 26693, Epicoccum orvzae ATCC 716, Curvularia lunata ATCC 12017, Cunninghamella blakesleeanai, ATCC 8688a, And Pithomyces atro-olivaceous IFO 6651 泛 XXXVI 11 pan-hydroxyandrost-4-ene-3,17-dione, or other compound, and then converted to 11α-hydroxy-3,4-enol of formula (101) Ether: (Please read the back of the note first and then fill out this page)

Μ 中 中 标准 标准 员工 员工 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - In the presence of an acid catalyst, it is counter-reacted with an etherification reagent, such as a trialkyl orthoformate. To effect this conversion, the 11 α -hydroxyl acceptor is acidified by mixing with an acid such as benzenesulfonic acid hydrate or toluenesulfonic acid hydrate. Re-dissolved in a lower alcohol solvent, preferably ethanol. Trialkyl orthoformate, -129- This paper scale is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 B7 127 V. Description of invention ( The car is preferably triethyl orthoformate, gradually introduced in 5 to 4 minutes, while the mixture is kept in a cold place, preferably about 〇. (: to about 15 〇 c. The mixture is heated again, and the reaction is About 2 (TC and about 6 (under TC. Preferably, the reaction is carried out at 3 〇 _ 5 0 C for 1 to 3 hours, and then heated to reflux for a period of time, usually 2 to &amp; hour, to complete the reaction. The mixture is cooled, preferably to 〇15., preferably about 5 ° C, and then the solvent is removed under hollowing. Said, the same reaction scheme for converting the compound of the formula XX into a compound of the formula XXXνπ, the part of the formula XXXIIIi17_spirolactone can be introduced into the compound of the formula 101. For example, the reaction of the formula 1〇1 with the decanoate, in the presence of a base such as a metal The hydroxide 'in a suitable solvent such as Dms〇 to produce an intermediate equivalent to the formula 102: (Please read the back of the note before filling out this page)

1T 102 wherein -A-A-, R3, R&quot;&amp;_b are each as defined in Equation 101. The intermediate of formula 1〇2 is further reacted with malonic acid diester in the presence of an alkali metal alkoxide to form a pentacyclosperin ring, and an intermediate of formula 1 〇3 is produced. 103 The paper scale applies to the Chinese National Standard (CNS). Λ4 specifications (210X 297 mm) f Department of Central and Secondary Standards Bureau of the Ministry of the Ministry of the Ministry of Science and Technology JT-消贽告竹社印f

CO-R1 1 淖 中 中 欢 局 局 局 局 二 二 二 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 - as defined by formula 102, and r12 is a Ci_C4 fluorenyl group, preferably an ethyl group. Finally, the compound of formula 〇3 is subjected to heat in a suitable solvent (e.g., methalin) and is present in the presence of a metal amide to open the alkoxycarbonyl group and produce an intermediate of formula :4:

The same -A-A-, R3, R11 and -B-B are as defined in the formula 1-2. Next, the '3,4-enol ether compound 1〇4 is converted into a compound of the formula xxnHt, i.e., a compound of the formula viii, wherein R8&amp;R9 together form a moiety of the formula. This oxidation step is carried out in the same manner as the humiliation step of the conversion of the formula χχπι intermediate (in the synthesis of the dead zone 4). Direct oxidation can be achieved by using reagents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or tetrachlorobenzoquinone (gas from Kun) to achieve 'or better two stages Oxidation, ie bromination first, such as a hydrazine-halogen brominating agent such as hydrazine-bromoammonium amide (NBS) or hydrazine, 3 • dibromo-5,5-dimethyllactone (DBDMH), The base is dehydrobrominated, such as with daBCO, and is present in the presence of LiBr and heat. When bromination is carried out in NBS, it is also necessary to use an acid to convert the 3-enol to an enone. DBDMH itself is effective in bromination and conversion of enol linkages to alkenones. It is an ionic state rather than a free radical bromination reagent. The compound of formula VIII is further converted into the epoxidized memicol-131 of the formula I by the above procedure. The paper size scalp® ϋ _ (7^)^4 specification (2 hemp 297 mm) ' ' 111I IITn (please Read the precautions on the back and fill out this page.) 1248443 A7 B7 V. INSTRUCTIONS (129) Rhenone or other compounds. The intermediates of the formula 101 ' 102 '103 and 104 are novel compounds which have substantial commercial advantages in the preparation of the intermediates for the preparation of the epoxy meclorone or other compounds of the formulae I and I. In each of the compounds of the formulae 101, 102, 1〇3 and 104, -A_Aj_Β-Β· is preferably -CHyCH2·, and R3 is hydrogen, lower alkyl or lower alkoxy. Preferably, R3 is hydrogen. Preferably, the compound of formula 101 is 3-ethoxylated _u^_hydroxyandro-3,5-dien-17-one, and the compound of formula 102 is 3-ethoxy snail [xiong-3,5-diindole- 17 cold, 2'-oxirane]-11 "-alcohol, the compound of formula 1〇3 is ethoxy-11^17^ dipergestyl _3,5-diene_21,21-dicarboxylic acid Ethyl acetate in the vinegar, and the compound of the formula 104 is 3-ethoxy-u-^.-------- 3,5--- _ 2 1 - decanoic acid ' 7* - internal remedy. In the process of Process 6 as a whole, proceed as follows: Order ~ (Please read the notes on the back and fill in the page) The Ministry of Economic Affairs, the Sub-standards Bureau KJ-Consumer Hezhushe Print ¥132 - This paper scale applies to China Standard (CNS) Λ4 size (210X 297 mm) 1248443 A7 B7 V. Description of invention (130)

Biotransformation androstene (AD)

NaCi, 〇mf

(Please read the notes on the back and fill out this page.)

technology

Shown in process I

: 'Ministry' &lt;#准局员T; 贽 贽 印象 印象 印象 印象 印象 印象 有 有 有 有 有 有 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 印象 环氧 环氧 环氧 环氧 环氧Compound preparation in which it has been hydroxylated. In other words, the equivalent of the formula Cyclohexanone and other compounds can be prepared according to the general process shown in Scheme 6, using the α-hydroxylated substrate of the formula XXXV or equivalent 0 • Hydroxylation by the mud straw 7 Contains wheat germ alcohol, cholesterol, stearin or its 133 paper size 巾 _ home _ "CNS" Λ 4 specifications (1248443 A7 B7 V, invention description (131 he χχχ νπ compound starting quality, synthetic formula Method for ketones of methacrylate and other compounds

In the XXXVII &amp; drop section, the standard bureau is J-consumer and the company is printed with -Α·Α-, R3 and -B_B- as defined by the formula χιπ, D d· is _cHr called -or-CH=CH And Ri3, Rl4, Rl5 and Rl6 are each independently selected from hydrogen or an alkyl group. R3 is preferably 氲. In the first step of the synthesis, 1 丨I hydroxyandrostenedione or other oxime compound is prepared by biotransformation of a compound of formula XXXVII. Biotransformation (a method of performing hydrazine I hydroxylation substantially in accordance with the above-mentioned ketones (or other χπι receptors). 1 In the synthesis of 11 hydroxyandrostenedione, rensene-3,17-dione This is first prepared by biotransformation of a compound of formula XXXVII. This initial biotransformation can be carried out in the manner described in U.S. Patent No. 3,759,791, the disclosure of which is incorporated herein by reference in its entirety. Conversion to 11 〇 hydroxyandrostenedione, which is essentially carried out according to the above-mentioned ketone ketone method (or other formula XIII). The remainder of the synthesis of Scheme 7 is the same as in Scheme 6. In the specific example of the special case, the overall process of the process 7 is as follows: -134- ί paper scale is suitable for the national standard; Π cns (2i〇xl^:^y clothing - (please read the notes on the back and fill in the form) Page), 1Τ f 1248443 A7 B7 V. Description of invention (132)

Wheat germ alcohol

heating

NaCI, 〇Mf

technology

Shown in process I

After the ruling of the Ministry of Manchuria, the τ 贽 贽 社 社 社 指出 指出 指出 指出 指出 指出 指出 指出 指出 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧The biotransformation product of the χχχνιπ compound is 11 Θ·踁-androstenedione or other compound of the formula XXXV which has been hydroxylated-hydroxylated, which can be prepared according to the general procedure shown in Scheme 7. In other words, equivalent to the formula of epoxidone and other compounds, when Θ _ 麦 麦 曰 或 or other bio-transformation of the compound of formula XXXVIII results in the preparation of the χχχ ν ν ν ν ν It can be prepared according to the general process shown in Scheme 7. -135- This paper ϋ ϋ 家 家 ( ( 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210 210

1248443 The full-scale sub-standard rate of the Bureau of the Department of Labor, the consumption of Zhu Zhushe printed f A7 B7 V, invention description (133) — ' ~ ~ mouth in the synthesis of epoxy meclorone and related compounds, a significant confusion is needed The π-alkoxycarbonyl substituent is introduced into the 7 • carbon upon stereoselection, and there is no desire for modification at other positions in the steroid structure. According to the present invention, it has been found that after the introduction of a 7-oxime oxygenated carbonyl substituent synthesis route, and the following steps (1) first cyanidation on the 7-carbon of the steroid, (ii) hydrolysis 'cyanosteroid formation-carboxyl a mixture of an acid and a 7-carboxylic acid sterol, (iii) a 5J-lactone steroid from the 7-carboxylic acid sterol, and (iv) a small acid steroid from the 5,7-lactone steroid. The 5,7-lactone steroid and the burn-in reagent are subjected to a ring-opening reaction mediated by a base to produce a desired 7-cardoalkyloxycarbonyl steroid. 4 Because of this, the process of Scheme 8 refers to the preparation of Δ^ sterol substituted with 3-keto-7 alkyloxycarbonyl, including the burning agent and 3-keto-4,5-dihydrogen. The -5 a lactone type solid gas tannin is reacted in the presence of a base. The vinegar is replaced by a ketone group, which further includes the following parts: Therefore s?(u^V7)

A ZZ • mm 〇~\

XXX wherein c(5) represents 5·carbon, and c(7) represents 7-carbon of the steroid structure. The conversion of the 5,7-lactone to the alkoxycarbonyl group is preferably achieved by reaction with an alkyl group in the presence of a base. The alkyl group reagent is preferably an iodide, and is preferably methyl 硖0-136- -------------- I - This paper scale applies to the Chinese National Standard (CNS) Λ 4 specification ( 210Χ 297 mm)&quot;~------, 野^__w- (Please read the notes on the back and fill out this page) 1248443 A7 B7 V. Invention Description ( 134 淖 戎摞 中 中 中In accordance with the present invention, a beneficial process for the preparation of 4,5-dihydro-5,7• steroids (4 above; compounds) has been found to be a beneficial process in this process. The keto group ^ △, -7 ^ cyano substituted cardiac steroid is converted into a 7-carboxylic acid, and the acid is further reacted with a trialkyl orthoformate in an acidified lower alcohol solvent to form a 57_ internal target. The orthoformate reaction can also convert the 3-keto group into a non-cyclic or cyclic acetal 5,7-lactone (it should be understood that a lactone will be formed first). Preferably, the 3_acetal is 7 7 3-Dialkyl acetal 5J-endo vinegar. More preferably, the alkyl portion of the alcohol solvent is the same as the alkyl portion of the alkoxy group of the orthoformate (and preferably all is methyl) because: acetal The oxy moiety may be derived from orthoformate or alcohol The mixed acetal is not preferred; and 3-dimethoxy is preferred. When the acetal is B&amp; acetal, the alkyl group of the alcohol solvent is not necessarily the alkoxylate of the orthoformate. The base moiety is the same. The 3-acetal_5,7-lactone can be easily hydrolyzed to a 3-ketoester, a crystalline compound which can be easily purified. Since only 7"-carboxylic acid will undergo a lactonization reaction, The full body specificity of jl is known. The 70-acid can be removed from the reaction mixture in its salt form, such as by a mild treatment of 7 cold-acids, such as sodium bicarbonate. The 7-cyano acceptor of the lactone can be prepared in a known manner. For example, an unsubstituted support on a 7-carbon can be reacted with a slight excess of cyanide ions, preferably about 1.05 per equivalent of substrate. About ι·25 equivalents, and in a weak acid solution containing a water/DMSO solvent mixture. Preferably, the reaction mixture includes a complex acid such as about 1 equivalent of acetic acid per equivalent of the substrate. 7 α _ and 70 0 -CN isomers It can be formed with the 7 ^ isomer as the main isomer. Other methods known in the art can be used for this auxiliary method. = Usually according to the process 8, 5, 7 - vinegar Formed from a 7-carboxy intermediate (its -137- 'this paper scale applies to Chinese National Standard (rNS) Λ 4 specifications (210x297 mm) ---------0------ order-- ---- (Please read the note on the back and then fill out this page) 1248443 A7 B7 V. Inventive Note (135 is prepared by hydrolysis of 7-cyano intermediate, ^ ^ ^ β I), which is at 17 The _ position is a ketone, substituted by R8 or R9, wherein R8 and r94 u are as described above, and there are aliphatic, chain oxime, epoxide or #i group substitution configurations on C-9 and C-11. , which is

XL (please read the notes on the back and fill out this page)

-LP.

〇

XLII

, 1T by the full division of the rate of the Bureau of the staff X consumption of the Zhushe Society, the production of -AA- '-BB- and R3 as defined above, &quot;ο such as R8 and R9, or R80 and R9〇 - constituting a ketone group, and RU is as follows, and -EE- is selected from the following > see in step 9. %1 -138 This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 B7 V. Description of invention (136 \1 R21 R22 C &quot;&quot;&quot; '* C - 如, CH- CHa

XLII I I ;c = c- as &quot;C - CH-

XLIV I -c / /

R I 2 o-c-R

Hi o mt c H- c

V L X ---------β _ — (Read the first note on the back and fill out this page)

XLVI , 1Τ C-^CRf1 , usually, the compound of formula XLII is converted to 7 α -alkoxy-carbonyl

XLVII MM Department of the ruling #导局员丁-consumption and eii printing R β·0

〇 XLII , Ρ. R «·〇 〇

XLVIII This paper scale applies to China National Standard Rate (CNS) Λ4 size (210Χ 297 mm) 1248443 A7 B7 V. Inventive Note (137) In XL, XLI, XLII and XLVIII, R80 and R90 preferably contain ketone together. Base or

:C( 1 imi( CH,) 2 . C - X

XXXIV where Y1, Y2, X and C(17) are as defined above, and preferably R80 and R contain 90 ..... I. II i - —I — — In h I (please read the back first) Note on this page)

Preferably, R3 is Η, R1 is preferably methoxycarbonyl, and each of -A-A- and -B-B- is preferably -CH2-CH2-. It will be appreciated that the reaction can also be carried out under the protection of a 3-keto group, i.e., converted and maintained in each ether or acetal form, as such throughout the reaction sequence. An additional process for Scheme 8 involves the use of various intermediates within the scope of Formulas XLI and XLII, as indicated above. It is noted that the reagent for forming 5,7-end vinegar from 3-keto-indenyl 4,5]-carboxylic acid in Scheme 8 is tricarboxylic acid formic acid triacetate, and the conversion of oxandione dione by Scheme 6 11 ^- The 3-enol ether-3,5-diene-11 π-hydroxyl intermediate 1〇1 is the same reagent, and the reaction route of the salt flow is determined by the substitution of C-7. The reaction with the orthoformate in the presence of Η+ forms an intermediate cation with a carboxyl group on C-7, and its positive charge is balanced between C-3 and C-5. Once the proton is lost, the c 3 cation carbon ion can form a compound of the formula ι〇1, and the c-5 cation carbon ion forms a lactone. When C-7 is hydrogen, the salt 3,5-dienyloxy (enol ether) is suitable for the Chinese national standard · fcNS ) A4^ ( 210X 297^4 )榡 榡 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - If 7 α _c〇2 is substituted at C_7, the c-5 cation carbon ion can be a carboxyl group capture&apos; and a 5,7-lactone can be formed. At this point, the 3-keto group can be differentially converted to an acetal, which drives the reaction to completion. A preferred embodiment of the tile 8 is described in Schemes 9 and 1 below. Scheme 9 Scheme 9 begins with the same substrate as Scheme 4, a compound of formula XX. This is first emulsified into a compound of formula B:

Where -Α·Α, R3 and as defined in the formula xm. The oxidation reaction is carried out according to any one of the reaction schemes in which the compound of the formula 4ιν in the above Scheme 4 is converted into an intermediate of the formula. Conversion of the hydrazine compound to the 7-cyano intermediate of formula C using the method described in Scheme 8

Wherein -Α-Α, R3 and -Β_Β_ are as defined in the formula. Next, the formula c-141 - the paper size applicable specifications (21 〇 > ^ 97 mm 1 --- --------------- IT------ φ - (Please read the notes on the back and fill out this page) 1248443 A7 _______ B7 V. Inventive Note (139) Conversion of the compound to the 5,7-lactone of formula D:

Wherein -A-A, R3 and -B-B- are as defined in formula XIII, and the RPSCrQ alkyl group utilizes a trialkyl orthoformate reagent as previously described in Scheme 6. The 5,7-lactone of formula D can be easily separated from the unreacted 7-/?-COOH, such as the removal of the acid via a bicarbonate wash, which develops the desired C-7 stereochemistry and prevents subsequent reactions. The difference is the isomerization, which is the reaction that will be carried out under the conditions of the test. The esterified lactone of formula 11 can be formed as described in Scheme 8 with an alkyl-esterified esterified lactone. Following the synthesis of Scheme 9, the compound of formula D can be converted to the compound of formula 11. The 3-keto group is protected by conversion to an acetal, and the 20-spirooxane of the formula is selectively introduced at the 17_ position according to the reaction schemes described in Schemes 3 and 6, and the compound of formula E is produced. Read the notes on the back and fill out this page.

-142- 孓 Paper scale applies to Chinese national standard ((&quot;NS)A4 specification (210X297 mm) 1248443 A7 -------------- - _ - V. Description of invention (14〇) ~ ' ~ Q is protected by 3 ketones, the hydrolysis conditions can be selected to make 1 ketone optimally depleted, and no by-products are formed in the 3 · position reaction. The hydrolysis of the 3 - carboxylic acid compound into formula F After the 3-keto structure

The latter intermediate is reacted with an alkyl iodide in the presence of a base, and according to the conversion of Scheme 8, an intermediate oxime ester of formula II can be produced. Finally, the intermediates can be converted to epoxy meclorone or other compounds using the process described above. The process benefits are not only derived from the stereochemistry provided by the 5,7-lactone intermediates. Further advantages include greater hydrolysis conditions without interfering with 17-spirolactone. It is said that the reaction of Scheme 9 can be used for the reaction other than the one described above, as in the other synthetic schemes of the present invention. Thus, for example, a 3-keto or a 3-acetal cyanosteroid is converted to a 3-keto or 3-acetal-5,7-lactone, or a 3-keto or 3-furfural-5,7- The lactone is converted to an alkoxycarbonyl group which may be substituted with R and R on the i7_carbon (as defined above) or, more particularly, a compound substituted with a substituent of the formula below: _____-143- 4^ 涵0 ------IT------φ— (Read the first note on the back and fill out this page) 1248443 Α7 Β7 V. Invention description ( 141

[A] wherein X ′ Υ 1 and Υ 2 are as defined above, and C ( 17) represents 17-broken. However, important advantages should be understood, especially in the economics of the process, using a specific reaction sequence with a 17-keto substrate, and following the specific reaction procedure described above to introduce 17-spirolactone and 7 π-burning oxycarbonyl. Ketone steroids. Formula D, hydrazine and F lactone are novel compounds which can be used in accordance with the synthesis of Scheme 9 for the preparation of epoxigenone and other compounds of formula I and hydrazine. Among these compounds, -Α-Α- and -Β-Β- are preferably -CH^CH2·, and Han 3 is hydrogen, lower alkyl or lower alkoxy. Preferably, R17 is a methoxy group in the formula. In the specific example, the overall process of the process 9 is as follows: I 1 j - 1 - - - - - ϋ i - - - I - - 1-: ΎΝ, -tl (please read the notes on the back first) Fill in this page j by the Ministry of Consumer Affairs, the Department of Standards, Bei.T.

[B] 144- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (21 ΟΧ 297 mm)

1248443 A7 _______________B7 V. Description of the Invention (142) Scheme 1 0, Scheme 1, 0 is the same as Scheme 9, and is formed by the 7-cyano intermediate of the formula. In the next step of the scheme, the 7-cyanosteroid is reacted with the trialkyl orthoformate in an alkanol solvent, preferably a trimethyl orthoformate in methanol to simultaneously protect the 3-ketone and 17- A ketone group converts the former to an enol ether and converts the latter to an acetal. Thereafter, the 7-cyano group is reduced to a 'mercapto group, such as a reaction with a dialkylaluminum hydride, preferably diisobutylaluminum hydride, from which a compound of formula 203 is produced: 203 wherein R3, and Β-Β_ As defined in formula XIII, and rU is a k group. Before the keto group protection, as described above, it can be prevented from being reverted by dialkyl hydrogenation. The intermediate of formula 2 3 is then reacted with a dilute aqueous acid solution to selectively hydrolyze the acetal and produce an intermediate of formula 204 in the presence of excess alcohol (R19〇H): (Please read the notes on the back first) Fill in this page)

[204] -145- This paper scale applies to China's national standard rate (&quot;&quot;('NS ) Λ4 specification (210X297 mm) 1248443 A7 B7 V. Invention description (144) 〇

Wherein -A-A-, -B-B-, R^Rl9 are as defined above, and r25 is Ci_C4 alkyl. After the '3-position is protected by conventional hydrolysis, the $-keto group and the 5,7·half-acetal can be reintroduced to produce a further intermediate equivalent to Equation 2〇9: --------- #! (Please read the notes on the back and fill out this page)

[209}

, 1T wherein -A-A-, -B-B- and R3 are as defined above. Next, the 9,u epoxide moiety is introduced according to either the compound of the above formula 11 or the conversion of the compound of the formula. Under the oxidizing conditions of the oxidation reaction, the hemiacetal can be partially converted into Z,7-lactone, which produces a further intermediate corresponding to the formula 211. t211) ΦΙ. The sub-standard rate in the extinction part - Consumption Hezhu Society Printing $ 〇

1248443 A7 V. INSTRUCTIONS (145 B7 I-A_A_, _B-B_ is, ο . U as defined above. Any remaining formula 210, 1 epoxy-5,7-half ^ φ n &amp; , receiving the reaction product of the τ substance 210 ·· ......... - - ·-

[210] ', H H ' _ Β Β and R3, as defined, can be readily converted into the compound of formula 211 by conventional methods. Finally, the intermediate of Formula 211 utilizes the procedure "5" to convert 5,7-lactone to 7 "-alkoxycarbonyl compound, ^ oxime meclirone or other compound of formula j. Because &amp;, overall: 2 Process 10 is carried out as follows, it should be understood that at least the following steps can be used to recycle intermediates. Overall, the synthesis of process 1〇==2, ---------#II (please read the notes on the back and fill out this page), 11 ^91. J-consumer zhuzhusheyin f -148- This paper scale applies to China National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 V. Description of invention (146

OR ’&quot;&quot;CH. [2. 3]

-------- (Please read the notes on the back and then fill out this page) Book the 漭 中 决 决 绎 , τ τ τ τ τ τ τ τ τ τ

------ ------m ΕρΙ«Γ·ηΰη« As in the case of Process 9, the reaction of the above process provides important benefits, especially with regard to process economics; but the novel reaction of Process 1 There are also more general applications for the quality of the interviewer. For example, 7 _ 酼 酼 149 - paper scale applies to Chinese National Standard (CNS) Λ 4 specifications (210X297 mm) ir. 1248443 A7 B7 V. Description of invention (147) Introduction of 3-enol ether steroids, protection generated 7_methylmercapto_Δ5,6_3,4·% alkyd, hydrolyzed to 5,7-hemi-acid, and then on the steroid with r8 and r9 substituted at the I? position Deprotection on a steroid substituted with a substituent: r : C( 1 7&gt;"&quot;·( CHf) ! ♦ c

XXXIX where X, Y1, Y2 and c(17) are as defined above. An additional process of Scheme 10 includes the use of various intermediates within the scope of Formulas A203 through A210, respectively, as described above. Each of the intermediates of formula A203 to formula A2 11 is a novel compound which can be used in accordance with the synthesis of Scheme 10 to prepare epoxigenone and other compounds of formula I and I A. In the specific example, the overall process 1 process is as follows:

The Department of Economics and Trade in the Ministry of Economic Affairs, SCJ·.

1. lactonization 2. deprotection 3. epoxidation 4. oxidation

------IT------ (Please read the notes on the back and fill out this page) -150- This paper size is common Chinese national standard bee: (CNS) Λ4 specification (210X297 mm) 1248443 A7 Through the full ^ ^ standard rate bureau s <Jr-consumer Hezhu $ India 5, invention description (148) From the above many processes, it should be understood that the steps used in the process of the present invention, in the preparation of epoxy On the merudone and related compounds, 'r: < 可 可 &; 关 特色 特色 特色 特色 特色 特色 特色 尤其 尤其 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关 关; α _ or 9 α _ hydroxy derivative (also converts f-germogenic alcohol to 17 keto structure); (8) from the dehydration of the original &quot; ^ or 9-based compound to introduce 9, u double bond, by the mouth 9 η, the oxidation of the bond leads to the epoxy group; (4) the formation of the amine is attached to the m-acid group, the guanamine is hydrolyzed to the diketone, and the diketone is reacted with the metal oxide; (4) at the η position Form 2 〇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Ether or acetal in a 3 _ protection (including oxygen embankment spiro ring 20 is formed in the 17- position). With few restrictions, these four components (8) to (4) can be performed in almost any order. Process requirements (4) and (1) k are available for comparison <variability. It is simplistic in comparison with the process of the process of the invention, in which the process of the method of the invention is compared with the process of the process of the U.S. Patent No. 4,559,332. Furthermore, it provides important benefits in terms of productivity and productivity. In the reaction scheme described above, the recovery, separation and purification of the reaction product can be carried out by a method well known to the artisan. Unless otherwise indicated, the conditions: solvent and reagent are either conventional, &lt;not narrowly defined, or one is uniform. However, certain specific steps described above may provide advantages that may result in beneficial overall yields and/or yield forces for various process steps and processes, and/or may provide high quality intermediates and ultimately 9 , u_ steroid product. ___ -151- 冢 paper scale 1| / 〗 towel home office (&quot;cNS) (210^297^1) ------IT------φ- (Please read the back of the precautions Fill in this page again. The Department of Standards and Regulations of the Ministry of Economic Affairs, J-Xingyi, Hezhushe, India, 1244843 A7 I-______ B7 V. Inventions (149) ~-- 20-spirooxane produced according to the present invention Compound, its availability, human Gn &gt; b ILS. Patent No. 4,559,332, the disclosure of which is incorporated herein by reference in its entirety in its entire entire entire entire entire entire entire entire entire entire entire entire entire portion For example, the dragon has a strong aldosterone-antagonism because it reduces the inappropriate high sodium retention and potassium excretion caused by aldosterone and normalizes it. Therefore, it can be used as a potassium-sparing diuretic, and important therapeutic applications such as treatment = blood pressure, cardiac dysfunction or cirrhosis. · 20-spirooxane derivatives having aldosterone-antagonism are known, see, for example, Fieser and Fieser; Steroids; p 708 (Reinhold PUM· Corp., New York, 1959) and British Patent No. L04U34 Similar to the active 17-3⁄4-yl-21-carboxylic acid and its salts are also known, see, for example, U.S. Patent No. 3,849,404. Such compounds have previously been used in the treatment of 'however' because they always have certain sex-specific activities and therefore have considerable disadvantages. This has a trouble causal relationship sooner or later in their traditional long-term treatment. What is particularly undesirable is that it can be attributed to the cumbersome effects of anti-androgenic activity of known anti-aldosterone formulations. The process, process and composition of the present invention, as well as the conditions and reagents used herein, are further illustrated in the following examples. Example 1 Preparation of slant culture medium, wherein the growth medium is as shown in Table 1. -152- This paper scale applies to Chinese national standard fcNS) 八7^7210χ 297 mm) Order ~~ (Please read the back note first and then fill in this page ) 1248443 V. Description of invention (

Protein moon east glucose

Steam the water, add the appropriate amount to -pH 6.7 - adjust to pH ratio with H3P〇4 10% w/v (please read the notes on the back and fill out this page). Incubate on slope: 7.5 ml at 180 X 18 亳- in the culture tray (10 cm diameter) 25 ml in a 200 X 20 mm tube sterilized at 120 ° C for 20 minutes after sterilization pH 値: 5

, 11 -Φ, the final rate of the cadres in the cadres _ τ 贽 贽 竹 社

To produce the first generation culture, the Aspergillus oryzae colonies were suspended in test tubes, distilled water (2 ml), and 0.15 ml each of the suspensions were taken to the sloping surface, which was previously prepared as described above. The slope was incubated at 25 ° C for 7 days, after which the surface culture was visualized as a white cotton-like hyphae. The lower half of the reverse side is orange, earthy, and yellowish orange. I -153- The paper size applies to the Chinese National Standard (CNS) Λ4 specification (210Χ 297 mm). The 73⁄4' department of the middle and the second squad, J-Chan 贽 竹 社 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 DESCRIPTION OF THE INVENTION (151) ~~ ----- One&quot; The first generation of slant cultures are suspended in a sterile solution (4 liters) containing Tween 20 nonionic surfactant (3% by weight). A suspension of 0.15 ml of the suspension was inoculated on a second generation bevel, which was prepared in the growth medium shown in Table 2. Table 2 ^~ (for the first generation and the case of the common slant, malt extract 20 g protein gland 1 g --- glucose 20 g agar 2 0 g steamed water added to • pH 5 · 3 - dispensed in a test tube (180 X 1 8 mil) 7.5 ml - sterilized at 120 ° C for 20 minutes 1000 ml first generation slant at 25 ° (: cultivating for 1 day, producing large golden yellow spores; Reverse surface ·^ standard orange 0 Prepare a protective medium with the composition shown in Table 3. -154- This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) ----------- ----Book ------AWI (Read the first note on the back and fill in this page) 1248443 A7 The full section of the Ministry of Finance and the Ministry of Finance ί. Consumers Zhu Zhushe qi 5, invention instructions (152) Table 3 - Protected medium skim milk 10 g distilled water 100 ml In a 250 ml flask containing 50 ° C distilled water and added skim milk. Sterilize at 15 ° C for 15 minutes, cool at 3 3 C and Use 5 suspensions of the second-generation slant culture in a 100 ml flask of the protective solution before the end of the day. Suspension (0.5 ml) at 1 〇 () &gt;&lt; 1 〇 The tubes are dried at $. These are pre-extended to _7 in argon/dry ice bath (rc to _8 (rc = frozen for 20 minutes, then immediately transferred to pre-cooled to _4 (rc to _5 〇〇 c drying) The pre-cooled portions of the Middle East are freeze-dried at 50&quot;Hg and f3 (TC). At the end of freeze-drying, 3 pieces of sterile silicone are added to each tube, and moisture is used to indicate the flame seal. The deaf is suitable for industrial scale. The mother culture of the yeast was slanted, and a single lyophilized culture prepared in the above manner was suspended in distilled water (丨 ml), and a 0.15 ml suspension was used for inoculating the slope, and the slope was The growth medium of the composition shown in Fig. 2. The mother slant culture was incubated at 25 〇 under the armpit for 7 days. At the end of the cultivating, the culture developed on the slant surface was kept under. For the preparation of the usual slant culture, the culture from the mother slant The culture is suspended in a sterile solution containing Tween 8 〇 (3% by weight) (4 ml), and 155- This paper scale is used for the towel scale (-CNS) Λ 4 specifications (210X29^^ Read the precautions on the back and fill out this page. j 1248443 A7 B7局贝h消贽合竹社印?^ V. Inventive Note (153) The resulting suspension is placed on a sloping surface in a portion of 〇·15 ml, and the growth medium coated with 士2 is applied. A normal bevel culture can be inoculated into a first/human seed flask for experimental or industrial fermentation. To prepare a first seed flask culture, the culture in the usual bevel (from the above preparation) is removed, And suspend in a solution containing Tween 8 〇 (3 % by weight) 4 (10 ml). The resulting suspension was introduced into a 5 liter refractory flask containing 1 ml of each mash, and there was a growth medium having the composition shown in Table 4. Table 4 Glucose 20 g protein gland 20 g yeast autolysate 20 g distilled water added to pH 5.2 - adjusted to pH 5.8 with NaOH 20% - 100 ml flask dispensed in 500 ml refractory plate - dispensed in 2000 ml round bottom Flask (3 barriers) 500 ml - sterilized at 120 ° C for 20 minutes - pH after sterilization 値 about 5.7 Seed flasks were incubated in a 2 8 X: rotating oscillating tank (200 rpm, 5 cm displacement) Hours, which can produce pellets with a diameter of 3-4 mm -156-

This paper size thorn towel home office (CNS) AAim ( 210X 297^f J

Aw order (please read the note on the back and fill out this page) 1248443 A7 B7 A, invention description (1S4) — (please read the note on the back and fill out this page) Mycelium tissue. Under the microscope, you will find The seed culture is a pure culture that has a similar nematode production, has large hyphae and is fully curled. The pH of the suspension is 5.4-5·6. The PMV is 5-8% by centrifugation (3000 rpm X 5 Minutes. Preparation of the flask culture was carried out by inoculating the biophore (1 ml) (from the seed culture flask) into the growth medium (100 ml) having the composition shown in Table 4 and placed in the second 500 ml. The flask was shaken and the resulting mixture was incubated in a rotary shaker (2 rpm, 5 cm displacement) for 18 hours at 28 Torr. The culture was examined and found to contain pellets of 3-4 mm in diameter. Silk tissue. Under microscopic examination, it can be determined that the culture is a pure culture with nematode-like and cilia-like growth, in which the top cells are filled with cytoplasm and the old cells are few empty. The pH of the culture suspension is 5-5.2, and the PMV is determined by centrifugation. Between 10% and 15%. Therefore, the culture is indeed suitable for the transformation of Kenyrone to 11 π-hydroxykenrestone. Kirrifone (1 g) was micronized to about 5 # and suspended in sterile water (2 ml). The following suspension was added to the suspension: 40% (w/v) sterile glucose solution; 16% ( w/v) sterile autonomously dissolving yeast solution; and sterile antibiotic solution; all of the above are in the proportion of the reaction time as shown in Table 5. The preparation of the antibiotic solution is oxytetracycline (40 mg), tetracycline hydrochloride (4 mg) and cefalexin (20 mg) are dissolved in water (1 ml). In the culture of the shake flask, a steroid suspension, a glucose solution and an autonomously dissolved yeast solution are gradually added. -157- _ί, paper tooth ϋ standard one (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 V. Description of invention (155) Table 5 Steroids and solutions in the bioreversion process of Kirreone in a shake flask Addition refers to a steroid suspension of approximately 0.5 ml of glucose solution l antibiotic solution soaring autonomously dissolving yeast solution, soaring

---------9-- (Read the first note on the back and fill out this page)

1T When the reaction proceeds, the reaction mixture is periodically analyzed to determine the amount of glucose, and thin layer chromatography is used to determine the conversion to u^_hydroxykenrein. In the reaction, add additional nervonic acid and nutrients to the fermentation reaction, and control the rate to maintain the glucose content in about 1% by weight. The procedure for adding a suspension-type suspension, a glucose solution, an autonomously dissolved yeast solution and an antibiotic solution is shown in Table 5. The transformation was carried out in a rotating oscillating tank and continued at 25 ° C for 96 hours. (200 rpm & 5 cm displacement). In the fermentation, the pH range is between 4.5 and 6. When the PMV rises above 60%, the -158-$ paper size is appropriate for the A Chinese National Standard (CNS) A4S (210X 297 mm) 1248443 After the cadre of the cadres of the squad, the 贽 贽 贽 $ $ $ 4 Α Α 7 Β 7 V. Description of the invention (156) Take a portion of 10 ml of gravy and replenish it with 毫升 0 ml of distilled water. In the reaction, samples were taken at 4,7,2 3,3 1,4 7,5 5,7 1,8 〇 and 9 6 hour intervals after the start of the fermentation cycle to track the disappearance of ketone and 1 i "The appearance of monohydroxy ketones and analysis of gravy samples by TLC. The reactions determined by these samples are shown in Table 6.

The first seed flask was prepared as described in Example 1. Preparation Camp-159- 3, Paper H is applicable to China National Rate (('NS 210X 297 mm Factory'~ (Please read the note on the back and fill out this page again), 1Τ 1248443 A7 B7 V. Invention Description (157) The mixture has the composition shown in Table 7. Glucose protein gland Table 7 is used for 10 liter glass fermentation tank. Transformation culture volume 80 g 80 g/L 20 20 Mainly dissolved yeast 80 g 20 Anti-foaming agent SAG 471 0.5g Please read the back of the matter and then fill out this page. 4 liters of the Ministry of Economic Affairs, the Department of Standards and Regulations, the second 贽 贽 贽 社 社 社 社 离 离 - - - - - - - - - - - - - 130 130 130 130 130 130 130 130 130 130 130 Deionized water, heated at 40 ° C - stirring; added to the medium component - 15 minutes of stirring, the volume reached 3.9 liters - pH 5.1 - adjusted to pH 5.8 with NaOH 20% w / v - at 120 Sterilize at °C for 20 minutes - pH after sterilization is 5.5-5.7 The initial filler (4 liters) of this nutrient mixture is introduced into the 10 liter table volume and volume of the fermenting tank. The fermentation tank is cylindrical and has 2.5 8 The ratio of the height to the diameter. It is equipped with a 400 rpm turbine stirrer and has 6 blades each. 2 160 paper Zhang scale applies to China National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 ____________—B7 V. Invention description (158 ) ~~ Round wheel 2 pay. The outer diameter of the vane is 8 mm, each blade has 25 The radial diameter of the millimeter and the height of 30 mm, the upper wheel position is 28 mm from the top of the container, the lower wheel is 365 mm, and the resistance plate of the container is 21 mm high, and extends radially inward from the inner side wall of the container. 5 mm. The seed culture (40 ml) was mixed with the nutrient-based filler in a fermentation tank and incubated at 28 ° for 22 hours at a rate of 〇 5 liters / liter - 〇 5 kg / cm 2 The pressure develops into a transforming culture. At 22 hours, the culture has a PMV of 20-25% and a pH of 5 to 5.2. Prepare a suspension containing the amount of water in sterile water (4 liters).酉 酉 (80g), and add 1 〇 ml to the mixture in the transfer vat. At the same time, 40% (w / v) sterile glucose solution, 16% (w / v) sterile Autonomously dissolving the yeast solution' and the sterile antibiotic solution, according to the ratio shown in Table 8 in the hour-hour reaction time. Antibiotic solution The preparation was carried out in the manner described in Example 1. ^------tr------ (Please read the notes on the back and fill in this page.) 漭中中摞绛局兵J-消贽告竹社印嗽161 - This paper scale applies to China National Standard Rate (CNS) Λ4 Specification (210X297 mm) 1248443 A7 B7 V. Invention Description (159) Table 8 10 liters of broken glass fermentation tank, Kenridone Indications for steroids and solutions (additives and antibiotics) during the addition of reaction time hrs of steroid suspension in milligrams of glucose solution, milliliters of yeast autonomous solution, milliliters of antibiotic solution, ml 0 10 4 25 12.5 40 4 25 12.5 8 10 4 25 12.5 12 25 12.5 16 10 4 25 12.5 20 25 12.5 24 10 4 25 12.5 40 28 10 4 25 12.5 32 12.5 5 25 12.5 36 12.5 5 25 12.5 40 12.5 5 25 12.5 44 12.5 5 25 12.5 48 12.5 5 25 12.5 40 52 12.5 5 25 12.5 56 12.5 5 25 12.5 60 12.5 5 25 12.5 64 12.5 5 25 12.5 68 12.5 5 25 12.5 72 12.5 5 25 12.5 40 76 12.5 5 25 12.5 80 ' 84 88 -162- (Please read the back first Refill This page) One use • Moderate ruler paper Chinese standard ((, milk) / \4 specification (210X297 mm) 1248443 A7 B7 —______________ --------------- -- ---丨晒1-1 1&quot;1 广一1 11 1 1 i ·.·.1' '··-· ·»&quot; β &quot;' '-一' - ^^ ^________ V. Invention Description (16〇) As the reaction proceeds, the reaction mixture is periodically analyzed to determine the glucose content and is determined by thin layer chromatography to the conversion of 11-hydroxykenrene. According to the TLC analysis of the reaction broth samples (as described below), when the ketone is consumed, additional ketone is added to the reaction mixture. The glucose level is also tracked, and when the glucose concentration drops below about 〇·〇 5% by weight, an additional glucose solution is added to bring the concentration up to about 〇·25% by weight. Nutrients and antibiotics are also added at different times in the reaction cycle. The procedure for the addition of the steroid suspension, the glucose solution, the self-dissolving yeast solution and the antibiotic solution is shown in Table 8. The transformation reaction was continued for 90 hours. The aeration rate was 5 times the volume of air per minute (VVm) and had a positive head pressure of 0.3 kg/cm2. The temperature was maintained at 2 8 C ' until the P VM reached 45 %, then decreased to 26 ° C, and maintained at this temperature when the PVM rose from 45% to 60%, and then controlled at 24 ° C. The initial agitation rate was 400 rpm and increased to 700 rpm after 40 hours. The pH 値 was maintained between 4.7 and 5.3 and 2M positive scale fe or 2M NaOH was added as indicated. Add a few drops of Antifoam SAG 471 to control foam formation. The broth was analyzed by TLC during the reaction, and the disappearance of nicrosone and the appearance of 11α-hydroxykenrestone were followed by a small time interval of 4 hours. When most of the same ruthenium disappears from the gravy, an extra amount can be added. Once all of the renrolone has been added, the TLC analysis shows that the reaction can be halted by a decrease in the concentration of the nervonic acid compared to the 11α-hydroxynorrein product to about 5%. Summary of the reaction cycle, the mashed broth was filtered through gauze to separate the mycelial tissue from the liquid broth. The mycelium fraction was resuspended in ethyl acetate for approximately 65 volumes per gram of load per gram of load throughout the reaction (read the instructions on the back before reading this page) • eg, 1Τ 1 163- The paper ruler (4) financial materials (CNS specifications (210X 297 public f) Once the cadres of the squad, the squad, the employee, the sputum, the sputum, the sect of the sect of the sect of the sect of the sect of the sect of the sect of the sect. The mycelial suspension in acetaminophen was refluxed under disturbance, and the cold-P soil was about 20 C' and filtered on a Buchner funnel. The mycelial masses were successively washed with acetic acid (5 times volume per gram of kendresyl load; 〇·4 liters) and deionized water (500 ml) to wash the extract of acetic acid in the replacement block. The block can be discarded. The rich extract, solvent wash and water wash were collected in a separator and allowed to stand for 2 hours to separate the phases. The aqueous phase was discarded and the organic phase was concentrated under vacuum to a residual volume of 35 mL. Cool to 15 ° C and hold for about i hours with agitation. The resulting product was filtered, and the crystalline product was removed, and the filter was washed with ethyl acetate (4 mL). After drying, the yield of 11-hydroxy hydroxy ketone was determined to be 6 gram. Spore suspensions were prepared from conventional slant cultures as described in the Examples. In a 20003⁄4 liter round-bottomed flask with a baffle plate (3 baffles, each 5 mm mm x 30 mm), a portion (〇·5 ml) of the spore suspension was introduced into the nutrient solution of the composition π of Table 4 ( 500 ml). The resulting mixture was incubated in a flask at 25 C for 24 hours, and the culture was produced in an alternating shaker (12 rpm per minute; 5 cm displacement). Under the microscope, the hyphae were fully distorted and pure. Cultures. The pH of the culture was between about 5.3 and 5.5, and the PMV (determined by centrifugation at 300 rpm for 5 minutes) was 8-10%. Using the culture thus prepared, seed cultures were prepared in a vertical cylindrical stainless steel fermentation tank having a geometric volume of 160 liters and an aspect ratio of 2.31 (鬲 = 985 mm; diameter = 425 mm). The fermentation tank has a disk turbine agitator with two vanes, each of which has six outer diameter 240 mm pieces, each of which has a radial diameter of 80 mm and a height of 50 mm. The upper wheel is positioned at the Fermentation-164- This paper scale is applicable to the Chinese National Standard (CNS) Λ4 specification (210Χ297 mm) I I-I — ~ (Please read the notes on the back and fill out this page; &gt;中部中中标准局βχ消贽合竹社印 f 1248443 A7 ——-一_----------- -B7 V. Invention description (162) —~-- = Top 碲 780 3⁄4 At the meter, the second wheel is 995 mm. The vertical block is 8 columns*m high, and the inner side of the fermenter is radially inwardly extended by 4 mm. The agitator operates under η〇ΓΡΙΏ. It will have the appearance shown in Table 9. The composition of the nutrient mixture (1 liter) was introduced into the tank, and a part of the pre-inoculation (1 liter) having pH 57 was prepared as described above. Table 9 - Checking the growth-producing rolls in the 1^±^ tank and Diluted q. Production of fermentation tanks g / liter of glucose 2 kg 20 protein glands 2 kg 20 autonomously isolated yeast 2 kg 20 anti-foaming agent SAG 471 0.010 kg trace deionized water added to - empty fermentation tank Sterilize at 130 ° C for 1 hour - fill 6 liters of deionized water, heat at 40 ° C - add and stir; mix the components of the medium - 槚: mix 15 minutes to make the volume 95 liters - sterilized at 120 C for 30 minutes - pH after sterilization is 5.7 - plus sterile deionized water to 1 liter of 100 liters / inoculum mixture incubated at a rate of 〇 5 liters / liter - 22 hours , Head -165- This paper size applies to China National Standard (CNS) Λ 4 specifications (210X 297 mm) ---------0------, 玎 ------%! (Read the first note on the back and fill out this page) 1248443 A7 B7, invention description (163) ^~ The pressure of the rock is 0.5 kg / cm 2. The temperature is controlled at 28 ° C until the PMV reaches 25%, then lower to 25 °C. The pH値 is controlled at 5.1-5.3. The growth of mycelial tissue is shown in Table 10, plus the pH and dissolved oxygen profile of the seed culture reaction. Table 10 Time course of mycelial growth in seed culture fermentation Hypophyseal pH volume (pmv) % (3000 rpm 5 min) Dissolved oxygen % 0 5.7 Soil 0.1 100 4 5·7 ± 0.1 100 ~ 8 5·7 ± 0.1 12 ± 3 85 ± 5 ^ 12 5.7 ± 0.1 15 soil 3 72 soil 5 16 5.5 soil 0.1 25 soil 5 40± 5 — 20 5·4± 0.1 30± 5 35 soil 5 22 5·3± 0.1 33± 5 30± 5 ^ 24 5.2± 0.1 35 5 25± 5 (Read the first note on the back) Write this page)

If. 、, 口 口 Γ Γ Γ Γ Γ Γ Γ Γ χ χ χ χ 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用The fermented yeast is fermented in the fermentation tank. The fermenter has a turbine agitator with two vanes, one at 867 cm from the top of the reactor and the other at 1435 cm. Each vane has six obstructions, each having a radial diameter of 95 cm and a height of 75 cm. The vertical resistance piece is 1440 cm high and extends 100 cm inward from the inner side wall of the reactor. A nutritional mixture was prepared having the composition shown in Table 11. -166- The paper size applies to the Chinese national standard ((, NS) Λ 4 specifications (210X297 mm) '— --, — I. 1248443 V. Description of the invention (164 Table 1 1 Chemical culture 16 kg

Glucose protein gland main dissolved yeast anti-foaming agent SAG 471 Deionized water added to - empty fermenter sterilized at 130 ° C for 1 hour - filled with 600 liters of deionized water; heated at 40 ° C - added and stirred Drop the medium component - stir for 15 minutes to make the volume up to 650 liters - sterilize at 120 ° C for 30 minutes - the pH after sterilization is 5.7 - add sterile deionized water to 700 liters (read the first note on the back) Page) The initial load (7 liters) of this nutrient mixture (pH 5.7) was introduced into the fermentation tank by the Ministry of Health and Economics of the Ministry of Education, and the seed of this example prepared above was added. Inoculum (7 liters). The nutrient mixture containing the inoculum was incubated for 24 hours at a pressure of 升5 liter/liter per minute and a pressure of 55 kg/cm head, and the turbulent rate was i 1 rpm. The growth of mycelial tissue volume is shown in Table 2, pH 値 and dissolved oxygen profiles. To raise the anti-167- This paper scale applies to China National Standard (CNS) Λ 4 specifications (210X297 mm) 1248443 A7 B7 V. Invention description (165) Table 12

Compact hyphal volume (pmv) % (30 〇〇 rpm X 5 minutes) Dissolved oxygen % 0 丨.6 soil 0.2 4 5.5 ± 0.2 100 12 ± 3 100

At the time of the culture summary, the mycelial tissue was observed to be agglomerated, but the agglomerates were usually small and relatively loosely clustered. The scattered hyphae tissue is suspended in the gravy. The final pH 値 is 5.1-5.3. To the thus-transformed culture, a suspension of kansinone (1.2 5 kg; micro-knife into 5 彳 米) in 囷 囷 (5 liters) was added. Sterile additive solution and antibiotic solution were added in the proportions indicated in Table 14 when the reaction was thresholded. The composition of the additive solution is shown in Table 13. J 1· Γ ^^1 —^^1 I— mi I mi ml ·ϋ-ϋ ϋϋ in I mi —^ϋ \ , mu —ϋ —^ϋ —^ϋ (Please read the notes on the back and fill in this ) 中 中 中 _ _ _ _ _ _ 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 168 Solution 彡 culture) dextran 40 kg self-dissolving yeast 8 kg anti-foaming agent SAG 471 0.010 kg deionized water added - empty (15 liters) fermentation tank sterilization at 130 ° C 1 Hours • Add 70 liters of deionized water; heat at 40 ° C - add the ingredients of the "additive solution" under good load - stir for 30 minutes to bring the volume to 95 liters - pH 4.9 4.9 - at Sterilize at 120 °C for 20 minutes - pH after sterilization is about 5 1 liters (please read the notes on the back and fill out this page) - Determine the standard of the foreign bureau 炅J- Xiao 贽

Biotransformation is carried out for about 96 hours, including a ventilatory rate of 升·5 liters/liter-minute, a head pressure of 0.5 kg/cm 2, and a pH range between 4/7 and 5.3, as necessary. M NaOH or 4 M H3P04 adjustment. The agitation rate was initially 100 rpm' increased to 165 rpm at 40 hours and 250 rpm at 6.4 hours. The initial temperature is 28 ° C, when the PMV reaches 45%, it is reduced to 26 ° C, and when the PMV -169- paper size is suitable for China National Standard (CNS) Λ 4 specifications (210X 297 mm) 1248443 A7 B? 5. Description of invention (167) When it rises to 60%, it drops to 24 °C. Imitation v 1. It is necessary to add a small droplet of SAG 471 to control foaming. The sorghum, ', ^ 搪 levels in the yeast were tracked at intervals of 4 hours, and when the concentration of arsenic was reduced to 12, ^ SP was added to the sterile addition solution (10 liters). In the reaction, 乂 HPLC traced the disappearance of nicrosone and the appearance of 11 α-squirrel. Going to Tian Xingjin's initial Kenridone has at least 90/. When converted to ιΐα _ jikurenone, τ added 1.250 kg of renrolone. When 90% of the carbaryl ketones have been shown to be 屮μ &amp; w, the other i.250 kg is introduced. Using the same criteria, incremental increments (125 lbs each) until the total reaction load (2 〇 kg) is introduced. Once all of the ruthenium was delivered to the reactor with the load, the reaction was stopped when the unreacted concentration of encerone was 5% compared to the n^ gram of quinolone produced. The procedure for the addition of kansinone, a sterile additive solution and an antibiotic solution is shown in Table 14. -- (Please read the notes on the back and then fill out this page) 订 中 中 中 中 中 二 二 二 二 二 二 二 二 - 170 - This paper scale using Chinese national standard bee (rNS) Λ 4 specifications (210X297 1248443 A7 B7 V. INSTRUCTIONS INSTRUCTIONS (168) 经 中 中 标准 标准 表 表 表 表 表 f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f Addition of the reaction time suspension of the ketone ketone aseptic η solution antibiotic solution volume hour kilograms progressive kiloliter liters rise 0 1.250 1.25 10 8 700 4 10 8 1.250 2.5 10 12 10 16 1.250 10 20 10 24 1.250 5 10 8 800 28 1.250 10 32 1.250 10 36 1.250 10 40 1.250 10 44 1.250 10 48 1.250 12.5 10 8 900 52 1.250 10 56 1.250 10 60 1.250 10 64 1.250 10 68 1.250 10 72 1.250 20 10 8 1050 76 0 80 84 88 1 \ 92 , &lt;^,, 口 (Read the first note on the back and fill out this page) 171 - ^ Paper ruler Chuanchuan China National Standard _ ((, 吣) Eight 4 specifications (210/297 mm) 1248443 A7 —_______________ B7 V. Description of invention (169) ~ ~ When the biotransformation is complete, centrifuge in a basket centrifuge to separate the mycelium from the meat, ten The filtrate is determined by HPLC and can be discarded when the total amount of U ^ hydroxy ketocretone in the harvested gravy is only 2%. The mycelial tissue is suspended in ethyl acetate (1000 liters) and placed in an extract of 2 m 3 . In the tank, the suspension was heated under stirring and ethyl acetate reflux for 1 hour, then cooled and centrifuged in a basket centrifuge. The hyphae tissue block was washed with ethyl acetate (200 liters), and then discarded. The steroid-containing solvent extract is allowed to stand for one hour to separate the aqueous phase. The aqueous phase is extracted with ethyl acetate solvent (200 liters) and discarded. The mixed solvent phase is centrifuged to make it clear, and then placed in a thickener (5 (10) liters. The volume is concentrated under vacuum to a residual volume of 100 liters. When evaporating, the initial loading of the combined extract and washings in the concentrator is 100 liters::: The mixed solution is added continuously or periodically (when the solvent is reduced) This volume remains solid. Once the bursting step was completed, the bottom was cooled to 2 01 and stirred for 2 hours and then filtered on a Buchner funnel. The concentrator was washed with ethyl acetate (20 L) and the wash was used to wash the filter in the filtrate. The product c was dried overnight for 6 hours. The yield of Uf hydroxy ketone was 14 kg. Example 4 Aspergillus oryzae NRRL 405 lyophilized spores were suspended in a cereal-impregnating solution growth base (2 ml) with a composition shown in Table: ', -172- 尺 尺 尺 Z ΐ ( CNS ) A4 ^ ( 210xT97^t ) i - -1...... i - — (Please read the notes on the back and then fill out this page. j. 淖 中 中 J J - - 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 124 B7 V. Description of invention (17〇) Table 15 - Grain impregnation liquid (growth base for primary seed culture) Grain dipping solution 30 g yeast extract 15 g of pre-test scaly acid 3 g of glucose (after sterilization) Add), steam the remaining water, add to 1000 ml pH 4.6, adjust to pH 6.5 with 20% NaOH, dispense 50 ml to 250 ml triangle flask, it has been sterilized at 121 ° C for 20 minutes 30克 (Please read the note on the back and fill out this page) i# The resulting suspension can be used in the inoculum to proliferate the spores on the agar plate. Prepare 10 agar plates, each with the composition shown in Table 16. Solid Glucose/Yeast Extract/Phosphate/Agar Growth Base:

, 1T glucose (added after sterilization) Table 16 - GYPA (glucose / yeast extract / sulphate agar for plate) 10 grams of the sub-standard 绛 绛 ,, τ consumption and bamboo private printing f yeast extract K2hpo4 agar steaming water, add to 1000 ml pH 値 adjust to 6.5 at 121X: sterilize for 30 minutes 2.5 g

Transfer a 0.2 ml suspension to the surface of each plate. After 2 days, the spores from each plate were collected to contain Table 17; the composition was as follows: 10 10 bacteria under low Ψ -173 This paper scale applies to China National Standard (CNS) Λ 4 size (210X297 mm) 1248443 A7 B7 V. INSTRUCTIONS (171) Warm protective growth base: Table 17-GYP/glycerol (glucose/yeast extract/phosphate/glycerol medium for liquid storage bottle) Glucose (added after sterilization) 10 g yeast extract 2.5 g k2hp〇4 3 g glycerol. Distilled water, add to 1000 ml and sterilize at 121 ° C for 30 minutes and 20 g (please read the note on the back and fill out this page). The resulting suspension is packed into 20 vials. And in each vial is 1 ml. These vials constitute a basal cell bank that can be used to generate a library of manipulated cells for the preparation of inoculum for biotransformation of renrenone to 11 alpha hydroxy hydroxy ketone. The vial containing the basal cell bank was stored in a -130 Χ: vapor phase of a liquid nitrogen refrigerator. To begin preparation of the operational cell bank, spores from a single basal cell bank vial were suspended in a sterile growth medium (丨 ml) of the composition shown in Table 15. The suspension was packed in 10 portions in 0.2 liter portions, and each portion was used to inoculate an agar plate having a solid growth group of the composition shown in Table 16. These plates were incubated for 1 day at 25 days. In the 3-day incubation, the growth base was brownish orange. At the end of the cultivation, thick golden yellow spores can appear. The spores from the dish were recovered in the above-described step of preparing a basic cell bank. A total of 1 vial can be prepared, each containing 1 liter of suspension. These vials constitute an operational cell bank. The operating cell vial vials were also stored in the vapor phase of the -13 0 C liquid sad nitrogen refrigerator for storage. Add the growth base (5 liters) of the composition shown in Table 15 to 25 liters of -174- • 孓 paper scale suitable for 1] one Chinese national standard time (CNsTa4^&quot;&quot;( 210X 297 ^f T----- 1248443 A7 B7 V. Description of the invention (172) In a conical flask. Take a portion (0.5 ml) of the operating cell suspension into the flask and mix with the growing mixture. The inoculated mixture is at 2 5 Incubate for 24 hours at ° C to produce a seed culture having a compact mycelial tissue volume of about 45%. Once the culture is visually inspected, it can be found to contain a similar pellet-like mycelium of 1-2 mm diameter; Once examined by microscopy, the culture medium with pure culture 0 secondary seed culture was introduced into a 2.8 liter Fernbach flask with a growth medium of the composition shown in Table 15, and in portions (1 ml) In this example, a seed culture was inoculated to the culture medium, and the preparation was as described above. The inoculated mixture was incubated in a rotary shake tank (2 rpin, 5 cm displacement) at 25 ° C for 24 hours. The culture exhibits the same characteristics as a single seed culture and is suitable for transfer In the form of fermented yeast, Kenridone can be biotransformed into 11 α-hydroxykenrein. (Read the first note on the back and fill out this page.) After the cadre of the cadres, the τ 贽 贽 cooperative impression The effect is carried out in a Brann E BiostatSf fermentation tank, which is constructed as follows: Capacity: 1 5 liters, round bottom south degree · 5 3 cm Diameter: 2 0 cm H/D: 2.65 Vane: 7.46 cm diameter, 6 each 2.2&gt; Arrangement of vane space: 65.5, 14.5 and 25.5 cm from the bottom of the barrel: 4 1.9 X 48 cm' Sprayer: 10.1 cm diameter, 21 holes to 1 mm Temperature control: Use the steam jacket outside the container -175 A7 B7 f; After, the second - part of the secondary 摞 摞 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X A portion (2 liters) of the growth substrate having the composition shown in Table 18 was added while the mixture in the fermentation tank was stirred at 300 rpm. Table 18 (for biotransformation culture in a 10 liter fermentation tank) Base) —---- Quantity / l Dong ^ sugar (added after sterilization) 160 g 20 g protein gland 160 g 20 Bio-drink 160 g 20 g anti-foaming agent SAF471 4.0 ml 0.5 ml renrel deionized water, add 7.5 liters and sterilize at 121 ° C for 30 minutes 160 g 20 g of the resulting suspension for 15 minutes, Deionized water was then added to bring the volume to 7.5 liters. At this point, a 20% by weight Na〇H solution was added to bring the pH of the suspension from 5.2 to 6.5 ′ suspension to the Braun ESt fermentation tank and sterilized by heating at 121 Torr for 30 minutes. The pH after sterilization was 6.3 ± 0.2 and the final volume was 7.0 liters. The green liquor of the bacterium was inoculated with a sub-seed culture of Shao (5 liters) which was prepared as described above and was added to a volume of 8 liters by the addition of a 50% sterile glucose solution. The acid fermentation is carried out at 28 °C until the PMV reaches 50%, then drops to 26 °C, and when the PMV exceeds 50%, the temperature is lowered to 24 °C, with a consistent PMV of about 60% or less. . The air is introduced via a nebulizer at a rate of 0.5 vvm depending on the initial liquid volume, and the pressure in the fermentation tank is maintained at 7 〇 0 mbar -176-scale_} - ?: (210X 297^1 ) &quot; —— (Please read the notes on the back and fill out this page)

, 1T i.. After the Ministry of the Ministry of the Ministry of Justice, J-consumer, Zhu Zhushe, 1248443 A7 *——________ B 7 V. Invention Description (174) ~~ ' ' Start agitation at 600 rpm and gradually increase to (7) (10) 卬 (5) as needed, = keep the oxygen loss above 30% by volume. Track glucose concentration. After the initial high concentration of glucose is reduced to less than 丨% due to the consumption of the fermentation reaction, the whole batch is circulated with more than eight doses of the aseptic glucose solution; the degree can be maintained at 〇. Μ % to 1 Scope. The pH before inoculation is 疋6.3 ± 0.2. During the initial fermentation, after the pH has dropped to about 5.3, the pH of the remainder of the cycle can be maintained in the range of 5.5 ± 0.2 by the addition of ammonium hydroxide. To control foaming, an anti-foaming agent, polyethylene glycol, which is commercially available under the trade name SAG 471 from 〇si Specialties, Inc., may be added. The growth of the culture was mainly in the first 24 hours of the cycle, at which time the PMV was about 40%, the pH was about 5.6, and the dissolved oxygen was about 50% by volume. Even if the culture is growing, the conversion of the ketone can begin. In biotransformation, daily samples can be traced to the concentrations of ketone and 11 alpha-hydroxynorrenone. The sample was extracted with hot acetic acid, and the resulting sample solution was analyzed by TLC and HPLC. When the residual concentration of kandrone is about 1% of the initial concentration, the biotransformation is indeed complete. The conversion time is approximately 110-130 hours. When the biotransformation is complete, the mycelial biomass can be separated by centrifugation from the gravy. The supernatant was extracted with an equal volume of ethyl acetate and the aqueous layer was discarded. The mycelial fraction was resuspended in ethyl acetate and added to the ethyl ketone in the acid fermentation tank using 65 volumes of ethyl acetate per gram. The mycelial suspension was refluxed for 1 hour under agitation, cooled to about 20 ° C, and filtered through a Buchner funnel. The mycelial filter block was washed twice with 5 volumes of ethyl acetate (calculated per gram of the keel, ketone in the fermentation tank), and the residual ethyl acetate was replaced with deionized water (1 liter). The aqueous extract, concentrated solvent, solvent wash and water wash are all mixed. The remaining consumption -177- ((independent) eight 4 specifications (210 &gt;&lt; 297 mm)

---------#! (Read the first note on the back and fill in the hundred C

, 1T

Awl. 1248443 V. INSTRUCTIONS (NS) The mycelial mass can be discarded or re-extracted, depending on the analysis. The steroids remaining in the mixed liquid phase for 2 hours were discarded, and the organic phase was concentrated under a hollowing out until the water phase of the knife was further raised. Steaming proud bottles and then easing (four) - small on; The solvent was removed from the crystals by evaporation, and the filtrate was dried. The corrugated house is at 55X: under the hollow. Example 5 Aspergillus oryzae ATCC 185 is cold; the eastern dried spores are suspended in a growth medium (2 ml) as in Example*. Prepare the loam disk, which is also the same as the example 4. The plates were incubated and recovered as described in Example 4 to generate a basal cell bank. The vial containing the basal cell bank is present in the vapor phase of the _13 generation liquid and the second tank. Μ Prepare the cell bank from the basal cell bank vial as described in Example 4 and store in a nitrogen refrigerator at -1 30 °C. A growth group (3 (10 ml)) having the composition shown in Table 19 was added to a 2-liter flask having a hindered sheet. A portion (3 ml) of the operating cell suspension was introduced into the flask. The seeded mixture was incubated for 20-24 hours in a shaking tank (200 rpm, 5 cm displacement) at 28 °C to produce a seed culture in which the compact mycelium volume was about 45%. Once the culture is visually inspected, pellet-like mycelia containing a diameter of 1-2 mm can be found; while microscopic examination is a pure culture. -178- 'This paper scale is inferior to China National Standard (rNS) Λ4 specification (210X297 mm) ---------#! (Please read the back note and fill out this page)

-,11——I ——I.^,3⁄4部中^&lt;#准局负,χ消在竹竹印印1248443 A7 B7 滴分部中标准标准局_τ Consumption Hezhusheyin V. INSTRUCTIONS (π) Table 19 _ Growth-based glucose for primary and secondary seed ablation (added after sterilization) 20 g protein gland 20 g yeast extract 20 g distilled water added to 1000 ml at 121 ° C Sterilization of the secondary seed culture for 30 minutes began with the introduction of 8 liters of the growth substrate of the composition shown in Table 19 into a 14 liter glass assay cell. A seed culture of this example was inoculated into a fermenter from 16 ml to 2 ml. Its preparation is as described above. The inoculated mixture was incubated at 28 ° C for 18-20 hours, agitated at 200 rpm, and aeration rate of 0.5 vvm. At the end of the proliferation, the culture exhibited the same characteristics as the previous seed. The transformation was carried out in a 60 liter fermenter, as described in Example 7, except that the growth medium had the composition shown in Table 20, and the initial load of the secondary seed culture was 350 ml to 700 ml. The agitation rate was initially 2 rpm, but was increased to 5 rpm as needed to maintain dissolved oxygen above volume. The biotransformation time for 20 g/l of konrifreone is approximately 8 〇 丨 6 〇 hours. -179- —-&quot;&quot;&quot; ..._一丨_ — This paper size applies to the Chinese national standard _ ( rNS ) A4 specification (210X 297 mm) - set (please read the notes on the back and fill in this I ) __ 1248443 A7 B7 V. Description of invention (177 ) Table 20 Growth basis amount for bio-word Mb culture in a 60-liter fermentation tank ----- Quantity - liter of glucose (added after sterilization) 5 g of steam ------ 0.5 g protein gland 0.5 g------___ 0.5 g yeast extract 1 7.5 g - ~·---- 0.5 g of carbaryl ketone (20% in sterile water slurry type Add) 7 grams of 20 grams of deionized water, add to 35 liters and sterilize at 121 ° C for 30 minutes --------- #! (Read the first note on the back and fill out this page) Example 6 Primary and secondary seed cultures were prepared using the spore suspension in the manipulated cell bank produced by the method of Example 4, in a manner substantially as described in Example 4. Using the secondary seed culture produced in this manner, the secondary biotransformation can be carried out according to the changing process shown in Fig. 2, and the secondary biotransformation is carried out according to the process shown in Fig. 2. The transformation growth base, the addition procedure of the ketone, the time of collection and the degree of conversion of these strokes are shown in Table 2! Used in the R2A itinerary: The principle of the addition of the ketones is the same as that of the example 3, and the R2c process is the process of the example 3 of the chemistry, only the second addition, at the beginning, the other: after 24 hours. In the R2B and R2D strokes, the entire ketone was initially introduced, and the process was generally carried out as described in Example 4, except that the genus was sterilized in a different container before the kelly was added to the acid fermentation tank, and the glucose was in-180. This paper size is suitable for China's national standard ((, NS) Λ 4 specifications (210X 297 mm). Ψ 中 标准 标准 标准 标准 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 Use the Waring blender to reduce the production of sterilized medium chunks. In the process R2A and R2B, the ketones are introduced into the tank in methanol solution, wherein the processes are different from those of Examples 3 and 4. Note: Please fill in this page) i# 订-181 - This paper size applies to China National Standard Bee (CNS) Λ 4 specifications (210X297 mm) 1248443 A7

B V. Description of invention ( 79

Biotransformation harvest time Kenyronone medium (g/L) 丨 Grain impregnation yeast Yeast 霄νη4η2ρο4 Glucose OSA pH Process number table 2 1 - Initial kenerike biotransformation process | 45·9% 143 hours 10 g / 80 ML Me〇H, at 0, 18, 24, 30, 36, 42, 50, 56, 62 and 68 hours, add 30 15 3 15 0.5 ml with 2.5N NaOH to 6.0 ^ _1 95.6% 1 66 hours 80 g /640ml MeOH at 0 hours all in one time and R2A with R2B 98.1% 125 hours 1 + 〇^ ^ &gt;=桊S# to &quot;Τ〇30 15 1 3 30 0.5 ml with 2.5N NaOH adjusted to 6.5 R2C Lh h—* 104 hours 4 % Know the same R2D as R2C (Read the first note on the back and fill in this page) L#

, 1T φι. -182- ^ paper scale applicable + national standard cooling ((, NS) Λ 4 specifications (210X 297 mm) 1248443 A7 B7 180 V. Description of the invention (in the R2 A and R2B processes, methanol is in the 酦The %, "/time" accumulated in the fermentation tank is about 6.0%, and it is found to inhibit the growth and biotransformation of the culture. However, based on the results of these processes, it can be concluded that methanol or other water soluble solvent is lower. At the concentration, it can be effectively used to increase the Kiri, #-J &lt; load, and make the Kenyrone a fine particle precipitate type, so the breeze hurricane t, the large interface area makes the ketone can be more reactive. At the sterilization temperature (121 ° C) it has been shown that the ketone is stable, but will condense into a thick mass. The block is crushed into fine ruthenium using a Waring blender, which can be successfully converted into a product. Example 7 Primary and secondary seed cultures were prepared using a spore suspension of the operational cell bank produced by the method described in Example 4, in a manner substantially as described in Example 4. The description and results of Example 7 are shown in the Table 2 2. Using the secondary seed culture produced in this way, it can be substantial Biotransformation (R3C) was carried out as described in Example 3, and three biotransformations were carried out according to the procedure described in Example 5. In the last three processes (R3A, R3B & R3D), the ketone was sterilized in a portable tank, wherein Adding a growth base other than glucose. Glucose is added aseptically in another tank. The sterilized suspension of kansinone can be introduced into the fermentation tank before inoculation or early stage of biotransformation. In the R3B process, the supplemented sterile Keny The ketone and growth medium are introduced at 46.5 hours. The thick (K) chunk formed during sterilization is broken by a Waring blender to produce a fine particle suspension that can enter the fermentation. , the ketones addition step 'nutrient addition step' recovery time, the degree of conversion is shown in Tables 22 and 23. -183- The paper size _ quiet remarks (CNS) (that is, read the back of the note before you fill in this page )

, 1T by the Ministry of the Ministry of Justice, the tender of the Bureau of the Ministry of the Ministry of the T-disastrous cooperatives, the water, 124483 A7 B7 Ming said that the five biotransformation recovery time when the ketones are added i -_j ^ g ^ ^ ^ |; > charm &gt ; Save the wheat! ^ ^ ^ ^ ^ ^ ^ ^ Process Number ‘Table 2 2 - Steps of Mercuryone Biotransformation 93.7% 1 18.5 hours See Table 23 ^ ^ ^ ; 1 ♦ Lu · · u Ϊ 〇 〇 S ® 30 15 3 15 0.5 ml with 2.5Ν Na〇H adjusted to 6.5 OJ &gt; 94.7% 1 18.5 hours see Table 23 Private-ro, 〇\ 〇\ ^ ^ ί -...· S ^ ^ &gt; 1 1 3 〇〇一〇一° and R 3 A with π OJ C0 60.0% 1 18.5 hours see Table 23 t ·· 滋 S 〇 丨 丨 办 ^ ^ ^ Μ ΰ > ❹ $ ··齑%务^ UJ . · ^Q\. ·. Spear Λ . ·. NJ ^ ^ 〇〇Ο HP- W Ε ο OJ η 68.0% m See Table 23 5; S spear ^ ·* Co ^- 〇&gt;Public&gt; Redundant»—k μ—〇 and R3A with j LO α (Read the first note on the back and fill out this page) This paper size applies to China National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 A7 B7 V. Description of Invention (182 The Ministry of the Ministry of Economic Affairs, the ninth 椋 椋 ,, τ consumption cooperatives printed f 70.5 64.5 oo U\ On Ο OJ private U\ KJ oo Ui 120.5 ” 、 , · ra 〇 〇〇〇 〇〇〇 \ o ON o oo oo 1 1 1 1 Kensinone 200g/2L Sterile DI 克 LO η 〇»—* 00 〇H—» o H—* h〇o H—* oo o »—* 〇&gt; —-k O 〇4^ 〇1 1 ο ο 1 1 Glucose 50% solution gram table 23 - in development In the test, ren toone, ho to ro Ln NJ NJ N-) ro Oh K) K) 1 1 Κ) 1 1 as t _ ^ 2&gt; \ 1 50 ml 1 1 1 1 1 1 5 0 ml 1 1 1 I 1 1 1 I 50 ml 1 1 1 Sr Ξ Ο Ο ^ Chiche bowl _ glucose and growth base supply step 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 no gram / 1.2 liter 1 1 50 Gram / 0.4 liter of rendrazole / growth medium see Table 22 g / liter L 〇 > 1 1 1 1 1 1 1 1 80 g / 0.8 liter 1 1 1 1 1 喔 1 1 1 10 gram / 1.2 liter 1 1 50 g / 0.4 liters of rendrone / growth medium 1 table 22 g / l υ〇 1 1 1 1 shed 1 flat 1 1 1 1 1 1 1 1 1 1 110 g / 1.2 liters I 1 1 50 g / 0.4 liters Ken Rhenone / growth medium see Table 22 g / l σ -185- This paper scale applies to China National Standard (CNS) Λ 4 specifications (210X 297 mm) ---------#! Note on this page)

1T 1248443 A7 V. INSTRUCTIONS (183) Due to the growth of cilia, highly viscous broth can be seen in the four processes of this example. In order to overcome the hindrance of the south dryness in aeration, mixing, pH control and temperature control, the aeration rate and agitation speed are increased in these processes. Under relatively stringent conditions, the conversion can proceed satisfactorily, but thick agglomerates can form on the surface of the gravy liquid. Some unreacted ketones will carry gravy outside this mass. Example 8 The description and results of Example 8 are summarized in Table 24. The fermentation process was carried out 4 times, and the kenrenone was produced by the conversion of the ketones. In these processes, both (R4A and ^D) are essentially bio-transformed in the same way as in the case of the illusion and the case (1). In the process R4C, the hydroxy kenre _ is generally described in the third example The method is transformed from the same ruthenium. In the process, the above steps are carried out according to the method of Example 4, that is, before the inoculation, the Kennedy and the growth base are sterilized in the fermentation tank, and all the nitrogen and scales are used. The nutrients were introduced at the beginning of the batch, and the addition solution containing only glucose was added to the fermentation tank to maintain the level of glucose in the process. The soot system +, one _, and N 卞 in the latter process (R4B) ), every 5 hours to chase 5 to show the Portuguese sugar > Chen Duan' and the Portuguese sign to go to the death of 4 匕 丄,, Yangshuo 匍 糖 依 依 依 依 依 依 依 依 依 依 依 、 、 、 、 、 、 、 。 。 。 。 。 。 。 。 。 。 Process &lt;Kensone Addition Steps are shown in the table. ---------%------ίτ------ (Please read the notes on the back and fill out this page) Ministry of Justice, Standards Bureau, Beibei consumption, Hezhu private printing, water I, home, country I, I, I, a ruler, a piece of paper, I, 86

Ns 一厘公1248443 Α7 Β7 Ming Mingfa, Wujing 淖部中榡 榡 员工 员工 贽 贽 社 社 社 社 生物 生物 生物 生物 生物 生物 生物 生物 何 何 何 何 何 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯 肯Extract nh4h2p〇4 Glucose OSA pH Process No. 95.6% 122 hours See Table 25 ΰ 4 4 — Ξ 命 命 · 30 1 5 3 15 0.5 ml with 2.5N Na〇H adjusted to 6.5 R4A 97.6% 122 hours see table 25 160 g of ketone ketone in the sterilization I with R4A R4B 95.4% 122 hours see table 25 ^ a. Special S but thin 1 滋 5 | beep ^ ^ ^ i 11> 9 ^ ^, · i 务 · · monument & quot JWM .. to ^ ο Ο Ο Semi NJ> Ε Ο R4C 96.7% 122 hours &amp; Table 25 Kensinone Sterilization and Mixing BI: 40 g 23.5 hours: 120 g with R4A R4D Outside 2 4 -^祺1^爹恭^~碜^,声^澄(Read the first note on the back and fill out this page) i#. 订Ι. -187- • 孓 Paper ruler (which) / \4 specifications (210'/ 297 1248443 A7 7 Β Wuming instructions 26IT&quot; ^1lif w~ 『 ^1 7T~ 『 ^1 wIW iw 3,

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I r1* ^ % ^f\ ^ 50*丰50柳半50Λ半20^&gt;^M 玲20^^3^ Ling 100州^温众®芩50咖半奇(才咎4苏伊芩殊t ) 1205.Ϊ Ϊ24

SA a 忠霈^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (210X 297 mm) H39, ί 24

R4B to v- 188- 1248443 A7 V. INSTRUCTIONS (186 All fermented yeasts are carried out under high agitation and aeration in the A large number of cycles in the winter, and the acid fermentation tank will become within 9 days of the m example. Highly viscous. The degree of sleep and conversion of this routine procedure is shown in Table 26. The renrolone addition step, the harvest time R5t conversion process is essentially carried out according to the process R4B of Example 8. In process R5B, for other furnaces Occupy, π,,, Wang Zhong I top round wheel of the full round, with the lower millet, ', &&lt; marine wheel replacement. Down pumping effect, can pour the gravy axially into the h Central, minus Φ, 戸城, 一子鬼&lt; formation. Immediately after inoculation in the R5D process, add methanol (2〇〇亳 and \ 可). Since the ketone is sterilized in the fermentation tank, except for the Portuguese Nutrients are added at the beginning of the process, do not need to connect, the performance of adding nitrogen source, phosphorus source or antibiotics. Do not l,, 虱---------0------ order--- ---Φ— 2f first read the notes on the back and then fill in this page j. The 决 中 中 β β β 〈 〈 〈 〈 〈 〈 189 189 189 189 189 189 189 189 189 189 189 189 189 189 189 189 189 本 本 本 本 本 本 本 本Quasi-commissioner, τ消Λ合Mii印f 1248443 A7 B7 V. Description of invention (187) Biotransformation 1 Harvest time medium supply Kenyrone ketone addition medium (g/L) Grain immersion liquid yeast extract NH4H2P〇4 Glucose 0SA pH Process No. 96% 1 19.5 hours of glucose filling ^ ° 蕤JSi 33 Private: 30 15 3 15 0.5 ml with 2.5N Na〇H adjusted to 6.5 R5A Η-* μ-^ ^ 5; 53 Garlic 〇 w '奇奇&gt; LA &gt;&gt; m Let V+4 〇〇〇〇Η—* ο 激^|哳L/飞〇\.激^ ^ Hh n ι _-/ , 2 · · Miscellaneous 03 ^ OJ · · 3 and .· ^ ^ to .. Μ ^ 1 〇 half 0 W ° Ε Ο \〇K) h-ka; Ζ3 rt\ 4^ Ό ^ 1 σ L/1 ' &gt; '...·· &gt; 箓砵\. ΣΧ3 Order 33 ---------0—, (Read the first note on the back and fill out this page) ΦΙ. -190- This paper scale applies to Chinese national standards (( NS) Λ4 size (210X 297 mm) 1248443 A7 B7 V. Description of invention (188) In order to maintain the immersion condition of the solid phase of the liquid surface, the process begins. At the beginning of the 6th hour, a growth base (2 liters) was added to each fermentation tank. The addition of a growth base or the use of a downward pumping of the vanes (R5B process) does not completely overcome the mixing problem, but the process results demonstrate the feasibility and advantages of the process and demonstrate a satisfactory blend of conventional practices. Example 10 Three bioconversion processes were performed essentially as described in Example 9. The conversion growth group of this example, the addition step of the carbaryl ketone, the recovery time and the degree of conversion are shown in Table 2 7 : (Read the first note on the back and fill out this page) ^91.消贽合竹社印 f -191 - ^ Paper I degree 适州 China National Standard Bee 1 ('NS ) Λ 4 specifications (210X 297 mm) 1 [248443 A7 B7 V. Invention Description (189) Department Standards Bureau Bamboo Society Sealing Block Balanced Biotransformation Recovery Time Medium Supply j Kendryone Addition 1 Medium (g/L) Grain Leaching Yeast Extract nh4h2po4 Glucose OSA pH Process Number Table 27-10 liter scale conversion process description 59% 95% 120 hours 〇 a扒; Ϊ ^ ^ ^ ^ ^ J ^ X Ϊ &gt; 1 60 0 sterilized in the tank 30 1 5 3 15 0.5 ml with 2.5N Na〇H adjusted to 6.5 R6A 54% 96% 120 hours 妒.^ = Brewing t ΐ 1 60 0 sterilized in the tank 1 ! J _1 with R6 A ί i _1 R6B 80% 90% 120 hours | Μ Noisy Φ ^ Wear - 1 6 0g at Sterilization in the tank | Disk 5 1 _ A MG running game φ ag ··杂 莽 · · · ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -1T------^w, (read first Read the back of the note and fill out this page) -192- ^ Paper scale i with Chinese national standard bee ((:NS) Λ4 specification (210X297 mm) 1248443 A7 V. Invention description (19〇) In the R6A process, After 71 hours, a growth base (13 liters) and sterile water (〇·8 liters) were added to immerse the mycelial masses, which grew the surface of the liquid gravy. For the same purpose, the growth base was added after 95 hours in the process R6B ( 0.5 liters) and sterile water (0.5 liters). The material balance data shows a better agglomerate balance when the agglomerates on the surface of the liquid are minimized. The process is performed to compare the pre-sterilization of ketones and Sterilization of retort and growth base. In process R7A, 'as shown in Figure 2, the conditions can be

Compared with R2C ' R2D ' R3A, R3B, R3D, R4A and R4D. Process R7B is illustrated in Figure 3, and the conditions can be compared to Examples 4, 9 and 1 and Process R4B. In this example process, the transformation growth medium, the addition of the step-recovery of the ketones, and the degree of conversion are shown in Table 2: (Please read the notes on the back and fill in the page) i# Sub-standards Bureau staff 贽 贽 竹 竹 印 印 f, Table 2 ^ 1 〇 规模 生物 生物 生物 说明 R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R Irri 1 , --______ 30 15 3 15 0.5 ml with 2.5 N NaOH adjusted to 6.5 with R7A with the same amount of Τα~^~~T r --- 160 grams of ketone in the tank sterilization and mixing 160 Kekenreone in the tank sterilized &gt; mouth fragrant base eight glucose supply; kandrone plus 1 · 6 liters of growth base added 蜀 糖 供给 无 supply no other added recovery time j, «土杰----- ------ 11 8.5 hours Ding 18.5 hours bio-conversion 93% - 89% -193- This paper scale applies to China's national standard net (〇^8 4 specifications (210>&lt; 297 mm) 1248443 A7 B7 , invention description (191 group to take the final sample of the self-made process, which is 89.5%, no significant loss or decline in biotransformation It is determined that the mixing in each process is suitable. During the first 80 hours, the residual concentration of glucose is above the control. The process performance is obviously not accumulated in the head space of the fermentation tank. The effect of the block. Child case 1 2 Determine the extraction efficiency in the -system m-liter extraction process, and combine them in Table 29, each of which is extracted from the mycelium by acetic acid. #口鲜(1L/L_ Volume). In each process, the second successive extraction is carried out. According to RP-HPLC, about 8〇% of the total, class _ can be recovered in the first extraction = and recovered in the second extraction. Can be increased to (4). The third time = take another 3% of steroids. The remaining 2% is lost in the supernatant water phase ° ^ hollowing out the extract to dry 'but not washed with any additional solvent ▲ attack Process economic judgment 'solvent removal can increase the recovery rate from the initial extraction. --C read the notes on the back and fill out this page." -5- 口经满部中级标准局员J-消资合竹Social printing

P 1248443

In the rule of liter gravy, the temperament of the kiln is: 占 ^ 土 ” ” ” MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI MI 。 。 。 。 。 。 。 。 。 。 。 。 。 In terms of extraction efficiency and crystallinity, ΜΙΒΚ and 甲 盥 can be 盥iim" for ethyl vinegar. At the beginning of the fermentation cycle of the two processes, the research on the minerals of Ken's minerals was carried out. This is part of the process evaluation of Figures 2 and 3. As above, the eric acid to the W1 process is micro-teaching before inoculation to the yeast cell. In this process, 'Kenruthone is not reduced, but not microbes. . The processes of Figures 2 and 3 are in the process of the process of Figure 2 in the process of the ketones and _ sterilizing. In the process of Fig. 3, in the growth medium, 亍 万 、, I privately sterilized in the tank. As described above, sterilization is highly likely to cause aggregation of the kansone particles. Because the ketone has a positive solubility in the aqueous growth base, the production capacity of the process depends on the transfer of the agglomerate from the solid phase, and therefore is expected to be determined by the interface area exhibited by the solid particle. The particle size depends on the knife cloth. These considerations are first used as the determining factor for the process of Figures 2 and 3. Fc's 1st turn rate ^U3C, T consumption Hezhusheyin (read the first note on the back and fill in this page) However, the agitation in the mixer of Figure 2 and in the fermentation tank of Figure 3 The agitation, coupled with the shear pump used in the batch transfer of Figure 2, was found to degrade the aggregates to a range of particle sizes that were not sterilized and that had been micronized to a reasonable approximation of the particle size of the process of Figure 1. This can be illustrated by the particle size distribution obtained at the beginning of each process reaction cycle. See Table 3 and Figures 4 and 5 \. -195- The paper size is 诵川ΐ国囤家埤((,NS ) Λ4 specification (210X 297 mm) 1248443 Λ7 B7 V. Invention description (193 Table 30_ three different. Sub-distribution 45-125 micro 180 micro Kenyui Ships 75% 95% Submicron Bioconversion% ----- R3C: 93.1% (120 h) R4C: 96.3% (120 h)

----------»! (Before reading the back of the note and then fill out this page) 軤Μ 屮 / rate / 3⁄4 employee spending and still shirt printing ^, by the data of 30 can be noticed The agitator and shear pump can effectively reduce the average particle size of the ketone heart by the reduced fungus, so that the same size as the unsterilized substrate, but the unsterilized substrate has significant size difference. In addition to this difference, The reaction performance data shows that the pre-sterilization process is at least the same as the process of the production process. Further advantages can be understood from the process of Figure 2, that is, by subtracting y from the 7 and making certain steps of the particle size, such as Reduced bacteria's ketones wet honing and/or bacteriostatic method by pasteurization instead of sterilization. Example 1 4 Seed cultures were prepared as described in Example 5. At 2 b hours, inoculated in a fermenter Mycelium accounts for 4〇% pMv. Its pH値 is Η, and the glucose used is 14.8 g/L. Tian-196- This paper scale is suitable for the national standard of Pingli) Ψ. Bureau β-τ.消贽告竹社印来1248443 A7 --------_______B7 V. Invention description (194)^ ^ ~^ 'Preparation of the group shown in Table 20 Transforming growth of the group (35 liters). In the preparation of the addition medium, the glucose and yeast extracts were separately sterilized and added together at a time, wherein the glucose had a concentration of 30% by weight and the yeast extract was 10% by weight. The pH of the filling is adjusted to 5s7. Using this medium (Table 20), a secondary biotransformation process was performed to convert the ketone to 11 heart hydroxy ketone. Each process was carried out in a 6-liter fermenter's tank, which was equipped to include a Rusht〇n full wheel and two Lightnin’A315 blades. The growth medium was initially loaded to 35 liters in the fermentation tank. Micronized and un-reduced ketopurone was added at an initial concentration of 0-5%. The medium in the fermentation tank was inoculated with a seed culture, which was prepared as shown in Example 5, and the initial inoculation ratio was 2.5%. Fermentation is carried out at 28 ° C, 200-500 rpm agitation rate, and 〇 5 vvm aeration rate, and the reaction should be sufficient to maintain a dissolved oxygen level of at least 2% by volume. The transforming culture developed in the production process is a very small pellet type (about 1-2 mm). The ketones and the supplemented nutrients were continuously added to the fermentation tank as described in Example 1. The nutrient is added every 4 hours at a ratio of 3.4 grams of glucose per liter of fermented broth and 6 grams of yeast extract. Table 31 shows the aeration rates, agitation rates, dissolved oxygen, PMV and pH, and the addition of glucose in each batch in the various processes of the present invention. Table 3 2 shows the conversion profile of the ketone. The Rll A process was aborted after 46 hours; the R11B process continued for 96 hours. In the latter process, 93% conversion was achieved at 81 hours and added again at the 48th hour; It can be noted that there is a significant change in viscosity between the stop of the addition and the end of the process. -197- Mid-Shop Home Office (CNS) A4 Specifications (21 (^297 mm 1 ~~&quot; '——- ---------#! (Read the first note on the back and fill in this Page), 11 1248443 A7 95 1 ____, Explain that the cadres in the cadres of the squadrons are inferior to the squad, the squad, the scorpion, the scorpion, the scorpion, the smuggling, the smear, the smear, the smear, the smear, the smear &lt; ^ Lh 46.2 | 30:2 to EL:1. 1 O Time Acid Fermentation R1 ΙΑ 1 Table 31 bO 〇Μ Air (1pm) ο ro o NJ 〇NJ 〇to o NJ 〇to oo NJ 〇Air (1 Pm) 400 300 200 200 rpm 500 500 500 500 500 400 300 200 200 rpm 〇〇49.5 82.3 92.9 %D0 1 hO LO 100 18.8 25.5 50.2 85.1 OJ %D0 〇〇〇〇Back pressure On 1—kooo 〇o Back pressure to PMW(%) OJ OJ oo hO PMW(%) 5.48 5.48 5.98 bo 5.57 |4·81 5.01 ro t'O 6.98 [5.43 6.03 6.17 Ό '-r1 〇L/1 Gluccc (g/L) 1 o 〇On oc Glue cc (g/L) (Please read the note on the back and fill out this page) This paper size applies to China National Standard #(CNS) Λ4 Specifications (210X 297 mm) 1248443 A7 B7 V. Invention Description (196) Secondary department Peel Board member J- consumer cooperatives Zhi India f

杂 济 济 。 。 。 。 Ο h〇o ho o NJ 〇NJ 〇to o hO 〇hJ 〇Ο ο LA Ο ο oo U~\ ooo U\ 〇ooo § 〇ίΌ Μ ho ro ^sO L〇二 V ON Ln Ln L〇bo LTi 〇 \ 〇ro 4^ 〇Lh 00 〇\ 00 hJ UJ Lj σ&gt; OJ ΓΟ OJ Lj iO Ul ο ο Κ) L/io hO o Ln hO 〇〇J (Read the first note on the back and fill out this page) ' This paper scale applies to China National Standard Rate (CNS) Λ 4 specifications (21〇'〆297 mm) 1248443 V. Inventions (197)

A ||RllB-22 1 ||RllB-7 1 ||RllB-0 | Sample concentration (g/L) 鑤R11A-46 1 R11A-36 R11A-29 R11A-22 R11A-7 R11A-0 Sample concentration (g / liter) Fermentation R11A: Kirenone conversion table 32 21.8 ^0 〇〇μ-^ ΕΠ Order 46.20 35.70 29.00 21.80 7.00 0.10 3 2.51 0.20 0.00 OH-can 7.09 6.68 3.67 2.02 0.18 0.00 OH-can [2.46 4.98 5.60 Ken Rhenone 0.41 1.44 4.14 2.12 4.89 5.41 Kensinone 4.97 | 5.18 5.60 Total IH—^ I 7.51 8.12 7.81 4.14 5.07 5.41 Total 50.49 3.78 Conversion 43⁄4 -X, 94.48 82.27 47.03 48.75 OJ Ln 00 Conversion 2.52 0.19 (g/L Calc OH-can 8.59 7.74 4.48 2.44 I 0.18 (g/L) Calc OH-can 0.16 0.03 Estimated 値 conversion rate (g/L/hr) 0.08 Control .49 0.28 0.15 0.03 II Estimated 値 conversion rate (g/L) /hour) 0.16 0.03 値 0.04 0.45 0.23 ^2 0.03 値 値 -200- (Read the first note on the back and fill out this page) φ φ>. Paper scale applies to China National Standard (rNS) Λ 4 specifications (210x 297 PCT) 1248443 A7 B7 V. Description of invention (Ministry of MM Ministry of Justice, β, ι'. Ψ t— 00 H—k &gt;—k Dd and K—* &gt;—k to 1 oo σ> H—* td oo H—* k—a 00 ίο s 5 6\ Η—» μ—t CO 1 Ln \〇CD 1 U\ ^r\ OJ 1 On 5 Η-^ Η—* Ln 〇〇L^i b&gt; oo H—* G\ •\〇00 〇, 〇\ (A o 卜o &gt;° o to H—k hO LO 乇Lh to 〇\ 00 NJ OJ NJ to to tO K) og I— s OO 00 4^ k On 00 K·) s NJ b L/i LO On 00 NJ 1——i one LfJ 二tO 〇&gt;_丨.,_·* Lj 3; \〇Μ &lt;1 Ό K&gt; to oo bo 00 tO )Q 00 UJ 〇bO u&gt; OO OJ NJ LO 〇NJ oo Lh υ』 NJ H —* \〇LO Ό LO s \〇K) jo oo 00 NJ g 〇\ OJ ON Lj oj NJ 〇OO k&gt; Os to K&gt; H—* H—1 OJ Lo to NJ CTs tO &gt;° in OO On 〇oooopoos 〇in » 1 : i V 〇o ON oo OJ to o \1 〇Lj ooo ό k&gt; ό oso 5 oso Lj 〇La (VI o 卜 o ---------#! (Please Read the notes on the back and fill in this page) ΦΙ. 20 The paper scale is suitable for the Chinese national standard rate (rNS) Λ4 specifications (210X 297 public | The Ministry of the Ministry of Economic Affairs and the Ministry of the Ministry of Foreign Affairs and the Ministry of Foreign Affairs A7 B7 V. Description of invention ( 199) According to the above generally described method, the potency of the bioreversion of kansinone to 丨i α _ per kigenrexone can be tested. Aspergillus niger ATCC Η394, Rhizopus arrhizus VIII1 (: 11145 and Rhizopus genus octatus (^ 622713) operating cell bank. The growth group having the composition shown in Table 18 (5) was prepared as described in Example 5. 0 ml) was inoculated with a spore suspension from the operating cell bank and placed in an incubator. The seed culture was prepared in an incubator and fermented at 20 ° C for about 20 hours. The incubator was at 2 rpm. Stirring was carried out. One (2 ml) seed culture of each microorganism was inoculated into a rotating flask containing the growth medium (30 ml) of Table 18. Each culture was inoculated with two flasks, a total of 6. Ken Rhenone (2 mg) was dissolved in 36 χ: methanol (4 ml), and 5 ml of this solution was introduced into each flask. Biotransformation was carried out under the conditions described in Example 5, and each bottle was added 5 〇. % by weight of glucose solution (1 ml). After the first 72 hours, the development of mycelium was observed in separate transfer flasks: ATCC 1 1394 - good consistent growth ATCC 11145 - in the first 4 Good growth in 8 hours, but the mycelium group formed a spherical shape; no obvious in the last 24 hours Growth; ATCC 6227b - good growth; mycelium clumps form a group of balls, and the gravy samples are taken out to analyze the degree of biotransformation. After three days, using eight diced (^ 1 1394 fermented to provide 11"-hydroxykenry Ketone 8〇_9〇()/() conversion; ATCC 11145 provides 50% conversion; while ATCC 6227b provides 80-90% conversion 0-202- This paper scale applies to Chinese national standard (CNS) jWm (210X 297/&gt ;f ) Order ^_wl (please read the notes on the back and then fill out this page) 1248443 A7 B7 V. INSTRUCTIONS (2〇〇) EXAMPLE 1 6 Using the method described in Example 1 5, testing additional microorganisms will be Kenry The potency of ketone conversion to 11 π-hydroxy ketone. The microorganisms tested and the results are shown in Table 3: ---------^------ Please read the note on the back and then fill out this page.) The full-scale decision of the Bureau of the Ministry of Justice, the Department of Health, the Department of Health, the Department of Health, and the 203- The paper size is applicable to the national standard of China ((, NS) Λ 4 specifications (210Χ 297 public) PCT) 1248443 A7 B7 V. Description of invention (2〇1) m- Mai but 1 ΠΠ Tong ^ 4&amp; 3⁄4 Discrimination vhrg & Discrimination CS4 • Da·dou ye ♦ Today U- Φ 1— 1 〇00 Os 00 Ι-—k κ&gt; h—^ 1—k Ό Private KJX I—^ 4^ LO t—* o bo L〇o N-&gt; LO I—1 o bo oo LO t-—^ Ο to oo h~* OO Ui oor 〇H--k Η—» L〇Ό Η«α Η—^ NJ 〇\ CTn to ΙΌ cr Public U\ &gt; HH n 〇C/3 η c/5 r Ο r η r Rp η mr 〇C/) r Rp nrnr Rp n ϋ0 r 〇(7) r η r η on r Ο C/5 r 〇oo rnr u- + + + + + 1 1 1 1 + + + + + + Λ Λ *ο * oc o •¥r \j\ % 〇% 〇〇% 〇00 〇1 〇〇00 1 o on o 容恭Λ Η—^ Ο Ό Ο * o * H—^ 〇00 o * * ooo O Ό Ο 1 OO o 1 1 -------- 如—(Read the first note on the back and fill out this page)

, 1T -204 - This paper scale applies to Chinese national standard (rNS) Λ4 specification (210X297 mm) 1248443 A7 B7 V. Invention i see (202) After the Ministry of Standards, the Bureau of Standards and Consumers Co., Ltd. -®蓥痂娣渖;TSB-^^^I3&gt;^(4)a';f ; PRPCSL-^Φ 枭泠婵参净铋涔BP-+ and 潍##_1]&gt;Raspberry

(Please read the notes on the back and fill out this page) -205- ^The paper scale applies to China National Standard Pool ((,NS) Λ4 specifications (2丨0X297 mm) 1248443 A7 B7 V. Invention description (203) Part of the Ministry of Education, Department of TCM, Tsang, Hezhushe, ¥1, Example 1 7 Test various microorganisms to convert the ketones to 9 1 han-jing. The fermentation medium of this example process is prepared according to Table 34. 34 Soy flour: Dextrose 20 g Soy flour 5 g NaCl 5 g Yeast extract 5 g KH2P〇4 5 g water to 1 liter pH 7.0 Protein gland/yeast extract/glucose: Glucose 40 g protein gland 10 g yeast dipping Paste 5g water to 1 liter Mueller-Hinton · Beef dip 300g tyrosine 17.5g starch 1.5g water to 1 Isobacteria cultured in soy flour medium and protein gland-yeast extract glucose; put (please read first Note on the back side of this page) 206- This paper scale applies to China National Standard (CNS) Λ4 specification (210X 297 mm) 1248443 Five 204 by the Ministry of the Ministry of the Ministry of Military Affairs A7 B7, invention description (C. faecalis and sputum culture in soybean (Add 〇_9% by weight of formic acid steel, ^ (, bio-equivalent) and Mueller-Hinton gravy. The initial culture is inoculated with frozen spore stock (20 ml of soy poplar in 250 ml) Triangular flask). The flask is covered with milk filter paper and prevents the organism. The k-culture of the mouth (2 4 or 48 hours) is used to inoculate the metabolic culture (also 2 liters in a 250 ml flask) _ having a cross volume of 10-15% - and the latter is incubated for 24-48 hours before adding the steroid acceptor for the transformation reaction. Kendrone is dissolved/suspended in methanol (2 〇 mg/ml), sterile filtered, and Add to the culture to give a final concentration of 1 mg/ml. All the transformed fermentation flasks are temperature controlled at 250 rpm (2, stroke) at 26 ° C and 60% humidity ^. Biotransformation was recovered at 5 and 48 hours after the addition, or 24 hours, and ethyl acetate (23 ml) or dichloromethane was added to the fermentation flask to start recovery. The flask was shaken for another 2 minutes. The contents of each bottle were then poured into a 5 〇亳t conical tube. For phase separation, the tube was centrifuged at 4 rpm for 2 室温 at room temperature. The organic layer of each tube was transferred to a 2 ml borosilicate glass vial and evaporated under a free moving device. The vial was capped and stored at -20 ° C. In order to obtain a substance that can determine the structure, the mixture was shaken and fermented. Increasing the number of bottles to 25 expands the biotransformation to 5 〇〇 ml. At the time of recovery (after 24 or 48 hours of addition of the substrate), ethyl acetate is added individually to each flask, and the flask is capped and re-swinged. Back in the shock tank for 20 minutes. The contents of the flask were then poured into a polypropylene bottle and centrifuged to separate the phases or poured into a separatory funnel where they were separated by gravity. The organic phase is dried to form a crude steroid extract contained in the reaction mixture. -207- ί, paper size thorn towel home office (;) ^ 4 specifications (21GX 297 mm)

The Ministry of Economic Affairs and the Ministry of Economic Affairs and the Ministry of the People's Republic of China _ τ consumption Hezhushe Yinfan 1248443 A7 ______ B7 V. Invention Description ( 205 ) The reaction product was first analyzed by thin layer chromatography on the enamel (250 micron) glory plate (254 nm). Ethyl acetate (500 microliters) was added to a vial containing the dried extract of acetic acid from the reaction mixture. Further analysis was carried out by high performance liquid chromatography and mass spectrometry. The TLc plates were developed in a 95:5 Wv chloroform/methanol solvent mixture. Further analysis of the performance of liquid chromatography and mass spectrometry in the south, using HPLC, equipped with Millennium software, light dipole array detection crying and automatic sampler. Reverse phase HPLC was performed using waters Novapak C18 (4 micron particle size) RadialPak 4 mm hydrazine. A linear solvent gradient of 2 minutes starting with water: acetonitrile (75:25) and ending with water: acetonitrile (25:75). This was followed by a 3 minute gradient to 1% acetonitrile, and the column was regenerated under the initial conditions for an additional 4 minute wash. In L C /M S, a concentration of 2 nM of ethyl acetate was added to both acetonitrile and the aqueous phase. Chromatography was not significantly affected. The eluate from the column is 22: i split, most leading to a PDA detector. The remaining 4.5% leads to Sciex Αρι πι, Jingyi's EFI Li ionization chamber. Quality is completed in positive mode. A similar data line is available in the PDA detector on the HPLC to transfer a single wavelength chromatogram to the mass spectrometer for simultaneous analysis of U V and M S data. The segment pattern of mass spectrometry has been shown to be useful for classifying hydroxylation. Two expected perrenalones, 11 ^ _ light base and 9 ^ - obtain base, lose water at different frequencies, and this consistent approach can be used for diagnosis. At the same time, 9 α -hydroxy kennel S is easier to form with the ammonium adduct than 1 丨 ^ hydroxy quinone. Shown in Table 3 5 is the kansone fragment TLC, HPLC/UV and LC/MS data. -208- ί. Paper scale for Chinese 标准家标准(FnS) Λ4 specification 72丨〇&gt;&lt; 297 mm ) ' (Read the first note on the back and fill out this page) Book 1244843 A7 B7 V. Inventive Note (206), showing that the microorganisms tested can effectively biotransform the ketopurone into 9 α -hydroxy quinone . The preferred microorganism herein is S. serrata ATCC 16718. (Read the first note on the back and fill out this page)

, 1T by the Ministry of Standards, the Ministry of Standards, the consumption of the standard, the contract of the company, the f-209- This paper scale applies to the China National Standard (CNS) Λ 4 specifications (210Χ 297 mm), the sub-standards of the sub-standards贽合竹社印繁1248443 A7 V. Description of the invention (207) Table 35 - TLC, HPLC/UV and LC/MS data overview of the ketone ketone fermentation 1 9αΟΗ_Kenresone evidence culture at 9 a QH -TL of TLC at 9 π OH-Kenresone HPLC-peak MS: 357 (M+H), 339 (-H20) &amp; 375 (+nh4) Blue Absidia ATCC 6647 η yy/n ash Absidia glabrata ATCC 22752 η E. faecalis ATCC 6476 tr y tr Aspergillus oryzae ATCC 1030 tr Aspergillus fumigatus ATCC 26934 tr yn Aspergillus nidus ATCC 11267 tr yy Aspergillus niger ATCC 16888 nyy Aspergillus niger ATCC 26693 nyn Aspergillus oryzae ATCC 18500 nyn Cyclobacillus ATCC 12673 n tr n Beauveria bassiana ATCC 7159 tr yy Beauveria bassiana ATCC 13144 yyy vine cavity fennel IMI 038560 y tr tr 丽赤壳 ATCC 14767 n tr y snail shell ATCC 10195 tr tr y/n Monocytogenes ATCC 11996 tr tr n lentils of the genus ATCC 16718 yyy short thorns of the genus A. sinensis ATCC 8688a yyy汉 银 AT ATCC 3655 yyy 雅小小克银汉霉 ATCC 9245 yyy Curculaxia clavata ATCC 22921 nyy/n (please read the back note before filling this page) -210- This paper scale applies to Chinese national standards ((, NS) Λ4 specification (210X 297 mm) 1248443 A7 V. Invention description (2〇8) 消 中 中 中 中 Τ Τ Τ 贽 贽 贽 贽 贽 AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT AT Humucola ATCC yyy 12722 Phytophthora infestans ATCC 12724 tr tr tr Fusarium oxysporum ATCC 7601 tr Fusarium oxysporum f.sp. n cepae ATCC 11171 Gibberella citrinum ATCC 14842 tr y viscous mold ATCC 10097 y tr tr ATCC 22822 yy UV? y Gymosporus parasitic IMI 109891 yyy oil-producing yeast ATCC 10792 n black spore ATCC 26180 tr nn Helminthosporium ATCC 42613 yyn gray blue mold ATCC 1207a n large mold ATCC 4605 tr yy sporadic Mycobacterium NRRL B8119 Fusarium oxysporum ATCC 9095 tr tr y Nocardia yellow ATCC 12674 n tr n Nocardia canis ATCC 31548 yyn Nocardia ATCC 19070 n Canine Paecilomyces sinensis ATCC 46579 nyn Penicillium chrysogenum ATCC 9480 n Penicillium sp. ATCC 24550 yyy/n Penicillium chrysogenum ATCC 46581 tr yy Pithomvces atroolivaceus tr y tr ATCC 665 1 211 - This paper scale applies to the Chinese national standard ((, NS ) Μ Specifications (210X 297 mm) (Read the first note on the back and fill out this page) i#.

, 1T 1248443 A7 B7 V. Description of the invention (2〇9)

Pithomyces cvnodotis η tr tr ATCC 26150 Bacillus licheniformis IMI 1 18496 yyy/n M. occidentalis ATCC 1223 1 yyy/n Helicobacter pylori ATCC 36060 Rhizopus arrhizus ATCC 11145 tr yn Rhizopus genus ATCC 6227b n Rhodococcus equine ATCC 14887 n tr n Rhodococcus equiogenes ATCC 21329 tr tr n Rhodococcus ATCC 19070 nnn Rhodococcus erythropolis ATCC 19150 n tr n Erythromycin saccharolyticus ATCC yyy 11635 Tumor spore IMI 203033 nnn Yellow spore ATCC 13378 n Septomvxa affinis ATCC ny UV y/n 6737 Stachvlidium bicolor yyy/n ATCC 12672 Streptomvces californicus n ATCC 15436 Streptomyces faecalis ATCC 3443 n Streptomyces coelicolor ATCC 10147 n Streptomyces sp. ATCC 25453 Streptomyces elegans ATCC 10745 n Streptomyces griseus gray subspecies n ATCC 13968 Streptomyces griseus ATCC 11984 n Streptomyces hydrogenophilus ATCC 1963 1 n Streptomyces hygroscopicus ATCC 27438 yyy Streptomyces glabrata 105 n Streptomyces sp. ATCC 25489 n ---------1-- (Please read the notes on the back and fill out this page) Γ -212- This paper scales Chinese National Standard (CNS) Λ4 specifications (210X 297 mm) 1248443 A7 B7 V. INSTRUCTIONS (210) Streptomyces faecalis ATCC 25489 η tr tr Rose Streptomyces ATCC 13400 Spectacular Streptomyces ATCC 27465 η Microsporum ATCC 2833 General Streptomyces ATCC 18192 η Elegant Mycobacterium ATCC 18191 Thamnostvlum piriforme y tr y ATCC 8992 Thielavia shell ATCC 13807 n Trichoderma viride ATCC η 26802 Trichoderma virgin ATCC 12543 tr yy/n Cocoa var. ATCC 12474 y tr tr (Please read the notes on the back and fill in On this page, the 标准 中 中 标准 β β β 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 测试 测试 测试 测试 测试 测试 测试 测试 测试 测试 测试 测试Basically, as described in Example 4, Aspergillus oryzae NRRL 405 (ATCC 18500); Aspergillus niger ATCC 1 1394; Aspergillus nidulans ATCC 1 1267; Migen #_ATCC 11145; Rhizopus oryzae ATCC 6227b; 19 and ATCC 86 85 operating cell banks. The raw substrate (50 ml) having the composition shown in Table 18 and the spore suspension (1 ml) from the operating cell bank were seeded and placed in the incubator. The seed culture can be prepared in an incubator by aging at 20 ° C for about 20 hours. The incubator was agitated at 200 rpm. A portion (2 ml) of each microbial seed culture was taken and inoculated into a rotating flask containing the growth medium (30 ml) of Table 15. Each culture was inoculated into two calcined -213- | degrees - ft. I sheets of paper, one ΛΝ C standard (2.1X 297 mm), 1248443 A7 B7, inventions (211) bottles, a total of 16. Androstenedione (300 mg) is dissolved in 3. _ , l &lt; in methanol (1 6 (please read the back of the note before filling this page) ml) and take a 0.5 ml portion of this solution into each flask. The biotransformation was carried out, generally under the conditions described in Example 6, for 48 hours. After 48 hours, the gravy samples were pooled and extracted with ethyl acetate as described in Example 17. Ethyl acetate was concentrated by evaporation, and the sample was analyzed by thin layer chromatography to determine that there was no chromatographic mobility similar to the product of 羟基^hydroxyandrostenone standard^=two Chemical Co., St. Louis. presence. The results are shown in Table 36. The positive results are indicated by "+ 。. Table 36: Male and female, transformed into α · gas-based male 晞 酉 培养 AT ATCC# medium TLC results Rhizopus oryzae 11145 CSL + Rhizopus sinensis 6227b CSL + Aspergillus nidus 11267 CSL + Aspergillus niger 11394 CSL + Aspergillus oryzae NRRL 405 CSL + Aspergillus oryzae 18500 CSL + Trichothecium sinensis 12519 CSL + Trichomonas sinensis 8685 CSL + Table 3 6 Proof that each culture listed can be produced from androstenedione a compound having the same R f 和 as 11 α aryl ketone. ^ 满 中 卑 局 二 二 二 ^ ^ ^ ^ ^ ^ ^ NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR The normal phase was subjected to a hose column chromatography, and methanol was used as a slag to separate and purify the culture product. The fraction was analyzed by thin layer chromatography. The TLC plate was 60 for Whatman K6F silicone, 10×20 size, 250 μm thick. The solvent mixture was -214. - The paper size is applicable to the Chinese National Standard, (CNS) AUm (210X 297^1) - the second-order sample of the Ministry of the Ministry of Economic Affairs, βχ消χ合合竹社印来1248443 A7 B7 V, invention description (212) chloroform··methanol , 9 5 : 5, v/v. Crystalline product and 1 1 α - The ketosine diketone standards were analyzed by LC-MS and NMR spectroscopy. Both compounds gave similar profiles and molecular weights. Example 1 9 A According to the basic methods of Examples 17 and 18, various microorganisms were tested in androstenedione. Biotransformation to 11α-Equivalent to Isoflavones. Aspergillus fumigatus ATCC 26934, Aspergillus niger ATCC 16888 and ATCC 26693, O. sphaeroides ATCC 7156, Curvularia sp. ATCC 12017, Pseudomonas sp. ATCC 8688a, and Pithomyces Atro-olivaceus IFO 665 1 was grown essentially as described in Example 17. The growth and fermentation medium (30 ml) had the composition shown in Table 34. The same method was used to identify the products using Examples 1 7 and 18. 11-L-hydroxylation of androstenedione by microorganisms. The results are shown in Table 19A-1. Table 19A-1 Androstenedione 11-hydroxyl group of various microorganisms Tobacco A. fumigatus ATCC 26934 Aspergillus niger ATCC 16888 and ATCC 26693 Rhizopus oryzae ATCC 7156 Curvularia sp. ATCC 12017 Short-spotted scutellariae ATCC 8688a In Table 19A-1, π + &quot; indicates a positive result, ie Rf as in thin layer chromatography - 215 - Table paper scale applies to China哗家标哗CNS ) Eight 4 specifications (210X 297 mm) (Please read the notes on the back and fill out this page) TLC + + LC/MS + + + + + + + + 1248443 A7 B7 V. Description of invention (213 g of hydroxyl 11 The gram grows as expected, and approximates the correct molecular weight on the LC/MS. These results prove that the listed ★ P~^ can be subjected to the 1 1 p -3⁄4ization of androstenedione by the organism. 1 Test various microorganisms, and convert the scent of scented saponin, λ- 卞 克 ke, and ketone to 丨 ^ _ hydroxy mercapidone ^ ^ * fermented 杧 nucleus as described in Table 3-4. The fermentation conditions and analytical methods of the cockroaches are the same as those of the ruthenium, such as Lu, 1 and 幻1. D-LC plate and solvent system: as described in Example 18. Chromatographic analysis of the terminal ketone and Ur#i kemeikeru Gongji Wu odor tone m π. The chromatographic mobility of j-phase. 11 α _ 舄 舄 ketone and 9 hydroxy ketone ketone are Μ base materials _ the same mobile type ^ ketone ketone and ruthenone should have a phase like 9α _ hydroxy quinone; / ' compound extracted from the medium : Emotional. Therefore, it is self-generated. The results are shown in Table 36. Kekenreone is a standard product (said to read the back of the note before you fill out this page) Λ-· 经 屮 经 θ θ θ θ τ τ τ τ τ τ 仍 仍 仍 仍 仍 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; this

1248443 A7 B7 V. INSTRUCTIONS (214) 经 部 中 〈 〈 〈 〈 〈 〈 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表 表1 point characteristic of microbial culture medium 2 Absidia bluetooth ATCC 6647 M, S strong Aspergillus nicot ATCC 16888 s, p weak (8) ? (p) Autofrocus ATCC 7159 P Strong self-fungal ATCC 13144 s, p ? ? • ? Grape genus IMI 038560 Weak short thorns, silver worm, ATCC 8688a s, p, strong thorns, silver worm, ATCC 3655 s, p strong, elegant gram, silver worm, ATCC 9245 s5p, strong rot spore ATCC 12017 s strong ovate Toxoplasma ATCC 22822 s, p Penicillium sp. ATCC 24550 s, p strong Penicillium chrysogenum ATCC 46581 s, p strong Pithomvces atro-olivaceus IFO 6651 s, p Leuconostoccal ATCC 14887 M weak erythromycin saccharide Bacteria ATCC 11635 M, SF Streptomyces hygroscopicus ATCC 27438 M, SF Streptomyces faecalis ATCC 25489 S, P Astragalus fuliginea ATCC 18191 S?P Weak Thamnostvlum piriforme ATCC 8992 S, P P. sinensis ATCC 12543 P, S Weak (p) ? (S) -217- This paper scale applies to China National Standard (CNS) ΜSpecifications (210X 297 mm) (Please read the notes on the back and fill out this page), v5 Γ 1248443 A7 ____________ Β 7 V. Inventions (215) ^^'1~~~~ M=Mueller-Hinton Ρ -ΡYG (Protein/Yeast Extract/Glucose) s = Soybean meal SF = Soybean meal plus formate 2 Differences with untreated control group These data show that most of the tables listed in this table Organisms can produce

, similar or identical to the point of methicone from methicone. Aj^Ll9C tests various microorganisms and converts meclirenone to U α _hydroxy meclorone, Λ 1,2- melixone, _hydroxy mecroreone, 12y5-hydroxy meclorone, and 9^ The efficacy of hydroxy meclorone. Meyer ketone according to Weier, U.S. Patent No. 3,787,396 and R.M. Weier et al, j Med. Chem.,

Prepared in the manner described in Vol. 18, PP_ 817-821 (1975), which is incorporated herein by reference. The fermentation medium was prepared as described in Example 17, except that it included Mecco. The fermentation conditions were basically the same as those described in Example 17; the analytical methods were also the same as in Examples 17 and 18. The TLC plate and solvent system are as described in Examples 17 and 18. The microorganisms tested and the results obtained are shown in Table 19c%1. Order (please read the notes on the back and fill out this page) m部-s#Quasi-commissioner, τ consumption 仂 印印繁-218- This paper scale applies to China National Standard Rate (CNS) Λ4 Specification (210X 297 mm) 1248443 A7 B7 V. Invention Description (216) 19C-1 Produced by various microorganisms from melixone 11 ^ ketocrestone organism 417: 399 Beauveria bassiana ATCC 7159 Beauveria bassiana ATCC 13144 Helminthosporium fulvum ATCC 42613 Short thorn gram silver Hanlu ATCC 8688a孢小克银汉霎 ATCC 3655 雅致小克银汉露 ATCC 9245 Blue Phytophthora ATCC 6647 Aspergillus niger ATCC 16888 Ovary sphaeroides ATCC 22822 Pithomyces atro-olivaceus ATCC 6651 Streptomyces hygroscopicus ATCC 27438 HPLC mVz + + + + + + + + + + + + + + + + + + 4- + + + 5:1 10: 1:1 1:1 1:2 1:1 1:1 4:1 3:1 3:1 3: 1 Pre-requisites of the Ministry of Fine Arts in the Ministry of Fine Arts, Wu Erxiao, and Zhu Zhu, the private printing f, in Table 19CM,,, +, indicate positive results, if there is Rf値 in the middle of thin layer chromatography, and as expected by HPLC The length of stay. m/z4l7:399^ shows the peak height ratio of 4丨7 molecules (light base melix) and 399 molecules (mecrarone). The standard has a 10:1 ratio of m/z 417 and m/z 399. The product from Beauveria bassiana ATCC 13144 was isolated from the J-culture mixture and analyzed by NMR and confirmed by the structural profile to be hydroxy meclirenone. Similarly, the products obtained from other organisms listed in Table 19C-1 are also assumed to be u 219. The paper size is inferior to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) 1248443 A7 ------ — -- -________ — B 7 V. INSTRUCTIONS (217 ) ^ Hydroxy meclorone. Table 19C-2 Various microorganisms produced by melixone △ Shark 酉 酉 有机 有机 有机 LC LC LC TLC Horse blood red ball AT AT ATCC 148S75 + + + 椁 椁 AT ATCC 17 673 + + + Phytophthora ATCC 11996 + + + Yellow Nocardia Fantasia ATCC 12674 + + + Rhodococcus equine ATCC 21329 + + + ---------0! (Please read the notes on the back and then fill out this page) in Table 19C- In 2, "+ &quot; indicates a positive result, such as Rf値 expected in thin layer chromatography, and the expected residence time in HPLC. The product obtained from the epoxy bacillus ATCC 12673 is isolated from the incubation mixture and The NMR analysis confirmed by the structural profile was Δmecroreone. Similarly, the product obtained from the other microorganisms listed in Table 19C-2 was also confirmed to be ^1'2-mecrarone. 6/?- and 12 The production of mega-hydroxy meclorone was carried out in the presence of melixridone as described in Example 17. The acid fermentation product was isolated and purified by flash chromatography. The purified product was LC/ MS was analyzed as in Examples 1 7 and 18, and was also analyzed by proton NMR and carbon-13 NMR. The data showed that the product included 6 /?- and 12 /?-light Mectorone. -220- The paper size is cumbersome + national standard (, NS) Λ 4 specifications (210X 297 mm) - Bid cadres in the Ministry of Standards and Bureaux Department of Consumers and Hezhushe Printing 128443 A7 B7 V. INSTRUCTIONS INSTRUCTIONS (218) Table 19C-3 Various microorganisms produced by melixone 9α-hydroxy meclironone organism Streptomyces hygroscopicus ATCC 27438 Ovovo sphaeroides ATCC 22822 Short thorns sclerotium ATCC 8688a thorn spores Helminthosporium erythraea ATCC 3655 elegant gram gram silver mold ATCC 9245 Helminthosporium fulvum ATCC 42613 Blue worm fungus ATCC 6647 Beauveria bassiana ATCC 7159 Aspergillus niger ATCC 16888

ι/ζ 417 HPLC + + + + + + + + + + + + + + + + + + + TLC + + + + + + + + + + (Please read the note on the back and fill out this page) The subfamily J-disintegrated J. sinensis was found to grow under the same conditions as described in Example 17 and had the presence of melixone. The fermented product was analyzed by TLC and LC/MS as in Examples 1 7 and 18. "+ '' indicates a positive result, such as the Rf expected in thin layer chromatography, and the expected residence time in HPLC, etc. The data suggests that the product includes 9 α -hydroxy meclirone. Example 1 9 D The efficacy of various microorganisms to convert the ketones to Δ9 il ^ rendruffone was tested. The fermentation medium and growth conditions were essentially as in Example 177 except that the gram is included in the medium. Analytical methods such as Examples 1 7 and 1 8 Microorganisms and results are shown in Table 19D-1 below. -221 - This paper scale applies to Chinese National Standard (CNS) Λ4 size (210X 297 mm) 1248443 A7 B7 V. Description of invention (219) Table 19D-1 Kenridone Λ9'11-Kenrexone organism Bacillus licheniformis ATCC 12673 C. elegans ATCC 11996 Cyclospora ATCC 11011 Pseudomonas sphaeroides ATCC 46579 Septomyxa affinis ATCC 6737 Rhodococcus ATCC 19070

m/z 339 HPLC + + + + + + + + + + + + TLC + + + + + + (Read the first note on the back and fill out this page.) After the Ministry of Economic Affairs, the Department of Standards and Regulations The yeast extract was analyzed by TLC and LC/MS as described in Examples 17 and 18. Indicates a positive result, such as the Rf expected in thin layer chromatography, and the expected residence time in HPLC. The product from Comomonas testosteroni ATCC 11996 was isolated from growth medium and analyzed by UV spectroscopy. The spectroscopic profile confirmed the presence of Λ9,11-kelidone. Similarly, products from other microorganisms listed in Table 19D-1 are also assumed to be Λ9'11-Kenresone. Example 20 Scheme 1: Step 1: Method A: Preparation of 5'R(5' a ), 7'y5 -20'-Aminohexadecyl-11' /?-hydroxyl〇'a, 13f π-dimethyl -3',5-dione snail [furan-2 (3,17'"(5'11)-[7,4] methylene [411[cyclopenta[3]phenanthrene]-5'_月青In a 50-gallon glass reaction tank, add 61.2 liters (57.8 kg) of DMF, add 23.5 kg of 11-hydroxynorreone L, and mix with stirring. At -222 - the paper scale applies to the Chinese national standard rate. () Λ4 size (210X297 mm) 1248443 A7 B7 V. Description of the invention (22〇) Add 7 _ 1 kg of lithium chloride to the mixture. Mix the mixture for 20 minutes, then add 16.9 kg of acetone cyanohydrin followed by With 5.1 kg of triethylamine, the mixture was heated to 85 ° C and maintained at this temperature for 13-1 8 hours. After the reaction, 3 53 liters of water was added, followed by 5.6 kg of sodium bicarbonate. The mixture was cooled to 0 ° C, transferred The 200-gallon glass reactor was slowly quenched with 130 kg of 6.7% sodium lactate solution. The product was filtered and washed with 3 χ 4 liters of water; the strip produced 21.4 kg of product guanamine.

〇 W

(Please read the notes on the back and fill out this page)

, 1T by the Ministry of the Ministry of the ruling of the ruling of the J-xiao 贽 竹 社 社 社 H H H1 NMR (DMSO-d6) U (2Η, bd), 4·53 (1Η, d, J=5·9), 3 ·71 (1H,m), 3.0-1.3 (17H,m)5 1·20 (5H,m)5 0.86 (3H,s)' 0.51 (1H,t,J=10) 〇Example 20B Preparation 7 Cyano -11 dihydroxy-3-keto-17 α-pregnene-2 bromate, r-lactone

This paper scale applies to China's national standard ((, NS) Λ 4 specifications (210X 297 mm) %1. The Ministry of Economic Affairs and Standards Bureau of the Ministry of Foreign Affairs and the Department of Consumers and the Zhuhe Society printed 1244843 A7 ___________ Β Ί V. Invention Description (221) '1~^5〇·〇克的基基瑞瑞_ and 15〇.〇ml dimethyl ethanoamine added to: clean, dry three-necked flask equipped with a mechanical stirrer, condensed 1. It is a dipole and a heating cover. Add 6 ml of sulfuric acid to the mixture (mixed with 50.0 ml of sulfuric acid (98 7% Baker grade) and 5 ml of water). Sodium solution containing 15.6 grams of sodium cyanide and 27 liters of dilute water.

The resulting mixture was heated at 8 Torr for 7 hours and the degree of conversion was checked by IK or HPLC. After about 7 hours, the HpLc of the mixture showed the presence of a 7-cyano compound. The mixture was stirred for another night and allowed to cool to room temperature (about 22 ° C). 2 ml of water was added to the mixture, and 2 ml of methylene chloride was added thereto, and the resulting two-phase mixture was stirred off and then phase-separated. The water layer is a gel. Add 1 ml of sodium bicarbonate solution to the aqueous layer in an attempt to break the gel. The water layer is discarded. The separated methylene chloride layer was washed with 100 ml of water, and the resulting two-phase mixture was stirred. The phases were separated, and the separated methylene chloride layer was filtered through a celite (AldHch 200-4 〇〇 9-mesh sieve, 60 persons). The filtrate was concentrated to dryness under reduced pressure of 45, and about 53 g of crude solid product was obtained using an aspirator. The crude solid product was redissolved in dichloromethane and treated with 4 mL of EtOAc (br.). The dichloromethane layer was washed with 5 mL of water. The mixed aqueous layer was taken with 5 liters of di-methane. The mixed dichloromethane layer was dried over sodium sulfate to give 45 g of a solid touch of ιΐα-severage quinine copper and a product, cyanodiyl-17 α-pregn-4-ene-21-carboxylic acid, r a mixture of lactones. The product sample was analyzed by HPLC (column: 25 cm χ 46 mm, 5 micro--------0II (please read the back note first and then fill out this page)

, 1T Φ— -224- The Ministry of Economic Affairs and the Ministry of Standards 萸Jr. 贽 贽 竹 社 12 12 1248443 A7 __ B7 V. Inventions (222)

Altima C18LL); solvent gradient: solvent A = water / trifluoroacetic acid = 99.9 / 0.1, solvent B = acetonitrile / trifluoroacetic acid = 99 _9 / 0.1, flow rate = 1.00 ml / min, gradient = 65:30 (v / v ) (A: B - initial), 35: 65 (ν / ν) (A: B, after 20 minutes), ΐ〇: 90 (ν / ν) (Α: Β - · 2 5 minutes later); Dipole array detector) shows 23 8 nm; I max. The reaction mixture was analyzed by HPLC-NMR using the following conditions: HPLC-column: Zorbax RX-C8 (25 cm X 4.6 mm, 5 micron) using 75% D20, 25% acetonitrile to 25% D2 〇, 75% Solvent gradient of acetonitrile <25 minutes, flow rate 1 ml/min; 1H-NMR (obtained with WET solvent): 5.84 (s, 1H), 4.01 (m, 1H), 3.2 (m, 1H), 2.9 - 1.4 (m 'integration is meaningless because acetonitrile is a solvent to suppress it), 〇, 93_ 0.86 (s, overlap 3Η, and t, 2Η).

Example 20C Preparation of 5 cold, 7 α dicyanyl-17-hydroxy-3-keto-17-progestane-21·carboxylic acid, r-lactone

In a one liter, two-necked round bottom flask, 1 〇 2 g (0.3 萼 Π) Π _ _ ke ketone -17 π - gestation _ 4, 6 ate diene - carboxylic acid, r • Stuffed (Kenruthone) with 46.8 g (〇·72 mol) of potassium cyanide, 78·6 ml (1 356 mol) acetic acid and 6 〇〇 --225- this paper scale towel (CNS) A4%i7Ti〇X 297^f ) ---------#! (Please read the notes on the back and fill out this page), can be 1248443 A7 B7 V. Inventions (223) ^Methanol Mix in the slurry. Add 64.8 ml (〇.78 mol) of the ^ bite to the mixture; the field is obtained by heating the slurry to reflux (4), and then keep it about "small" (please read the back note before filling this page). Let the temperature of the slurry drop by 9 s 1. And, 25 L _30 C, for a minute (using a cooling bath). Add 12 liters of concentrated chlorous acid slowly during cooling in brown solid # 卜 3 bar U / 焱. Mix the mixture at 25O_3 (rC for 1.5 hours, then add 5 ml of water for 30 minutes. The mixture is cooled to 5 in an ice bath. 〇, by adding 1 〇〇 ml of 9.5 M sodium hydroxide (0 · 95 moles) Adjusted impotence to 3_55 (tracked with pH bar). Excess cyanide is destroyed by the addition of household bleach. Add 25 ml (ο.ογοm) to achieve a negative starch iodide test. Cold mixture (10 C), and the solid was washed with water until the rinsing liquid was neutral bismuth (strip). The solid was dried at 60X: to 14 g constant weight. The solid isolated was hot in Fisher j〇hns The plate is 244. 〇 246 ° C will be 'chemical. The solution containing solid methanol in the 210 ~ 240 亳 micron. ν region and the absorption. IR (CHC13) cm -1 2222 (cyanide), 1775 (lactone) , 173 2 (3-keto), 4 NMR (pyridine d5)) ppm 〇·94 (s,3H), 1.23 (s,

3Η) 〇Example 21A Scheme 1: Step 2: Preparation of 4'S(4,a),7,a-hexadecahydro-η,α-hydroxyl 10, via the drop section of the standard board member J-Xingqi Hezhushe 3,13'/?-Dimethyl-3',5,20'-trione snail [吱 _2_2(311),17,&gt;5-[4,7] Methylene [17Η] Cyclopenta[a]phenanthrene]_5'cold (2Ή)-nitrile In a 200 gallon glass reactor, 5 〇 kg of guanamine 2 _, about 445 liters of 0.8 N dilute hydrochloric acid and 75 liters of methanol were added. The mixture was heated to 80. (: 5 hours, cooled to 0 °C for 2 hours. Solid product filtration can produce 3 6.5 kg -226- This paper scale is suitable for China National Standard ((, NS) Λ 4 specifications (210X 297 mm) 1248443 A7 B7 V. INSTRUCTIONS (224) Anhydrous product diketone

HCI, CHjOH, H20 80*Ct 5h Step 2 o 0

II o (Please read the precautions on the back and fill out this page.) After the Department of Standards and Regulations of the Ministry of Consumer Affairs, τ消贽合竹社印来

H1 NMR (DMSO-d6): 4_53 (1H,d,J=6),3·74 (2H,m) 2 73 (lH,dd,J=14,7)2.65-2.14(8H,m),2.05 (lH,t5&gt;U),198-1·71 (4H,m),1.64 (1H,m),1.55 (1H,dd,J=l3, 5), 1451 2〇(7H,m),0.86 ( 3H, s). Example 21B Scheme 1: Steps 1 and 2: Preparation of f-hydroxy-HV/?,13'/?-dimethyl-3',5,20,-trione snail [furan_2(3H) 17, in situ Lu-[4,7] Methylene-[17H]cyclopenta[a]phenanthrene]·5'θ (2, decarboxyl-nitrile, prepared from u" Hydroxy ketone is equipped with a cooling condenser, mechanical stirrer, Add 100 grams (280.54 millimoles) of U-several Kirk-Resin (prepared by the method of Example 1) to the heating hood and the reactor for controlling the crying and funnel, and add 300 liters - A | r, "a τ base Acetamide (Aldrich). The mixture was taken up until 11 _ 基 肯 肯 瑞 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克10. (: to 15. (:. and then 2 to 3 minutes period Z, 11 -227 - 1248443 A7 __________ B7 5. Invention description (225) into sodium cyanide solution, the latter from 31_18 grams (617.20 millimoles) ( The 8 1 (!1^11) cyanide steel is prepared by dissolving it in 54 ml of deionized water. The resulting mixture will rise to 2 〇 ° C to 25 ° C after the addition of sodium cyanide solution. The mixture is heated to 8 0 °C, at this temperature can maintain 2 - 3 small Once analyzed by HPLC, it is known that the conversion of 11-hydroxyluronone to enamine is essentially complete (more than 98% conversion) heat source. The enamine contained in the mixture is not separated. After that, add an additional 148 ml of 50% sulfuric acid in 3 - 5 minutes. After 10 minutes, add 497 ml of deionized water. The mixture is heated to 1 〇 2. (:, and maintained at this temperature until it is in the mixture. Approximately 500 grams of distillate was removed. Within the reaction enthalpy distillation, 5 liters of deionized water was added to the mixture four times 125 liters of water. The fractions were removed in equal amounts of distillate (125 liters). It was added to the mixture afterwards. The reaction was continued for 2 hours. When HPLC analysis showed that the reaction to hydrolyze the enamine to diketone was substantially complete (greater than 98% conversion), the mixture could be cooled to about 8 for 2 minutes (Γ(: The mixture was filtered through a fritted funnel. The reactor was rinsed with 2 liters of deionized water to remove the residual product. The solids on the filter flask were washed three times with an equal amount (about 〇 4 liters) of rinse water. Prepare a solution of soared methanol and deionized water (1:1 v/v) in a reactor and filter The solution is then used in milliliters (4). The filtrate is washed a second time with the remaining 500 ml of methanol/water solution. The straight space is applied to the funnel, and the filtrate is dried for transfer. The filtrate is transferred to a drying oven (here) Drying under 眞2 for 16 hours yielded 84 g of dried product diketone, 4, s (4, hexadecahydro) hydrazine, hydrazine, 13, broad dimethyl j 5 2 〇, -trione snail [b -2_,17,H4,7]Methylene-[17H]cyclopentane (5)-phenanthrene] (2Ή)·nitrile. HPLC analysis showed 94% of the desired diketone. -228- The paper size "Women _: Office (CNS) hUm ( 2T 〇 T297 ^ f ) (Read the first note on the back and fill in this page)

, 1T 1248443 benzyl-3-one pregnancy A7 B7 V. Description of invention (226) Flowing spear king 1: Step 3 A: Method A: Preparation 11 α,17 -4-ene-7 π,2 1 -di-skin acid A vinegar,, - inside the purpose. A 4-neck, 5-liter round bottom flask equipped with a mechanical stirrer, a pressure balanced addition funnel and a nitrogen inlet line, a thermometer and a condenser with a bubbler. The bubbler was connected via polyethylene tubing to two 2 liter valves, the first being empty and placed to avoid back-feeding of the material in the second valve (soaked concentrated sodium hypochlorite solution) into the reaction vessel. Diketone (79.50 g; [weight uncorrected, purity 85%]) was added to the flask in 3 liters of methanol. 25% methanol sodium methoxide solution (64.83 g) was placed in a funnel, and then added dropwise under a period of 10 minutes under stirring and nitrogen. Once fully added, the orange reaction mixture was added to the soil for 20 hours. After this period, 16 7 liters of 4 N HCl was added dropwise to the reaction mixture which was still refluxed via an addition funnel (caution: HCN will escape at this point). The color of the reaction mixture will be lighter and lighter in color. The condenser was replaced by the removed head and 5 liters of methanol was removed by distillation, and 1.5 liters of water was simultaneously added to the flask via a funnel, consistent with the distillation rate. The reaction mixture was cooled to ambient temperature and extracted twice with 2·25 liters of dichloromethane. The combined extracts were washed successively with 75 mL of cold saturated NaC1 solution 'IN NaOH and saturated NaCl. The organic layer was dried over sodium sulfate overnight, filtered, and then reduced to &lt Toluene (300 ml) was added and the remaining methylene chloride was evaporated under reduced pressure, during which time the product began to form a white solid on the wall of the flask. The contents of the flask were allowed to cool overnight and the solid was removed by filtration. It was washed with 250 ml of toluene and twice with 250 ml of diethyl ether and dried over a hollow funnel to yield 58.49 g of a white solid. 229 paper scales applicable to China National Standard (CNS) Λ4 (210X 297 mm) (Read first Note on the back side of this page), 1Τ 标准 中 中 _ _ 124 124 124 124 124 124 124 124 124 124 124 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 844 When the mother liquor is concentrated, 6 76 grams of additional 77.1% purity product is obtained. The total yield is adjusted for purity. 4 NMR (CDCl3): 5 70 (1H, s), 4·08 (1H, s), 3.67 (3H, s), 2 9-16 (19H, m), 15-12 (5H, m), 1.03 (3H. s). ZM23_ Condition 1 ··Step 3B ··11α,17α-dihydroxy-3-keto-inhibited 4-4-ene-7 heart 21-dicarboxymethyl ester, r _ lactone converted to 17f hydroxy-11α gas methyl sulfonate Oxy-3-one pregnant _4_ene-7", methyl 21-dicarboxylate, 7^ lactone. A 5-liter four-necked flask was placed as above, except that no trapping system was provided on the bubbler. 138. 7 g of hydroxy ester was added to the flask, and 1425 ml of dichloromethane was added thereto, and the mixture was stirred under nitrogen. The reaction mixture was cooled to _5 C with a salt/ice bath. Methane sulfonium chloride (5115 g, hydrazine) was added rapidly. · 477 moles, then slowly add triethylamine (54.37 grams) to 225 ml of di-methane. Adjust the rate of addition, which takes ~3 〇 minutes to make the reaction temperature never exceed about $ ^. After the redundancy, stirring was continued for 1 hour, and the reaction contents were transferred to a 2 liter separatory funnel, and 21 ml of dichloromethane was added thereto. The solution was aspirated with 7 (10) of each of IN HC1, IN NaOH and a saturated aqueous solution of NaCl. Washing, mixing with aqueous washing solution, and extracting with 3500 ml of dioxane. All organic washings are mixed in a 9-liter bottle, which is added to 5 gram of medium. Bauxite, active engineering grade ' and 500 grams of anhydrous sodium sulphate. The contents of the bottle are mixed for 3 ' 8 'filtered. The filtrate is dried under the hollow to form a gelatinous yellow, coated foam. Dissolve in 350 ml of dichloromethane, then add 180 ml of diethyl ether dropwise with stirring and mixing. Adjust the rate of addition, so that half of the ethyl bond is added in portions. After about 75 ml, the product begins to appear. Crystalline solids can be eight-230- 'this paper scale applies to Chinese national standard 1 rNS) Λ4 specifications (210X 297 mm) (please read the notes on the back and fill out this page)

By the full section of the decision-making rate of the Ministry of the Ministry of the Ministry of the People's Republic of China, the ruthenium of the ruthlessness of the ruthlessness of the ruthlessness of the ruthlessness of the ruthlessness of the ruthlessness of the ruthlessness of the ruthlessness of the ruthlessness of the ruling (228) Departure. The remaining ether was added in 1 minute. The solid was removed by filtration and the filter was washed with 2 L of diethyl ether and then 50. (: Drying overnight in a hollow oven produces 144.61 g (8 8 ° / 〇) almost white solid, mp 149 〇 c. The substance prepared in this way is usually 9 讧 99% by HPLC. / 〇). In a single process, a melting point of 153M53.5X: is obtained, and the purity determined by HPLC area is 99.5 〇 / 〇. H NMR (CDC13): 5·76 (1H, s), 5.18 ( 1H,dt),3.68 (3H,s), 3.06 (3H,s),2·85 (1H,m),2·75·1·6 (19H,m)5 i.43 pH, s), 1.07 (3H, s) 0 Magic column 2 4 Scheme 1: Step 3 C: Method a: Preparation of 17 a-hydroxy-3-keto-pregnant-4,9(11)·di-fine--, 21-di-oroxic acid 7 - Methyl vinegar, the purpose of the internal remedy. A 1-liter four-necked flask was installed as in the second example. Formic acid (2 50 ml) and acetic anhydride (62 ml) were added under nitrogen with stirring. Potassium formate (6.17 g) was added, and the reaction mixture was heated to an internal temperature of 4 Torr under an oil bath. 〇 (This point can be followed by repeating at 70 °C for better results) for 16 hours. After 1 6 hours, the mesylate was added to raise the internal temperature to 1 〇〇 °C. Heating was continued for 2 hours, after which the solvent was removed on a rotary evaporator. The residue was mixed with 5003⁄4 liters of ice water; it was dropped for 30 minutes and then extracted once with 500 ml of ethyl acetate. The organic phases were combined and washed successively with a cold 250 ml saturated sodium chloride solution (one time) &lt;1&gt;N hydroxide steel solution, and again with saturated sodium carbonate. The organic phase was dried over sodium sulfate, filtered and dried in vacuo to give a yellow-white foam which was smashed into glass when contacted with a spoon. The formed powder was analyzed to have 14.65 g (in terms of HPLC area%), and was -231 - 冢 paper scale suitable for A Chinese National Standard (CNS) i specification (210X 297 mm 1 _ ~ (Please read the back of the note first) Matters and then fill in the tribute)

1248443 A7 B7 V. INSTRUCTIONS (229) 82.1% 17 π-hydroxy-3-yl-keto-pregnant 4,9(11)-diene·7 α,21-dicarboxylic acid 7-methyl ester, r-lactone ;7·4% 17 α-hydroxy-3-ketopregna-4,11-diene-7 α,21-dicarboxylic acid 7-methyl ester, lactone; and 5.7% 9 α,17-hydroxy-3 a mixture of keto- 17α-pregn-4-ene-7α,21-dicarboxylic acid, bis(r-lactone). NMR (CDC13): 5.74 (1H, s), 5.67 (1H, m), 3.61 (3H, s), 3.00 (1H, m), 2.84 (1H, ddd, J 2, 6, 15), 2.65-2.42 (6H,m), 2.3-2.12 (5H,m),2.05-1.72 (4H,m),1.55-1.45 (2H,m),1·42 (3H,s),0.97 (3H,s ). tjH 2 5 Scheme 1: Step 3 C: Method B: Preparation of 17 a-carbyl-3-ketopregna-4,9(11)·diene·7 a,21-dicarboxylic acid methyl ester, r − ester. After the pouring of the Ministry of Standards Bureau, the contracted consumption of the Zhuzhu Society &lt; tight (read the first note on the back and fill out this page) Prepare a 5-liter four-necked flask as in the above example, then add 228.26 g under nitrogen and stirring. Acetic acid and 41.37 g of sodium acetate. The mixture was heated to an internal temperature of 100 ° C using an oil bath. Mesylate (123.65 g) was added and heating was continued for another 30 minutes. At the end of this period, stop heating and add 200 ml of ice water. The temperature was lowered to 40 ° C and stirring was continued for another hour, after which the reaction mixture was slowly poured into 1.5 liters of ice water in a 5 liter stirred flask. The product was isolated as a gelatinous oil. The oil was dissolved in 1 liter of ethyl acetate and washed with 1 liter of cold saturated sodium chloride solution, 1 N sodium hydroxide, and finally saturated sodium chloride. The organic phase was dried over sodium sulfate and filtered. The filtrate is hollowed out to form a foam which can be shrunk into a gelatinous oil. Grind with ethanol for some time and finally cure. The solid was filtered and washed with diethyl ether to give a pale yellow solid. This includes 70.4% of the desired quinone 9,11 enester, 12.3% Δ11,12 decyl ester 1, 10.8% 7-heart 9-"-lactone 2 _ and 5.7% unreacted 5 _ -232- This paper size applies China National Standard (rNS) Λ4 Specification (210X 297 mm) 1248443 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs 五7. Invention Description (23〇)

Example H Scheme 1: Step 3D: Method A: Synthesis of u1&quot;-epoxy-17"-carbyl-3-one-pregnant _4·晞-7 π, methyl 21-dicarboxylate, r-endo vinegar. Four-necked 5 〇〇 ml reactor equipped with a mechanical stirrer, condenser/foamer, thermometer and addition funnel with nitrogen inlet. Add 8_32 g of crude enester to 8 3 ml in the reactor. Dichloromethane was calcined under nitrogen and stirred. 4.02 g of dibasic potassium phosphate was added, followed by 12 ml of trichloroacetonitrile. The external cooling water was passed through the reactor jacket and the reaction mixture was cooled. Up to 8 Torr. Add 3 6 ml of 30% ruthenium peroxide in the addition funnel over 10 minutes. Once fully added, the initial pale yellow reaction mixture turned almost colorless. The reaction mixture was maintained throughout the addition. 9 At 1 ° C, stirring was continued for one night (for a total of 23 hours). Dichloromethane (150 ml) was added to the reaction mixture, and the whole was applied to ~250 ml of ice water. Extract three times. The mixed dichloromethane extract is dissolved in 400 liters of cold 3% sodium hydrogen sulphate. Wash to decompose any residual peroxide, then wash with 330 ml of cold 1 N sodium hydroxide, 400 ml of cold 1 N hydrochloric acid, and finally 400 ml of water. The organic phase is dried over magnesium sulfate and filtered. The filter was washed with 80 ml of dichloromethane. The solvent was removed under a vacuum to give 9.1 g of crude product as a pale yellow solid. Recrystallized from ~25 ml of 2-butanone to yield 5.52 g. Almost white crystals. Finally recrystallized from acetone (~5 〇 ml) to produce 3 · 16 g long, acyclic, mp 241-243 ° C. 'Η NMR (CDC13): 5·92 (1H , s), 3.67 (3H, s), 3.13 (1H, d, Bu 5), 2.89 (1H, m), 2.81-2.69 (15H, m), 1.72 (1H, dd, J=5, -233- This paper scale applies to the Chinese National Standard (CNS) Αϋ (210Χ 297ϋΊ&quot; one-' ------1Τ------ (please read the notes on the back and fill out this page) 1248443 A7 —___ B7 — I. A _· --------- . __«__ . _ V. Invention description (231 ) 15), 1.52-1.22 (5H, m), 1.04 (3H, s). Example 2 7 Process 1 : Step 3: Select 1st: by 4'8(4'&lt;^) 7'&lt;^-hexadecahydro-11, •hydroxy-10'/?,13,々-dimethyl·3,,5,20'-trione snail [furan-2(3H), 17'/ [4,7]Methylene [17H]cyclopenta [a]phenanthrene]-5,y? (2Ή)·nitrile, to 9,11 epoxy _ 17α - sulpho-3-one pregnancy -4-晞- 7α, 21-diacid acid, the purpose of the end. Diketone (20 g) is added to the clean and dry reactor, plus 820 ml

MeOH and 17.6 mL of a 25% NaOMe / MeOH solution. The reaction mixture is heated to reflux (~67 ° C) for 16-20 hours. The product was quenched with 40 mL of 4N HCl. The solvent was removed by distillation under atmospheric pressure.丨〇〇ml of toluene was added and the residual methanol was removed by azeotropic distillation with toluene. After concentration, the crude benzyl ester 4_ was dissolved in 206 ml of di-methane and then cooled to 〇 °c. Add methane 28 驴 chlorine (5 liters) and then slowly add 8 8 ml of triethylamine. The product was stirred for 45 minutes. The solvent is removed under a hollow distillation to produce a crude methane sulfonate! _. In a separate dry reaction, 5.93 g of formic acid 4A, 240 ml of formic acid and 11 8 ml of acetic anhydride were added. The mixture was heated to 7 Torr for 4 hours. The Central Standards Bureau of the Ministry of Economic Affairs, the employee consumption cooperative, printed the methanol mixture and added it to the concentrated mesylate solution prepared above. The mixture was heated to 95-105 ° C for 2 hours. The product mixture was cooled to '5 Torr and the volatiles were removed by vacuum distillation at 50 °C. The product was partitioned between 275 ml of ethyl acetate and 275 ml of water. The aqueous layer was extracted with 137 liters of ethyl acetate and extracted with 240 ml of cold (3) chlorinated steel and then saturated with 12 liters of water. After phase separation, the organic layer is subducted under the hollow steaming hall to produce an enester. -234- This paper size applies to Chinese National Standard (CNS) 1248443 A7 _ _____ B7 · ~ 二-&quot; '-------一....______ '. 丨 ― V. Inventions (232) Product soluble In 1 80 ml of dichloromethane, cool to 〇-1 5 °C. Add 8 · 6 8 gram of hydrogen to the second, then add 2.9 ml of trichloroethane. To the mixture was added 7 8 ml of a 30% hydrogen peroxide solution over 3 minutes. The reaction mixture was stirred at 0 -1 5 C; it was mixed for 6 - 24 hours. After the reaction, the two phase mixture was separated. The organic layer was washed with 126 liters of 3% sodium hydrogen sulfate solution, 126 ml of 0.5N sodium hydroxide solution, 126 ml of 1 N hydrochloric acid and 126 ml of 10% brine. The product was dried on the magnesium salt of the water, or passed through Celite, and the solvent, methylene chloride, j: was removed by distillation under atmospheric pressure. The product was crystallized twice from methyl ethyl ketone to give 7.2 grams of epoxy meclirone. (Read the first note on the back and fill out this page 〇

, 1T - Φ. Printed by the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Commerce 2 8 Process 1: Step 3: Select 2: Transform to ^ '勾夕心六氢·... π-hydroxy-10'/?, 13'y5-dimethyl-3,5,20,-trione snail [furan-2(3H),17, _[4,7]methylene [17H]cyclopenta[a]phenanthrene]-5, /? (2Ή)-Nitrile to 9,11 (^_epoxy-17 α-hydroxy-3-ketopren-4-ene-7 α,21-dicarboxylic acid methyl ester, r • lactone, not separated Intermediates -235- This paper scale applies to China's national (CNS) ICP (210>&lt;297 public's good ^ '~~一—,----- Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed 1244843 A7 --- V. Description of the invention (233) Prepare a four-necked 5-liter round bottom flask equipped with a mechanical stirrer, an addition funnel with a nitrogen inlet, a thermometer and a condenser with a bubbler, The secondary acid steel scraper. Diketone (8 3 _ 2 gram) was added to the flask in a 3. 5 liter of methanol. Add 67.85 grams of 25% (w:w) sodium methoxide to the addition funnel. A solution of methanol. The methoxide was added dropwise to the flask over a period of 15 minutes under nitrogen and stirred to develop a dark orange/yellow In the slurry, the reaction mixture was heated under reflux for 20 hours, and then 175 ml of 4N hydrogen acid was added dropwise under continuous reflux (caution, HCN will escape in this operation!). The reflux condenser was replaced with a removable head, and then 1.6 liters of methanol was removed by distillation, while 1.6 liters of 1 〇% sodium chloride aqueous solution was added dropwise via a funnel at a rate corresponding to the distillation rate. The reaction mixture was cooled to ambient temperature, and then 2 to 25 liters of two gas. The mixture was extracted twice by heating, and the mixed extract was washed with cold 75 ml of 1 Ν sodium hydroxide and a saturated sodium carbonate solution. The organic layer was dried by azeotropic distillation of methanol at atmospheric pressure to a final volume of 1 liter. (A total of 5% was removed for analysis).

The concentrated organic solution (via the base ester) was added back to the original reaction flask, which was prepared as before - but without the HCN valve. The flask was cooled to 〇 ° C, and 3 〇.7 g of methanesulfonium was added under nitrogen with stirring. The addition funnel was filled with 32.65 g of triethylamine, which was added dropwise over a period of 15 minutes, and the temperature was maintained at 5. Stirring: Mix for 2 hours' while the reaction mixture is warmed to ambient temperature. A column containing 250 grams of Dowex 50 W X 8-100 acidic ion exchange resin was prepared and used 2503⁄4 liters of water, 250 milliliters of methanol and 5 milliliters of dichloromethane strip before use. The reaction mixture flows through the column and is collected. Prepare a fresh column and repeat the above process. The third 250 g column, containing Dowex 1 X -236- This paper scale applies to China National Standard (CNS) Λ 4 specifications (210X297 public #) ---------------, order - -----^#1 (Please read the notes on the back and fill out this page) Department of Economics Central Bureau of Bureau employees' consumption cooperatives print 1244843 _________ B7 —_ V. Inventions (234) 8 - 2 〇 Test The ion-ion parent-replaced resin was prepared and pretreated as an acidic resin as described above. The reaction mixture flows through the column and is collected. A fourth test resin column was prepared, and the reaction mixture was again flowed through the column and collected. The column was washed twice with 250 ml of two-gas methane through each column for a total of ~10 minutes each time. The solvent wash was mixed with the reaction mixture, and the volume was reduced to ~5 〇〇ml under 眞 2, and the mixture was taken out for 2% for use in the product. The rest was further reduced to a final volume of 15 〇 ml (crude mesylate solution). In the original 5 liter reaction apparatus, 960 ml of formic acid, 472 ml of acetic anhydride and 23.70 g of potassium formate were added. This mixture was heated to 7 〇 C ' for 16 hours under stirring with nitrogen. The temperature is increased to 1 〇〇. 〇, and the crude carboxylic acid solution was added via an addition funnel over a period of 3 Torr. When methylene chloride was distilled off from the reaction mixture, the temperature was lowered to 85 °C. After all of it was removed, the temperature was again raised to 10 ° C and held for 2.5 hours. The reaction mixture was again cooled to 40 ° C and the formic acid was removed under pressure until a minimum of agglomerated volume was reached (~10.5 liters). The residue was cooled to ambient temperature and then 3 75 mL of dichloromethane was added. The dilute residue is washed with a cold 1 liter saturated sodium chloride solution, 1 N carbon and sodium carbonate solution. The organic phase was dried over magnesium sulfate (1 5 g) and filtered to give a dark red-brown solution (cr. A 4-necked 1 liter reactor was prepared equipped with a mechanical stirrer, a condensing/foaming state thermometer and an addition funnel with a nitrogen inlet. The reactor was filled with a crude solution of olefinic vinegar (estimated to 6 g) in 600 ml of a rat, and stirred under nitrogen; 24.0 g of the two-test citric acid was added, and 8 7 ml of dichloroacetonitrile was added. The external cooling water flows through the reactor jacket and the reaction is -237- ---------------IT------MW (please read the notes on the back and fill out this page) This paper-scale scarves are turned on (CNS) (210X 297^&gt; f ) 1248443 A7 V. Inventive Note (235) The mixture is cooled to 10X. 147 ml of hydrogen peroxide was added to the addition funnel for 30 minutes. Upon completion of the addition, the initial dark reddish brown reaction mixture returned to a pale yellow color. The reaction mixture was maintained at 1 〇 ± 1 ° C throughout the addition and stirring was continued overnight (23 hours total). The phases were separated, and the aqueous portion was extracted twice with 120 ml of dioxane. The combined organic phases were washed with 2 10 ml of a 3 % sodium hydrogen sulfate solution. This was repeated twice, after which the organic and aqueous fractions were known to be peroxide negative by the starch/iodide test paper. The organic phase was washed with 210 liters of cold 1 n sodium hydroxide, 1 n hydrochloric acid, and finally brine. The organic phase is azeotropically dried to a volume of ~ 丨 00 ml, then fresh solvent (250 ml) is added and co-boiled to the same 1 (8) ml, and the remaining solvent is removed under an empty space to produce 57 〇 5 g. The crude product is a gelatinous yellow foam. A portion (5 丨 · 01 g) was further dried to a constant weight of 44.3 g, and then quantitatively analyzed by HPLC. Analyzed as 271% epoxy meclirone. Straight J column 2 9 - from 11! Di-androstenedione forming 3 _ ethoxy η "-hydroxy-androst-3,5-diene-17-ketone Ministry of Economics Central Bureau of Standards Bureau employee consumption cooperative printing 11 Zinc-indolinone (429.5 g) and toluenesulfonic acid hydrate (7·) were added to the reaction flask under nitrogen. Ethanol (2.58 L) was added to the reactor and the resulting solution was cooled to 5 °C. Triethyl orthoformate (3 34.5 g) was added to the solution over 15 minutes at 0-15 C. Once the triethyl orthoformate was completely added, the reaction mixture was warmed to 40 ° C at this temperature. After 2 hours, the temperature was increased to reflux, and the reaction was refluxed for another 3 hours. The reaction mixture was cooled under a hollow, and the solvent was removed under venting to give 3 _ ethoxy 4 i α- thiol-male- 3,5-dien-17-one. Example 11 ^ -Hydroxygen quinone to form enamine-238- This paper scale applies to Chinese National Standard (CNS)

1248443 A7 ____ ___ ”37 V. INSTRUCTIONS (236) Scheme 1: Step 1: Method B: Preparation of _2〇, _Amino-10-κ Hydrogen-1 Γ /?-Light base·1〇Ή' α-dimethyl Base_3,,5-dione snail [吱然·2(3, 174(5,11)-[7,4]methylene [411[cyclopenta]&gt;] phenanthrene]-5,-carbonitrile .

Sodium cyanide (1.72 g) was placed in 25 ml of a 3-neck flask equipped with a mechanical stirrer. Water (2.1 ml) was added and the mixture was stirred under heating until the solid particles were dissolved. Add dimethylformamide (15 ml) and add 11^-hydroxyluronicone (5.0 g). A mixture of water (〇4 ml) and sulfuric acid (1.49 g) was added to the mixture. The mixture was heated to 85 °C for 2.5 hours at which time HPLC analysis showed complete conversion to product. The reaction mixture was cooled to room temperature. Sulfuric acid (0.83 g) was added and the mixture was stirred for 1.5 hours. The reaction mixture was added to 60 ml of water in an ice bath. The flask was washed with 3 ml of DMF and 5 ml of water. The slurry was stirred for 40 minutes and filtered. The filter block was washed twice with 40 ml, and dried overnight at 60 C with an empty baking phase to produce '11'-light decylamine, ie, -20'-aminohexadecane-u丨 light _1 〇丨,13,_Dimethyl-3,,5-dione snail [furan-2(311),17'"(5'11)-[754]methylene[411]cyclopenta[a] Philippine-5,-carbonitrile (4.99 g). -239- Use the Chinese national standard $( CNsTAA^m ( 210X 297^#&quot;*) ^ ' to order (please read the note on the back and then fill out this page) Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed 1244843 Ministry of Economic Affairs The Central Standards Bureau employee consumption cooperative printed A7, &quot;*~~一--·» 匕一-.-一...,一一一丨-II, V, invention description ( 237 ) — example; 3 卜 11 ketone To the second

Sodium cyanide (1.03 g) was added to a 50 ml flask equipped with a mechanical stirrer. Water (1.26 ml) was added and the flask was heated slightly to dissolve the solid. Dimethylacetamide (or dimethylformamide) (9 ml) was added followed by 11α-hydroxynorprene (3.0 g). A mixture of sulfuric acid (0.47 ml) and water (〇_25 liter) was added to the reaction flask with stirring. The mixture was heated to 95 ° C for 2 hours. HPLC analysis showed the reaction was complete. Sulfuric acid (0.27 ml) was added and the mixture was stirred for 30 minutes. Additional water (25 liters) and sulfuric acid (0.90 liters) were introduced and the reaction mixture was stirred again: 16 hours. The mixture was cooled to 5 -1 Torr in an ice bath. Hey. The solid was separated by filtration through a fritted glass filter and washed twice with water (20 mL). Solid diketone, ie, 4'S(4'α), 7'--hexadecahydro-11丨, hydroxy-1〇丨, 13,-dimethyl-3',5,20'-trione snail [furan-2(3H),17'y5-[4,7]methylene[17Η]cyclopenta[a]phenanthrene]-5'θ (2Ή)-nitrile, dried in a hollow oven to produce 3.0 g s solid type. Example 32Α-1 Scheme 1: Step 3: Method Β: Preparation of Ιΐα, ΐ7α-dihydroxy-3-pre-1 -4-ene·7α,21-dicarboxylic acid methyl ester, r-lactone. -240- This paper scale applies to China National Standard (CNS) Λ4 (21〇x 297 蝥) (Please read the note on the back and fill out this page) Department of Economics Central Standards Bureau Employees Consumption Cooperative Printed 1244843 A7 __ ___ V. Description of the invention ( 238 ) —— — —~ — 5.2 g of diketone (prepared as described in Example 3) in a suspension of methanol (丨 (10) ml), heated to reflux, and then! A 25% solution of methacrylic acid-depleted methanol (5.8 ml) was added in minutes. The mixture became homogeneous. After 15 minutes, the &gt; precipitate appeared. The mixture was heated under reflux and became again qualitative after about 4 hours. Continue to reflux for a total of 23.5 hours and add 4·〇Ν hci (1 liter). A total of 60 ml of hydrogen cyanide in methanol was removed by distillation. Water (57 ml) was added over 15 minutes to the distillation residue. The temperature of the solution was raised to 8 1.5 C in water, and 4 ml of hydrogen cyanide/methanol solution was removed from the distillation. Once fully added, the mixture becomes cloudy and the heat source can be removed. The mixture was stirred for 3 · 5 hours' and the product was slowly crystallized. The suspension is filtered, the collected solid is washed with water, dried under a stream of air under a funnel, and dried at 92 ° C (26 忖 H g column) to form 2 · 9 8 gram of white after 16 hours. solid. The solid was 91.4% hydroxy ester, i.e., 11α, 17α-dihydroxy-3-keto-pregnant-4-indole-7,21-di-orrogensic acid methyl ester, r-lactone, by weight. The yield was 56.1%. Example 32A-2 Preparation 11 Dihydroxy-3-ketopren-4-ene-7α,21-dicarboxylic acid methyl ester, r-lactone. The diketone (40 g) produced in the manner described in Example 31 was added to a clean, dry, jacketed 1 liter reactor equipped with a bottom drainable, condensing tube, RTD probe and fraction collection. groove. Methanol (800 ml) was added to the reactor and the mixture was stirred. The resulting slurry was heated to about 60 ° C to 65 ° C and a 25% potassium methoxide solution (27_8 mL) was added. The mixture became homogeneous. The mixture was heated under reflux. After about 1.5 hours of reflux, add -241 - I paper scale to the Chinese National Standard (CNS) Λ4 specification (gong ^) ---------9------^---- --Φ (Please read the note on the back and fill out this page again) 1248443 A7 B7 Ministry of Economic Affairs Central Standards Bureau Staff Consumer Cooperative Printed 5, Invention Description (239 into an additional 16.7 ml of 25% potassium methoxide while maintaining reflux The mixture was maintained at reflux for another 6 hours. The conversion of the diketone to light vinegar was analyzed by hplc. Once HPLC showed a ratio of diketone to hydroxy ester of less than about ι%, then 7 7 ml of 4 Μ HC1 was added to the mixture. (1.5 Μ-3 Μ comparable amount of sulphuric acid can be substituted for hydrochloric acid), and reflux is continued for about 15 minutes. The mixture is distilled again, about 520 ml of methanol/HCN distillate is collected and discarded. The concentrated mixture is cooled to About 65 ° C. About 520 ml of water was added to the mixture in about 9 minutes, and the temperature was maintained at about 65 ° C during the addition. The mixture was gradually cooled to about 15 ° C in about 4 hours, and then Stir and maintain at about 15 ° C for another 2 hours. The mixture is filtered, and the product is filtered and 200 ml of water was washed twice. The filtered product was dried under a hollow (9 〇, 25 mm Hg) to obtain about 25-2 7 g of a white solid containing the main 11α, 17α-dihydroxy group. 3_ketopregn-4-ene-7α,21_dicarboxymethyl, r - internal g. Example 32B-1 Preparation 5 -Daki-11 a,17 - a 'transyl- 3 -fluorenyl-- 17 α -precipitate _ 7 with 21 - carboxylic acid 7 - methyl ester, r - lactone

In the reaction flask, 4 · 1 g of diketone-242 produced in the manner described in Example 31 was applied. The applicable Chinese National Standard (CNS) VIII 4 specification (210X 297 public --------- 譬-- ----1T------^0- (Please read the notes on the back and fill out this page) 1248443 The Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Print A7 V. Inventions (24〇) Soaring Methanol And 1 ml of 1N methanolic sodium hydroxide. The suspension was stirred at room temperature. A homogeneous solution was obtained in a few minutes, and the precipitate was observed after about 2 minutes. Stirring was continued for 7 minutes at room temperature. At the end of this time, the solid was filtered off and washed with methanol. The solid was dried in a steam chamber to give 3.6 g of 50-cyano-11 &lt;^,17-di-l-propyl-3-keto- 17 _Pregnant?? α,21-Di-acid 7-A 酉 ,,厂-内酉. 1H NMR (CDC13) ppm 0.95 (s,3H),1.4 (s,3H),3.03 (d 1H,J15 ), 3_69 (s5 3H), 4.1 (m, 1H). 13C NMR (CDC13) ppm 14.6, 19.8, 22.6, 29.0, 31·〇, 33 9 35.17, 35.20, 36.2, 37.7, 38.0, 38.9, 40.8, 42.8 , 43.1, 45.3, ' 45.7, 47.5, 52.0, 68.0, 95.0, 121.6, 174.5, 1 76.4, 207.0., Example 32B-2 Preparation 5 β-Cyano-9,11 i-epoxy-17-hydroxy-3-yl-yl-17 α _ 孕 烧 α,2 1 - 7 _甲酉γ - internal

To 2.0 g (4.88 mmol) of 9,11-epoxydione (Formula 21) was suspended in 3 mL of anhydrous methanol, and 0.34 mL (2.4 mmol) of triethylamine was added. The suspension was heated to reflux, and after 4.5 hours, no starting material was left by HPLC (zorbax 88-€8 150\4.6 mm, 2 ml/min, linear gradient 35:65 八::6 to -243- this paper scale Applicable to China National Standard (CNS) Λ4 Specifications (21〇X297々f) ~ 1111---------9------, 玎------S, (please Read the precautions on the back and fill out this page.} Printed by the Central Bureau of Standards and Staff Consumer Cooperatives of the Department of Drips 1244843 A7 —- — _ B7 - one; — **·&quot; — &quot; 1 — 1 ' V. Invention (241) 45:5 5 A:B for 1 minute, A = acetonitrile / methanol, 1:1, B = water / 0.1% trifluoroacetic acid, detected at 210 nm). The mixture is cooled and maintained After about 6 5 C for 16 hours, the resulting suspension was filtered to produce 1.3 g of 5 /?-cyano-9,11 epoxy-π-hydroxyketo- 17 α-pregnane-7π, 21 - 7-methyl dicarboxylate, r - lactone, as a white solid. The filtrate was concentrated to dryness (on a rotary evaporator) and the residue was triturated with 3-5 ml of methanol. /?-Cyano-9,n epoxy- 17-hydroxy-3-keto-17α-pregnant fe_7a,21-two Retinoic acid 7_甲酉, lactone. Yield 74.3% 〇lH-nmr (400 MHz, hypochloroform) d ! 〇〇(s,3Η), 1.45 (m,1Η), 1·50 (s, 3H),1·65 (m,2H),2·1〇(m,2H), 2.15-2.65 (m,8H), 2.80 (m, 1H), 2.96 (m,1H),3.12 (d,J =13,1H), 3.35, (d, J=7, 1H), 3.67 (s, 3H).

Example 32C Preparation of -Cyano-11",17-diheptyl-3-keto--17-pregnant 4-7 (^,21-dicarboxylic acid, r-lactone

To the reaction flask was added 6.8 g of diketone (prepared as described in Example 31), 68 ml of acetonitrile, 6.00 g of sodium acetate and 6 ml of water. The mixture is warmed and applied to the Chinese National Standard (CNS) at -244- this paper size. 2丨οϋϋΐ--- IT (please read the notes on the back and fill out this page) 1248443 The Central Bureau of Standards and Staff of the Ministry of Economic Affairs prints A7 V. INSTRUCTIONS (242) Stir under reflux. After about 1.5 hours, the mixture was almost homogeneous. At the end of 3 hours, add 1 liter of water to the 50 ml acetonitrile steaming plant. The mixture was cooled and the precipitated solid (1.7 g) was removed by filtration. The filtrate (ρΗ ==5·5) was treated with hydrochloric acid to lower the pH to 4.5, and a solid was precipitated. The solid is separated, washed with water and dried to give 4.5 g of 5 /?-cyano-??, 17-di-light--3-keto-17-π-pregnane-7?,21.dicarboxylic acid, Γ-brewed . NMR (DMSO) ppm 0.8 (s5 3H)? 1.28 (s5 3H)? 3.82 (m? 1H). 13C NMR (DMSO) ppm 14.5, 19.5, 22.0, 28.6, 30_2, 33.0, 34.1, 34.4, 36.0, 37.5, 37.7, 38.5, 42.4, 42.6, 45.08 45 14, 47.6, 94.6, 122.3, 176.08, 176.24, 207.5 〇 Example 3 3 Scheme 1 : Step 3A: Method C: Preparation of ΐια, 17α-dihydroxy-3-enketopregna-4-ene-7α,21-dicarboxylic acid methyl ester, lactone. The diketone (3 gram) prepared according to the procedure of Example 31 was filled in a clean and dry 3 _ neck reaction flask 'which was equipped with a thermostat' Dean_stark valve and a mechanical stirrer. Methanol (24 ml) was added at room temperature (22 ° C), and the resulting slurry was stirred for 5 min. 25% by weight of a solution of sodium methoxide in methanol (52 8 ml) was added to the reactor, and the mixture was stirred for 1 Torr, at room temperature, and the reaction mixture was converted into a light brown clear solution. A slight exotherm (2-3 X:) was observed. The rate of addition is controlled to avoid temperature in the bath exceeding 30 °C. The mixture was then heated to reflux (about 67 Torr) and refluxed for a further 16 hours. Samples were taken and analyzed for conversion by HPLC. The reaction is continued under reflux until the residual diketone does not go, ~, 1 is free of % in the ketone. -245 - This paper scale applies to the Chinese National Standard (CNS) (210x29^ ~ ------- --9II (Please read the note on the back and fill out this page) Order the Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printing « 1248443 A7 ____ ______ V. Invention Description (243 ) 3%. 4 NHC1 (120亳 in reflow) Addition to the reaction tank can cause HC1 formation, which is then quenched in the rejector. Once the reaction is summarized, 90-95% of the medium alcohol solvent can be taken from the reaction mixture at atmospheric pressure. The remaining head temperature changes at 6'75 ° C and the steam containing HCN is treated with alkali and bleach before disposal. After the methanol is removed, the reaction mixture is cooled to room temperature and the mixture is cooled to 40 ° - 4 5 C, the mixture begins to sink. Add 25% by weight (as needed) of sodium bicarbonate (12 〇〇 ml) at 2 5 °C to the cold The resulting mixture is cooled to hydrazine in about 1 hour. The treatment of sodium bicarbonate can effectively eliminate the reaction mixture. The unreacted diketone remains in the residue. The slurry is stirred at 〇 ° C for 2 hours to complete the precipitation and crystallization, after which the solid product 11 α , 17 α - dimethyl keto-3-keto-4-ene-7 α , 21-di-acid methyl ester, the factory-inner vinegar was recovered by filtration, and then the filter was washed with water (1 ml). The product was dried to constant weight at 8 〇 _9 〇 ° c and 26 ' mer mercury hollow. The water content after drying is less than 〇25% by weight. The adjusted molar concentration yield is about 77_8〇% by weight. Example 3 4 Scheme 1: Step 3 A: Method D: Preparation 11 a, I7 · Dihydroxy_3_ketopren-4-ene-7 α,21-di-acid methyl ester, plant·lactone. Preparation of diketone (1 equivalent) according to Example 3 1 and present in zinc telluride The lower (丨 equivalent) is reacted with sodium methoxide (4.8 eq.) in a methanol solvent. The reaction product is treated or extracted according to the process described herein, or a non-extraction process is used, wherein the extraction of the chloroform, the salt is omitted. And the washing step, and the sodium sulfate drying step. At the same time, in the non-extraction process, the toluene is replaced by 5% by weight of sodium bicarbonate solution, and the product can be separated, that is, U dihydroxy_3_keto-pregnant_4_晞_ -246- This paper scale applies to China National Standard Rate (CNS) Αϋ 210χϋΤ&quot;------- Order (please read the note on the back and fill out this page) A7 B7 1248443 V. Invention Description (244) 7α521- 2. Slimic acid formazan is intended for 'factory-inner's purpose. Example 3 5 Scheme 1: Step 3C: Method C: Preparation of 17 "-hydroxy-3-ketoprogestyl-4,9 (11)-diene-7 alpha,2 Di-dimethyl ester, r · lactone. The hydroxy ester prepared according to Example 34 (1.97 g) was mixed with tetrahydrofuran (20 ml), and the resulting mixture was cooled to -70 ° C, sulphur chlorobenzene (〇·8 ml) was added, and the mixture was mixed for 30 minutes. 'Add Mimi (1 · 3 grams). The reaction mixture was warmed to room temperature and stirred for additional 2 hours. The mixture was diluted with dichloromethane and extracted with water. Concentration of the organic layer gave the crude product, &lt;EMI ID=9.1&gt;&gt;&lt;&apos;&gt;&gt;&gt;&lt;/RTI&gt; A small sample of the crude product was taken for HPLC analysis. Analysis showed that the ratio of 9,11-olefin: 11,12-olefin: 7,9-lactone was 75.5:7.2; 17.3. When carried out at 0 ° C, and other as described above, the ratio of the product formed by the reaction was 77.6:6.7:15.7 of 9,11-olefin: 11,12-olefin: 7,9-lactone. This step can be combined into a single step, that is, the introduction of the leaving group and its elimination to introduce the 9,11-olefin structure of the oxime ester, that is, reacting with sulfonium gas, so that the hydroxy group of the formula hydroxy ester is a hydrazine. Substituted, followed by dehydrogenation to form a Δ 9,1 1 structure. Thus the formation of the olefin ester can be achieved without the use of a strong acid (such as formic acid) or a desiccant (such as vinegar liver). A reflow step of the process in which carbon monoxide is produced.

Example 3 6 A 泚 1 : Step 3 c : Method D : Preparation 17 α _ hydroxy · 3 ketone pregnancy _ 4, 9 (U) _ diene-7 α, 21-dicarboxylic acid methyl ester, r - ester. Prepare a baseless ester (2 gram), and add a second gas to burn (4 〇 ml) -247- This paper scale applies to China National Standard (CNS) A4 gauge (2丨0X297 public#) ~ ^ One by one ' ---------0------1T------ (Please read the notes on the back and fill out this page) Cooperatives Printed Economy Ministry Central Standards Bureau Staff Consumer Cooperatives Printed 1244843 A7 ------β7 V. Inventions (245) — ~^ ^ ~ ^ Dry and clean three-necked round bottom flask, which is equipped There are mechanically approved 'addition funnels and hot dipoles. The resulting mixture was sanded at room temperature until a complete solution was obtained. The solution was cooled to 5 using an ice bath. Quickly add a sulfonate chloride (5 ml) to a solution containing the hydroxy ester in ch^-CH2, and slowly add triethylamine dropwise (1. 8 ml). Adjust the rate of addition so that the reaction temperature does not exceed 5 C. The reaction is extremely exothermic; therefore it must be cooled. The reaction mixture was scrambled at about 5 C for 1 hour. When the reaction was complete (analyzed by hplc and TLC), the mixture was concentrated under about 〇X: and &lt;26&gt;Hg vents until it became a thick slurry. The resulting residue was concentrated in CH2C12 (160 mL). The purity of the concentrate (the methyl decyl ester product of formula IV, wherein Η, and - and -B_B- are both -CH2-CH2·, ie 11 α,17 α -dihydroxy-3-keto-pret-4-ene- 7 α,21-carboxyl, 甲 酉 ' ' 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内 内The plant-lactone was 82% (HPLC area%). This material can be used in the next reaction without further separation. Potassium formate (4.7 g), formic acid (16 ml) and acetic anhydride (8 ml, 0.084 mol) were added to a clean and dry reactor equipped with mechanical stirring, which was cold: tube 'thermal dipole and Heating the cover. The resulting solution was heated to 7 ° C and stirred for about 4-8 hours. The addition of acetic anhydride is exothermic and produces a gas (CO), so the rate of addition must be adjusted to control temperature and gas generation (pressure). The reaction time required to prepare the activity abatement reagent depends on the amount of water present in the reaction (potassium formate and potassium formate contain about 3 5 Torr / Torr of water). The elimination reaction is sensitive to water; if there is &gt;%% water (KF), the level of 7,9-lactone purity may increase. This by-product is difficult to remove from the final product. When -248- This paper scale applies to China National Standard (CNS) A4 specification (210X 297^1 ---------Φ------1T------ (please read the back first) Note: Please fill out this page again) 1248443 A7 B7 Five inventions description (2 milk KF shows &lt; G. 1% moisture, the activity is eliminated by the transfer to the former - step prepared in the methyl hydrazine concentrate (0. 〇7〇莫耳). The resulting solution is heated to 95 Ό, and the volatile matter is distilled off and collected in the stark intercept valve. When the volatile matter &lt; escaping stops, the valve is replaced by a condensing tube, and the reaction mixture is further The mixture was heated for a few hours at 95X: once it was completed (TLC and HPLC showed &lt;0.1% starting material), the contents were cooled to 5 〇χ: and then 瘵 2 retort (26 Hg / 50 ° C). The mixture was concentrated to a thick layer of water, which was then cooled to a temperature of EtOAc. The resulting mixture was diluted with ethyl acetate (3 liters of liters), and the mixture was stirred for 15 minutes and then diluted with water (137 ml). Layered, and the aqueous lower layer was re-extracted with ethyl acetate (7 liters). The mixed acetonitrile/liquid mixture was washed once with brine (120 liters) and then ice-cold. The N Na〇H solution (120 ml each) was washed twice. The aqueous solution was detected for 11 値, and the organic layer was washed while measuring the pH of the washing solution 。 L8. When the washing liquid 1 &gt; 11 値 &gt; The ethyl acetate layer was washed with brine (120 ml), and then concentrated to dryness by rotary evaporation using a 5 hr water bath. The resulting enester, solid product, 17α-hydroxy-3- ketone gestation _ 4,9 (11)- Methyl 晞-7^21-dicarboxylate, ?-lactone, weighs 92 g (77% molar yield). Example 36 制备 Preparation 17 α-Hydroxy-3-one pregnant _4,9(11)_ Diox-7 ", 21_dicarboxylic acid methyl ester, oxime-lactone. For a clean and clean 250 ml three-necked round bottom flask equipped with a mechanical smasher, an addition funnel and a hot dipole, add 2 5 g (5 3 · 12 mmol) of dihydroxy-3-yl ketone y-4_ene _7α, methyl 21 carboxylate, vinegar (as prepared in Example 34), plus 15 〇 Mm of dichloromethane (Burdick &amp; -249- This paper scale applies to China National Standard (CNS) A4 (210X297 public i) ---------Ψ------1T---- --ΜΨ (Please read the notes on the back and fill out this page) Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs • 1248443 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs A7 137 V. Inventions (247)

Johnson). The resulting mixture is stirred at ambient temperature until a light colored slurry is obtained. The solution was cooled to -5 °C using a water bath. Methanesulfonium chloride (7.92, 69.06 mmol) was quickly added to a solution of the hydroxy ester-containing di-methane, followed by a slow dropwise addition of triethylamine (7.53 g) (Aldrich). Adjust the addition rate so that the temperature of the reaction does not exceed 0 °C. The reaction is extremely exothermic and must be cooled. The addition time is 3 5 minutes. The reaction mixture was stirred at about 0 ° C for an additional 45 minutes. When the addition was complete (1% less by the HPLC and TLC analysis), the mixture was concentrated under reduced pressure of about 100-125 ml of dichloromethane solvent at atmospheric pressure. In steam scrubbing, the reactor temperature reaches about 40 ° C -45 °C. After 45 minutes, if the reaction is not complete, an additional 0. 1 equivalent of methanesulfonate and an additional 1 equivalent of triethylamine may be added to the reactor, and the reaction is checked for completeness. The resulting mixture contained the crude product, 17^-yl-l-methyl (methylsulfonyl)oxy-3-keto-pregnant-4-indene-7,21-di-orthoic acid methyl ester, r-lactone. This material can be used in the next reaction without isolation. Anhydrous acetic acid steel (8.7 g) (Mallinkrodt), glacial acetic acid (42.5 ml) (Fisher) and acetic anhydride (0.5 ml) (Fisher) were added to a second 250 ml clean and dry reactor equipped with machinery Mixer, condenser, hot dipole and heating hood. The resulting solution was heated to 9 Torr. (;, and stir; mix for about 3 minutes. The addition of acetic anhydride is exothermic, so the rate of addition must be adjusted to control the temperature and pressure. Add acetic anhydride to reduce the water content in the solution to an acceptable level (less than about 0.1%). When KF shows &lt;〇. 1% water, the acetic acid solution is transferred to the mesylate concentrate (prepared as described in the first paragraph of this example). The resulting mixture &lt; temperature is about 5 5 after transfer °C - 60 ° C. The use of acetic acid and sodium acetate instead of formic acid and potassium formate (in Example 30A) can reduce the gas produced. -250- This paper scale applies to China National Standard (CNS) A4 specification (210X297SH-- ------ ---------Φ------1T------^9 (Please read the notes on the back and fill out this page.) Consumer Cooperatives Printed 1244843 A7 ------------ B7 V. Invention Description (248) —— ---------------------- ------------------------------------------- The mixture is heated to Π5τ and Maintain this temperature for about 6〇-9〇 minutes until the escape of volatile substances stops. Collect volatiles distilled from the mixture. Dean Stark valve. Once completely (tlc^hplc analysis; &lt;0.1% starting material), the heat source can be removed. When the temperature of the mixture reaches 8 °C, 150 ml of water can be slowly added to the mixture. 6〇_9〇 minutes. At the end of the addition of water, the mixture has cooled to about 35. (: _45 ° C, and a slurry begins to form. The mixture is further cooled to 丨 5. (:, and maintained at this temperature about 30- 60 minutes. The mixture was filtered through a glass funnel. The filtrate was rinsed with 1 ml of water. The filtrate was washed twice with 1 ml of water. The resulting filtrate was dried under a hollow of 70 to produce 2 5 · 0 g of dried product vinegar, 1 7 α -mercapto-3-one gestation 4,9(11)-diene-7", 21-dicarboxylic acid methyl ester, 7--lactone. ^^1^ Analysis shows that 70% of the desired 9,11-chain enthalpy, 15% 11,12-alkenyl, and 5% 7,0_ have the following beneficial results (compared to similar processes) · (i) reduction The amount of solvent, (ii) the number of separate steps necessary to reduce the production of oxime ester from the hydroxyester, (iii) the reduction of the necessary washing, (iv) the extraction of the final water by precipitation, and ( v) can reduce the safety concerns associated with the formation of mixed anhydrides and gas generation associated with the use of formic acid instead of acetic acid.

Example 37A Scheme 1: Step 3C · Method E: Preparation 17 α-Hydroxy-3·ketonepregna-4,9(11)-diene-7, methyl 21-dicarboxylate, r-lactone. The hydroxy ester prepared according to Example 34 (100 g; 0.22 mol) was added to a 2-liter three-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, and a thermocouple-251 - the paper scale for China National Standard (CNS) Λ4 Specifications (210 Parents 297 Public ¥) - --------- Φ------, 玎 ------ Line (Please read the notes on the back first Fill in this page) Ministry of Economic Affairs, Central Bureau of Standards and Staff, Consumer Cooperatives, Printed 1244843 Μ 〜 ---一- Β7 Γ ·«&gt; Ρ II ΜΜΜΜΙ II ··.—Electric ^丨...^ V. Invention Description (2 Ming) Extreme. Use a circulating cooling bath with automatic temperature control. The flask was dried before the reaction because methane sulfonium was extremely sensitive to water. Dichloromethane (1 liter) was added to the flask, and the hydroxy ester was dissolved therein with stirring. The solution was cooled to 0 ° C, and methanesulfonium (25 liters; 0.32 mole) was added to the flask via a funnel. Triethylamine (5 liters; 0.59 moles) was added to the reactor via an addition funnel and the funnel was rinsed with additional dichloromethane (3 4 swell). The addition of triethylamine is highly exothermic. Add for about 10 minutes' and mix with stirring and cooling. The mixture was cooled to 0 ° C and then stirred at this temperature for another 45 minutes, at which time the nitrogen in the head space of the reaction flask was flushed. The reaction mixture samples were analyzed by thin layer chromatography and high performance liquid chromatography to check whether the reaction was complete. The mixture was then stirred under hydrazine for another 30 minutes and the reaction was checked again for completeness. Analysis showed that the reaction was essentially complete at this point; the solvent dichloromethane was in hydrazine. 2626" Mercury 眞 下 下 。 。. Gas chromatography of the distillate showed the presence of methane sulfonium gas and triethylamine. Then dichloromethane (8 〇〇 ml) was added to the reactor, the resulting mixture was Stir for 5 minutes at a temperature range of 〇-15. (: Solvent at 〇-5 ° C, 26 ° Hg again steam &gt; strip, can produce formula IV methyl phthalate, where r3 is 幵, _ A_A- , is -CH^CH2·, and R1 is methoxycarbonyl. The purity of the product is about 90-95 area%. For the preparation of the elimination reagent, formic acid _ (23.5 g; 0.28 mol), formic acid (8 〇 ml) and vinegar The anhydride (40 ml) was mixed in separate dry reactors. Formic acid and acetic anhydride were pumped into the reactor and the temperature was maintained at no more than 4 Torr. (In addition to the vinegar fiber addition) The elimination reagent mixture was heated to 7 〇°C to eliminate moisture in the reaction system. This reaction continues until the water is measured by Karl Fisher analysis. -252- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X29h>^Ti- ---- -----Φ------IX------Line· (Please read the notes on the back and fill in this page) 1248443 Central Bureau of Standards of the Ministry of Economic Affairs Labor consumption cooperative printing bag A7 V. Invention description (25〇) ————~ less than 0.3% by weight. Eliminate the reagent solution and transfer to the reactor. 'There is a concentrated crude prepared as described above. The methyl ester solution is heated to a maximum temperature of 95 ° C and the volatile distillate is collected until a further distillate is produced. The distillation is stopped at about 9 Torr. The mixture was stirred at 95 ° C for another 2 hours, and the reaction was checked by thin layer chromatography. When the reaction was completed, the reactor was cooled to 50 C, and then self-reacted at 5 Ο 2, 2 6 眞 mercury. The mixture was removed from the mixture and the formic acid was removed. The concentrate was cooled to room temperature, then ethyl acetate (688 mL) was then taken to ethyl acetate and concentrate and stirred for 15 minutes. At this time, 12% brine solution (688 ml) was introduced. ) to help remove water-soluble impurities from the organic phase. The phase is allowed to settle for 20 minutes. The aqueous layer is transferred to another container and an additional 1 of ethyl vinegar (3 50 halo) is added. This extraction is carried out for 3 minutes, then ordered After the sedimentation, the ethyl acetate layer was further mixed. In the mixed ethyl acetate layer, a saturated sodium chloride solution (6 ml) was added, and the mixture was stirred for 3 Torr. The phases were allowed to settle again. The aqueous layer was removed. Additional sodium chloride (6 〇〇 ml) was washed and the organic phase was separated from the second wash. The organic phase was washed with 丨N hydroxide steel (600 liters) for 3 ounces with stirring. Settle for 3 minutes to remove the water layer. The pH of the water layer was checked and found to be &gt; 7. Further washing was carried out with saturated sodium chloride (6 mL) for 15 minutes. The organic phase was finally concentrated at 26, mercury venting and 50 Torr, and the product was recovered by filtration. The final product was a foamy brown solid upon drying. Further at 4 5 . (:, drying under reduced pressure for 24 hours, can produce 9.5 4 grams of the product, 17 ^ _ light base _ 3 ketone gestation-4,9 (11) _ diene-7α, 21_ dicarboxyl Methyl ester, r-lactone, analysis was 68.8%. For the initial hydroxy ester and final enester correction, molar concentration ___ -253- This paper scale is suitable for the family (CNS) (210 X297^i &quot;)~~ ^ (Please read the notes on the back and fill out this page)

, 1T Ministry of Economic Affairs, Central Bureau of Standards, Contracted Consumer Cooperatives, Printing 1248443 A7 p------__B7 V. Invention Description (251) ~ The yield is 74.4%. Preparation of 17-methyl-3-keto-18-negative-4,9(11),13-triene-7",21-dicarboxylic acid 7-methyl ester

To a C〇〇H reaction flask was added 5·5 g of the methic acid prepared according to Example 2, 55 ml, 94.3% formic acid and L38 g of potassium formate. The mixture was heated and refluxed (104 ° C) for 2 hours. At the end of the 2 hour period, the formic acid was distilled under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1% EtOAc (5 mL). The aqueous fraction recovered was yellow. Ethyl acetate was washed with 5% steel hydroxide (50 mL). The aqueous portion was mixed and acidified with dilute hydrochloric acid, and the insoluble matter was extracted with ethyl acetate. Ethyl acetate is designed to evaporate to dryness under reduced pressure to give 1.0 g of residue, 17-methyl-3-keto-18-negative-4,9(11),13-triene-7,21 - 7-methyl ester of dicarboxylic acid. iH NMR (CDC13) ppm 1.5 (s, 3 Η), 1.4 (s, 3 Η), 3.53 (s, 3 Η), 5.72 (m, 1H). 13C NMR (CDC13) ppm 25.1 and 25·4 (18 CH3 and 19 CH3), 40.9 (10 C), 48·5 (17 C), 51.4 (OCH3), 118.4 (11 CH), 125.4 (4 CH), 132.4 (9 C), 138.5 and 139.7 (13 C and 14 C), 168.2 (5 C), 254- This paper scale applies to the Chinese National Standard (CNS) A4 Regulation (210 Parent 297) ¥ IT line (please first Read the notes on the back and fill out this page.) 1248443 A7 B7 V. Inventions (252) 172.4 (7 C0), 179.6 (22 C0), 198·9 (3 CO) 0

Example 37C Preparation of 5y5-mercapto-17-3⁄4yl-3-keto-17α-pregnant-11-晞-7 π,21-bis-succinic acid 7-methyl,r-inner 〇

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs In the reaction flask, 5.5 g of methanesulfonic acid prepared according to Example 2 3 was used to remove 5 5 ml of 9 4 · 3 % formic acid and 1 · 35 g of formic acid. The mixture was hot and stirred at reflux (104 ° C) for 2 hours. At the end of the 2 hour period, formic acid was distilled under reduced pressure. The residue was dissolved in ethyl acetate and washed with EtOAc EtOAc. The aqueous part recovered is yellow. Ethyl acetate was washed with 5% sodium hydroxide (50 mL). Ethyl acetate was evaporated to dryness under reduced pressure to yield 3.7 g of residue. 3. 4 g of the residue was layered on 267 g of Merck silicone (40-63 micro). The product was recovered in a dissolution procedure of ethyl acetate and toluene 37:63 (v/v). After drying the product, 0.0698 g of residue, 5 cyano-17-hydroxy-3-keto-17α-pregnant-11-晞-7, 21-dicarboxylic acid 7-methyl ester, r-in ester. NMR (CDC13) ppm 1.03 (s, 3H), 1.22 (s, 3H), 3.70 (s, 3H), 5.60 (d, 1H, J10), 5.98 (d, 1H, J10). MIR centimeters - 1 2229 (CN), 1768 (lactone), 17 10 (ester).

Example 37D -255 - This paper scale applies to China National Standard (CNS) Each () 1~ 'The Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed 1244843 Α7 S 扪 丨, 丨·· &quot;1·· ---------一...------------ V. Description of the invention (253) I ^ Separation 9 α,17-dihydroxy-3-keto-17 α -pregnancy 4-ene-7 α,21-dicarboxylic acid bis(plant-lactone)

9α,17-II#-mercapto-3-keto-17α-pregnant-4-晞-7α, 21_di-oxoic acid bis(i-lactone) is a by-product of the elimination of 11-methanesulfonate. Separation of the pure sample from the reaction mixture of Example 37 was carried out by preparative liquid chromatography followed by reverse phase preparative HPLC. Therefore, 73 g of the residue was chromatographed on a 2.41 kg of Merck (40-63 μl) using acetic acid, ethyl acetate and toluene (2〇:8〇, 30:70, 40:60,60). :40, v/v) gradient elution procedure. A mixture of enamine and 7,9-lactone plus agglomerate (1 〇/5 g) was obtained in 6 〇:4 Torr. The purification process was observed by TLC on an EMF plate using 60:40 (Wv) of acetic acid; a toluene eliminator, and sulphuric acid, SWUV imaged. A portion (10.4 g) of the mixture was further purified by reverse phase HPLC on Kromasil C8 (7 micro) with 30:70 (v/v) milliQ water and acetonitrile as mobile phase. The 7,9-lactone (2.27 g) as a crystal can be separated from the mobile phase.

NqR cm-1 1762 (7,9-lactone and 17-lactone), 1677, 1622 (3-keto-Δ 4,5). -256- __________ ___________________---- This paper scale applies to China National Standard (CNS) Α4 Regulations (210Χ 297 漦) ---------Φ------, 玎---- --S (Please read the back of the note first and then fill out this page) 1248443 A7 B7 V. Inventions (254) JH NMR (CDC13) ppm 1.00 (s, 3H)? 1 4 . ^ ), 4 (s, 3H ), 2.05 (d, 1H), 2.78 (d, 1H), 5.87 (s, 1H). 13C NMR (CDC13) ppm 13.2,19.0, 22 2 〇〇. ·Ζ,23·2, 26.8, 28.8, 29.5, 30.8, 33.1,34.4, 35.1,42.5, 43.6, 43 Q 〇•y,45.0, 45.3, 89.9, 94.7, 129.1, 161.5, 176.0, 176.4, 196.9. Theory 値 C, 71.85, H, 7.34; measured 値C, 71.68, H 7%. Example 37E, isolation of 5-cyano-17-hydroxy-3-keto-17α-pregn-11, plate, ^ α,21-dicarboxylic acid 7-methyl ester, r-lactone

Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperative, printed compound 5-alkayl-17-3⁄4-yl-3-keto-17α-pregnant^, ene-7-, 2-dicarboxylic acid 7-methyl ester, r_lactone The reaction mixture obtained after the elimination of U_methanesulfonyloxy group was isolated by multi-preparation liquid chromatography and then isolated (Example 24). It is known as TLC as a part of the less polar impurity group. This TLc is carried out on an emf plate with a 30:70 (v/v) ethyl acetate and dichloromethane dissolution system, and is imaged in sulfuric acid (SWUV). Chemical. In general, these less polar impurities are separated from the crude guanamine by preparative liquid chromatography. In particular, 9 κ soil 30 has no crude enamine solution and is chromatographed on 534 g Merck silicone (40-63 micro), using B-257 - paper scale for Chinese National Standard (CNS) Λ 4 specification (210X29h>¥ 1248443 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printed f A7 V. Description of Invention (255) Acid Ethyl Ester and Toluene Gradient Dissolution Process (20:80, 30:70, 40:60, 60:40, v/v). Less polar impurities are concentrated in 30:70 fractions. 12.5 grams of less polar impurity pools can be collected in this manner. This material was further chromatographed on 550 g of Merck (40-63 micro), using a gradient elution of ethyl acetate and dichloromethane (5:95, 10:90, 20:80, 30:70, v/v) . The addition of 20:80 aliquots produces 1.2 grams of residue. Additional chromatogram of 1.2 g of residue in 53 g Merck tape (40-63 micro) using acetone and dichloromethane gradient (3··97, 6:94, 10:90, 15:85, v/v) 0.27 g of 5-cyano-1 7-hydroxy-3-keto-17 α _pregna-11-ene-7 α,21-dicarboxylic acid 7-methyl ester, r-lactone, which is derived from 10 : 90 parts of the Kafon part. MS M+425, estimated C25H31N05 (425.52). MIR 2222 cm-1 (nitrile), 1767 cm (lactone), 1727 cm-1 (ester and 3-ketone). lH NMR (CDCls): ppm 0.92 (s5 3H)5 1.47 (s5 3H)? 2.95 (m? 1H), 3.65 (s, 3H), 5.90 (m, 1H) 〇13C NMR (CDC13) ppm 14.0 (18 CH3) ), 23.5 (15 CH2), 27.0 (19 CH3), 37.8 38.5 and 40.9 (7, 8 and 14 CH), 52.0 (OCH3), 95.0 (17 C), 121.5 (23 CN), 123.5 (11 CH), 135.3 (9 C) 5 174_2 and 176.2 (22 and 24 CO), 206 (3CO).

Example 37F Preparation of 17-Hydroxy-3-keto-11-α-(2,2,2-trifluoro-1-one ethoxy)-17α-pregnant-4-晞-7 α,21-dicarboxylic acid 7 -Methyl ester-258- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X29^^ (Please read the back of the note first and then fill in this page)

, 1T line wins the Ministry of Economic Affairs Central Bureau of Standards Bureau staff consumption cooperatives printed 1248443 A7 r---a five, invention description (256) one

A hydroxyester prepared according to the procedure of Example 34 (2.0 g, 4-8 mmol) was added to 40 liters of monomethane in a clean, dried three-necked round bottom flask equipped with a mechanical stirrer. Then add ternary _61 g, 61 毫 millimolar to the solution and three qi vines (1-47 g, 7,0 mmol). This mixture was stirred overnight at ambient temperature. The cream was then diluted with a further 40 ml of dichloromethane. The mixture was washed successively with 40 liters of water, 403⁄4 liters, 1N HCi and 4 liters of 1N Na〇H solution. The resulting solution was dried over magnesium sulfate and concentrated to dryness to yield 3.2 g of pale brown solid, &lt;&quot;&&&&&&&&&&&&&&&&&&&&& -17 α-pregnene-21-dicarboxylic acid 7-methyl ester. The residue was further analyzed and purified by chromatography. HPLC conditions: column -

Water*s Symmetry C18 (150 mm X 4.6 mm, inner diameter, 5 micron particle size) 'column temperature-ambient temperature; mobile phase-acetonitrile/water, 30/70 by volume; flow rate -1·〇ml/min Injection volume of 20 μl; sample concentration -·1·〇4 g/ml; detection, UV at 210 nm; pressure 1500 psi 'period of minutes. TLC conditions: adsorbent - Merck second gel 60 F254; solvent system - ethyl acetate / toluene, 65 / 35 by volume; image technology - a short wave; application amount of 100 micrograms. -259 - t ( 210 X 297^&gt;II~^ ~ Φ------1T------Stupid (please read the notes on the back and fill out this page) 1248443 Central Bureau of Standards and Staff of the Ministry of Economic Affairs Consumer Cooperatives Printed Α7 Β7 V. Inventions (257)

Example 37G Preparation 11 (Ethyloxy)_17α-hydroxy-3-keto_17-pregnene-7,21_di-skin acid 7-methyl quinone, γ-inner 酉

The light base ester (2.86 g, 6.87 mmol) was prepared according to the procedure of Example 3 4, added to 15 ml of methylene methane, and then cleaned and dried to a three-necked round bottom flask equipped with a mechanical stirrer. Further, triethylamine (1.39 g, 13.7 mmol) of 'dimethylaminopyridine' (8 g, 0.6 mmol) and acetic anhydride (1_05 g '10. 3 mmol) were added to the solution. The mixture was stirred at ambient temperature overnight. The mixture was diluted with 1 50 liters of ethyl acetate and 25 ml of water. This acetic acid ethyl acetate solution was washed with 25 ml of a citric acid solution. The solution was dried over anhydrous magnesium sulfate and concentrated to dryness to give 3 33 g of pale brown solid, 丨丨α _(ethyloxy)-17-hydroxy-3-keto-17 π-pregnant-4-#-7 , 21-dicarboxylic acid 7-methyl ester, r-lactone. The residue was further analyzed and purified by chromatography. HPLC conditions: column one

Waters Symmetry C1 8 (150 mm X 4.6 mm id, 5 μm particle size); column temperature - ambient temperature; mobile phase - acetonitrile / water, 3 〇 / 7 〇 by volume; flow rate... 1.0 cc / min; Into the volume... 2 〇 microliters; sample concentration - 260- This paper scales the towel to turn off the home (CNS) A4 gauge $ (210Χ 297ϋΤ——————一 (Before reading the back of the note) )

The Central Bureau of Standards of the Ministry of Economic Affairs bears the burden; the consumer cooperatives prints 1244843 Α7 ________ Β7 V. Inventions (258) ~ degrees - 1.0 mg / liter; detection - _1 ^, 210 nm; pressure - 1500 psi; Time - 45 minutes. TLC conditions: adsorbent - Merck(R) gel 60 F254; solvent system - digas methane / methanol, 95/5 by volume; image technology... short wave, and application amount... 1 microgram.

Example 37H Scheme 1: Step 3C: Method F: Preparation of 17-hydroxy-3-keto-17α-pregnant-4,9(11)·a-7-21,2-di-treatin 7-methyl ester . 〇

Formic acid _ (1.5 g '0.018 mol), formic acid (6 〇 ml, 16 mol) and acetic anhydride (29.53⁄4 liters '〇·3 ΐ Moel) was added to a clean, dry 25 ml reactor, which was prepared It is equipped with a mechanical stirrer, a condenser, a hot dipole and a twisted P solution and then stirred for 4 hours in 7th generation, and cooled to ambient temperature to generate an elimination reagent, which can be used to convert MV sulphuric acid vinegar into a cost example. The product. The preformed TFA/TFA anhydride elimination reagent was added to 7 〇 〇 (〇 142 摩尔) as a general example. 2 3 prepared by the method; The resulting mixture is heated to hydrazine. . 105 C for 2.5 hours. The degree of conversion can be checked regularly by TLc or HpLc. The cold part of the product s5 (rc, diluted with ice water (14 liters), and taken away for 1 hour. The mixture is allowed to stand at ambient temperature - night. Layering, and the water layer -261 - This paper scale applies to China Su (please read the notes on the back and fill out this page again) Order 1124443 A7 ____ B7 ----------------------- ----- , invention instructions (259) with ethyl acetate (75 ml), another water / brine mixture (6 ml), 1N sodium hydroxide (60 ml) and a third water / brine mixture (6 ml) The brine concentration was 12 〇 /. The weight of the product was determined by HPLC. It is about 50/15 (area). The main product obtained from this reaction is an impurity, which is known as 17-3⁄4 base _3_keto-17 α-pregna-4,9(11)_diene_7, 21_ II Slimic acid 7 - for the purpose of sputum. The mixture was purified by column chromatography to yield 1.9 g of analytically pure 17-hydroxy-3-keto-17 α-pregnant-4,9 (11 )-二晞-7,21-di-acid 7-A . Purpose, the unitary purpose residue was further analyzed and purified by chromatography to .HPLC conditions: column -

Waters Symmetry C18 (150 mm X 4.6 mm id, 5 micron particle economy, Central Bureau of Standards staff consumption cooperative print size); column temperature... ambient temperature; mobile phase - acetonitrile / water, 3 〇 / 7 〇 by volume Flow rate: 1.0 ml/min; injection volume... 20 μl; sample concentration - 1.0 mg/ml; detection - UV at 210 nm; pressure... 15 psi; flow time - 45 minutes. TLC conditions: adsorbent ~ Merck Shijiao 6 〇 F254; solvent system ... chloroform / methyl third - butyl ether / isopropanol, 70 / 28 / 2 by volume; imaging technology __50% by volume H2S 〇 4 aqueous solution / LWUV and 50% by volume of H2S04 / phosphomolybdic acid; and the amount of application _ 100 micrograms. Example 371 Preparation of 17-hydroxy-3,11-dione- 17 π-pregn-4-ene-7 α,21-di-tresine 7-methyl ester, r-lactone-262- This paper scale is applicable to China Standard (CNS) Λ4 gauge (210X297 public i) 1248443 A7 B7 V. Description of invention (260)

The Jones reagent was prepared by dissolving 6.7 g of chromic anhydride (Cr03) in 6 ml of concentrated sulfuric acid, and then mixing it with distilled water to 50 ml and carefully diluting. One milliliter of this reagent is sufficient to oxidize 2 millimoles of the second alcohol to the ketone. The hydroxyester (1 〇.〇, 24.0 mmol) prepared according to the procedure of Example 34 was dissolved/suspended in 1200 ml of acetone. To this mixture was added 8.992 ml of Jones' agent and the mixture was mixed; it was mixed for 1 minute. A portion of the reaction mixture was taken up in water and extracted with di-methane and then analyzed by HPLC (column: Beckman Ultrasphere ODS C18, 4.6 mm X 250 mm, 5 μm; solvent gradient: acetonitrile/water = 1/99 Up to 100/0. Flow rate 1.5 ml/min in 20 minutes; detector: UV 210 nm). The reaction is characterized by the absence of any significant amount of starting material in the reaction mixture to demonstrate completeness of the reaction. The HPLC residence time of the starting material (hydroxy cheese) was 13.37 minutes and the product ketone was 14.56 minutes. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page). Add 200 ml of water and 300 ml of di-methane to operate. The organic layer was separated from the aqueous layer and washed with water (200 ml). The organic layer was separated from the aqueous layer and dried over magnesium sulfate. Evaporation of the solvent yielded 9.52 g of a white solid (95.6% crude yield) 17-light-methyl-3,11-dione-17"-pregnant-4-indole-7,21-di-resinic acid 7-methyl -263 - This paper scale applies to Chinese National Standard (CNS) (210X 297^ #1—~一一一 1248443 A7 ____ B7 V. Invention Description (261) Structural design by mass spectrometry (m/e 414 H NMR (DMF-d7) and C NMR (DMF-d7). In H NMR, the ii-H characteristic of hydroxy esters (4.5 1 ppm, double, j = 5.8 Hz) is not present. High school appears at 208.97 ppm, which is expected for 11-keto carbon. CNMR (400 Mhz, DMF-d7) 208.97 (1 1-ketone), 197.70 (3·ketone), 176.00 (22-lactone) ), 173.34 (7-COOMe), 167.21 (C5), 125.33 (C4), 93.63 (Cl 7), and other peaks in the range of 15-57 ppm.

Example 3 7 J Preparation 11 α,17·Dihydroxy-3-keto-17 α-pregn-4-ene-7α,21-dicarboxylic acid dimethyl ester, r-lactone (please read the back note first) Fill in this page again)

3·5 g (8.4 mmol) of the hydroxyester prepared according to the procedure of Example 34, mixed with 4 ml of methanol 4N potassium hydroxide (8 mmol) in 42 ml of methanol. The slurry was disturbed overnight at room temperature and heated to reflux for 1 hour. The methanol was evaporated under a vacuum and the residue was combined with 50 mL of ethyl acetate. Ethyl acetate was evaporated in vacuo and the residue was taken up in 50 mL ethyl acetate. The dried solid was mixed with 50 ml of acetone and 2 ml of methyl meth (32.1 mmol). The mixture was stirred at room temperature for 18 hours. At this point most of the solid particles will dissolve. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue is hydrolyzed with ethyl acetate, the solid particles are removed by filtration, and the solvent is distilled in the hollow-264 - This paper scale is applicable to China National Standard (CNS) Λ4 桔4 (1〇x297々&gt;#) - Line Economy Department The Central Standards Bureau employee consumption cooperative printed 1228443 A7 B7 V. Invention description (262) Moved down. The residue was determined to be 78:22 (v/phantom η α,17-dihydroxy-3-keto-17 α-pregn-4-ene_7 α , 2 dimethyl dicarboxylate, r _ A mixture of the ester and the starting material without base vinegar, which was confirmed by iH NMR. This mixture is suitable for use as an HPLC mark without further purification. lH NMR (CDC13) shows the following characteristics: ppm 0.93 (s, 3H), 1.37 (s, 3Η), 3.64 (s, 3Η), 3.69 (s, 3Η).

Example 37K Preparation 11 α,17·Dihydroxy-3-enketone_17^pregnant _4_ene-7", 21-dicarboxylic acid, plant-lactone (Please read the back note first and then fill out this page)

1T 11.86 g (28.5 mmol) of the hydroxy ester prepared according to the procedure of Example 3 4, 50 ml of methanol and 20 liters of 2.5 M NaOH were added. The suspension is heated to reflux. After 2 minutes, part of the starting ester was judged to be unreacted by hplc (Zorbax SB-C8 150 X 4.62 亳m, 2 ml/min, linear gradient 35:65 A: B to 45:55 A: B, calendar 1 5 minutes, A diacetonitrile / methanol l: 1, B = water / 〇 1% trifluoroacetic acid, detected at 210 nm), and 1 liter of 1 〇M NaOH was added. After 1 hour, it was judged by HPLC that the trace amount of the brew remained unreacted. The reaction mixture was allowed to stand at about 25 ° C for about 6 hours. -265- The paper size applies to China National Standard (CNS) A4im (210X2^#7 line wins the Department of Standards Bureau staff consumption cooperatives print 1244843 A7 B7 V. Inventions (263) The mixture is diluted with 100 ml of water, then The strong acid was made with 20 ml of concentrated HC1. The resulting gelatinous precipitate was stirred until the precipitate became a suspension. The solid was separated by filtration, resuspended in methanol, and filtered to give 3 · 75 g of a ochre solid. Dissolved in 8 ml of hot DMF, and the mixture was diluted with 40 ml of methanol. The acid crystallized and isolated by filtration to yield 1.7 g of a cotton-white solid, η α, 17-mono--3-keto-17-α -pregnant 4-晞-7α, 21-di-skin acid, plant __ lactone. lH-nmr (400 ΜΗζ, dimethyl sulfoxide) d 〇.8〇(s, 3H), i 25 ( s, 3H)? 1.2-2.7 (m, 20H)? 3.8 (brs? 1H)? 4.45 (m5 m)5 5.50 (s! 1H). The carboxyl proton has 11〇1) peak at 3_4卯111 observed. Example 3 8 Scheme 1: Step 3C: Method G: Preparation of 17-hydroxy-3, _17^pregnant 4,9(11)-diene-7,21-dicarboxylic acid 7-methyl ester, ? ^ Internal vinegar. The procedure of Example 37A was repeated except that the solution was treated with an ion exchange resin, alkaline alumina or an assay to avoid multiple washing steps. The conditions for the treatment of the test soil or the test stone stone are shown in Table 38. #这南WX ^&quot;Two treatments have found that the impurities can be effectively emptied, without the need for the example 4 4, 1 mi μ heart wash, can produce 17-hydroxy-3-keto-17^pregnant-4, 9(11)_diene, 1 -杈铋7-methyl ester, factory _ Central Bureau of Economics - Ministry of Industry and Commerce Cooperative Printed -266- This paper scale applies to China National Standard (CNS) Λ4 gauge (210X 297; f Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printed 1244843 V. Description of the Invention (264) Table 38 Factors for the purpose of the experiment. The results of the test were 2 g / 125 g of the test soil. The reaction mixture was treated with an expansive bauxite to remove the El. ^N.HCl salt, and omitted in NaOH and IN HC1 washing ΪΫ93%~~ alkaline bauxite 2g/125g product treated with vermiculite to remove the Ε1:3Ν·Η(:1 salt, And 1N NaOH and IN HC1 washing yield 95% were omitted. Example 3 9 Mud 1 : Step 3 C : Method Η : Preparation of 17-carbyl-3-keto- 17 α _pregnant _ 4,9(11)- Diene-7,2dicarboxylic acid 7-methyl ester, 7^-lactone. Potassium acetate (4 g) and trifluoroacetic acid (42_5 ml) were mixed in a 100 ml reactor. Additional trifluoroacetic acid (9.5) ML) to the mixture The rate of addition can be controlled to a temperature below 30 ° C. The solution is reheated to 3 〇t for 3 〇 minutes to form a elimination reagent which can be used to convert the mesylate of formula IV to the oxime ester of formula π. The formed TFA/TFA anhydride elimination reagent was added to the previously prepared methanesulfonic acid solution as in Example 37. The resulting mixture was heated at 4 Torr for 4 1/2 hours, and the degree of conversion was periodically checked by TLC or HpLC. When the reaction was completed, the mixture was transferred to a one-necked flask and condensed to dryness under reduced pressure and room temperature (2 2). Ethyl acetate (137 ml) was added to the mixture to give a solid phase material. All dissolved, then add water/brine mixture (137 ml), and the resulting two phases were stirred for another minute. The phases were separated for 2 〇 minutes. The brine concentration was 24 〇 / 〇 by weight. Ethyl acetate is contacted (68 ml) and the biphasic mixture thus prepared is stirred for 丨〇 minutes, then __ - 267 _ this paper size applies to CNS) &amp; Please read the note on the back and fill in this page)

, 1T - line at 1248443 V, invention description (265) Stand for 15 minutes to separate the phases. Mixing the ethyl acetate layer from the secondary extraction with 24% by weight of brine (120 ml), another 24% by weight of brine (60 ml), 1 n sodium hydroxide solution (150 ml) Wash with another brine (60 ml). After the aqueous phase was added, the mixture was stirred for 1 minute and allowed to stand for 15 minutes to separate the phases. The resulting solution was concentrated to dryness using a water aspirator under reduced pressure of 4 5 Torr. The solid product (8.09 g) was analyzed by HPLC and found to contain 83.4% by area of 17-hydroxy-3-keto-17--pregnant-4,9(11)-di-consin-7,2-di-resinic acid 7 - methyl ester, plant-lactone; 2.45 area% of njh olefin; ι.5〇/ο 7,9-endo vinegar; and ι·1% unreacted mesylate. Example 4 0 Scheme 1: Step 3C: Method I: Preparation of 17-hydroxy-3-keto-17α-pregnane-4,9(11)-diene-7,21-dicarboxylic acid 7-methyl ester, 7^ - lactone. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page). The wire table is prepared according to the example 2 3 mesylate (1 · gram), isopropenyl acetate (10 g) and p-toluenesulfonic acid (5 mg) were placed in a 5 ml flask and heated with stirring at 90 °C. After 5 hours, the mixture was cooled to 25 t and concentrated in a 1 liter Hg. The residue was dissolved in Ch2-CH2 (20 mL). The CH2C12 layer was concentrated under a hollow to produce 1.47 grams of brown oil. This material was recrystallized from CH2C12/Et20 to give 0.50 g of the formula iV(2) enol acetate. This material was added to a mixture of sodium acetate (0-12 g) and acetic acid (2.0 ml) which had previously been heated to 丨〇〇 °C under scramble. After 6 minutes, the mixture was cooled to 25 ° C and diluted with CHW 2 (2 mL). The solution was washed with water (2 () pen liter) and then dried on MgS 〇4. The desiccant is removed by filtration, and the filtrate is hollowed out to form 0.4 g of the desired 9,11-alkene, 17-hydroxy-3-keto-17α-__-268- This paper size is suitable for the family (CNS) 10X29 ^ #^ —-------- 1248443

Kl V, invention description (266) pregnancy-4,9 (11)-diene-7,21-dicarboxylic acid 7-methyl ester, plant-lactone. The crude product contained less than 2% of the 7,9-lactone impurities. Example 4 - Thermal elimination of mesylate in DMSO Procedure 1: Step 3C: Method J: Preparation of 17-hydroxy-3-keto-17α-pregnant-4,9(11)-diene-7,21 - 7-methyl ester of dicarboxylic acid, 7^-lactone.

A mixture of 2 g of the mesylate and 5 ml of DMSO was placed in a flask and heated at 80 ° C for 22·4. HPLC analysis of the reaction mixture showed no starting material to be tested. Water (10 ml) was added to the reaction, and the precipitate was extracted three times with di-methane. The mixed dichloromethane layer was washed with water, dried over magnesium sulfate, and concentrated to give the ethyl ester 17-hydroxy-3-keto-17--pregn-4,9(ll)-diindole-7,21-dicarboxylate. Acid 7-methyl ester, r-lactone. Example 4 2 Scheme 1: Step 3D: Method Β: Synthesis of 9,11α-epoxy-17α-hydroxy-3-onepregn-4-ene-7α,21-dicarboxylic acid methyl ester, lactone. In a 50 ml pear-shaped flask, the olefinic ester (1.07 g, analyzed with 74.4% enester), trichloroacetamide (0.32 g), dipotassium hydrogen phosphate (0·70 g) was stirred under stirring. It was solid) mixed with dichloromethane (15.0 mL). Hydrogen Peroxide-269- This paper scale applies to China National Standard (CNS) Α4 specification (210X297 public f) (Read the first note on the back and fill out this page) Order the Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Print Economy Ministry Central Bureau of Standards Staff Consumer Cooperatives Printed 1244843 V. Inventions (267) (30% by weight; 5 · 0 ml) via the drip tube calendar! Join in minutes. The resulting mixture was stirred at room temperature for 6 hours, at which time hplC analysis showed a ratio of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Additional tri-ephthylamine (0.32 g) was added to the reaction mixture, and the reaction was allowed to proceed for a further 8 hours or more after agitation, after which the ratio of the enester remained was reduced to 1%. Additional trichloroacetamide (8 g) was added and the reaction mixture allowed to stand overnight. At this point, the reaction mixture was compared to the methicone, leaving only 5% of the unreacted vinegar. Example 4 3 Scheme 1: Step 3D: Method C: Synthesis of 9,11α·epoxy_17α-hydroxy-3-ketopren-4-ene-7 α,21-dicarboxylic acid methyl ester, r-endo vinegar. The enester of formula IIA (5.4 g, analysis of 74. 4% enester) was added to a 1 mL reactor. To the oxime ester, trichloroacetamide (49 g) and dipotassium hydrogen citrate (3 · 5 g) were added in a solid form. The mixture was cooled to 1 $ and 30% hydrogen peroxide (25 g) was added over 1 〇. The reaction mixture was allowed to reach 2 ° C and stirred at this temperature for 6 hours at which time the conversion was checked by HpLC. The remaining oxime ester was determined to be less than 1% by weight. The reaction mixture was added to water (100 ml), then phase separated, and the methylene chloride layer was removed. Sodium hydroxide (〇·5 N ; 5 〇 ml) was added to the digas methane layer. After 20 minutes, the phases were separated and HCl was added to the methylene chloride layer, followed by phase separation and the organic phase was washed with saturated brine (50 liters). The aerated layer was dried over anhydrous magnesium sulfate and the solvent was removed. A white solid (5.7 g) was obtained. The aqueous layer of oxynitride steel is acidified and extracted to treat the extract to produce an additional 2 g of product. The yield of the epoxy group meclirone was 9 〇.2 〇 /. . -270- This paper size applies to Chinese National Standard (CNS) A4fm ( 21 OX 297^3⁄4^--------------- (please read the notes on the back and fill out this page)

1T Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Print 1244843 A7 _____^B7 V. Inventions (268) Example 4 4 Process 1: Step 3D: Method D: Synthesis of 9,11α-epoxy-17 π-hydroxy- 3-ketopren-4-ene-7 α,21-dicarboxylic acid methyl ester, lactone. The olefin of formula IIA is converted to the epoxide meclirone according to the procedure described in Example 43, with the following modifications: the initial hydrazide contains decyl ester (5. 4 g analysis of 74.4% enester), Trichloroacetamide (3.3 g) and dipotassium hydrogen phosphate (3.5 g). Hydrogen peroxide solution (12.5 ml) was added. The reaction was carried out overnight at 20 ° C, after which HPLC showed a conversion of the enester to the cyclomethicone to 90%. Additional trichloroacetamide (3.3 g) and 30% hydrogen peroxide (5.0 ml) were added, and the reaction was further carried out for 6 hours, at which time the residual olefin was only 2% based on the amount of the hydrazine. . After operation as described in Example 4, 5·71 g of epoxigenone can be produced. 0 Example 4 5 Scheme 1: Step 3 D: Method Ε: Synthesis of 9,11 α-epoxy _ 17 α -light base 3-keto-pregnant-4-wolk-7 α,21-dicapric acid methyl ester, γ-lactone. The olefin of formula IIA is converted to the epoxigenone by the method described in Example 43. In the reaction of this example, the amount of oxime ester added was 5.4 g (analysis of 74.4% decyl ester), the amount of ruthenium ethoxide added was 4.9 g, the hydrogen peroxide was 25 g, and the potassium dihydrogen phosphate was 3.5 grams. The reaction was carried out at 20 ° C for 18 hours. The residual olefin is less than 2%. After treatment, 5.71 grams of epoxy meclorone was produced. Example 4 6 Scheme 1 ··Step 3D ··Method F: Synthesis of 9,111 epoxy-l-hydroxy-3-one-pregnant-4-indole-7α,21-di-sodium lactate, r-inner Purpose. Formula II is converted to epoxy meclorone as described in Example 4 3, except for -271 - This paper scale applies to Chinese National Standard (CNS) A4 Specification Orange (210X297 male f) (Please read the back of the note first) Please fill out this page again)

1248443 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of invention (Nove) The reaction temperature in this example is 2 8 . The materials charged in the reactor include vinegar (2.7 g), trimethylacetamide (2.5 g), dipotassium hydrogen phosphate (1.7 g), hydrogen peroxide (17.0 g) and dichloromethane (50 ml). ). After 4 hours, the unreacted enester in the reaction was only 2% based on the amount of the incorporation. After treatment as described in Example 4 3, 30 grams of epoxy meclorone was obtained. Example 47-1 Scheme 1: Step 3D: Method G: Synthesis of 9,11^-epoxy-17^-hydroxy-3-ketopren-4-ene-7 α,21-di-l-acid methyl ester, hydrazine - Inside vinegar. The oxime ester (4·〇〇, analysis of 68.4% of the enester) was filled in 1000 ml, placed in a reactor, and dissolved in 175 ml of dichloromethane. When trichloroacetamide (22.3 g) and dipotassium hydrogen phosphate (6. g) were added in a solid particle form, the solution was stirred. The mixture was stirred at 400 rpm and the temperature was adjusted to 27 °C using a constant temperature bath to control the circulation of liquid through the reactor jacket. Hydrogen peroxide (72.8 ml, 30% analysis) was added over a period of 3 - 5 minutes. After the addition of hydrogen peroxide, the mixture was stirred at 400 rpm and 27 °C. HPLC analysis showed that the reaction reached 99% complete within 5 hours. At the end of 6 hours, 72.8 ml of water was added. An aqueous solution of hydrogen peroxide was separated and extracted once with 5 ml of dichloromethane. The mixed di-gas methane was washed with 6% sodium hydrogen sulfate (62. 3 ml) to destroy any peroxide present. Dichloromethane was removed by atmospheric distillation and terminated under hollowing. A yellow residue (48.7 g, 55.4% analysis) was obtained. This is consistent with the analysis of 94.8% adjusted for molar concentration yield. A portion (47.8 g) of the residue was mixed with 498 ml of ethanol 3A (95% ethanol denatured with 5 Torr/0 methanol). The mixture is heated to reflux and then steamed at atmospheric pressure. -272- This paper scale applies to the Chinese National Standard (CNS) A4 gauge (210X297 public #) (please read the notes on the back and fill out this page)

1T Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed 1248443 Α7 Β7 V. Invention Description (270) Distillation removed 249 ml. The mixture was cooled to 25 ° C and filtered. Rinse with ethanol 3 A (53 ml) to aid transfer. The desired solid weight was 27.6 g (87. 0% analysis), which was consistent with the 91% recovery. A portion of the solid (27.0 g) was dissolved in 292 mL of methyl ethyl ketone in reflux. The hot solution was filtered through a disk of s〇lka floc (cellulose powder) and transferred with another 48-6 ml of methyl ethyl ketone. 146 ml of methyl ethyl ketone was removed via atmospheric distillation. The solution was cooled to 5 ° C and stirred for 1 hour as the product crystallized. After 丨 hours, the mixture was cooled to 25 °C. Stirring was continued for an additional hour and the solid was filtered under rinsing with 48.6 ml of methyl ethyl ketone. The solid was dried to 20.5 grams of constant weight, which represents 87.2% recrystallization recovery. The reaction yield and ethanol, methyl ethyl ketone recovery were combined to obtain a total yield of 75 Å / Torr. The methyl ethyl ketone mother liquor is suitable for recycle with a new dichloromethane solution from the subsequent reaction. The mixed methylene chloride and methyl ethyl ketone mixture was evaporated to dryness in the atmosphere and in a standstill. The residue was mixed with 9 times the volume of ethanol 3 a', based on the methacrylone content. Remove half of the falling agent under atmospheric distillation. After cooling to 25 ° C, the solid was filtered and dried. The dried solid was dissolved in 1 2 volumes of methyl ethyl ketone in reflux. The hot solution was filtered through solka floe, and 2 volumes of methyl ethyl ketone was added as a rinse. The filtrate was concentrated by 6 volumes of methyl ethyl ketone in the atmosphere. The solution was cooled to 50 ° C and stirred for 1 hour while the product was crystallized. After 1 hour the mixture was cooled to 2 5 C. Stirring was continued for 1 hour, and the solid was rinsed with 2 volumes of methyl ethyl ketone. The solid is dried to constant weight. The inclusion of methyl ethyl ketone mother liquor increases the overall yield to 80-85%. This side seems to be particularly suitable for expanding the scale, because it can expand the results to the maximum _- 273 - the paper size _ Θ---- (please read the note on the back and then fill out this page), - Central Economic Department Bureau of Standards Staff Consumer Cooperatives prints 1244843 A7 ________ B7 V. Invention Description (271) and the washing volume and waste liquid are minimized.

Example 47A &gt; Watt 1 : Step 3 D: Method Η : Synthesis of 9,11 α-Epoxy-17 with -3 -3 - 酉-pregnant-4 - sulphur - 7α, 21-detreic acid vinegar , within the purpose. The oxime ester (17 g, analysis of 72% enester) was dissolved in dichloromethane (15 mL) then tris-acetamide (14.9 g) was added with slow stirring. The temperature of the mixture was adjusted to 25 C' and a solution of bismuth dihydrogen (10.6 g) in water (1 〇 6 ml) was stirred to a solution of the olefinic substrate under stirring at 400 rpm. Hydrogen peroxide is added to the matrix of the acceptor/phosphate/tri-glyoximine in 3-5 minutes. No exothermic or oxygen evolution was observed. The reaction mixture thus prepared was stirred at 400 rpm and 25 ° C for 18.5 hours. The evolution of oxygen was not observed throughout the course of the reaction, but the consumption analysis of hydrogen peroxide showed some oxygen formation in the reaction. The reaction mixture was diluted with water (69.4 mL) and the mixture was applied at about 250 rpm for 15 minutes. No temperature control is required in this operation and it is carried out essentially at room temperature (temperatures in the range of 5-25 Torr are acceptable). The water and the organic layer are separated, and the lower two-gas-fired layer is removed. The aqueous layer was extracted with a solution of dichloromethane (69.4 ml) at 250 rpm for 15 minutes. The layers are separated and the methane layer below is removed. The aqueous layer (177 g, pH = 7) was determined by hydrogen peroxide. The results show (丨2.2%) that 0.0434 moles of hydrogen peroxide is consumed in the 0.0307 mole chain reaction. Excessive hydrogen peroxide consumption can be used to detect oxygen production in the reaction. Extraction with a small amount of methylene chloride is sufficient to ensure that the methacrylate is not lost in the aqueous layer. This result was confirmed by extraction with the first large f-dichloromethyl fe, in which only trichloroacetamide was recovered. -274-

This paper scale applies to China National Standard (CNS) A4^ (210X2^f T ---------ΦII (please read the notes on the back and then fill out this page j - Book the Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperative Printing 1244843 A7 --------— _____ B7 V. Description of invention (272 ) —~ a — ..., —- know that the mixed solution of dichloromethoxide from the above extraction is mixed, and then 3% by weight Washed with sodium bisulfate solution (122 ml), at a temperature of about 25 rpm, y 1 5 knives at the end of the stirring period, a negative starch iodide test (KI test paper; no color can be observed; positive) In the test, purple shows the presence of peroxide.) The hydrophobic and organic layers are separated, and the lower layer is removed: the gas is burned. The water layer is discarded. Note that the addition of the hydrogen sulfate steel solution may cause a slight exotherm, so the addition should be The reaction was carried out under temperature control. The methylene chloride phase was washed with 〇·5 Ν sodium hydroxide (61 ml) at a temperature of about 25 rpm and 15-25 ° (pH = 12-13) for 45 minutes. In the process, the impurities in the chloroformamide can be removed. The acidified alkali water fraction is extracted with dichloromethane to confirm Very little methacrylone in this operation is lost. The methyl chloride phase is stirred with 0.1 N chlorous acid (61 ml) at 25 rpm and at 15-25 ° C for 5 minutes. The lower layer of methylene chloride was removed and washed with a 3% by weight aqueous solution of sodium chloride (61 ml) for 15 minutes at 250 rpm and 15-25 ° C. The layers were separated again and the organic layer was removed. The organic layer was filtered through a solka fl〇c disk and evaporated to dryness under reduced pressure. Drying was carried out at a water bath temperature of 650. White solids were obtained and subjected to HPLC analysis. Ethyl ketone analysis was 66. 〇 5%. The molar concentration of the molar concentration adjusted for the reaction was 93.1%. μ The product was dissolved in hot methyl ethyl ketone (189 ml), and the resulting solution was distilled under atmospheric pressure until 9 5 ml was removed. When the product is crystallized, the temperature can be lowered to 50. (: Continue stirring at 5 ° for 1 hour at rC = = 20-25 ° C, and continue stirring for 2 hours. Me^ -275- The paper size is suitable for Guanjia County (CNS) Λ4^ (&quot;210x2^17 (please read the notes on the back and fill in the form) Page)

1248443 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs A7 ------One ______ β7 V. Description of invention (273 ) ^

(24 ml) was rinsed and the solid was dried to a constant weight of 9.98 g, which was analyzed by HPLC to contain 93.63% of methicone. This product was redissolved in hot MEK (106 liters) and the hot solution was filtered under pressure through a 10 micron filter. Another 8 ml of MEK was used as a lotion, and the filtered MEK solution was distilled under atmospheric pressure until 5 3 ml of solvent was removed. When the product crystallized, the temperature was lowered to 50 ° C; stirring was continued at 50 ° C for 1 hour. The temperature was then lowered to 20-25 ° C and maintained at this temperature while continuing to stir for 2 hours. The solid product was filtered and washed with MEK (18 mL). The solid product was dried to 8.32 grams of constant weight with each quantitative HPLC analysis containing 99.6% epoxy meclorone. The final loss after drying is less than 1.0%. According to the reaction and operating this example, the overall yield of methacrylate was 65.8%. This overall yield reflects 93% of the reaction yield, 78.9% of the initial crystallization recovery, and 89.5% of the recrystallization recovery. Example 47B Preparation 11 α,12 α -Epoxy-17-hydroxy-3-keto-17 α -pregnant-4-晞_7 α,21-dicarboxylic acid 7-methyl ester, r _ lactone 〇

The enester 11,12 olefin is a by-product of the 11-methanesulfonate elimination. Pure samples can be separated from the reaction mixture (prepared according to Example 37A) using repeated preparative liquid chromatography. Therefore, 7 3 grams of residue (as described in Example 37A -276- This paper scale applies to Chinese National Standard (CNS) Λ 4 桔 Orange (210Χ297^Ϊ) (please read the notes on the back and fill out this page), order 1244843 Α7 Β7 V. Description of the invention (274 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs) Chromatography on 2.4 1 kg of Merck (40-63 micro), using ethyl acetate, toluene gradient dissolution process (20 :80,30:70,40:60,60:40, v/v). Addition of △ π, ΐ 2 olefin part is mixed from the selected 3 〇: 7 〇 part. TLC on EMF board Ethyl acetate / toluene 60:40 (v / ν), and with SWUV sulphuric acid, the choice is suitable for the guidance of the fraction. After the solvent is removed, 7.9 g of crude Λ11,12 olefin (80) is obtained. % area%, by HPLC) Chromatography on 53 1 gram of Merck(R) gel (40-63 micro), with an ethyl acetate/dichloromethyl gradient gradient (1 〇:9 〇, 20:80, 35: 65, ν / ν). From the selected 20:80 part, pure 17-hydroxy-3-keto-17 α-pregnant-4,11·diene-7, 21-dicarboxyl can be obtained. Acid 7-methyl ester, r-lactone (3.72 g) The choice of fractions is based on the TLC assessment, as in the previous case. “111 cm-11767 (lactone), 1727 (ester), 1668 and 1616 (3-keto-Δ 4,5). NMR (CDC13): ppm 1.05 (s, 3H), 1.15 (s, 3H), 3.66 (s, 3H), 5.58 (dd, 1H), 5.80 (s, 1H), 5.88 (dd, 1H). 13C NMR (CDC13) ppm 17.41, 18.58, 21.73, 28.61, 32.28, 33.63, 34.91, 35.64, 35.90, 38.79, 42.07, 44.12, 48.99, 49.18, 51_52, 93.81, 126.43, 126.69, 133.76, 166.24, 172.71, 176.64, 198.56 〇1.6 g (3.9 mmol) Ear) 17-hydroxy-3-keto- π Q -pregnant _4,n-dioxin_7 π,21-monomethyl ester, τ&quot; _ vinegar in 16 ml of dichloromethanone solution 'mixed 2.2 ml of trichloroacetonitrile (22.4 Torr) and 0.75 g of dipotassium a citrate (4.33⁄4 mol). The mixture was mixed and mixed with 6.7 liters of 30% hydrogen peroxide (6 6 mM). Stirring at 5 °C for 4 5 hours. At the end of this time -277- This paper scale applies to China National Standard (CNS) eight 7 rules orange (210X297^1 a &quot; ----- -- (please read first Note on the back side of this page), 1Τ Line { 1248443 A1 A7 B7 Economy Printed by the Central Bureau of Standards and Staff Consumer Cooperatives. 5. Inventive Note (275), add 28 ml of dichloromethane and 39 ml of water. The organic fraction was separated and washed successively with a) 74 ml of 3% sodium hydrogen sulfate, b) 62 ml of 1 N sodium hydroxide, c) 74 ml of 1 N hydrochloric acid, and d) 31 ml of 10% brine. The organic portions were separated again, dried over magnesium sulfate and evaporated to dryness under suction. 1.25 g of residue was chromatographed on 138.2 g of Merck(R) (40-63 micro) using a methyl tertiary-butyl ether and toluene gradient system (40:60, 60:40, 75:25, v/v ). A suitable fraction of 60:40 and 75:25 was mixed after TLC evaluation to yield 0.66 g of pure 11α,12 epoxy-17-hydroxy-3-keto-17α“pregn-4-ene-7 α,21-dicarboxylic acid 7-methyl ester, lactone. The TLC system utilizes EMF plates and 75:25 (Wv) methyl-tertiary-butyl ether and toluene dissolution processes to characterize sulfuric acid and SWUV. Towel NMR (CDC13): ppm 1.09 (s, 3H), 1·30 (s, 3H), 3.05 (ΑΒ11,12 2Η), 3.67 (s,3Η), 5.80 (s,1Η) 〇13 C NMR (CDC13 ) ppm 14.2,18.0, 21.2, 28·8, 31.9, 33.5, 34.6, 34.7, 35.1, 35.5, 37.4, 38.3, 41.8, 46.0, 47.2, 50.4, 51.7, 56.7, 94.0, 126·7, 165.2, 172.5, 176.7, 198.1. Theoretical 値: C, 69·54 and Η, 7.30; measured 値: C 69.29 and Η, 7_17 〇 Example 47C separation 4α, 5 α : 9α, 11 diepoxy-17-hydroxy-3-keto-17 α -pregnane-7", 21-dimethyl ester of 21-dicarboxylate, ^_lactone

This paper scale applies to China National Standard (CNS) Α4 specifications (210X 297 public f) (please read the notes on the back and fill out this page), \sTi Dingliang Economics Department Central Bureau of Standards Staff Consumer Cooperatives Printed 1244843 A7 One —_一B7 V. INSTRUCTIONS (276) -...— - Crude epoxy meclorone (157 g) was prepared from 2 gram of Example 26 vinegar and received 4.4 kg of Merck Shijiao (40-63) Micro) chromatography. A &gt; 1 gram portion was recovered by a 10:90 (Wv) dissolution procedure of acetonitrile and toluene. The isolated solid was dissolved in 880 ml of hot methyl ethyl ketone and filtered through a pad. Another 8 8 liters of methyl ethyl ketone was applied as a lotion. The filtrate was concentrated by removal of 643 ml of solvent and the mixture was cooled to room temperature. The solid particles were filtered and rinsed with methyl ethyl ketone. After drying, 6 〇·2 g of epoxigenone was obtained, and analysis was found to be 96.8% (HPLC). The filtrate was concentrated to dryness under reduced pressure. 9.3 g of residue was recrystallized from 99 ml of methyl ethyl ketone to give 2.4 g of dry solid. A solid sample of 400 mg was subjected to reverse phase preparative HPLC on a YMC ODS AQ column. The pure 4α,5:9α,11α_dicyclooxy-17-lightyl-3-yl-ketone group can be isolated by the separation process of acetonitrile (24%), methanol (4%) water (72〇/〇). Ϊ́7α-pregnant fe ·7 from, 21-detreic acid 7-methyl ester,,-lactone (1〇3 mg) 〇'H NMR (CDCls): ppm 0.98 (s? 3^ 1.32 (s? 3H)5 2.89 (m5 1 H), 3.07 (s, d, 2H), 3.73 (s, 3H) MS, M+430, estimated C24H3O〇7 (430.50).

Example 47D Separation 17_By-based _3,12-diketoyl _17 α _pregnant 4,9(!丨)-diene ", 2i-dicarboxylic acid 7-methyl ester, r-lactone

-279 - This paper size is applicable to China National Standard (CNS) 210IΤ (please read the notes on the back and fill out this page). Order to win 1244843 A7 ____ B7 V. Invention description (277) ~ ~ (Please read the note on the back first) The matter is refilled with this page. The methyl ethyl ketone mother liquor obtained in the manner of Example 2 6 was evaporated to dryness under reduced pressure. 4 to 4 grams of the residue was subjected to a layer of 58.4 g of BTR Zorbax LP (40 micro). Dissolving with a gradient of methyl ethyl ketone and dichloromethane (25:75 to 50:50, wv) yielded 1.38 g of material. 1.3 g of this material was further purified by reverse phase preparative HPLC using acetonitrile (30%), methanol (5%) and water (65%) as mobile phase and using a YMC ODS AQ column (10 micro). The product was extracted from the portion of the abundance via dichloromethane. Dichloromethane was evaporated to dryness, and 175 g of residue was purified by reverse phase preparative HPLC using acetonitrile (24%), methanol (4 〇 / 〇) and water (72%) as mobile phase and YMC ODS AQ column . The extract of Jiafeng is extracted with dichloromethane to form 30.6 mg of pure 17-hydroxy-3,12-dione-π-pregn-4,9(11)-diindole-7α,21-dicarboxylic acid 7-methyl ester. , lactone. NMR (CDC13): 1.17 (s5 3Η), 1.49 (s, 3Η), 3·13 (m, 1Η), 3.62 (s, 3H), 5.77 (s5 1H), 5.96 (s, 1H).

13C NMR (CDC13) ppm 13.1, 21.0, 28.0, 29.4, 33.1, 33.4, 33.9, 35.5, 36.7, 40.3, 41.5, 43.0, 43.4, 52.0, 55.0, 91.0, 123.7, 126.7, 163.2, 167.9, 171.8, 176.8, 197.4, 201.0 〇 Example 47E Preparation of 9,11 epoxy-17-hydroxy-3-keto-17 "-pregn-4-ene-7", 21-diacid, dihydrate, dipotassium economy Central Bureau of Standards staff consumption cooperatives cracked

1248443 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing A7 V. Inventions (278) —— ~-- 1 Containing 2.0 g (4.8 mmol) of Epoxy Meike A suspension of ML water, 3 liters of Erizaki and 9.3 liters of 1 〇 4n sodium hydroxide solution (9.7 ml). The mixture is at 25. (: Stir for 3 hours. A homogeneous yellow solution was formed within the first 2 hours. The temperature was raised to 7 〇π, and stirring was continued for another 3 hours. The solvent was removed by suction distillation, and the residue was passed through 9 gram C 1 8 矽 gel was purified by reverse phase chromatography, and water was used as the leaching agent. The desired fraction was mixed with TLC after EMF plate, and dichloromethane, methanol (7:3) was used as the leaching agent, and SWUV was visualized. The fractions were concentrated to dryness under venting and the residue was subjected to reverse phase purification as previously described. The desired fractions were concentrated to dryness under reduced pressure and the residue was dissolved in ethanol. Adding heptane to completely precipitate. 0.55 g of product, 9,11 α-epoxy-17-hydroxy-3-keto-17π-pregnant-4-#-7π,21-dicarboxylic acid, Hydrate, dipotassium salt, yellow solid. Carbon analysis is consistent with hydrated structure, [33Η28〇7Κ2·1·75 Η20 ·· theoretical 値C, 52.50 to 55.85 (anhydrous type); measured 値C, 52.49. in EMF board Upstream TLC with dichloromethane, methanol, water (6:3:0.5, v/v) as the dissolving agent, and visualized by SWUV' can be observed to be 0.29. .

Example 47F Preparation of 9,11 Epoxy-17-hydroxy-3-keto-17 from-pregn-4-ene-7",21-dicarboxylic acid, disodium salt (please read the notes on the back before refilling This page) - Ding, ,, words

1248443 A7 B7 V. INSTRUCTIONS (279) The Ministry of Economic Affairs' Central Bureau of Standards and Staff Employees' Cooperatives Printing Restricted 5 mg (〇.〇1 mmol) Epoxy Meclirone prepared according to Example 4 3 was suspended at about 200 μm In a liter of methanol, dilute in a 4 ml vial and dilute about 2 liters of 2.5 N NaOH. The resulting mixture was yellow homogeneous. The mixture was then heated in a 70 ° C oil bath. After 丨〇 minute, take i μl of the sample for HPLC analysis (Zorbax SB_C8 15〇χ46 亳m, 2 liters/min, gradient two 35:65 (ν/ν) Α: Β, acetonitrile/methanol (1:1), Bu water / 〇 1% trifluoroacetic acid, detected at 210 nm) showed two substances at 4.86 and 2.93 minutes residence time, with hydroxy acid (opening lactone) and ring opening lactone 7-carboxylic acid , respectively, meet. After 30 minutes, a second sample (〇〇5 ml) was taken and acidified with 〇·〇5 liter 3 N HCl and neutralized with about 5 ml of sodium hydrogencarbonate. HPLC analysis showed that the closed-loop retinoid with the expected appearance of 6 59 and 1 〇 · 71 min was 9,11 epoxide-17-3⁄4 yl-3-exyl I -17α-pregnant-4-晞·7α, 21 - 7-methyl dicarboxylate, plant-lactone (1 〇 · 71 min) for a comparable 7-carboxylic acid ratio of 7:89. Selective hydrolysis of the lactone is possible under mild conditions. The second 4-liter vial was prepared as above but not heated. The mixture oscillated for 5 minutes. 0.05 pen-liter sample was diluted with a mixture of 1:1·5 liters of 1:1 (ν/ν) methanol/acetonitrile and analyzed by HPLC without first acidification. The resulting ring-opened lactone carboxylic acid 7 - hydrazine had a residence time of 4 · 85 minutes, as observed above, and was not stained with 7-rebel. Example 47g_ is 9", 11 θ, 17-trihydroxy-3-keto-πα-pregnant-4-晞-7 α, 21-dicarboxylic acid 7-methyl ester, r-lactone-282- ( Please read the precautions on the back and fill in this!), v&quot; Line Thai paper scale suitable for financial purposes (210X 297 public f 1248443 A7 B7 V. Invention description (280

And 12 α,17-dihydroxy-3-keto-17 α _pregna-4,9(11)-diene_7 α,21-diacid 7-methyl ester, r-lactone f please read first Back &gt;1 meanings and then fill in 'write this page'

- Ding, - A member of the Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperative, printed 9 α,11 ,17-trihydroxy-3-keto-17 α-pregnant-4-晞-7 α,21-dicarboxyjuxa 7-A Ester, r-lactone and 12α,17-diheptyl-3-keto-17,pregnant, 4,9(11)-diene-7,21-dicarboxylic acid 7-methyl ester, r_lactone 2 - Dings are separated from the mother liquor by preparative liquid chromatography, which is recovered by epoxidation of the enester described in Example 26 (three gas acetonitrile strategy). Therefore, the first crystallization was carried out using 2-butanone as shown. However, the crystallization is to replace acetone with 2-butanone (1 倍 volume/g). In this way, 2.8 g of residue ' was obtained and purified by reverse phase preparative HPLC. The Cromasil C8 (10 micro) is used as the stationary phase; while the mobile phase contains milliQ water and acetonitrile in a ratio of 70:30 (v/v) ° at -283- This paper scale applies to the Chinese National Standard (CNS) See (210X 297 Male i) 1248443 A7 B7 V. Description of the invention (281) Crystallization can be observed in a Kafon fraction. The solid (46.7 mg) was isolated and identified as 9α,11 /?,17-trihydroxy-3-keto-17 α-pregnant-4-晞-7 π,21-dicarboxylic acid 7-methyl ester, r - lactone. The mother liquor was evaporated to dryness under reduced pressure, and the residue (123 mg) was identified as 12α,17-dihydroxy-3-keto-17 "pregnant-4,9(11)-diene-7", 21-Dicarboxylic acid 7-methyl ester, 7^ lactone. 9 α,11 ,17-trihydroxy-3-keto-17 π -pregna-4-晞-7 α,21-dicarboxylic acid 7-methyl ester, r-lactone·· MS M+432, estimated C24H3205 (432.5 1). lU NMR (CDCls): ppm 1.23 (s5 3H)9 1.54 (s5 3H)9 3.00 (m? 1H), 3.14 (m,1H)5 3_74 (s,3H), 5.14 (s,1H, slowly exchangeable) , 5.79 (s5 1H). 13C NMR (CDC13) ppm 16.8, 22.7, 24.8, 29.0, 29.3,32.1, 34.1,34.7, 35.2, 35.7, 36.8, 40.7, 43.0, 45.0, 45.9, 52.9, 72.8, 77.4, 95.9, 127.4, 163.7, 176.7, 177.3, 199.4. 12",17-dihydroxy-3-keto-17"-pregna-4,9(11)-diene-7", 21-dimethyl ester of 21-dicarboxylate, r-lactone: MS M+441 , estimated C24H30〇6 (414.50). lU NMR (CDCI3): ppm 0.87 (s5 1H)? 1.40 (s5 1H)5 3.05 (m5 1H), 3.63 (s, 3H), 3.99 (m, 1H), 5_72 ( s, 1H), 5.96 (m, 1H). 13C NMR (CDC13) ppm 14.8, 24.0, 26.1, 29.7, 33.6, 33.8, 34.0, 36.3, 37.0, 37.4, 40·7, 40.9, 43.8, 48.1, 51.9, 69.1, 95.5, 122.7, 126.3, 145.9, 164.5, 173.2, 177.6, 19L2. Example 47H Preparation of 9,11 α-epoxy-3-ethoxy-17-hydroxy-17 pregnancy-4-晞-7 α, 21-284- i Paper size i using China National Standard (CNS) Λ 4 specifications (210X 297 mm) (please read the note on the back and then fill out this page), 11 lines &lt; 1248443 A7 B7 V. Invention description ( 282) rim acid 7-methyl ester, r-lactone

CH

And 6 cold, 17-dihydroxy-9,11-epoxy-3-keto- -17 _pregnant _4·ene-7 α,21_dicarboxylic acid 7-methyl ester, r-lactone (please Read the notes on the back and fill out this page.

Line &lt; Department of Standards and Regulations S<_T consumption of Hezhushe Indomethacin 9,11 α _ epoxy _3_ethoxy-17_hydroxy_17 α _pregnant _4_晞", 2 Bu 7-methyl dicaptanate, r lactone is prepared according to the method of R m· Weier and L M. H〇fmann (j. Two edChem B77, Boy, which is the reference of this case. 8 g prepared according to the method of Shell 43 Oloxi) epoxide η hydroxy ketone -17α_pregnant _4_ 晞dicarboxylic acid octadecene, guang, _, / ma with 31 1 liter absolute ethanol and 1 $ 5 liters (932 mA Mohr) original 285- The paper size is applicable to China's national 榡淳 ((, NS) Λ 4 specifications (210X 297 mm) 1248443 淖 中 中 β ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( B7 V. Invention (283) Triethyl acid. The slurry was stirred at room temperature, and 10.4 g (54.7 mmol) of toluene acid (monohydrate) was added as a catalyst. Stirring was continued; 捽 30 minutes And the reaction was added 41_4 g (505 mmol) of sodium acetate powder and 20.7 ml (2 56 mmol) of p-pyridyl to quench. The solid particles (70.2 g) were removed by filtration, and the filtrate was concentrated to dryness under vacuum. The residue was hydrolyzed with 300 ml of ethyl acetate Further, 9.8 g of solid particles were removed by filtration. The filtrate was concentrated to dryness, and the residue was crystallised eluted with 100 ml of methanol containing 2 ml of pyridine. 29-7 g of solid particles were removed by filtration. An additional precipitate was observed in the filtrate. It was filtered again to remove an additional 21.9 g of solid particles. The filtrate was concentrated to dryness and the residue was hydrolyzed with 50 ml of methanol containing 1 ml of pyridine. 3 3.8 g of solid particles were separated by filtration. Quantitative HPLC showed this last The solid particles are sufficiently pure (90 area% of 9,11 α-epoxy-3-ethoxy-17-#Riki-17"-pregnancy_4·ene-7 pan, 21_detreic acid 7-A Ester, plant _ 酉 )) can be used in the next reaction step. 9,11 epoxy-3-ethoxy-17-radio-17α-pregnant-4-return--7α,21-diacid 7 - 甲酉的' Γ - Internal purpose: 4 NMR (CDC13): ppm 1.02 (s, 3Η), 1·27 (s, 3H), 1.30 (t, 3H), 3_12 (m, 1H), 3.28 (m,1H),3·66 (s,3H), 3.78 (m,2H), 5.20 (s,1H),5_29 (d,1H). 8 g of sterol ether (9,11&lt;^-ring Oxy-3-ethoxy-17_light base_17"_pregnant_ 4- 晞_7 α,2 1 -di-rebel 7- Esters ,, - caprolactone) (18 mmol) prepared by previous steps' fall on 12 0 ml 1,4 - in Kawasaki. Solution with 6.8 g of 5 5 % meta-chloroperbenzoic acid &amp; (20.9 mmol), 18.53⁄4 liter of 1.0 N hydroxide steel (ΐ8·5 mmol) and 46 ml of dioxane/water (9: 1) Mixing. The temperature was maintained and the mixture was stirred for 2 hours. The temperature rises to 2 5 °C, and continues to fall again 2 〇 small -286- This paper scale is wrapped around the Chinese national standard (. called eight 4 specifications (210', 297 mm) '------- --#! (Please read the notes on the back and fill out this page)

, 1T 1248443 A7 B7 V, invention description (284). The mixture was mixed with 400 ml of cold water (1 ° C) and 23.5 ml of 1.0 N sodium hydroxide (23.5 mmol). The mixture was extracted 4 times with 1 mL of dichloromethane (each time). The combined dichloromethane fractions were dried over magnesium sulfate and the supernatant solvent was removed under vacuo.丨3·9 g of the residue was ground in 5 ml of diethyl ether to give 2.9 g of a white solid. 2.4 g of solid was chromatographed on a 100 gram Merck(R) gel (60 micro). After washing with 1 liter of 1:1 ethyl acetate / heptane, the product was dissolved in 7:3 ethyl acetate / heptane. The mixed abundance fraction (EMF plate; ethyl acetate/heptane 7:3 (v/v) dissolving agent; SWUV conformation) was evaluated according to Tlc. Therefore, '0.85 grams of Kafeng material' can be recrystallized from milliliters of isopropanol to form 0.7 grams of 6y5,17-dihydroxy-9,11α-epoxy-3-keto-17α-pregnant_4 _ene·7 α,21-di-rebel acid 7-methyl ester, plant_lactone. Mixing with the more contaminated part, you can get 〇_87g of crude 6/?,17-dihydroxy-9,11 epoxy-3-keto-17α_pregnant-4-晞-7 α,21- 7-methyl dicarboxylate, r-lactone. This material was chromatographed on 67.8 g of Merck silicone (40-63 micro). 0.69 g of product was recovered in toluene containing 0.5-2.5% methanol. 6 , 17-dihydroxy-9,11 α -epoxy-3 keto-17 -17-pregn-4-ene-7 α,21-dicarboxylic acid 7-methyl ester, r-lactone: Theoretical 値: C, 66.96 and H, 7.02 ; Measured 値: C, 66.68 and H, 7.16 〇iH NMR (CDC13): ppm 1.06 (s, 3H), 1.36 (dm, 1H), 1.63 (s, 3H), 2.92 (m,1H), 3.02 (dd,1H),3·12 (d,1H), 3.64 (s,3H), 4.61 (d,1H), 5.96 (s,1H) 〇, 13C NMR (CDC13) ppm 16.17, 21.32, 21.79, 24.36, 27.99, 28.94, 30.86, 3 1.09, 32.75, 33.19, 34.92, 36.77, 39.16, 43.98, -287- This paper ruler Hi towel is closed ( (, NS ) Λ 4 size (21 OX 297 public ^&quot;7 (Read the first note on the back and fill out this page), 1Τ 1248443 V. Description of invention (285) A7 B7 Ministry of Economic Affairs in the middle of the stipulations of the squad, χ 贽 竹 竹 社 社 ¥ = ¥ = 74 51·56, 5 1.66, 65·36, 72.23, 94.79, 165.1〇, 17136 176.41, 199.59. · ^^1471 Preparation 9,11π·epoxy-17-monoyl·3__yl_17^pregnant_4 7-diphenyl 7-methyl ester, r-lactone

For 2 grams (4.8 millimoles) 9, H-epoxy quinones _3_ fluorenyl-~pregnant-4-seven, 21-two tacrotic acid 7-a scorpion, Bu vinegar, according to Prepared by the method of (4), adding 3.3* liter (14.4 mmol) of 25% sodium methoxide to methanol. The resulting yellow suspension was heated to 50 °C. The solid does not dissolve. To the mixture was added 3.3 ml of methanol (Aldrich, anhydrous). The mixture was heated to reflux conditions (65 ° C) and became homogeneous. After 30 minutes, solid precipitation hindered the agitation. Add about 25 ml of water to the drunk, and transfer the mixture to a 1 (9) ml bottle. The mixture was heated under reflux for 16 hours at which time the mixture was dark and homogeneous. The mixture was cooled to 25 ° C and 70 liters of 3 N HCl (exothermic) was added. A few grams of ice was added to cool the mixture, and the solution was successively extracted in two equal portions of 25 ml of dichloromethane. The dark solution is dried over sodium sulphate and passed through the 288- towel (4GX 297 public &quot; (Read the first note on the back and fill out this page), 11 1248443 A7 ------__________B7 V. DESCRIPTION OF THE INVENTION (286) ~ ^~— 2·5 cm 矽 盘 filter (Ε· Merck, 7〇_23〇 sieve, 6〇 size). The vermiculite is dissolved in 100 ml of dichloromethane. The methane was further concentrated under vacuum to give 1 g of a brown foam which crystallized upon addition of ethyl acetate. The crucible was dissolved in a second 1 ml of 10 〇 / 〇 ethyl acetate / dichloromethane. It can be concentrated to give 650 mg of brown foam. Thin layer chromatography (E· Merck 60 F-2549 silicone, 0.25 mm, toluene/acetic acid ethyl acetate (1; 1 'v/v)) shows the presence of two samples, 9, 11 α -Epoxy-17•hydroxy-3-keto-17 “pregn-4-ene·7 α , 21-dimethyl ester of 21-dicarboxylate, r-lactone, and 9,11α·epoxy Base _i7-radio-3-keto- 17π-pregnant-4_晞-7; 5,21-di-acid 7-methyl ester, r-lactone, however there are very few 7 in the first sample " _ carboxy epitope isomer. The first sample is hot acetic acid Ethyl ester (77 〇c) was ground and allowed to cool to 25 Ό. The mixture was filtered to give 4 〇〇 mg of a white solid, mp 254-258 Ό. Η, 13C and 13C-APT conformed to the established structure. A small amount of ethyl acetate was retained in the sample, but it was confirmed by HPLC that there was no starting material (Zorbax SB-C8 150 X 4.6 mm, 2 liters/min, isocratic concentration 40:60 (Wv) A: B, A = acetonitrile / methanol (1:1), and B = water / 0.1% trifluoroacetic acid, detected at 210 nm) (HPLC shows 98.6 area%), and TLC (toluene-ethyl acetate 1:1, v/v It is also known that FAB-MS confirmed the molecular weight of 414 and 415.2 iM+H.

4 NMR (400 MHz, hypochloroform) β 0·95 (s, 3H), 1.5 0 (s5 3H), 1.45 (m, 3H), 1.55_2·7 (m, 15H), 2.85 (t5 J=13, 1H), 3.25 (d, J = 6, 1H), 3.65 (s, 3H), 5.78 (s, 1H) 〇 Example 47J Preparation of 9,11 a-epoxy-17-hydroxy-3-keto-17 a -pregn-4-ene-7 a,21-di-289- f paper H is applicable to Chinese national standard ((^^)/\4 specification (210'乂297 mm) (please read the notes on the back first) Fill in this page) ·· 订线一1248443 kl B7 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printing 5, Inventions (287) Rebel, r - internal

774 mg (1·82 Torr) 9,11 α-epoxy-17-hydroxy-3-keto-17 π-pregn-4-ene-7 α,21-dicarboxylic acid 7-methyl ester , r - internal vinegar, prepared according to the procedure of Example 43, and suspended in 3 ml of acetonitrile, and added 3 ml (7.5 mmol, 2.0 equivalents) of 2.5 Μ sodium hydroxide. The mixture turned yellow and became homogeneous after 10 minutes. In order to follow the progress of the reaction, a mixture of 〇. 1 ml was quenched with 亳 1 亳 3 Μ Μ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Phase separation, using a pipette to remove the lower layer. The organic phase was flashed and the residue was purified by HPLC using the method described in Example 47. After 50 minutes at 25 ° C, there was little change in the composition of the mixture. The mixture was heated under reflux (about 9 〇 X:) for 5 〇 minutes. HPLC analysis of the mixture indicated that 6 area% of the starting material remained. The mixture is at 2 5 . Stir under the arm for 6 5 hours. Acidification, extraction and HpLC analysis as described above confirmed that no starting material remained. The mixture was strongly acidified with 4 ml of 3 Torr sulfuric acid and extracted with two portions (about 1 Torr) of dioxane. The organic phases were combined and dried over sodium sulfate.于-290- This paper scale applies to China National Standard (cns) (*&quot;) ---' ---------0------1T------Φ, ( Please read the notes on the back and fill out this page.) 1248443 A7 B7 V. INSTRUCTIONS ( 288 ) (Please read the notes on the back and fill out this page) Concentrate from the evaporator to produce 780 grams of solids. The solid was recrystallized from dimethylformamide/methanol to yield 503 mg (yield: 67%) of brown crystals. When heated rapidly, it melts at nearly 260 ° C and gas escapes. When slowly heated to 285 ° C, the sample slowly darkened but remained solid. 4 MMR (dimethyl sulfoxide d-6, 400 MHz) d 0.85 (s, 3H), 1.4 (s 3Η), 1·3·2·9 (m, 19H), 3.15 (m, 1H), 5.55 ( s,1H), 11_8 (br, 1H) 〇'

Scheme 1: Step 3D: Method i: Synthesis 9, ηα-epoxy-17-hydroxy-% 酉-pregn-4-ene-7α, 21-dicarboxylic acid methyl ester, lactone. 〇·2 decyl decyl ester in dichloromethane, with 2 equivalents of citric acid bis (in equal weight water, 50% w/w aqueous solution), 3 equivalents of difluoroacetamide and 2 2 equivalents of peroxidation Hydrogen (in the form of a 3% aqueous solution added) was mixed. The mixture was stirred at 2 5 C for 2 3 hours. The reaction was diluted with water equivalent to the added hydrogen peroxide, and the dichloromethane was separated. The di-methane portion was washed once with a 3% sodium hydrogen sulfate solution (volume equivalent to 75 times the amount of hydrogen peroxide added). The dichloromethane fraction was separated and dried over sodium sulfate. The solution was concentrated under atmospheric evaporation until it reached a head temperature of 70 °C. The residue was evaluated via hplc, ι Η and UC NMR (CDCh). The yield of methacrylate was determined to be 54_2 area % (HPLC).

Example 47L Scheme 1 ··Step 3D ··Method J··Synthesis 9,11α-epoxy-Ι7α-hydroxy-3-ketoprev-4-晞-7 α,21-dicarboxylic acid methyl ester, r - Lactone. Example 4 7 K step repeated, using heptafluorobutyramine (cf3CF2CF2CONH2) -291 - This paper scale is suitable for ffl Chinese national standard, (CNS) Λ 4 specification (210X 297 mm) &quot; 1248443 A7 B7 V. Invention description (289) Replace chlorodifluoroacetamide. The yield of methacrylone was 58 4 area% (known by HPLC). Ajj - utilizes a phenyl epoxidized decyl ester process 1: Step 3D: Method K: Synthesis of 9,11α-epoxy hydroxy-3-keto-pregn-4-ene_7α,21-dicarboxylic acid methyl ester , lactone. The olefin of formula IIA was converted to the oxime meclizol by the general procedure of Example 46 except that toluene was used as the solvent. The materials charged to the reactor included 2.7 g of 'dichloroacetamide (2.5 g), hydrogen ruthenium dihydride (1.7 g), hydrogen peroxide (17.0 g) and toluene (50 ml). The reaction is exothermic to 28 ° C and can be completed in 4 hours. The resulting three-phase mixture is cooled to 15 . (:, filter, wash with water, dry and dry can produce 2.5 grams of product. After the elimination of the Ministry of the squad, the τ 贽 啊 社 社 社%% (谙 read the back of the note and then fill out this page) Example 4 9 - Scheme 4: Method A: 9,11 - Dienone cyclization is carried out as a compound named XVIIA (χνΐΐ compound, wherein -A_A_&_n is -CH2_CH2-) (40.67 g) is dissolved in di-methane ( 250 ml), in a 1-liter three-necked flask, and externally cooled by a mixture of ice and salt. Dipotassium citrate (22.5 g) and tri-acetonitrile (83·5 g) were added and the mixture was cooled to dryness. Slowly add 30% hydrogen peroxide (2 gram) for 1 hour. The reaction mixture is stirred at 12 ° C for 8 hours at room temperature for 4 hours. Take a drop of organic layer and check if it contains any starting olefin. Ketone, and found &lt; 〇 · 5%. Add water (400 ml), stir for 15 minutes and then layer. The organic layer is saturated with 200 ml of potassium iodide (10%), 200 liters of sodium thiosulfate ((7) (6) and 丨〇〇 ml The sodium bicarbonate solution was washed successively and layered each time. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give a crude Epoxide (4 1g). The product is crystallized from acetic acid to form 14.9 g of pure substance. - 292- 41 Paper Z degree Chinese national standard (CNsTmm ( 210X 297^1 ) ' 1248443 A7 B7 V. INSTRUCTIONS (29〇): Method B: Compound XVIIA utilizes meta-chloro chlorpyrifos to administer Jii oxime oxidation. Compound XVIIA (18.0 g) is dissolved in 250 ml of di-methane and then cooled to 1 〇c. With stirring, solid meta-chloroperbenzoic acid (50-60 〇/〇 pure, 21.86 g) was added for 15 minutes. No increase in temperature was observed. The reaction mixture was stirred for 3 hours' and checked for the presence of dienone. The reaction mixture was successively treated with sodium hydrogen sulfate solution (10%), sodium hydroxide solution (0.5 N), and hydrochloric acid solution (5%). Finally, 5 ml of a saturated saline solution was dried over anhydrous magnesium sulfate. Evaporation yielded 17.64 g of epoxide and was used immediately in the next step. The product was found to contain Baeyer-Villiger oxidation product which must be removed from ethyl acetate and crystallized from di-methane. The size of the precipitate is filtered out -Chlorobenzoic acid, according to the usual method of treatment. Example 5 1 - Scheme 4: Method C: Compound XVIIA was epoxidized with tri-hexanes. Compound XVIIA (2 g) was dissolved in 25 mL of dichloromethane. Add trimethylacetamide (2 g), dipotassium phosphate (2 g), add 3 〇〇 /0 hydrogen peroxide (10 ml) with stirring at room temperature, and continue stirring for 18 hours to form epoxide (1.63 grams). The Baeyer-Villiger product was not formed. Example 5 2 Potassium hydroxide (56.39 g; 1005.03 mmol; 3.00 equiv) was added to a 2 mL flask and was then slurried with dimethylhydrazine (750.0 mL) at room temperature. Corresponding to the ketene of formula XX (wherein R3 is hydrazine, and both -AA- and -BB- are _ 匸112-(:112-) (100.00 g; 335.01 mmol; 1. 〇〇 equivalent) are added to Flask -293- 冢7 ft. S:( (,NS ) Λ4 size (210X 297 mm) (Please read the note on the back and fill out this page again), -= 口丁1248443 A7 B7 V. Description of invention ( 291), and THF (956.0 ml) was added, and trimethyl sulfonate (126.14 g; 670.023⁄4 mol; 2 〇〇 equivalent) was added to the flask, and the resulting mixture was heated under reflux. 80-85 ° C. From the reaction mixture, about liter of THF was carried out under venting, then water (460 liters) was added for 3 〇 minutes, and the reaction mixture was cooled to 15 ° C. The resulting mixture was filtered. The solid ethylene oxide product was washed twice with 200 ml of water each. The product was highly crystalline and easily filtered. The product was then dried at 40 ° C. 104.6 g of 3-methyl enol ether was isolated. 9,11,-17-epoxy Ethylene steroid product 0 Example 5 3 After the Ministry of Standards, the Ministry of Standards, the Department of Household Products, the bamboo shoots 40 water (please read the note on the back) Additional information on this page) Sodium ethoxide (41.94 g, 616.25 mmol; 1.90 eq.) was added to a dry 500 mL reactor under nitrogen. Ethanol (270.9 liters) was added to the reactor and oxidized. Sodium was slurried in ethanol. Diethyl malonate (1〇39 g, 648.68 mmol; 2.00 equiv) was added to the slurry, followed by the preparation of the ethylene oxide steroid as described in Example 52 ( 104.60 g; 324.34 mmol; 1 00 equivalent) was added and the resulting mixture was heated to reflux, ie 80-85 C. Heating was continued for 4 hours, after which time the reaction was completely checked by HPLC. Water (33 7.86 ml) Add to the reaction mixture for 30 minutes while the mixture is cooled to 15 ° C. Stirring is continued for 30 minutes, after which the reaction is filtered through a slurry to produce a filter cake containing finely divided amorphous powder. The filter block is water (2 mL each) Washing, then drying at ambient temperature and hollowing out. 13 8 g of 3-methyl enol ether-17-spirolactone-21, ethoxycarbonyl intermediate 0 5 4 -294- ϋ 尺度 速 囤Domestic standard (((,NS ) Λ4 specifications (2丨〇&gt;&lt;297 mm)浈部中次标卑局 MJr.消贽告竹社印来1248443 B7 V. Invention description (292) 3-methyl enol ether-^5,6,9,11,-17-spirolactone-21-B An oxycarbonyl intermediate (Formula XVIII wherein R3 is deuterium, and -AA- and -BB- are each -(:112-&lt;^2_; 133.80 g; 313.68 mmol; 1_0〇 equivalent) are produced according to Example 53, Add to the reactor and add sodium chloride (27.50 grams, 470.52 millimoles; 1.50 equivalents), then add dimethylformamide (709 ml) and water (5 ml) to the 2000 ml reactor. And fell to stir. The resulting mixture was heated to reflux, 138-142 ° C for 3 hours, then the reaction mixture was checked for completeness and was obtained by HPLC. Water was then added to the mixture for 30 minutes while the mixture was cooled to 15 °C. Stirring was continued for another 30 minutes, after which the reaction slurry was filtered to obtain an amorphous solid reaction product as a filter cake. The filter block was washed twice (200 ml each of water) and then dried. The product 3-methylenol ether-17-spirolactone was dried to give 91.6 g (82.3% yield; 96 area % analysis). Example 5 5 The enol ether (91.60 g; 258 mmol; 1.00 equiv), ethanol (250 mL), acetic acid (250 mL) and water (250 mL) from Example 54 were added to a 2000 mL reactor. The slurry was heated to reflux for 2 hours. Water (600 ml) was added over 30 minutes and the reaction mixture was cooled to 15 °C. The reaction slurry was filtered again, and the filter cake was washed twice with water (200 mL each). The filter cake was dried again; 84.4 g of the product 3-keto- 17-spirolactone (the compound of formula XVII wherein R3 is oxime and -A-A- and -B-B- is -CH2-CH2-; 95.9% yield) can be isolated. Example 5 6 Compound XVIIA (1 kg; 2 81 mol) plus four gasified carbon (32 liters) filled -295- 囤 标 ( (~-- (Please read the back of the note first and then fill out this page) Order 1244843 Α7 Β7 V. Description of the invention (293 liter in a 22 liter 4_neck flask. Add bromine·succinimide (tetra) imine (Buick) to the mixture, add B guess (3.2 liters). The resulting mixture is heated to reflux. And kept at the reflux temperature for about 3 hours, a clear orange solution can be formed. After 5 hours of heating, the solution becomes dark. After 6 hours, the heat source is removed and sampled. The agent is used to hollow the steam strip and then add acetic acid. B (6 liters) to the residue (which is at the bottom of the distillation pot). The resulting mixture was stirred, and a 5% sodium bicarbonate solution (4 liters) was added, and the mixture was stirred for 5 minutes, and the phases were allowed to settle. The layer was removed, a saturated brine solution (4 liters) was introduced into the mixture, and then stirred. The fraction was separated from the human phase, and the organic layer was steamed under 眞2 to produce a thick slurry. Indoleamine (4 liters), and continue to steam to a pot temperature of 55 。. Allow the bottom of the retort to stand overnight, then add DABC〇 (33 g) and lithium bromide (243 g). The mixture was heated to 7 Torr: After heating for 15 hours, the chromatographic sample was taken out and heated for 3.50 hours, followed by the addition of additional DABc(4 g). After heating for 4.5 hours, water (4 liters) was introduced, and the resulting mixture was cooled to 15 C. The slurry was filtered, and the filter was washed with water (3 liters) and dried overnight on filter paper. Wet block (978 g) was returned. Into a 22 liter flask, and add dimethylformamide (7 liters). The resulting mixture was heated to ι 5 Ό, at which point the filter was completely absorbed into the falling liquid. Heat was removed and the mixture was stirred in the flask. Drop the cold water and add ice water to the reaction hood, and the mixture in the reactor is cooled to 14 ° C for 2 hours. The resulting slurry is filtered and washed twice with 2.5 liters of water. Dry under the air for one night. Obtain 5 1 g of light brown solid product 0 \ Example 5 7 Add in a 2 liter 4-neck flask: 9, 丨丨 _ epoxy ketone, according to the example -296 - paper scale Use the Chinese national standard rate ("NS" eight 4 rules ~ ^ (2) 297 297 mm) (please read the notes on the back and fill out this page) --tv .II - 1— I..... 1248443 A7 ___________ B7 V. Description of invention (294) f Please read the notes on the back and then fill out this page.} Production system (100.00 g; 282.1 mmol) ; 1.00 eq.), dimethyl tilamine (650.0 ml), lithium chloride (30.00 g; 707.9 Torr; 2.51 eq.) and acetone cyanohydrin (72.04 g, 77_3 ml; 846.4 mmol; 〇〇 equivalent). The resulting suspension was mechanically stirred and treated with tetramethyl hydrazine (45 g·49.6 ml; 395.0 Torr; 丨.4 〇 equivalent). The system is then filtered with a water-cooled condenser and a dry ice condenser (filled with dry ice/acetone) to prevent Hcn from escaping. The outlet of the dry ice condenser is passed to a scrubber with a large amount of chlorine bleach. The mixture was heated to 8 Torr. After 1 hour, a dark red-brown solution was obtained, which was then cooled to room temperature. During the cooling process, nitrogen is charged into the solution to remove the residual Hcn, which is used to reach the bleaching water in the scrubber. After 2 hours, the solution was treated with B (7.4 g) and stirred for 3 minutes. The crude mixture was poured into ice water (2 liters) and mixed with stirring. The stirred suspension was further treated with 1% hci aqueous solution (400 ml) and stirred for 1 hour. The mixture was then filtered to give a dark red solid (73 g). The filtrate was placed in a 4 liter separatory funnel and extracted with dichloromethane (3×800 ml); the organic layer was mixed and extracted with water (2×2 liters). The solution was concentrated under a hollow. Generate 6 1 gram of dark red oil. After the aqueous strip was allowed to stand overnight, a considerable amount of precipitate could be developed. This precipitate was collected by filtration and determined to be the pure product enamine (14·8 g). After the original red solid was dried (73 g), it was analyzed by Hplc, and it was determined that the main component was 9,11-epoxyenamine. hplC further showed that the decylamine was the major component of the red oil obtained from the chloroform. The estimated concentration of guanamine is -297-degree suitable for Chinese national standard, r^T^i7210&gt;&lt; 297 mm) - 1248443 A7 B7 5. The invention (295) has a concentration of 46%. Example 5 8 9,11-Epoxyenamine (4.600 g, 0.011261 mol; 1.00 eq.) was prepared according to Example 57. To the mixture were added decyl alcohol (300 ml) and 0.5% by weight aqueous HCl solution (192 ml), followed by reflux for 17 hours. After that, the methanol is removed under the hollowing out, and the contents of the distillation tank are reduced to 50 ml' to form a white sediment. Water was added to the atmosphere, followed by filtration to produce a white filter, which was washed three times with water. The yield of the solid 9, oxime-epoxydione product was 3.747 g (81.3%). Example 5 9 The epoxy diketone (2 〇〇 mg; 0.49 mmol) prepared according to Example 58 was suspended in methanol (3 liters), followed by 1,8-dioxane [5, 4, 〇] eleven carbon _7 • dilute (DBU) into the mixture. Once heated under reflux for 24 hours, the mixture became homogeneous. It was concentrated to dryness on a rotary evaporator at 30 ° C, and the residue was partitioned from dichloromethane and 3.0 NH. The organic phase was concentrated to give a yellow solid (1, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The yield is 20%. f is the first thing to read the back of the note and then fill out this page}

• P* tr «non· -298- The paper size is suitable for the state '?&quot;1^^^7 (, milk) eight 4 specifications (210 father 297 mm) - ' 1248443 A7 _____ B7 ___ Λ, invention description ( 296) ^Μβο For 100 mg of diketone (prepared according to Example 58), it was suspended in 1.25 ml of methanol, and 10 μl (0.18 equivalent) of a 25% (w/w) solution of sodium methoxide in methanol was added. The solution is heated to reflux. After 30 minutes, no diketone remained and there was a 5-cyano group. To the mixture was added 4 6 μl of 25% (w/w) sodium methoxide in methanol; The mixture was heated under reflux for 2 3 hours, at which time the main product was judged to be methacrylone with hplC.

〇

(Please read the precautions on the back and then fill out this page) Example 6 1 Line Once in the Department of the Department of the Department of the Department of the Department of X Xiaoying Cooperative Printing ¥ 2 g of diketone (prepared according to Example 58) suspended in 30 ml of anhydrous methanol, 0.34 ml of triethylamine was added. The suspension was heated under reflux for 45 hours. The mixture was stirred at 25 ° C for 16 hours. The resulting suspension was filtered to give 13 g of 5-cyanoester as a white solid. To 6.6 g of diketone was suspended in 80 ml of methanol, and 2.8 ml of triethylamine was added. The mixture was heated under reflux for 4 hours and then at 25 rpm for 8 8 hours at which time the product crystallized from the solution. Filtration and washing with methanol gave 5 · 8 g of cyano ester as a white powder. The material is recrystallized from chloroform/methanol, -299-degree is suitable for Chinese national standard (mm) ------ solid-fixation combined with 1244843 5. Invention description (297) can produce 3.1 grams of crystalline substance, Hplc is known to be homogeneous based on the above description, and it can be seen that the enthalpy of the present invention is achieved. (The purpose of 汗 汗 及 and other beneficial results can be varied in the above-mentioned group composition and process, as long as it does not deviate from the scope of the present invention, all the things occupied by the water in the above description and The present invention is included in the drawings and is not limited thereto. The novel compound: the invention further relates to an additional polycyclic organic moiety which can be used as a chromatographic component to prepare a steroid compound having beneficial biological activity. Such as spironolactone or epoxigenone. In short, some compounds have been found containing a substituted or unsubstituted <steroid steroid' and a substituted or unsubstituted carbocyclic ring. , thick, steroid core &quot;, 17 position, can be used as a steroid preparation or chromatographic label 'such as spironolactone and dexamethasone. In particular, compound 2, 3, 3a, 4,6,7,9,10,u,lla,^,,13,dodecyl_'lla/?_dimercapto-dione, and (1)&amp;6α-carboxylic acid methyl ester·· J Non-(ci) can be used as a chromatographic marker. One of the slight features of this compound and related compounds is the adhesion of thick white carbon rings to the class. D-nucleus of sterol core. Spiral π-sterol and Epoxy 300- This paper scale is suitable for the Chinese national standard (rNS) Λ4 specification (21〇χ 297 public Chu) (called the first note on the back) Fill in this page) Set the rate of the rate in the Ministry of Economic Affairs, β, τ, 贽 贽

1248443 A7 B7 V. INSTRUCTIONS (298) Kreiber lacks this feature and replaces the 20-nail inner @ the ring. As used herein, the steroid of the compound corresponds to the following structure

The Ministry of Economic Affairs has made a number of times for the traditional numbering and ring naming of steroid compounds. Steroid cores can be saturated, unsaturated, substituted or unsubstituted. Preferably, it has at least 1 to 4 unsaturated bonds. Preferably, the a, c and d rings each have a stone unsaturated bond. The steroid nucleus can also be replaced, as described below more specifically. Preferably, the core is substituted with at least one C7 ester group. , f used in this, the carbocyclic ring is fused to the steroid nucleus, which is equivalent to a ring structure of 4 or 6 carbon. It can be saturated, unsaturated, substituted by 5 and unsubstituted. Preferably, it is saturated or has a double bond and is substituted with a ketone group or a keto group. Further, the carbon ring preferably has a π-direction α phase compared to the 2 alcohol nucleus. In a preferred embodiment, the carbocyclic ring contains a 5-carbon cyclic bone plus direction, and the compound is selected from the following including equivalent: ' compound: %

(C-3) cPlease read the precautions on the back and fill in this page. Order 301 paper sheets _ towel _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ----___B7 V. Description of the invention (2) where -AA- represents the following group -CR102R102a-CR103R1()3a- or -CR102=CR1()3-, where -CR102Rl〇2a and _CR102=equivalent C2 carbon, and _CR1〇3R1〇3a- and =CR1G3-equivalent to C3 carbon; -DD- represents -CHR104-CH- or -CR104 di-C-group; -EE- stands for -CHrCR11, or -CH=C - AE- stands for -CR102R1()2a-CH2- or -CR1G2=CH, where -CR102R102a- and -CR102=equivalent to C2 carbon, and -CH2- and =CH- correspond to C1 carbon; -GG· Equivalent to -CR106R106a-CHR107- or -CR106 = CR107-, where _CRi〇6Ri〇6a_ and -Cr106=equivalent to C6^, and _chr107_ and cr=107_ are equivalent to C 7 carbon; •JJ- stands for -CR108- CR109- or -OC-, where -CR108· is equivalent to C8 carbon, and -CR1G9_ is equivalent to C9 carbon; -LL - represents - or -CRin = CH-, where -CR111!^11. -and ·cRiik is equivalent to cii carbon, and -CHR2- and =CH- are equivalent to C12 carbon; _]-1^ stands for _匚11109-€1111111111, or -〇«1111-, where _(:11109-and- 〇 is equivalent to C9 carbon, and CRmRllla- and -CRni = equivalent to C11 carbon; -MM· stands for -CR114-CH2_ or -OCH-, where -CR114- and -C = equivalent to C14 carbon, and _ch2- and -C=H_ is equivalent to C15 carbon; -JM- stands for -CR108-CR114· or -C = C_, where -QR108- is equivalent to C 8 carbon and -CR114- is equivalent to C14 carbon; -QQ- stands for -CR120R120a- CR119R119a- or -CR120 = CR119-, of which 302- This paper size is applicable to Chinese national standard ((, NS) Λ4 specification (210X297 mm) (please read the note on the back and fill out this page)

, 1T 1248443 A7 B7 V. Description of the invention (3〇〇) -CR120R12()a- and _CR12G=CR119-equivalent to C20 carbon, and -CR119R119a and =CR119-equivalent to C19 carbon; -QT- stands for -cr^ Rh^chr118- or -CR119=CR118-, wherein -CR119R119a· and _cr119=equivalent to ci9 carbon, and -CHR118- and two CR correspond to C18 carbon; R1G2 is hydrogen, alkyl, alkenyl or block; R1G2a is hydrogen, or a bond between C2 carbon atoms and C3 carbon atoms. 18 18 淖 中 绛 _ _ _ _ _ _ _ 代表 代表 代表 代表 代表 代表 _ _ _ _ _ _ _ _ _ _ _ () 3- and -Λ-E- represents _CR or represents a bond between a C 1 carbon atom and a C 2 carbon atom, when _A_E_ represents -CR -CH- and - A_A- represents - CR102R102a_CR103R103a_; Hurricane, basal, protected base, R13G〇_, Ri3Gc(〇)〇_, R oc(o)〇-, or Ri 〇3a together form a ketone group; the constraint is _A_ A- -CRWRl〇2a_CRl〇3Rl03a_, when r1G3 plus ... (d) forms a keto group; R1〇3a is hydrogen or R1G3 is added to form a keto group; the restriction is _A_A_ is CRl〇3Rl〇3a_; R1G4 is hydrogen 'fe Alkyl, alkenyl or alkynyl; R is hydrazine, aryl or protected hydroxy , or by adding R1G6a to form a keto group L or by adding R and its carbon atom form &lt; cyclopropyl, cyclobutyl or cyclopentyl ring; the constraint is · G_G• is _CRl (&gt;6R1 () 6a_cRi()7Ri()7a_, when R1G6 plus R〗 G6a forms a keto group; R〗 6a is hydrogen 'hydroxyl or protected hydroxy group, or R106a forms keto group' or plus R106 and The carbon atom to which it is attached forms a cyclopropyl, cyclobutyl or cyclopentyl ring; or R1, which is attached to a hard atom to form a cyclopropane-ch2- (please read the back of the note first) page)

, 1T line - 303- This paper scale applies to China National Standard Tianjin (CNS) Λ 4 specifications (210X 297 mm by the Department of Central Bureau of Standards Bureau staff consumption cooperatives printed 1244843 A7 Γ —— ______ Β 7 5, invention description (3 〇 1) ^, a cyclobutyl or cyclopentyl ring; R1G7 is hydrogen; hydroxycarbonyl; lower alkyl, decyl, alkynyl, aryl, heteroaryl or aromatic; decyl; hydroxyalkyl; Oxyalkyl; lower alkyl alkanoyl, aryl, aryl, heteroaryl or aralkyl fluorenyl; lower oxycarbonyl carbonyl olefinoxycarbonyl, oxycarbonyl, aryloxycarbonyl, hetero An aryloxycarbonyl or a aryloxy group; a lower alkyl alkylthio group, an olefin thiol group, an alkynylthio group, an arylsulfonylthio group, a heteroarylsulfonylthio group, or an aralkyl fluorenylthio group; Lower alkylthio, sulfonyl, alkynylthio, arylthio, heteroarylthio or aralkylthio; aminemethanyl; alkoxycarbonylamine; or cyano; or R plus Rl() 0a and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl or cyclopentyl ring; or R107 and R114 plus a C7, C8 and C14 carbon atom to form a lactone; r1G8 is hydrogen, hydroxy, protected Hydroxyl Alkyl, alkyl, alkenyl, alkynyl, R O-'R 0C(O)〇-' or r140〇c(〇)〇-·' or a bond between C8&amp;C9 carbon atoms' when represented = and JM- represents _cr108-CR114; or represents a bond between C 8 and C 14 carbon atoms 'this when j_m_ represents _c==C_ and represents CR1G8-CR114-; R109 is hydrogen, hydroxyl, protected a hydroxy group, an alkyl group, an alkenyl group, an alkynyl group, R15°0-, R15°C(0)0-, or R15〇OC(0)0·; or a bond between the carbon atoms of €9 and C11, When -JL- represents -C two CRU1- and _J_J. represents -CR1G8-CR1G9; or represents a bond between C8&amp;C9 carbonogen, when small J- stands for -OC-, and -J_L- stands for CRm-CRiURUu · • 9 RU() is hydrogen or methyl; R疋 hydrogen 'meal base or protected sulphate' or plus 1 la to form ketone-304- This paper scale applies to Chinese National Standard (CNS) 210X 297 ^#! ~一...·__ (Read the first note on the back and fill out this page)

, 1T line _ 1248443 V. Description of the invention (302 ΑΊ B7 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printing Base, the restriction is -JL-representative-CRH) 9_CRlllRllla... and _l_l- represents when RU1 plus Rllla forms a ketone group When hydrogen is added or RU1 is added to form a ketone group, the restriction condition is _J_J_ for -CR R and -L_L- for -CRlnRllla-CH2-, when Rllla is added with RU1 to form a keto group; or the inverse 1113 is for C11 a bond between a carbon atom and a C9 carbon atom, when _j_L- represents bCRHi-, j_L_L- represents _CRiuRma_CH2_; or Han 111&amp; represents a bond between a carbon atom and a carbon atom, and when -LL- represents _CRni = CH- and -JL- represents _CR109R109a-CRluRln,; R114 is hydrogen, hydroxy, protected hydroxy, alkyl, alkenyl, alkynyl, Rl6G〇- 'r16〇C(0)0-, or R16G0C(O)O-; or R1"4 and Ri〇7 plus C7, C8 and C14 carbons form r-lactone; 4R114 represents a bond between c14&amp;C8 carbon atoms, when _j_M_ stands for -C = C_, and -Μ-M- represents -CR114-CH2; or R114 represents a bond between C14 and C15 carbon atoms, such that -MM· represents -OCH- and -JM- represents -CR1G8-CR114-; R118 is hydrogen, Alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylthio, alkylthio or cyano; R118 a is hydrogen, or a bond between C 18 and C 1 9 carbon atoms, -QT represents -CR118 = CR119- and -QQ- represents -CR119R119aXR12GR120a-; R119 is hydrogen, alkyl or sulfhydryl; R119a is hydrogen or represents a bond between C19 and C20 carbon atoms, when -QQ- Represents -CR12G = CR119- and -QT- stands for -CR119!^193. CRiuRU8a-; or represents a bond between ci9&amp;c18 carbon atoms, when -q_ 305 this paper scale applies to Chinese National Standard (CNS) Λ4 Orange (210X 297 public #) (Please read the note on the back and fill out this page) -δ Line 1 1244433 Printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs Α7 Β7 V. Invention Description (303) T stands for -CR119=CR118 · -QQ- represents -CR119R119a_CR12()R120a-; R12G is hydrogen' group, protected sulfhydryl group, or rl is added to form a keto group; the constraint is -QQ- stands for -CR119R119a_CR12()R12()a_, When R120 plus R120a forms a keto group; R12Ga is hydrogen, or R12G is added to form a keto group; the restriction condition is -Q_Q_ represents _CRn9Rll9axRl2〇Rl2〇a, When Rl2〇a plus r120 form a keto group; and R13G, R14G, R15G and r16G independently an alkyl group, an alkenyl group, the block group, an aryl group or a heteroaryl group. Preferably, the compound corresponds to a compound of the formula C-3, wherein R1G7 is hydrogen, a hydroxycarbonyl 'low carbon burnt group, a low carbon tiger base, a low carbon burnt oxygen base, a low carbon burnt sulfur base 'low so burned sulfur base 'Aminocarboxylic acid group' or R1 G 7 plus R1 G 6 a and a carbon atom with a mixture thereof form a cyclopropyl ring; R1G6 is hydrogen, a hydroxyl group, or a carbon atom bonded thereto and a carbon atom bonded thereto to form a cyclopropyl group a base ring; a hydrogen, a hydroxyl group, or a carbon atom bonded thereto and a carbon atom to form a cyclopropyl ring; or &amp;1〇6&amp; plus R1G7 and a carbon atom adhered thereto to form a cyclopropyl ring; And R12G is a ketone group. The following definitions are used to discuss the 13,17-fused ring compounds disclosed in this case: ''Lower alkyl'' means an alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, second-butyl and tert-butyl, pentyl and hexyl. The group may be straight, branched or cyclic and substituted (particularly substituted by an aryl group), unsubstituted or heterosubstituted. The π low carbon decyl group means a group which is preferably derived from a linear alkyl group having 1 to 7 carbon atoms, and is adhered to the parent molecular moiety via a carbonyl group. More preferably, it is -306- Γ ________ ___ -— ^The paper scale applies to the Chinese National Standard (CNS) Λ4 specification (21〇Χ29?^#) (Read the first note on the back and fill out this page)

1248443 A7 -________ B7 V. INSTRUCTIONS (304) - A ^Methyl and ethyl ketone. The M low carbon agglomerated carboxyl group '' denotes a group which is preferably derived from a linear alkyl group having 1 to 7 carbon atoms and which adheres to an oxygen atom which is adhered to the parent molecular moiety via a carbonyl group. More preferred are oxime carbonyl, ethoxycarbonyl, isopropoxycarbonyl and n-hexyloxycarbonyl. ''Lower alkenyl π means an alkenyl group having 2 to 6 carbon atoms such as a vinyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, a second-butenyl group, and a second-butene group; Base, pentenyl and hexyl. The group may be straight or branched and substituted, unsubstituted or heterosubstituted. "low carbon fluorenyl, and" lower olefinoxycarbonyl, 'and π low carbon sulfonyl" and "low carbon alkoxycarbonyl" are defined in the same manner, except that they are derived from linear alkenyl rather than straight Preferably, the oxygen attached to the sulfhydryl group of any oxime carbonyl group can be separated from any unsaturated carbon by at least one methylene group. Printed by the Central Bureau of Standards Bureau of the Ministry of Economic Affairs (please read the back first) Note: Fill in this page again. - Line &lt; Low stone anti-blocking group means a block with 2 to 6 carbon atoms, such as an alkenyl group, a propyl group, an isopropynyl group, a butynyl group, an isobutyne. a group, a second-butynyl group and a third-butenyl group, a pentynyl group and a hexynyl group. The group may be a straight or branched chain, and substituted, unsubstituted or heterosubstituted." Low carbon block fluorenyl group "And, low-carbon alkyne-based "' and ', low-carbon calcined thiol" and ''low-carbon alkoxycarbonyl, respectively, in the same way, I'm apart from the bamboo-to-direct bond block rather than straight Bond base. Preferably, the oxygen attached to the alkynyl group of any block oxycarbonyl group is separated from any unsaturated carbon by at least one methylene group. The aryl&apos;'s moiety preferably contains, or a variety of substituents, 5 to 15 atoms, and includes a phenyl group. ''Low-Carboalkylthio group' means better derived from a linear burnt-307 with 1 to 7 carbon atoms. This paper scale applies to the Chinese National Standard (CNS) Α4 specification (1 - 1 - A7 1248443 ______________ B7 5 The invention is directed to a group of (305) groups which are bonded to the parent molecular moiety via a sulfur atom. Particularly preferred is a methylthio group. ''Low-carbon fe-thiol' means a better derivative from 1 to a group of a straight-bonded alkyl group of 7 carbon atoms which adheres to a carbonyl group which is attached to a parent molecular moiety via a sulfur atom. More preferably, it is an ethyl thiol group. π lower alkenyl sulfide And π-lower olefin sulfonyl sulphur &quot; and "lower alkyl thio," and "lower alkyl sulfonyl thio" are defined in the same manner, except that they are derived from linear homing rather than linear fe Preferably, any sulfur atom of a mercaptothio group has at least one methylene group separated from any unsaturated carbon. M lower alkynylthio group and ''lower alkyne thiol group' and 'lower alkyl alkane sulfur The base, and, and the low-stone thiol group M are each defined in the same manner except that they are derived from a linear block group rather than a linear alkyl group. The sulfur atom of the sulfur group is separated from any unsaturated carbon by at least one methylene group. The n-amine methyl group π indicates that the -NH2 group is adhered to the parent molecular moiety via a carbonyl group. The amine carbenyl group may be mono- or disubstituted. And the substituent may include an alkyl group, an alkenyl group, an alkynyl group and an aryl group. The group defined above may be unsubstituted or additionally substituted. This additional substituent may include an alkyl group, an alkenyl group, an alkynyl group. , aryl, heteroaryl, carboxy such as alkoxy, carboxyalkyl, decyl, decyloxy, _ such as chloro or fluoro, _alkoxy, nitro, amine, decyl, and keto. As defined above, as well as additional substituents, it may also contain oxygen, sulfur, phosphorus and/or nitrogen. As used herein, "Me," means methyl, 'ΈΓ denotes ethyl; and 'Ac," denotes an acetate group. In still another preferred embodiment, the compound is selected from the group consisting of -308-^^---, . _ _- . ^ ^ ' ' TL &quot; ΜΙ _Ι·_&lt;Μ_1 —— applies to the paper scale China National Standard (CNS) Λ4 specification (210 X 297 public &quot; one (please read the note on the back and fill out this page again), 11 line one The Ministry of Economic Affairs, the Central Bureau of Standards, staff consumption cooperatives, printed together 1248443 A7 B7 V. Inventions (3〇6) Compounds:

(05);

(C-6); (Read the first note on the back and fill out this page)

(07); Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs

(C-8); -309- This paper scale applies to China National Standard (CNS) Λ4 specification (210X 297 public #) 1248443 A7 V. Invention description (307

(C-9);

(O10); (Please read the notes on the back and fill out this page.

(C-ll);

(C-12); Line - Printed by the Ministry of Economic Affairs, Central Standards Bureau, Staff Consumer Cooperative

(C-13a) -310 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public f) 1248443 A7 B7 V. Invention description (308)

Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives

Where R 107

R

120 106 , R1G6a and as defined above. Preferably, Ri. 7 is hydrogen, hydroxycarbonyl, lower alkyl, lower alkyl alkoxy, lower alkoxycarbonyl, low carbon sulphur, low carbon sulphur, amine carbyl, or with R1G6a Attached to the carbon atom to form a cyclopropyl group; R1G6 is hydrogen, hydroxyl, or 311 - This paper scale applies to China National Standard (CNS) Λ4 规 orange '(210X297 public') Ministry of Economic Affairs Central Bureau of Standards Bureau employee consumption cooperative printing 1248443 A7 &quot;&quot; ------s_______________·. - . . '- __~ V. Description of the invention (309) R1〇6a and the carbon atoms adhered thereto form a cyclopropyl ring; Rl〇6a is Hydrogen, hydroxy, or a combination of R1G6 and a carbon atom to which it is attached form a cyclopropyl ring; or R1G7 and a carbon atom to which it is attached form a cyclopropyl ring; and Ri2 is a keto group. Further preferably, the compound is further equivalent to the compound of formula c-5. In still another preferred embodiment, the compound of formula C-3 is selected from the group consisting of the following compounds: 312- This paper scale applies to the Chinese National Standard (CNS) (21C) x 297 () Matters in the filling of this f

1248443 A7 137 V. Description of invention (310

(C-14) 3',4',5',17-tetrahydro-17 lux-methyl-3,5'-dionecyclopentyl [13R,17]-18-原雄-4,8,14 -3_-7 Han-carboxylate (C-15) 3',4,,5',17-tetrahydro-17 lux-methyl-3,5^dionecyclopentyl [13R,17] - 18-原雄-4,8,14-tris-7-π-carboxylate

(C-16) 3,4',5,,17-tetrahydro-170-methyl-3,5'-dione cyclopenta[1311,17]-18-protox-4,8,14-three Alkene-7 π-carboxylate

(C-17) 3',4',5',17-tetrahydro-17;5-methyl-3,5'-dionecyclopentyl [13R, 17]-1 8-prostagland-4, 8,14-tris-7-carboxylate 1-methylethyl ester

Printed by the Central Bureau of Standards and Bureau of the Ministry of Finance (C-18) 3,4,5',17-tetrahydro-17々-methyl-3,5'-dionecyclopentane [13R, 17]-18-原雄-4,8,14-Triene-7"-carboxylic acid 2-methylpropyl ester

3',4',5&gt;,17-tetrahydro-17々-methyl-3,5,dionecyclopentyl [13R, 1 7] -1 8-原雄-4,8,1 4-three Alkenyl 7α-carboxylic acid 1-methylpropyl ester 313- This paper scale applies to China National Standard (CNS) Λ4 gauge (210Χ 297 gong#) !248443 ί! A7 B7 invention description (31

(C-20)

3>4 2,5丄,17·tetrahydro-17A •methyl-cyclopenta[1311,17]-Ui_rV 4,8,14-tetrazole-7^-3⁄4铋 戍 戍 ( (021) 3, ,4,,5,,17-tetrahydro-17/?-methyl-3,5f-diketonecyclopentyl [13R,17] -18-原雄-4,8,14-triene-7 α - Carbaryl carboxylate

(C-22) 3',4',5',17-Tetrahydro-170-methyl-3,5'-diketocyclopentyl [13R,17] 18-原雄-1,4,8, 14-Tetraene-7,-carboxylic acid oxime ester °v:

a (C-23) 3,,4,,5,,17-tetrahydro-17/?-methyl-3,5,dionecyclopentyl [13R, 17]-18-protosan-1,4 , 8,14-Tetraene-7 α _ carboxylic acid propyl ester by the Department of the Central Bureau of Standards Bureau of Bureau of Consumer Cooperative Printing

3',4,5,,17-tetrahydro-17/5-methyl-3,5'-dionecyclopentyl [πΐ^Π]-18-原雄-1,4,8,14-four Ethene-7-carboxylate

(C-25) 3 Gan, 4', 5', 17-tetrahydro-17/? · formazancyclopentyl [13R, 17] -18: protamine-i, 4,8,14-tetraene- 7 1-methylethyl carboxylate

-31V This paper size is applicable to China National Standard (CNS) Α4 regulations (210X 297 public) (please read the notes on the back and fill out this page)

1248443 A7 B7 V. Description of invention (312)

3> 4', 5', 17-tetrahydro-17/?-methyl; , 5, Diketone cyclopenta [1311,17]-1 male-1,4,8,1 4 -tetraen-7-carboxylic acid butyl ester (C-27) . 3', 4', 5, 17 -tetrahydro-17; 5-methyl-3,5,-dione cyclopenta[13R,17] -18-prosogenic-1,4,8,14-tetraene-7 π-carboxylic acid 1-methyl Propyl ester

(C-29) 3',4',5',17-tetrahydro-17/?-methyl-3,5'-diketylcyclopenta[1;3r, 17J-18-原雄-M, 8,14-tetra-7-carboxylate (C - 2 8) 3',4',5',17-tetrahydro-17-methyl-3,5 - one self-contained [131^ , 17]-18-原雄-1,4,8,14-tetraene-7 with 2-carboxylic propyl carboxylate (please read the back of the note first and then fill out this page)

, 1T line, after the Ministry of the Central Bureau of Standards, the contract of the consumer cooperatives

l,2,4bR(4bR*),5,5aS*,7,7 aR*,8,9,ll,12bS*-dodecyl-7a,12b-dimethyl-10aR*-cyclopropanal [1 ]Luo and [l,6a-a]phenanthrene-3,10-dione 4bR(4bR*)?5,5aS*,7,7aR*,8,9,11,12,1258*-decahydro-7A , 12b-Dimethyl-10R*-cyclopropionic acid (1), and [1,6a-a]phenanthrene-3,l-dione-315- This paper scale applies to China National Standard (CNS) Λ4 specification (210X 297 public #) 1248443 A7 B7 V. Description of invention (313

(C-32) l,2,4bS(4bR*),5,5aS*,8,9,1 l,12,12bR*-dodecyl-73,12-dimethyl-1(^8*- Cyclopropanal (1) and [l,6a-a]phenanthrene-3,10-dione

(C-34) 2丨,3,,3'a α,4丨,6丨,10',1 Γ, 114",12',13'-decahydro-3,aR,3,a,l l 'a-Dimethyl-13'aR*-spiro[cyclopropane-1,7' (9Ή)-[1Η]Large and [l,6a-a] phenanthrene]-oxime,9·-dione

2',3',3'a ^ ,4f,6M l'a ^ ,12',13 丨-octahydro-3'aR,3,a,ll,a-dimethyl-13faR*-spiro[ring Propane-1,7,(9Ή)-[1Η]Mosusu[l,6a-a]phenanthrene]-oxime, 9'-dione

5 Ac (C-35) 7 α -(ethinylthio)-3',4·-dihydro-17-methyl-cyclopenta[13,17]-18-原雄-4,8,14- Triene-3,5·(2Ή)-dione (please read the notes on the back and fill out this page), - mouth line &lt;

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (C-36) 3',4',-Dihydro-17-methyl(methylthio)-cyclopenta[13,17]-18-原雄-4 8,14-triene-3,5,(2,in-dione

(C-37) 3',4,,5,5',6,17-hexahydro-17 cold methylcyclopenta[13R,17]-18-prostaglandin-4,8,14-triene-3 , 5'(2Ή)·Diketone-316- This paper scale applies to China National Standard (CNS) Λ4 gauge (210Χ 297 public f) 1248443 A7 B7 V. Invention description (314

(C-38) ^,4',5',17-tetrahydro-6〇/-yl group·1 7 cold-methyl-3,5,dionecyclopentane [13R,17j-18-原雄- 4,8,14-triene-7 π-acid

(C-40) 3',4,5',17-Tetrahydro-6"-hydroxy- 17/?-methyl-3,5'-dionecyclopentyl [13R,17]-18-原雄- 4,8,14· tris-7-α-carboxylate

(C-39) $',4',5',17-tetrahydro-6&lt;^-light-based 17/?-methyl-3,5,dionecyclopenta["3 R,1 7]-1 8-原雄-4,8,1 4 tris-7-π-decanoate

(C-41) 3',4,,5',17-tetrahydro-6-hydroxy- 17/?-methyl-3,5'-dionecyclopentyl [1311,17]-18-原雄-4,8,14· Triterpene-7 propyl carboxylate (please read the notes on the back and fill out this page)

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (C-42) 3W, 5', 17-tetrahydro-6 α -hydroxy-17/?-methyl-3,5,dionecyclopentane [13R,17] -18-原雄-4,8,14-triene-7α-carboxylic acid 1-methylethyl ester

(C-43) 3',4',5',17-tetrahydro-6^hydroxy-17-cold-methyl-3,5^dionecyclopentyl [13R,17]-18-原雄-4 , 8,14-Triene-7 α-carboxylic acid butyl ester line &lt; 317- This paper scale applies to Chinese National Standard (CNS) Λ4 specification (210Χ 297 mm) 1248443 A7 B7 V. Description of invention (315)

(C-44) 3',4,,5,,17-tetrahydro-6"-hydroxy·17Θ-methyl-3,5,dionecyclopenta[13R,17]-18-protosan-4, 8,14· Triene-7 α-Fusic acid 1-methylpropyl ester (C-45) 3 Gan',1',?',17-tetrahydro-170-formed bamboo shoot, pentylene n3R,17]-18 - Yuan Xiong. ^8,14-Tridiketone

(C-47) Tetrahydro-carbyldiene-7a-decanoic acid formazan (C-46) ^,4',5',17-tetrahydro-6;5-carbyl·Π/? -Methyl-3,5,dionecyclopenta[13R,17]-18_harasta-4,8,14-triene-7α-carboxylic acid Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperative Printed

(Read the first note on the back and fill out this page)

, 1T line! (C-48) 3',4',5',17-tetrahydro-6;5-hydroxy. 17/?-Methyl-3,5'-dionecyclopenta[13R,17]-18-原Male-4,8,14-triene-7π-carboxylate (C-49) 3,4,5',17-tetrahydro-6/?-hydroxy·17/?-methyl-3, 5'-Diketonecyclopenta[13R,17]-18-prostagland-4,8,14-triene-7α·carboxylate-318- This paper scale applies to Chinese National Standard (CNS) A4 Regulation Orange ( 210X29h&gt;f) 1248443 Α7 Β7 V. Description of invention (316)

(C-50) 3',4',5',17-tetrahydro-6/?-hydroxy-17/?-methyl-3,5f-diketonecyclopentyl [1311,17]_18-原雄- 4,8,14-triene-7α-carboxylic acid 1-methylethyl ester

(C-51) 3\4',5,,17-tetrahydro-17-cold-methyl-3,5'-dionecyclopentyl [13R,17] -18-原雄-4,8,14- Trien-7α-carboxylic acid cyclopentyl ester (please read the notes on the back and fill out this page)

, 1Τ (C-52) 3',4',5',17-tetrahydro-6/5-hydroxy-17/?-methyl-3,5'-dionecyclopenta[13R,17]-18 - 原雄-4,8,14-triene-7α-carboxylic acid 1-methylpropyl (C-1) 2,2,3a,4,6,7,9,10,l 1,1 la, 12,13-dodecahydro-3 π Θ,1 1 π 0 -dimethyl-1,9-dione-1 fluorene-[L,6a-a]phenanthrene-6-carboxylate

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (C-53) 3',4',5',17-Tetrahydro-6/?-hydroxy-17/?-methyl-3,5,dionecyclopentyl [1 3R,1 7] -1 8-原雄-4,8,14-triene-7 α-carboxylic acid butyl ester This paper scale applies to China National Standard (CNS) Λ4 gauge (210Χ 297 public f ) 1248443 A7 V. Description of invention (317

V ^ w 1 ) - internal vinegar, cyclopenta [13,17]^8/originyl]7-methyl-3,5,-dione 4,9 (1 1 )-dioxin

(Please read the notes on the back and fill out this page) (C-202) [13S,17A ]-3',4,Dihydro-3-hydroxy-9 17 1,3,5(10)-triene_ 5丨[2丨HL]•ketone soil'17. Methylcyclopenta[13,17] gonads-

, 1T

(C-203) fl3S,17/5]·3\4'-dihydro-3-hydroxy-9,17· 1,3,5(10),6-tetraene-512Ή]-ketodimethyl ring E. [13,17] gonads - Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs

(C-204) -320 This paper scale applies to China National Standard (CNS) Λ4 specification (210X 297 public f) 1248443 A7 V. Invention description (318) In the best concrete example, you are a good person. 2,2,3a,4,6,7,9,10,U,Ua 12,13-dodecane-3 a ,U α p _Dimethyl A a, 7 methyl-1,9-dione- 1H-茂笑# [l,6a-a]phenanthrene-6-carboxylate: Asian

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, Consumers' Cooperatives (C-1): Compounds of formula C-1 are prepared for the preparation of epoxy meclizine. The novel compounds discussed in this column may also be in the form of their salts. . HMJi: Preparation of a Compound As described above, the above novel compound can be obtained by reacting a steroid having a ruthenium ring and a steroid core as described above with a tribasic alkanoic acid. Advantageously, the reagent in the reaction may further comprise an alkali metal salt which utilizes an alkanoic acid. Particularly preferred reagents for the reaction include trifluoroacetic acid and an alkali metal salt of the acid, such as potassium trifluoroacetate. Further, a desiccant such as difluoroacetic anhydride is preferably used in the reaction to reduce free water present in the acid. The steroid compound to be used as a starting material preferably has the following structural formula:

(03) (Please read the notes on the back and then fill out this page) -321 μ's Zhang-scale towel, Guanjia County (CNS) A4~210X297) 1248443 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Print A7 __ ' 1 '一一&quot;-&quot;&quot;一一一. _ __ V. Invention description (319 ) where - eight-eight, -〇-0,44-,-eight 4-,-〇-〇-, small -, -!^[-, small L- ' -MM- ' -JM- ' -QQ- ' and -QT- are defined as above. Such a starting material can be prepared and/or isolated analogously to the process described above for the process of synthesizing methacrylone. In addition, the starting materials are commercially available. The initial concentration of the steroid compound of formula C-3 is preferably at least about 0.1% by weight of the total reaction mixture, preferably from about 2% to about 20% by weight, and more preferably from about 5% to about 5% by weight. meter. It is preferred to have an excess of the tri-alkanoic acid. When difluoroethyl is used, it is present in a proportion of at least about 3 〇/0 of the total reaction mixture, preferably from about 5% to about 25% by weight, more preferably from about 5% to About 1 5 % by weight. In addition, the reaction temperature should exceed room temperature (22 ° C). Preferably, the reaction temperature is between about 40 ° C and 100 ° C, preferably between about 50 ° C and 80 ° C, and more preferably between about 6 ° C and 70 ° C, and preferably about 6 〇 ° C and 6 5 Ό. Increasing the reaction temperature to above 70 °C increases the amount of by-product c 14 lactone produced in the reaction. The reaction time should be at least about 30 minutes, preferably about 30 minutes and about 6 hours, more preferably about 45 minutes and about 4 hours, and more preferably from about 1 hour to about 2 hours. In a preferred embodiment, the reaction time is between about 1 hour and 2 hours, and the reaction temperature is maintained at about 6 Torr. Your majesty. The mud rig S-1 describes the specific examples of this process: Process S - 1 (Please read the notes on the back and fill out this page)

Line I 〇

1248443 A7 B7 V. INSTRUCTIONS (320) Central Bureau of Standards of the Ministry of Economic Affairs – Completion of Consumer Cooperatives condensed cycloalcohols with different substituents at different positions throughout the steroid can be prepared as shown in the following reaction scheme. Artisans should be aware of the different processes that lead to the introduction of various substituents to human sterols – some of which are not specifically disclosed. The starting material may be a fused ring steroid or a 2&quot; alkane producing steroid. When the starting material is a fused ring-like solid _, for the sake of simplicity, the following: The steroid-specific group and the specific (tetra) alcohol should be used as the starting materials for the description. However, it will be appreciated that the use of different fused ring steroids as starting materials in the same reaction series may result in the formation of other fused ring (tetra) alcohol-derived compounds. Similarly, when the starting material is a 20-spirostane steroid, some specific 2G-spirocyclic steroids can be used as a starting material for the sake of simplicity. However, it is understood that the use of different 20-spirooxane steroids as starting materials can produce other homologues of the steroidal steroid derivatives in the same reaction series. A steroid having a C7 carboxylic acid substituent may be prepared by sterolation of a steroid having a c7 alkoxycarbonyl substituent, such as a compound of formula (b). The M匕 action is carried out by treating the starting steroid with a basic agent such as sodium hydroxide or potassium in a suitable agent such as methanol, ethanol, isopropanol or the like at a temperature up to the boiling point of the solvent, and There may be or no water present. As described in Scheme 2, the saponification of the compound of formula C_1 can produce a carboxylic acid of the formula "." A steroid having a C7 group: a vinegar substituent (other than a formate), which can be an acid such as C-101. Prepared from the starting material. The carboxylic acid is treated with an alkylating agent such as alkyl li in the presence of a base (such as sodium bicarbonate, sodium carbonate, potassium hydrogencarbonate or diethylamine) in a reagent such as dimethylformamide. Examples of oximation agents suitable for the formation of the desired ester include ethyl iodide, ethyl bromide, isopropyl iodide, and the S-skinny-323-sheet paper scale applicable to the Chinese National Standard (CNS).

Λ4 regulation Taiwan (210X 297 public f) 1248443 Ministry of Economic Affairs Central Bureau of Standards Bureau staff consumption cooperatives printed t Α7 137 V, invention description (321) iodine, benzyl bromide, allyl iodine and so on. Carboxylic acid C-101 is also a suitable starting material for the synthesis of amine formamidines. The acid is treated with a chloroformate such as isobutyl chloroformate or ethyl benzoate to form a mixed anhydride in the presence of a base. The mixed anhydride is treated with an amine such as dimethylamine, methylamine or benzylamine to form an amine formazan wherein 1 and 112 are substituents on various amines. Process S-2

Using an unsaturated ketone, such as the compound of formula C-105 (shown in Scheme S-3) as a starting material, many changes can be made at the C7 position. Sulfides can be synthesized by adding a suitable thiol under alkaline conditions. Examples of suitable mercaptans are methyl mercaptan, ethyl stone, and others. Suitable tests include hexahydro-p-precipitate, triethylamine, and the like. Treatment of unsaturated ketones with thioic acid such as indoleacetic acid (eg compound of formula C-i05), -324 - i paper scale applicable to Chinese national rate (CNS) ΛϋΓ (21〇χϋ«Π --------- -------- (Please read the notes on the back and fill out this page), - mouth 1244843 A7 B7 Ministry of Economic Affairs Central Bureau of Standards Bureau of Staff Consumer Cooperatives Printing 5, invention description (322) can generate C 7 sulfur brewing a compound such as an ethyl thiol group. The fused C 6, C 7 cyclopropyl substituent may be added by treatment with an unsaturated ketone (a compound of the formula C-105) in the form of dimethyl sulfoxide, the latter being formed. It is produced by treating the trimethylammonium with a suitable base (such as sodium hydride) and is carried out in a suitable solvent. These various synthetic schemes are illustrated in the next Scheme S-3: Scheme S-3 η ^

-325- This paper size is applicable to China National Standard (CNS) Λ4 (210Χ 297 public f) (please read the notes on the back and fill out this page)

1T 1248443 —---------- 扪 V. Inventive Note (323) — --- The steroid having a C6 spirocyclopropyl ring is synthesized according to the procedure described in Scheme s_4. The compound of the formula C-110 is first protected as a material, and is treated with an orthoester in the presence of an acid (e.g., p-toluenesulfonic acid), such as tribasic orthoformate or _@@0. The resulting enol ether is treated with a Vilsmeier reagent which is produced by the addition of phosphonium chloride to dimethylformamide in situ to form a methylidene compound, such as a compound of formula c.112. The formic acid group can be reduced by a chloride reducing agent such as a tri-tertiary-butoxy-hydrogenation clock in a solvent such as tetrahydrofuran. This produces an intermediate alcohol which, upon treatment with an acid, removes water to form a 6-methylene compound, such as a compound of formula c_n3. Suitable acids include hydrochloric acid in an aqueous medium. Treatment of the 6-methylene compound with diazomethane produces the intermediate pyrazoline which, upon heating, decomposes to form the product spirocyclopropyl compound, such as a compound of formula C_u4. The protected enol ether (such as the compound of formula C_ln) is a variable intermediate and treated with a hydride reducing agent (such as sodium borohydride), followed by acid hydrolysis to form a hydroxy compound, such as formula C-115. C-116 compound. These various synthetic steps are described in the following process S-4: (Please read the notes on the back and fill out this page) I - - m 11 -- · Ordering a Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printing 32 Moderate Sheet of paper I is a standard one

Each \4 S N public 1248443 A7 V. Invention description (324) Process S-4

NaBH, (please read the notes on the back and fill out this page)

, 1T POC I 3 - Atenor

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs

-Line one 327- This paper scale applies to China National Standard (CNS) A4 Regulations (210X 297 mm)

1248443 ____B7 V. INSTRUCTION DESCRIPTION (325) A leaven having a C6 hydroxy substituent and a C7 ester substituent can be synthesized according to the procedure described in Scheme S-5 below. Protecting an ester (such as a compound of formula cl) on a C 3 carbonyl group using an orthoester such as triethyl orthoformate or trimethyl ester to form a 3,5-dodecanol ether in the presence of an acid (eg, a compound of formula C-117) ). A suitable acid is para-toluenesulfonic acid. Treatment of the enol ether with an oxidizing agent, such as chloroperoxybenzoic acid, can result in the formation of light-based compounds such as the compound of formula C-118. Process S-5

Oxidation Scheme S-6 illustrates the introduction of double bonds at the C1-C 2 position of the steroid. In order to carry out this process with a suitable oxidizing agent, such as dichlorodicyanobenzoquinone, the desired steroid (such as the formula, c-108 and C-114 compounds) can be treated in a suitable solvent (such as diazane). Boiling point. A C1-C2 unsaturated compound such as a compound of the formula C-127, C-128 and C·129 can be prepared by this procedure. (Please read the notes on the back and fill out this page)

, 1T - Line _ Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperative Print -328- This paper scale applies to China National Standard (CNS) Λ 4 gauge (210X 297 mm) 1248443 A7 B7 V. Invention Description ( 326 Process S - 6

(Please read the notes on the back and fill out this page)

1T Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperative Printing Process S-7 describes the introduction of double bonds into the fused ring. A steroid (e.g., a compound of formula c_n4) is treated with an orthoester (e.g., triethyl or trimethyl orthoformate) in the presence of an acid catalyst (p-toluenesulfonic acid) to form an enol ether wherein the C3 carbonyl is protected. In the formula C-114, since the C6 position is completely substituted, the enol ether formed is a C2-C3# alcohol ether (e.g., a compound of the formula CM3 1). Treatment of enol ethers with strong bases, such as lithium diisopropylamide, at low temperatures such as -78 ° C to -30 ° C, -329- This paper scale applies to Chinese National Standard (CNS) A4im (210X297^11 ——一- Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing 1244843 Γ ______ B7 V. Inventions (327) — ——~ — Treatment with selenizing agents, such as phenylselenyl chloride, can produce seleno derivatives A compound of the formula C-132. The selenium derivative is oxidized with an oxidizing agent, such as hydrogen peroxide, in the presence of a base such as pyridine in a solvent such as dichloromethane to cause selenium elimination and introduction of double bonds. Hydrolysis of the enol ether produces a ketone, such as a compound of formula C-134. Scheme S-7

Scheme S-8 illustrates the double bond isomer of a synthetic C-oxime compound. Various spirodecane compounds, as shown in Scheme S-8, are treated with potassium acetate, trifluoroacetic anhydride and trifluoroacetic acid. Under the conditions of the synthesis of a similar c-oxime compound, a can form formula C-121 and C-123 compound. -330- This paper size applies to Chinese National Standard (CNS) Λ4 specifications (210Χ 297 公漦 (Read the first note on the back and fill out this page)

, 1T 1248443 A7 B7 V. Description of invention (328) Process S-8

(Please read the notes on the back and fill out this page.) Scheme S-9 describes an additional method for the synthesis of double bond isomers in such sterol groups. Starting from a preformed ketene (such as a compound of formula C-24, which is synthesized as described above) and having a fused ring, the chemistry of a compound such as formula C-108 and C-109 can be synthesized by the above Scheme 3, and C6-C7 can be introduced. Fused cyclopropane. Process S-9, - Port Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs

331 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 public f) 1248443 A7 B7 V. Description of invention (329) A fused ring steroid with aromatic A ring, which can be trifluoroacetic acid, potassium acetate and Trifluoroacetate treatment is prepared as described in P. Compain, et al., Tetrahedron, 52 (3 1), 10405-10416 (1996), which is incorporated by reference in its entirety, in accordance with Scheme S-1. In substantially the same way. These novel fused ring steroids have an aromatic A ring and a 3-hydroxy substituent which are expected to undergo all of the typical chemical reactions of phenols. Scheme S-10 illustrates the synthesis of 3-phenol ether from this fused ring steroid. In particular, treatment of these phenolic compounds with bases and alkyl i or sulfonic acid alkyl esters is expected to result in comparable esters. See, for example, Feuer and Hooz, In The Chemistry of the Ether Linkage. Patai (Ed.), Interscience: New York, pp. 446-450, 460-468 (1967); and Olson, WT., J. Am. chem Soc·· 69, 2451 (1947); it is listed as a reference for this case. Process S-10 (Please read the notes on the back and fill out this page)

, 1T

Printed by the Ministry of Economic Affairs, Central Bureau of Staff, Consumer Cooperatives Similarly, Scheme S-11 illustrates the synthesis of 3-phenol esters from fused ring steroids having aromatic A and 3-hydroxy substituents. In particular, treatment of these phenolic compounds with carboxylic anhydrides or with carboxylic acid halides is expected to produce comparable phenolic esters. See, for example, March, J., Advanced Organic Chemistry. Wiley: New York, pp. 346-347 (1985), which is incorporated herein by reference. -332 - This paper size is applicable to China National Standard (CNS), νΐ规柏(2l〇'x297 公f) 1248443 A7 B7 V. Invention Description (330) Process S-11

Scheme S-12 illustrates the synthesis of a 3-phenolic carbonate from a fused ring steroid having an aromatic A ring and a 3-hydroxy substituent. In particular, treatment of these phenolic compounds with alkyl halocarbonates is expected to produce comparable phenolic carbonates. See, for example, March, J., Advanced Organic Chemistry, Wiley: New York, pp. 346_347 (1985), which is incorporated herein by reference. Process S-12 (Please read the notes on the back and fill out this page)

, 1T

Printed by the Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Process S-13 illustrates the synthesis of ortho-allyl substituted phenyl derivatives from fused ring steroids with aromatic A and 3-hydroxy substituents. In particular, these compounds are self-treated with bases and allyl groups and are expected to produce comparable allyl phenyl ethers. The allyl phenyl ether should form a mixture of ortho-allyl substituted derivatives under thermal rearrangement. See, Shine, H., J. Aromatic -333- This paper scale applies to the Chinese National Standard (CNS) A4 (210X 297 public i) 1248443 A7 137 V. Description of invention (331)

Rearrangements: Reaction Mechanisms in Organic Chemistry, Monograph 6. American Elsevier: New Yor? pp. 89-120 (1967), which is incorporated herein by reference. Process S-13

Printed by the Employees' Consumer Cooperative of the Central Bureau of Standards of the Ministry of Education (please read the notes on the back and fill out this page). Flowchart S-14 shows the synthesis of the ortho-position by a fused ring steroid with an aromatic A ring and a 3-hydroxy substituent. Dialkylated substituted phenyl derivatives. In particular, treatment of these compounds with alcohols and acids is expected to provide comparable ortho-dialkylated phenyl derivatives. See, for example, Calcott, W_S., J. Am. Chem. Soc. 61, 1010 (193 9), which is incorporated herein by reference. -334- This paper scale applies to China National Standard (CNS) Λ4 gauge (210X 297 public f) 1248443 A7 B7

V. Description of the invention (332) Process S-14

Scheme S-1 5 illustrates the allyl oxidation of a fused ring steroid having an aromatic A ring and a 3-hydroxy substituent. In particular, these compounds are oxidized at the allyl position and react with selenium dioxide and a third-butyl hydroperoxide to form a comparable alcohol. Dehydrogenation of this alcohol produces comparable olefins. See, for example, Schmuff, N.R., J. Org. Chem. 48, 1404 (1983), which is incorporated herein by reference. (Please read the notes on the back and fill out this page)

, 1T Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing Process S-15

-335- This paper scale applies to Chinese national standard (〇奶)/\4规桔(210/297公#) 1248443 A7 B7

(: kiss 3α 5. Inventive Note (333 Scheme S-16 illustrates the action of the novel fused ring steroid oxime carbonyl group of the present invention and the reduction of 20-carbonyl group. Tes, ^ Bamboo. Further, these compounds are triterpene. The orthoformate and the acid react to form an enol. The 3-enol ether can be reacted with sodium borohydride to reduce the C-20 carbonyl group to a comparable C-20 alcohol. The C-20 alcohol is acid. And water treatment, can make 3-sterol acid to promote the shape of the tank, and form a 3-keto derivative. Process S-16 (please read the notes on the back and fill out this page)

The Central Standards Bureau of the Ministry of Economic Affairs, the Consumer Cooperatives Printing Process s-n, illustrates the chlorine action of the key linkages in the novel fused ring steroids of the present invention. In particular, hydrogenation is expected to proceed step by step. C_6, c_7 double saturated, then saturated C8, C-14 double bond. ___ - 336 · This paper scale applies to Chinese national standards (cns key 1248443 A7 B7 V. Invention description (334) Process S-17

(Read the first note on the back and fill out this page), \呑 Printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs. Process S-1 8 illustrates the rearrangement of the protected 11 ^ _ hydroxy fused ring steroid of the present invention. In particular, the 1 1 α -hydroxy group of the compound is first protected with a suitable protecting group such as 2-methoxyethoxymethyl ether (MEM ether). Treatment of the protected 11^-hydroxysteroid with a metal salt and a trihaloalkane in the presence of acid fiber is expected to result in rearrangement of the lactone moiety in these molecules, as described below. The rearranged alcohol can be proposed by removing the MEM ether from zinc bromide. -337- This paper size applies to Chinese National Standard (CNS) Λ4 Specifications (210X 297^$) 1248443 A7 B7 V. Invention Description (335 Process S-18 u

.,〇

MEMC I

(Please read the notes on the back and fill out this page)

, 1T

MEMC I Alkali Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed

-338- This paper scale applies to Chinese National Standard (CNS) Regulations (210X 297 public f 1248443 V' invention description (336 A7 锃S- 1 9 illustrates the novel fused ring steroids of the present invention 3 _ carbonyl protection and 19 _Position &lt; Burning effect. In particular, the compound is first converted to 3 _ $ allyl ether, as described in Scheme s_16. The lithium isopropyl amide (LDA) is a 3-alkyl sterol ether. Further treatment with an alkyl halide can form an i9-alkyl derivative. Hydrolysis of the 3-alkyl enol ether protecting group can produce a 3-keto derivative. Scheme S-19

C R03.CH

(Please read the notes on the back and fill out this page)

1T Line 1 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economics Process S-20 illustrates the conversion of estrone methyl ether to equivalent spironolactone. The rearrangement of the lactone to a comparable fused ring steroid occurs when the lactone is treated with tris-hydrogenating acid, preferably in the presence of the alkali metal salt of the alkanoic acid utilized, under the reaction conditions previously discussed. See, for example, Otsube, K., Tetrahedron Letters· 27 (47), 5763 (1986) ° -339- ‘paper scale applicable to Chinese national standard (CNS) Λ4 rule orange (210X297 public # 1248443 A7, invention description B7 process S-20

^Methyl ester

Printed by the Ministry of Economics, the Central Standards and Consumers Association

The new compound can be further accepted by the previously described biotransformation process to produce another S, an additional novel fused ring steroid of the adult, such as having 9, 9 11 or 11 o-hydroxyl substitutions. Base steroids, as well as other hydroxylated fused dog sterols. On the right side, the steroid can be oxidized by the elimination of a few substituents, and a hydrazine is introduced into a chain double bond, such as a bond. Based on the above, it can be seen that many of the objects of the present invention can be achieved and other beneficial results can be obtained. There may be many interlacings in the above composition and method without departing from the scope of the invention. All matters intended to be included in the above description are for illustrative purposes only and are not intended to be limiting. The following non-limiting examples are used to illustrate various aspects of the invention. · fm χ-iA -340- This paper scale applies to China National Standard (CNS) A4 (210x 297&amp;§_ (please read the notes on the back first) Fill in this page)

1248443 A7 ______ B 7 V. INSTRUCTION DESCRIPTION (338) Methyl-1,9-diketo-1H-Lando[l,6a-a]phenanthrene-6-carboxylate (Compound C-1) ·

Potassium acetate (6.7 grams, 7.1 moles; Sigma_Aldrich 5128LG) was added to the clean and dry reactor equipped with a mechanical stirrer, condenser, hot dipole and heating mantle. Trifluoroacetic acid (25 ml, 8.1 mmol; 8丨811^-八1(11^117125]^0) and trifluoroacetic anhydride (4.5 ml, 31.0 mmol); sigma were successively added to the reactor. -Aldrich 1 1828PN). The solution is maintained at 30 ° C for 30 minutes at -30 ° C. The preformed TFA / TFA anhydride reagent is added to 5.0 g (9.6 Torr) 17-hydroxy-11α- (methyl Continued thiol) Oxygen-3_酉 with pregnancy-4_#-7α, 21-dicarboxylic acid 7 · methyl ester, cadaveric lactone: (Please read the back of the precautions and then fill out this page), 1Τ Central Standards Bureau, Bayer Consumer Cooperatives

It was prepared as described in Example 36. The resulting mixture is heated at 6 _ _ -341 - This paper scale applies to China National Standards ^ (CNS) I. 1248443 Printed by the Central Bureau of Standards and Staff of the Ministry of Consumer Affairs A7 B7 V. Inventions (339) 60 minutes 'conversion The degree is checked periodically with tlc and/or HPLC. When the reaction was complete (about 60 minutes), the mixture was transferred to a one-necked flask and concentrated under reduced pressure of 5 Torr until it became thick. The resulting slurry was diluted with a mixture of 150 ml of ethyl acetate and 8 ml of water/brine. The phases were separated and the aqueous layer was extracted with ethyl acetate (EtOAc). The salt concentration is 12% by weight. The combined ethyl acetate solution was washed once with 12 〇/〇 by weight of brine (80 ml) of 'IN NaOH solution (80 ml) and the last 12% by weight of salt water (80 liters). The mixture was allowed to stand to separate the phases, and the separated ethyl acetate layer was concentrated to dryness under reduced pressure at 45 ° C to give about 38 g of crude solid product using a water. HPLC analysis of the crude product showed the product to contain about 40% of compound C-1. The solid product was then purified by chromatography. Chromatographic purification yields 21 mg of 2,3,3&amp;,4,6,7,9,10,11,11-strong,12,13-dodecane-3&amp;5,11-strong/?-two Methyl-1,9-diketo-1H-moxasuto[l,6a-a]phenanthroline-6α-deoxymethyl ester (Compound 1) 睹 睹 睹 示 380 380 380 380 380 380 380 380 380 380 380 380 The data is known as 〇24^28〇4. The mass spectrum of £1 has 1!1/2 3 80]\4+ ridge. 八?(:1 mass spectrometer at 111/:2 381 (MH)+ and m/ z 398 (MNH4) + has a peak. Carbon and hydrogen analysis is consistent with the speculated molecular formula. IR spectrum has two fronts in the carbonyl absorption zone: 1722 cm-1 and 1677 cm-1. 1722 cm-1 peak belongs to a carbonyl group, because the 13c NMR spectrum has a signal at j 217.7, which is due to the unsaturated ketone, and at j 172·7, because of the methyl carbonyl group. There is no 1773 cm in the IR spectrum. Part. -342·

This paper scale applies to China National (CNS) (2—&gt;i 1 &quot;一-—~~ ----— _I (please read the notes on the back and fill out this page)

1T 1248443 Α7 Β7 V. Inventive Note (340) 13C APT and HETCOR NMR data show the presence of the following types of carbon: 3 carbonyl groups (d 217.7, 198.4, 172.2); 4 fully substituted chain ruthenium carbons (J i66. 3,141.8,139.3,121.8); 2 methine carbons (d 124.9, 122,0); 3 quaternary aliphatic carbons (d 61.1, 50.7, 39_7); 1 sub-methyl aliphatic carbon 43_3) 8 methylene carbons (d 46.0, 37.5, 34.1, 33.3, 32.9, 31.9, 23.7, 22.2); and 3 methyl carbons (d 51.9, 23.6, 23.1).

Example X-1B Preparation (7 a,13R,17 cold)-3',4',5',17·tetrahydro-14-3⁄4yl-17-methyl-3,5,-dione-indole Lactone, cyclopenta[13,17]-18-prostaglandin-4,9(11)-di-consin-7-skin acid (Compound C-201): (Please read the notes on the back and fill out this page)

Potassium acetate (8.9 g, 90 mmol), trifluoroacetic acid (150 ml, 1 48 g/ml) and trifluoroacetic anhydride (33 ml, 1.487 g/ml) printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs. Add to a 25 ft. round bottom reactor equipped with a mechanical stirrer, condenser, and heating mantle. The resulting solution was stirred at 25 ° C to 30 ° C for about 10 minutes. The preformed TFA/TFASf reagent is added to 15 g (30.0 mmol) of n with a certain _ 11α-(methyl-g-g)-oxy-3-yl-keto-17α·pregna-4-ene-7 - 二_酸7-甲酉的,r-内酉:-343- This paper scale applies to China National Standard (CNS) ϋϋϋιοχϋ#Τ 1248443 A7 —__________ ----————— — B 7 V. Description of invention (34!) —^—~一—

It was prepared as in Example 36. The resulting mixture was heated at about 6 〇 7 (rc) for about M. 5 hours. This mixture was concentrated under reduced pressure at 5 Torr to give a thick slurry. The slurry was dissolved in 1 liter of ethyl acetate. Then, wash twice with about 2% water/salt water (80 ml each), (7) sputum sodium oxide (8 liters), wash &quot; owe, then wash with about 2% water/saline (80 ml) The crude product was dried over magnesium sulfate. 'Filtered and concentrated to give about 8 g of crude wet material. This material was purified twice by column chromatography to yield about 3 g of pure (7 Ll3R, 17 L) - 3',4',5',17-tetrahydro-14_hydroxy-17-methyl-3,5,-dione-based Γ-lactone 'cyclopentane[13,17]_18-原雄-4 9(11)-diene-7-carboxylic acid (Compound C-201). Example X-1C Preparation of [13S,17々]-3',4,-dihydro-3-hydroxy-9,17-dimethyl Cyclopenta[13,17] gonad-1,3,5(10)-triene-5,[2Ή]-one (Compound C-202): (Please read the note on the back and fill out this page) 11 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs

-344 - _ This paper uses Chinese national standard (CNsTAolfe (210X 297 gong i T 1248443 A7 B7 V, invention description (342) acetic acid unloading (6 g, 61. 丨 millimoles), trifluoroacetic acid (15 〇 ml, 148 g/ml) and trifluoroacetic anhydride (26 ml, 1.487 g/ml) were added to a 25 ft. round bottom reactor equipped with a mechanical aspirator, a condenser, and a heating mantle. At about 2 5 C - 3 0. (: Katan fell about 1 〇 minutes. 'Preformed TFA / TFA anhydride reagent added to i 5 grams (43 7 亳二酉同基-17 ^pregnant H21-skin acid,卜内酉(also known as aid g叫 g d. Searle &amp; Co.):

(Please read the notes on the back and fill out this page)

1T The Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives printed the mixture to heat about 6 〇Ό -70 约 for about 5 hours. The reaction mixture was concentrated under reduced pressure at 50 ° C to give a thick slurry. The slurry was dissolved in 1 ml of ethyl acetate and washed twice with about 20% water/saline (8 liters each), 1N sodium hydroxide solution (80 ml), and then about 2 〇. Wash 1 time with water/saline (8 ml). The crude product was dried over magnesium sulfate, filtered and concentrated and dried to dryness <RTI ID=0.0> This material was purified twice by column chromatography to yield about 125 g of pure [138,17/?]-3',4,-dihydro-3-lightyl-9,17-dimethylcyclopenta[ 13,17] gonad - 1,3,5(1〇)-dioxa- 5*[2Ή]-one (Compound C-202). Example X-lg Preparation of [13S,17 0 ]·3',4'-dihydro-3-3⁄4yl'17-dimethylcyclopenta[13,17] _-345- The paper scale is in Guanjia County (CNS) λ4^Μ 210X 297^ f 1248443 A7 B7 η' 丨丨_| II 一--**-*私Μ·—— - ····..:·. V. Inventions (343) Gonad - 1,3,5(10),6-tetraene-5'[2Ή]-one (Compound C-203):

Potassium acetate (6 g, 61.1 mmol), trifluoroacetic acid (150 ml, 1.480 g/ml) and trifluoroacetic anhydride (26 ml, 1.487 g/ml) were added to a 250 ml round bottom reactor equipped with There are mechanical stirrers, condenser pipes and heating hoods. The resulting solution is stirred at about 25 ° C to 30 ° C for about 1 minute. The preformed TFA/TFA anhydride reagent is added to 15 g (45.9 mmol) of 17-hydroxy-3-keto-17-pregnant-4,9(11)·diene-21-skin acid, r- Lactone (also known as Λ9,11-aldona):

Printed by the Department of Standards and Staff of the Department of Standards of the Department of Drips (please read the notes on the back and fill out this page). Prepared from 3-methoxy-3,5,9(11)-androstene_17-one (1 ^〇1111). The resulting mixture is heated at about 60 ° C to 70 ° C for about 1-1.5 hours. The reaction mixture was concentrated under reduced pressure at 50 ° C to give a thick slurry. The slurry is dissolved in 丨〇〇ml of ethyl acetate and washed twice with 20% water/salt solution (80 ml each), -346- This paper scale applies to Chinese National Standard (CNS) A4 specification &quot;7 210X2^ 7^1 — --- 1248443 ________ V. Description of the invention (344 ) ~~ 1 N sodium hydroxide liquid wash 1 time (8 〇 ml), and about 2% water / saline solution wash once (80 ml ). The crude product was dried over MgSO.sub.4, filtered and concentrated to dryness <RTIgt; This material was purified twice by column chromatography to yield about 34 g of pure [丨3 s,j 7 Θ ]-3',4'-dihydrohydroxy-9,17-dimethylcyclopenta[13, 17] Gonad _ 1,3,5(10),6-tetraene _5, [2'- ketone (compound (:-203).

Example X-1E Preparation [138,17/?Bu 3,,4,-Dihydro-17-methyl-cyclopenta-[13,17]-18-原雄_ 4,6,8(1 4)- Triene _3,5,[2'H]-dione (compound (^2〇4): (Please read the notes on the back and fill out this page)

Potassium acetate (8 g, 81.5 mmol), trifluoroacetic acid (150 ml, 1.480 g/ml) and trifluoroacetic anhydride (33 ml, 1.487 g/ml) were printed by the Consumer Standards Agency of the Central Bureau of Standards. Up to a 250 ml round bottom reactor equipped with a mechanical stirrer, condenser and heating mantle. The resulting solution was stirred at about 25 ° C to 30 ° C for about 10 minutes. Preformed TFA/TFA anhydride reagent, added to 15 g (44.0 mmol) of 17-hydroxy-3-keto-17 α-pregna-4,6-diene-21-carboxylic acid, r-lactone ( Also known as Kenridone; GD Searle &amp; Co.):

This paper scale applies to the Chinese National Standard (CNS) A4 specification &quot; (210X297^7 1248443 A7 B7 V. Inventions (345) The resulting mixture is heated at about 60-70 ° C for about 1-1 · 5 hours. Concentration under reduced pressure at 50 ° C gave a thick slurry. The slurry was dissolved in 100 ml of ethyl acetate and washed twice with about 20% water / brine (80 ml each), 1 N hydrogen Sodium oxide was washed once (8 〇 ml), and washed with 20% water/salt aqueous solution once (80 ml). The crude product was dried over magnesium sulfate, filtered under reduced pressure at 5 ° C and concentrated to dryness. i 8 g of crude wet material. This material was purified by column chromatography twice to yield about 2.2 pure [13S,17]·3^-dihydro-17-methyl-cyclopentane-[13,17 ]-18·原雄_4,6,8(14)· 三晞-3 ?5'[2Ή&gt;dione (Compound C-204). Example Χ-2 Preparation: (Read the first note on the back) Fill in this page), 1Τ

漪α-hydroxykenrestone (3.6 g, 10 mmol) and triethylamine (1.2 g, 12 mmol) in two by the Central Bureau of Standards and Bureau of Peking Consumers Cooperatives t (Compound C-105) Stirring methane (2 〇 ml), cooling 1 〇) Add sulphonyl chloride (1 · 1 g, 1 〇 millimolar) to the solution. The mixture was stirred in the cold for 3 hours and then warmed to room temperature. Stirring is continued until the thin layer chromatography shows that the reaction has been completed. The mixture was diluted with ethyl acetate and extracted with water, 5% aqueous sodium hydrogen carbonate and water and dried over sodium sulfate. The desiccant is filtered, and the filtrate is concentrated under air to produce the following crude mesylate C-136, which is -348- This paper scale is applicable to China's ^^^·) 8 4 gauge (210'乂297 public 漦) 1248443 A7 V. Description of invention (346) applies to the next step:

(Compound C-136) Mesylate C-136 (4.3 g, 1 mmol) with trifluoroacetic acid (25 ml), trifluoroacetic anhydride (4.5 ml) and potassium acetate (6.7 g, 7.1 Millol) was reacted according to the procedure for the synthesis of compound C-1 in Example X-1. The crude product was isolated by the same procedure as for compound C-1 in Example X-1, and purified by chromatography on silica gel eluting with ethyl acetate and toluene or ethyl acetate and hexane as solvent. The product thus obtained can be further purified by recrystallization from an alcohol, an alcohol and water, or ethyl acetate and hexane to give a tetraene C-105. Example Χ-3 Preparation: (Please read the notes on the back and fill out this page)

, 1T Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing Π

(Compound C-110) Mesylate.

This paper scale applies to the Chinese National Standard (CNS) (210X 297^iT 1248443 A7 - &quot;BL_ -----—— ------ .., - ________- V. Invention Description (347) Separation (according to the procedure of Example X-2, synthesizing C-136 methylate) "Using 11^17-:3⁄4yl-3-keto-17-keto-pregnant-4-晞-21- complex Acid, r-lactone (3.6 g, 10 mmol), triethylamine (1.2 g, 12 mol) and methanesulfonyl chloride (1 g, 10 mmol) in di-methane (2 mL) The thus isolated mesylate C-138 is suitable for the following steps: mesylate C_138 (4.4 g, 10 mmol) with trifluoroacetic acid (25 ml), trifluoroacetic anhydride (4.5 ml) and Potassium acetate (6.7 g, 7.1 mol) was reacted according to the procedure for the synthesis of compound C-1 in Example X-1. The crude product C-11 was isolated in the same procedure as the compound C-1 in Example X-1, and Purification by chromatography, using a mixture of ethyl acetate and toluene or ethyl acetate and hexane as a solvent. The product is thus obtained and purified by recrystallization from alcohol, alcohol and water, or ethyl acetate and hexane. -4 Preparation 3' 4',5',17·tetrahydro-17 cold-methyl dad-3,5,diketylcyclopenta[13Κ,17]_ 1 8-原雄-4,8,14-triene·7 π -carboxylic acid (compound-101) ··

Printed by the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (Read the first note on the back and fill out this page) Compound CM (3.8 g, 10 mmol) and 1 Ν aqueous sodium hydroxide (3 5 liters) in ethanol The solution (60 ml) was refluxed for 8 hours. The reaction was cooled to room temperature, concentrated on a hollow rotary evaporator, and the remaining aqueous layer was extracted with ethyl acetate -350 - the paper scale was applied to the Chinese National Standard (CNS) A4 Specification (210X297 public f) &quot; —一~~ Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printed 1244843 A7 -------- ΙΠ 〜1~.·—— ——_- -.........,, V. Invention Description ( 348) ~ Take three times. The aqueous layer was acidified with 1N hydrochloric acid solution and extracted with ethyl acetate three times. The mixed organic layer was washed with water and dried over sodium sulfate. Concentration on the apparatus. The residual crude carboxylic acid C-101 was crystallized from ethyl acetate and recrystallized from ethyl acetate and hexane or methanol or ethanol and water. Example X-5 Preparation 3', 4', 5' ,17-tetrahydro-17々_methyl_3,5,_dionecyclopentyl [13r,17]_18_ protamine-4,8,14-triene_7α-carboxylic acid methyl ethyl ester (compound C_1〇2):

a mixture of sodium bismuth carbonate (3.5 g) and carboxylic acid C-101 (3.7 g, 10 mmol) and isopropyl broken (3 ml) in dimethylformamide (35 ml) at room temperature Stir under night. The reaction was poured into water and the aqueous solution was extracted three times with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The desiccant was filtered&apos; and the filtrate was concentrated under a vacuum. The residual crude isopropyl ester C-1 〇2 is crystallized by treatment with ethyl acetate or alcohol, and purified by chromatography on silica gel, and recrystallized from ethyl acetate and hexane or alcohol or alcohol and water. Example Χ-6 Preparation of 3',4',5',17-tetrahydro-17/? •Methyl-3,5f-diketocyclopenta[13R,17]-18·原雄-4,8, 14-Triene-7α-carboxylic acid ethyl ester: -351 - This paper size is applicable to China National Standard (CNS) Α4 specification (210Χ 297 public #) (Please read the back note and fill out this page)

1248443 Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs A7 V. Inventions (349

a mixture of sodium sulphate (3.5 g) and a solution of carboxylic acid c_1〇1 (37 g, 1 mmol) and ethyl broken (3 liters) in dimethylformamide (3 cc) Stir at room temperature overnight. The reaction was poured into water, and the aqueous solution was extracted three times with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The desiccant is over/under and the liquid is concentrated. The residual crude ethyl acetate c_丨〇3 is crystallized by treatment with acetic acid or alcohol, and purified by chromatography on a gel, and recrystallized from ethyl acetate and hexane or alcohol or alcohol and water. Example X-7 Preparation of 3',4',5',17-tetrahydro-17々_methyl_3,5,_dionecyclopentyl [1311,17]-18_ 原雄-4,8,14_ Trienylcarboxylate (Compound C·104):

a mixture of sodium sulphate (3.5 g) and carboxylic acid C-101 (3-7 g, 1 mmol) and n-hexyl iodide (3 liters) in dimethylformamide (35 ml) At room temperature - 352 paper size suitable for the home (210X297 public #) (please read the back of the note before you fill out this page)

1248443 Α7 Γ---- Β7 V. Invention description (350) ~~~ -- Stir one night. The reaction was poured into water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The desiccant was filtered and the filtrate was concentrated in vacuo. The residual crude n-hexyl ester c_l 4 is crystallized by treatment with ethyl acetate or an alcohol, and purified by chromatography on silica gel and recrystallized from ethyl acetate and hexane or alcohol or alcohol and water. Example X-8 Preparation of 3',4'-dihydro-17-methyl-7 "(methylthio)-cyclopenta[13,17]-18_protox-4,8,14-triene-3, 5'(2Ή)-dione (compound (^1〇6): C Please read the notes on the back first#fill this page)

A solution of tetraene CM05 (3.2 g, 10 mmol) in methanol (4 mL) and hexahydropyran (4 mL) was cooled to 5 °C. Methyl mercaptan was then introduced until a weight of 7 grams was obtained. Seal the pressure vessel and keep it at room temperature for 2 hours. The solution was poured into ice water, and the precipitate was filtered, washed with water and dried. The methylthio-based product C-106 was purified by recrystallization from methanol or ethyl acetate and hexane. See, for example, the steps in A. Karim and E.A. Brown, Steroids, 20, 41 (1972), which are incorporated by reference. Example X-9 Preparation 7 (Ethylthio)_3,4,dihydro-17-methyl-cyclopenta[13,17]_18_prosogenic-4,8,14-triene-3,5, (2,11)-dione (compound (:_1〇7): -353 - This paper scale applies to China National Standard (CNS) Λ4 Regulations (21〇X29h&gt;f) Line Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives 137 1248443 V. Description of invention (351 )

A solution of tetraene C-105 (3.2 g, 10 mmol) in thioacetic acid (10 mL) was heated to 85-95 ° C for 1 hour. Excess sulphuric acid is removed from the air and the resulting crude 7?-thioacetate C_107 is recrystallized from a suitable solvent such as methanol or ethyl acetate or ethyl acetate and hexane. See, for example, U.S. Patent Nos. 3,013,012, J.A_Celia and R.C. Tweit, Dec. 12, 1961, which are incorporated herein by reference. Example X-10 Preparation of 1,2,4bR(4bR*),5,5aS*,7,7aR*,8,9,ll,12bS*-dodecyl-7a, 1213-dimethyl-10&amp;11* - Cyclopropanal [1] and [1,6&amp;-&amp;]phenanthrene-3,10-dione (Read the first note on the back and fill out this page) Line Once the Department of Central Bureau of Standards Staff Employees Cooperative Printed

And 1, 2, servant 8 (servant 11*), 5, 5 &amp; 8*, 859, 11, 125 ft * - dodecahydro-73, 1213-dimethyl 10 &amp; 8*-cyclopropanal [1]茂落和[1,6&amp;4]phenanthrene-3,10-dione (Compound 0-354 This paper scale applies to China National Standard (CNS) Λ4 gauge (210X 297 public f) 1248443 A7 B7 V. Description of invention ( 352 109)

In a solution of trimethyl sulfonium iodide (1 g, 4.6 mmol) in anhydrous dimethyl hydrazine (20 ml), sodium hydride (22 〇 mg of a 5 〇 % dispersed phase in a continuous oil, 4.6 亳 耳). The mixture was stirred at room temperature under nitrogen until the evolution of hydrogen ceased. A solution of tetraene C-105 (1·12 g, 3.5 mmol) in dimethyl hydrazine (4 ml) was added and stirring was continued for 4 hours under nitrogen atmosphere. The reaction mixture was diluted with water and the resulting precipitate was filtered and dried. The product was a mixture of 6/?, 7/? (Compound C-108) and 6 π, 7 (Compound C-109) isomer. Separation of these isomers can be achieved by chromatography on the ground gel, and individual isomers can be further purified by recrystallization from the solvent, such as ethyl acetoacetate and hexahydrate, or alcohol and water. Example X-11 Preparation (Please read the notes on the back and fill out this page)

, 1T Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing

(Compound C-111) -355 This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 public f) 1248443 A7 V. Invention description (353) ~- ~ fluorenone C-110 (3.2 g, 10 m To a suspension of the original formic acid ethyl acetate (1 mL) and absolute ethanol (10 mL), p-toluenesulfonic acid monohydrate (0.05 g) was added. The reaction was stirred at room temperature for 3 minutes and a few drops of pyridine were added to quench. After stirring for another 5 minutes at 0 C, the resulting precipitate was filtered, washed with a small amount of methanol, and recrystallized from alcohol or ethyl acetate and containing a trace amount of (iv) to form a pure enol ether c_ln. . Alternatively, the reaction can be carried out after the addition of pyridine to remove all of the solvent (under venting) and the residue is crystallized by the addition of a solvent such as a bond, ethyl acetate or hexane. The crude 1 1 1 was recrystallized as described above. See R.M. Weier &amp; L M H〇fmann, J Med

The procedure of Chem., 20, 1304-1308 (1977), which is incorporated herein by reference. Example X_ 12 Preparation: (诮Read the back of the note first and then fill out this page}

, 1T

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (Compound C-112) According to 11.]\4.~616^11(11^]^.11〇加&amp;1111,].]^(1.(:116111 , 20 1304- 1308 (1977), which is listed as a reference for this case.

The Vilsmeyer reagent was prepared by adding hydrazine chloride (4 to 59 g, 30 mmol) to dimethyl acetamide (30 ml). After 5 minutes, a solution of the enol ether e-ill (3.5 g of '1 mM millimolar) in dimethylformamide (5 ml) was added and the reaction was stirred at 0 °C for 2 hours and at room temperature Next night. The reaction was poured into sodium acetate-356- This paper scale was applied to the standard of Zhongguanjia (CNS). Lin (2lQx29") - ^ 1248443 V. Inventive Note (354 A7 ΒΊ X solution, and stirred for 2 hours. Filter the sediment, And drying to form a crude spoon 趁C 112. From each agent, such as alcohol, alcohol and water or acetic acid, and re-crystallization from hexane to achieve purification. In addition, the crude aldehyde c-112 is separated from sodium acetate water solution, It is extracted with a solvent such as ethyl acetate. After drying over sodium sulfate and removing the solvent, the residue is purified by recrystallization or recrystallized on silica gel. t Example X-13 Preparation: ~

(Please read the notes on the back and fill out this page)

, 1T Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, printing f (Compound C-113) on a stirred cold solution of lithium tris-butoxide (3. 5 g, 12 mmol) in tetrahydrofuran, Aldehyde C-112 (3.78 g, 10 mmol) was added. The reaction was stirred at room temperature for 5 hours, and water and acetic acid were quenched, and care was taken to make the mixture slightly alkaline. The mixture was concentrated under reduced vacuo and the solid formed was taken from ethyl acetate. The solid was filtered and the filtrate was concentrated in vacuo. The residue is dissolved in a small amount of acetone and water (3:1) solution and added to an acidified aqueous acetone solution (pH 1.5-2.0). The acidic reaction mixture was stirred at room temperature for 1 hour and concentrated under a vacuum. The resulting crude dienketone C-113 is purified by recrystallization from a solvent such as an alcohol, an alcohol and water or ethyl acetate and hexane. Further, the crude dienketone C-113 was purified by chromatography on silica gel and recrystallized. As seen, shown in 357 This paper scale applies Chinese National Standard (CNS) Λ 4 rules (210X297 public --- line 1244843 Ministry of Economic Affairs Central Bureau of Standards Bureau of Staff Cooperatives Printing A7 B7 V. Inventions (355) RM Weier and LM Hofmann, J. Med. Chem, 20 1304-1308 (1977), which is incorporated herein by reference. Example X-14 Preparation 2',3,,3fa π,4',6,,l〇', Ll',ll,a α,12,,13,,dodecyl·3*aR,3'a,l l'a-dimethyl-13'aR*-spiro[cyclopropan-1,7' (9Ή)-[1Η]Luolu and [l,6a-a]phenanthrene]-Γ9'-dione:

(Compound CM14) To a solution of dienone (1.17 g, 0.05 mmol) in tetrahydrofuran (3 mL), EtOAc (EtOAc:EtOAc liquid. The resulting reaction; the trough is stored for several days at the main temperature. Additional acetic acid was added to destroy excess diazomethane and the reaction was concentrated under a hollow. The residue, which is the intermediate pyrazoline, is recrystallized after it is crystallized under a solvent such as acetone, hexane or ethyl acetate. This material is converted to spiropropyl c-114. Therefore, the solid ruthenium 114 is heated at 190 ° (: hollowing out, and produces: solid from alcohol, alcohol and water, acetone and water or ethyl acetate and hexane, and the gentleman's sputum, and the solution of pyrazoline in acetone Purification is carried out with boron trifluoride etherate and re-crystallization to obtain a purification. See, for example, FB Colton and RT Nicholson, U.S. Patent No. 3,499,891, March 10 (1970), which is incorporated herein by reference. This paper scale applies to China National Standard (CNS) A4 Regulations (210X 297 AGE)]&quot;'--~ -————--------One (please read the notes on the back and fill out this page) )

, 1T 1248443 A7 B7 V. Description of the invention (356 Preparation: Example X-1 5

C compound C-115) by medium k standard for η work elimination t

And (Compound C-116) To a solution of the decyl ether C-111 (3.2 g, 10 mmol) in methanol (2 mL) was added sodium borohydride (38 mg). The reaction was stirred at room temperature for 3 hours and treated with 1 N hydrogen for 3 min. The reaction was further diluted with water, and the precipitate was filtered, washed with water and dried. The product, including the two epitope isomeric alcohols / compound (compound C-115 and compound c-16), was chromatographed on a gel to achieve separation. The purified alcohols C_115 and C-116 are each recrystallized from a solvent such as an alcohol, an alcohol and water, ethyl acetate and hexane, and acetone and hexane. Further, the diluted reaction mixture was extracted with ethyl acetate, and the combined organic layer was dried over sodium sulfate, and the crude product was separated and chromatographed as above to give the respective alcohols C-1 15 and C-1 16 . _ - 359 _ This applies to China ^: Standard (CNS 2iGx2 "fy 1248443 A7 137 V. Inventions (357) Example X-1 6 Preparation:

(Compound C-117) Compound C-1 (3.8 g, 10 mmol) was converted to the enol _c_ii7 using ethyl orthoformate' (3.2 g, 10 mmol), ethanol (1 liter) and Para-toluenesulfonic acid monohydrate (〇·〇5g), according to the synthesis procedure of the compound c_i丄A in the example. Example X-17 Preparation of 3',4',5',17-tetrahydro-6"-hydroxy-17/?-methyl-3,5,-diindole with cyclopentyl [13R,17]-18_原Androst-4,8,14-triene-7 α-decarboxylate methyl ester (Compound c 118): (Please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Central Bureau of Standards and Staff Consumer Cooperatives

A solution of 57% meta-p-peroxybenzoic acid (3.64 g) in 1% aqueous solution of dioxane (2 mL) was semi-neutralized with 1 N sodium hydroxide solution. This solution is cooled to 〇-360- This paper scale applies to Chinese National Standard (CNS) Λ 4 掊 (2ΐΟΧ29ϋ7&quot; 1248443 -- -—— ί: Π 5, invention description (358 ) ^, and is added in batches to sterol ether匕11? (4.1 g, 10 mmol) in a stirred and cooled (〇Ό) solution of 1% aqueous dioxane (20 liters). The reaction was stirred at room temperature overnight and poured into ice water. Extracted with methylene chloride or acetic acid: ester. The combined organic layers were dried over sodium sulfate. The solvent was evaporated to give crude hydroxy ester CM 18, which was purified on silica gel, as shown in RM· Weier and LM Hofmann, J. Med. Chem, 20 1304-1308 (1977), which is listed in this case. Example X-18 Preparation: (Please read the note on the back and fill out this page)

, 1T (Compound CM 17) Preparation of Dimethyl Lithium Copper Phthalate, from methyl lithium (19 ml of a solution of 1·6 乙醚 in diethyl ether, 30 mmol) to iodide (2 86 g, 15 亳 Mo The ear was carried out in a stirred suspension of diethyl ether (3 mL) under an inert atmosphere of argon. After stirring for 15 minutes in the cold, a solution of tetradecene 1 〇 5 6 g, 15 mmoles in tetrahydrofuran (25 ml) was added dropwise over 25 min. The reaction was continued for another 30 minutes and the mixture was poured into a saturated ammonium chloride solution with vigorous stirring. The aqueous mixture was extracted with ethyl acetate or dichloromethane. The combined organic layers were washed with aqueous ammonium chloride and water and dried over sodium sulfate. The solvent is removed under the hollowing out' and the residue is dissolved in ethyl acetate or dichloromethane, and then the counter-A-361 - this paper scale is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 gong#) &quot; ———一—---- Department of Economics, Central Bureau of Standards, Staff Consumer Cooperatives, printing t 1248443 fKl V. Invention Description (359 benzenesulfonic acid (100 mg) in a steam bath for 3 minutes to i hours. The organic solution is It is washed with water and dried over sodium sulfate. The solvent is removed in vacuo to give the crude enone C-119. Purification is carried out by recrystallization from alcohol, alcohol and water, or ethyl acetate and hexane. The crude enone c_i i9 was chromatographed on silica gel and the product was recrystallized as shown in J K. Grunwell et al., Steroides, 27, 759-771 (1976), which is incorporated herein by reference. Real grade m Preparation: (Please read the notes on the back and fill out this page)

, 1T C compound C-121) ester C-120 (4.00 g, 1 〇 millimole)

(Compound C-120) (Prepared as shown in FB Colton and RT Nicholson, U.S. Patent No. 3,499,891, issued March 10, 1970, which is incorporated herein by reference in its entirety in its entirety) in Milligram), Trifluoroacetic acid (25ml) -362- - Printed by the Consumer Standards Agency of the Central Bureau of Standards

The paper scale is applicable to the Chinese National Standard (CNS) A4^ (210X 297^F 1248443 ΑΊ V, invention description (360) and trifluoroacetic acid (4_5 ml) according to the procedure in the synthesis of compound cl. The crude product C- 121 is isolated according to the same procedure as for the compound C-1, and purified by chromatography on silica gel, using a mixture of ethyl acetate and toluene or ethyl acetate and hexane, and the product thus obtained is further derived from alcohol, alcohol and Purified by recrystallization from water or ethyl acetate and hexane. Example X-20 Preparation:

(Compound C-123) (Please read the notes on the back and fill out this page) Order Enone C-122 (3.68 g, 1 〇 mmol)

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (Compound C-122) (as shown in FB Colton and RT Nichalson, US Patent No. 3,499,891, March 10, 1970, which is listed as a reference for this case. ) with potassium acetate (6.7 g, 7.1 mmol), trifluoroacetic acid (25 ml) and trifluoroacetic anhydride (4.5 ml) according to the synthesis of compound cl in Example X-1, anti-363 - applicable to this paper scale China National Standard (CNS) Λ4 Specifications (210X297^7&quot; 1248443 V. Invention Description (361 A7 B7 should be. The crude product is divided as described above, n, 7 L ^, 丄~u knife away, and in the silicone Purification by chromatography, using ethyl acetate and hexane or a mixture of ethyl acetate 7 m I ethyl ester and toluene as the eliminating agent. The purified C-123 is further recrystallized from the alcohol and the hydrazine. Purification preparation: alcohol and water, or ethyl acetate and

(Please read the notes on the back and fill out this page) Φ and (Compound C-125), 1Τ

The C-125 and C-126, which are printed by the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Economics, are synthesized according to the above, (compound (7)26) .λ , . , v I, ie, 50% of the compounds C-108 and C-1 law. Therefore, for the second trial f methyl sulfonium iodide (1 g, 4.6 mmol) in anhydrous dimethyl sulfoxide (2 〇 ml), hexahydrate, bismuth), sodium hydride (220 mg) 50% of the dispersed phase in the sulphur oil; 4 &amp; ancient poor set 4·6 篆 Mo ear). The mixture was stirred at room temperature under nitrogen until the evolution of hydrogen ceased. This paper scale applies to the Chinese National Standard (CNS) -364- (210X297 public #) ^248443 __ B7 V. Description of Invention (362) - Trienone oxime 124 (1.14 g, 3.5 mmol): 〇

(Compound C-124) A solution of monomethyl sulphate (43⁄4 liter) was added and stirred under nitrogen pressure for another 4 hours. The triketene C-124 was prepared according to the procedure shown in the example χ_2 for the preparation of tetradecene c"05, i.e., using keto ketone as a starting material instead of 丨丨α_hydroxy quinone S. The reaction mixture was diluted with water and the resulting precipitate was filtered and dried. The product is a mixture of 6y5, 7y5 (compound C-125) and 6", 7 from (compound C-126) isomer. The separation of these isomers can be achieved by chromatography on tannin, and the individual isomers Further purification is carried out from a solvent such as ethyl acetate and hexane, alcohol or alcohol and water. Example X-22 Preparation of 3',4',5',17-tetrahydro-17 /?-methyl- 3,5,-dione cyclopenta[13R,17]-18-protoandrazine-1,4,8,14-tetraene-7 α-remediate methyl ester (compound c-127): ^ clothing -- ( Please read the notes on the back and fill out this page.) #1 The Ministry of Economic Affairs, the Central Standards Bureau, the employee consumption cooperative, prints 〇

Dienone C-127 according to RM·Weier and LM Hofmann, J. Med·Chem. -365 - This paper scale applies to China National Standard (CNS) A4 (210X 297^$1248443 A7 B7 V. Inventions ( 363 18, 817 (1965) The steps are synthesized, and the beans are listed in the case of the horse. Therefore, the material (:-1 (3.8 g, 10 mmol, clever-#-〆一) and fluorodicyanide) Benzoquinone (2.72 g, 12 mmol) was stirred and refluxed for 2 hours in dioxane (8 liters, eve a ★ μ, liter). The reaction mixture was concentrated under vacuum, residue &gt ;, % field is hydrolyzed with a hydrazine, filtered, and the filtrate is washed with 2% sodium hydrogen sulphate, 5% sulphur sulphide & sulphate sodium and saturated sodium sulphate solution, and then The sodium sulfate is dried, the desiccant is filtered, and the filtrate is concentrated under a vacuum. The crude product dienone C_127 is purified by chromatography, and the mixture of ethyl acetate and toluene is used as a dissolving agent on the tannin extract, so the separated product is further self-generated. Further repurification in the alcohol for further purification. Equipment 2,3,3 a to 4,6',ll'a α,12,,13'-octahydro-3 丨aR,3丨a,ll,a-dimethyl-l3'aR*-spiro[cyclopropanone and [16aa]phenanthrene, diketone (compound C_128): ---------0^- - (Please read the notes on the back and fill out this page)

, 1T

The Ministry of Economic Affairs t-labeled the Bureau of Beigongxiao Co. Co., Ltd. to print the enzymatic C-14 (3.48 g, 10 mmol) conversion as described in Example X-22 for the synthesis of diindolone C-127. Diketone C-128 was carried out using dichlorodicyanobenzoquinone (2.72 g, 12 mmol) in dioxane (80 mL). Example Χ-24 -366- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210Χ297 棼2 1248443 A7 ___B7 V. Invention description (364) ~^~ Preparation servant (servant ruler*), 5,5&amp; 8*,7,7 sizing feet*,8,9,11,12,121)8*-decahydrogen.7in,1213_ dimethyl-10R*-cyclopropene (1) lamming and [l,6a- aHg _3, ι〇_dione (compound _ 129):

Using the procedure described for the synthesis of dienone CM27 in Example X-22, the enone 108 (3.34 g, 10 mmol) was treated with di-di-cyanobenzoquinone (2.72 g, mM). Dioxane (80 ml) was converted to the dienone c_129. Example X-125 Preparation: (Please read the notes on the back and fill out this page)

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• I 漓 中央 中央 中央 员工 员工 员工 员工 ( ( ( ( 化合物 化合物 化合物 化合物 化合物 化合物 化合物 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Mol) was added to the suspension of tetrahydrofuran (35 ml) (yield) and stirred to a mixture of &lt;RTI ID=0.0&gt;&gt; The reaction was stirred at 〇 C for 20 min, filtered and the filtrate was evaporated. The residue is a mixed anhydride' and is suitable for the next step. -367- This paper scale applies to Chinese national standard (210X 297^&gt;f) 1248443 A7 B7 I. — — _ I—V. Description of invention (365) Gaseous dimethylamine via mixed anhydride (4.6 g, 1 〇 mmol The cold (〇 ° C ) solution of tetrahydrofuran (40 ml) was effervescent in a pressure vessel. After 1 5 minutes, the pressure vessel was sealed and the reaction was allowed to circulate for 24 hours at room temperature. The reaction was warmed to 40 ° C for 30 minutes and then cooled back to 0 °C. After warming to room temperature, the vessel is vented to the atmosphere and excess dimethylamine is allowed to evaporate. The reaction was concentrated in the sputum and the residue was dissolved in ethyl acetate and extracted with 1 N sodium hydroxide and water. After drying over sodium sulfate, the organic layer was evaporated and the residue was purified by chromatography on silica gel eluting with ethyl acetate and toluene. The guanamine C-130 obtained above is further purified by recrystallization from an alcohol, an alcohol and water or ethyl acetate and a hexanone. t η Χ-26 Preparation: --------- Clothing -- (Before reading the back of the note and then fill out this page), - mouth

(Compound C-131) The Central Bureau of Standards, Staff of the Ministry of Economic Affairs, printed the ketone ketone C-114 (3.5 g, 10 mmol) in ethyl orthoformate (i 〇 ml) and absolute ethanol (1 〇 ml). To the suspension, p-toluenesulfonic acid monohydrate (0.05 g) was added. The reaction was stirred at room temperature for 3 minutes and quenched with a few drops of pyridine. After stirring for another 5 minutes at 0 Torr, the resulting precipitate was filtered, washed with a small amount of methanol, and recrystallized from an alcohol or ethyl acetate and a pit containing a trace of pyridine to yield a pure enol ether 13 1 . In addition, the reaction is applied to the Chinese National Standard (CNS) orange (210X29^1248443 A7 B7, invention description (366), into the leaf I: post-treatment after the addition of 368-paper scale, that is, it is necessary to be straightforward, All the solvents were prived, and the solvent was added, such as hexane-acetic acid, ethyl erythroacetate, and hexane to crystallize the residue. The crude enol ether C-13 was crystallized as above. ΑΑΧ-27 Preparation:

(Please read the precautions on the back and fill out this page.) Clothing. Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (Compound C-132) Lithium bis(dimethylalkylalkyl) guanamine (1〇1〇) A solution of the enol ether c-131 (3.8 g, 10 mmol) in tetrahydrofuran (2 mL) was added dropwise over 2 min portions over a cold (-78 ° C) solution. The reaction was stirred at -78 ° C for 1 Torr, and a solution of phenylselenochloride (1·9 g, 1 mM) in tetrahydrofuran (5 mL) was then added. The reaction was stirred for 5 minutes and 1% sodium sulphate solution was added. The reaction was further diluted with water and extracted with ethyl acetate. The combined organic layers were washed with 5% aqueous sodium bicarbonate and water and dried over sodium sulfate. The desiccant was filtered and the filtrate was concentrated under a vacuum. The residue is purified by chromatography on silica gel. Ethyl acetate and toluene or a mixture of ethyl acetate and hexane are used as the dissolving agent to produce pure selenide (%132. Example Χ-28 Preparation: 369 fv paper scale for China Standard (CNS) Α4 rules orange (210Χ297 public splash

, 1T I I -. 1248443 A7 V. Description of invention (367)

(Compound C-133) a solution of selenide C-132 (g, 10 mmol) and pyridine (1.61 ml, 20 mmol) in a cooled (〇 ° C) solution of di-methane (40 mL). A solution of hydrogen peroxide (3.1 g of a 30% solution, 27 mmol) in water (3 mL) was gradually added. The temperature is maintained at less than 30-35 °C. After a slight pause in any exotherm, the ice bath was removed and the reaction was vigorously stirred at room temperature for 15 minutes. The reaction was diluted with a second gas, washed with a 5% solution of hydrogencarbonate and water, and dried on sulfuric acid steel. The desiccant was filtered and the filtrate was concentrated in vacuo. The residue is purified by chromatography on a gel. The mixture of ethyl acetate and toluene or ethyl acetate and hexanes is used as a solvent to form a pure unsaturated ketone C-133 from ethyl acetate and hexane. It can be further purified by recrystallization from an alcohol. Example X-29 Preparation: Clothing order ~ (please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Central Bureau of Standards and Staff Consumer Cooperatives

(Compound C-134) 370

This paper scale applies to Chinese National Standard (CNS) 210X^ #T 1248443 Α7 _____ _ V. Description of invention (368) ~ One ketone C-133 (2 g) in acetone (15 ml) solution with 1N hydrochloric acid ( 4 ml) was treated at room temperature for 1 hour. The reaction was concentrated under a hollow. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over 5 % sodium bicarbonate solution and water &lt; The desiccant is filtered, filtered, and concentrated in vacuo to give the crude ketone C-134. The crude product is purified by silica gel chromatography. The mixture of ethyl acetate and toluene is used as a dissolving agent to form pure ketone 0134, which can be further purified from ethyl acetate and hexane or alcohol. ----- (Read the first note on the back and fill in this page), -5-port Ministry of Economic Affairs, Central Bureau of Standards, Negative Labor Cooperatives, Printing 37, This paper scale applies to China National Standard (CNS) A^m~( 210 X 297^&gt;# Τ

Claims (1)

1248443 ABCD Patent Application No. 087,109,305, Patent Application for Chinese Patent Application, Application for Specialist, 1. A preparation of 3-oxo, 7^, ....., a!, alkoxycarbonyl substituted Δ -4,5-steroids. The method comprises reacting an alkylating agent with a 4,5-dihydro-5,7-lactone steroid in the presence of a ketone which is a ketone on the carbon. Or di-alkoxy substituted - and further includes the following: ό ~ Λ where C (5) represents 5 · carbon ' and c (7) represents the 7 - carbon of the steroid structure. 2. The method of claim 2, wherein the steroid acceptor comprises a saturated or unsaturated core structure, further comprising: a 9,11-epoxide moiety or a precursor thereof; and at 17- A substituent on the carbon selected from the group consisting of spironolactone, ketone or other precursors which can be a spironolactone. 3. The method of claim 2, wherein the steroid acceptor and the steroid product are substituted at the 17-position with a spironolactone substituent corresponding to the formula xxxjh. Λ ' II Ml / 4. According to the scope of the patent application The method of item 1, wherein the steroid acceptor and the steroid product are substituted with a keto substituent at the 17-position. 5. The method of claim 1, wherein the lactone acceptor comprises a 3-quinoneoxy substituent. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1248443 VI. Scope of application for patents 匕/系于6. According to the method of claim 1, wherein the 5,7-inside 0曰..., reacts with the alkyl group in the presence. , the formula, the preparation of the 4,5-dihydro-5,7-lactone steroid compound, the steroid is replaced by a ketone or a dialkyloxy group on the 3-carbon 'see 〇 Including 'Shaofen· Wherein C(5) represents a 5-carbon 7-carbon, and the method comprises: and C(7) represents a lactone compound steroid structure 8. After converting the 7-cyano-substituted steroid to the corresponding 7-sterol, the carboxylic acid-substituted steroid is converted to a deer, a sterol-substituted steroid. % According to the method of claim 7 of the scope of patent application, Gan|,, among them, 7-vouchers, steroids including 3-keto-/^4,5,-7- several of them are replaced by 夂 ^ Sterol, and the formation includes 3 _ di-alkoxy-5,7-inner 兮, 兮一, $ - intermediate bamboo shoots 3 _ 一 ^ ^ ^ esters are hydrolyzed under acidic conditions to form 3 1 homologous Inside the fight. A method of preparing a compound corresponding to formula IIC: 〇 IIC -2- This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1248443 A8 B8 C8 D8 VI. Patent application scope: -AA- stands for -CH2-CH2- group; R1 stands for -C02Me; R3 is hydrogen -B-B_ represents a group of -CH2-CH2-; the method comprises: hydrolyzing an alkylated compound of E, and reacting with an alkylating agent in the presence of a base, the compound of formula E having the following structure: Wherein -A-A-, -B-B- and R3 are as defined above, and R17 is a CVC4 alkyl group. 10. A method of preparing a compound corresponding to formula E: This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1248443 A8 B8 C8 D8 VI. Patent application scope -A - A - generation ^ table - group, R3 is hydrogen; R17 is CVC4 An alkyl group; and -BB- represents a group of -CH2-CH2-; the method comprising: thermally decomposing a compound corresponding to the formula DE2 in the presence of an alkali metal halide, the compound of the formula DE2 having the following structure; Wherein 1112 is, and -Α·Α-, -B-B-, R3 and R17 are as defined above. 11. A method of preparing a compound corresponding to the formula DE2: This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 1248443 A8 B8 C8 D8 々, the scope of patent application where -AA- stands for -CH2-CH2- group; R3 is hydrogen; R12 and R17 are independently selected from The following includes an alkyl group; and -BB- represents a group of -CH2-CH2-; the method comprises: condensing a compound of the formula DE1 with a dialkyl malonate in the presence of a base having the following structure: Wherein -A-A-, -B-B-, R3 and R17 are as defined above. 12. A method of preparing a compound corresponding to the formula DE1: R17〇ό——^ where -Α-Α- stands for -CH2-CH2- group This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1248443 A8 B8 C8 D8 VI. Patent application scope R3 is a group of hydrogen; an alkyl group; and -B_B-CH2-CH2-; the method comprising: reacting a compound of formula D with a hydrazine compound in the presence of a base, the compound of formula D having the structure: Wherein -A-A-, -B-B-, R3 and R17 are as defined above. 13. A method of preparing a compound corresponding to formula D: Wherein -AA- represents a -CH2-CH2- group; R3 is hydrogen; an alkyl group; and -Β·Β- represents a group of -CH2-CH2-; the paper scale applies to the Chinese National Standard (CNS) A4 specification (210) X 297 mm) 8 8 8 8 A BCD 1248443 -------- VI. Scope of Application This method includes: Hydrolysis of a compound of formula C into a 7 α -carboxylic acid and under acidic conditions with di orthoformic acid dioxane In the ester reaction, the compound of formula C has the following structure: R3 〇 Wherein -Α-Α-, -Β-Β- and R3 are as defined above. 14. A method of preparing a compound corresponding to the formula I: Wherein -Α-Α- represents a -CH2-CH2- group; R3 is hydrogen; R26 is methyl; and -BB- represents a group of -CH2-CH2-; the method comprises: alkylating a compound of formula 211, In the presence of a base, it reacts with an alkylating agent. The compound of formula 211 has the following structure: This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). 1248443 Patent application scope 8 8 8 8 AB c D 〇 〇 211 wherein -A-A-, -B-B- and R3 are as defined above. 15. A method for preparing a compound corresponding to formula A211 〇 〇[A211] wherein -AA- represents a -CH2-CH2- group; R3 is hydrogen; and -BB- represents a group of -CH2-CH2-; R80 and R90 are the same as C(17); Λ ' III II / This method includes: oxidized hydrazine 210 compound, the Α210 compound has the following structure 8 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1248443 A8 B8 C8 D8 VI. Patent application scope [A210] wherein -A-A-, -B-B-, R3, R8G and R90 are as defined above. 16. A method of preparing a compound equivalent to the formula: [A211] wherein -A-A_R; ^-CH2-CH2- group; R3 is hydrogen; and -B-B- represents a -CH2-CH2- group; R8 and R9 are the same as C(17); The method comprises: reacting a 3-keto-5,7-hemiacetal intermediate of the formula A209C with a peroxide oxidation reagent, the compound of the formula A209C is equivalent to the following formula: The paper scale is applicable to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 1248443 Patent application range 8 8 8 8 A BCD 〇 R9 [A209C] wherein -A-A-, -B-B-, R3, R8 and R9 are as defined above. 17. A method for preparing a compound corresponding to the formula: R3 〇80 0 .R! 90 [A210] wherein -AA- represents a -CH2-CH2- group; R3 is hydrogen; and -BB- represents a group of -CH2_CH2_, R80 and R90 are together with a C(17) system; The method comprises: oxidizing 3-keto-5,7-hemiacetal intermediate of formula A209C with peroxide 10-- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1248443 A8 B8 C8 D8 VI. Reagent reaction in the patent application scope, the compound of formula A209C is equivalent to the following formula: Wherein -A-A-, -B_B-, R3, R8 and R9 are as defined above. 18. A method of preparing a compound corresponding to formula A209: [A209] wherein -A-A- represents a -CH2-CH2- group; R3 is hydrogen; -B-B- represents a group of -CH2-CH2-; R8G and R9G are the same as C(17); And -E-E-series-CH=CH-: This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1248443 A8 B8 C8 D8 Patent application scope This method includes: Hydrolysis of a compound equivalent to formula A208 [A208] wherein -A-A-, -B-B-, -E-E-, R3, R80 and R90 are as defined above. 1119 is an alkyl group or a R190- group which together form a 0,0-oxyalkylene bridge. 19. A method of preparing a compound corresponding to formula A205: [A2051 wherein -AA- represents a -CH2_CH2- group; R3 is hydrogen; -BB- represents a group of -CH2-CH2-: alkyl; wherein -EE- is -CH=CH-; The compound of formula A204 is reacted with CrC4 alcohol and acid, and the formula A204 is -12- This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1248443 A8 B8 C8 D8 The patented conjugate has the following structure: [A204] wherein -A-A-, -B-B-, -E-E-, R3 and R19 are as defined above. 20. A method of preparing a compound corresponding to formula A204: R [A204] wherein -AA- represents a -CH2-CH2- group; R3 is hydrogen; -BB- represents a group of -CH2-CH2-; alkyl; wherein -EE- is -CH=CH-: This method includes : Hydrolysis corresponds to the compound of formula A203, which has the following structure: -13- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1248443 VI. Patent application scope VA R18〇/^^^, ch〇 [A2 03] wherein -A-A-, -B-B-, -E-E- and R3 are as defined above, and the ruler is ^-C4 alkyl. 21. A method of preparing a compound corresponding to formula A204: [A204] wherein -AA- represents a -CH2-CH2- group; R3 is hydrogen; -BB- represents a group of -CH2-CH2-; an alkyl group; and wherein -EE- is -CH=CH-; The method comprises the following steps: protecting a keto substituent corresponding to the compound of the formula A201, and reacting with an alkanol in the presence of an orthoformate under an acid condition, the compound of the formula A201 having the following structure: -14- The paper scale is applicable to the Chinese national standard (CNS) A4 specification (210 X 297 mm) 1248443 A8 B8 C8 D8 Patent application scope [A201] wherein -A-A-, -B-B-, _E-E- and R3 are as defined above, which yields a 3-sterol ether intermediate corresponding to formula A202. And R. R1[A203] wherein -A-A-, -B-B., -E-E-, R3 and R18 are as defined above; and the corresponding compound of formula A203 is hydrolyzed to produce the compound of formula A204. 22. Method for preparing a compound corresponding to formula A203: -15- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A B c D 1248443 Patent application scope [A203] wherein -AA- represents a -CH2-CH2- group; R3 is hydrogen; -BB- represents a group of -CH2-CH2_; R19 is a C1 to C4 alkyl group; and wherein -EE- -CH;CH-; wherein alkyl; this method comprises: reducing a compound corresponding to formula A202: [A202] wherein -A-A-, -B-B-, -E-E-, R3 and R18 are as defined above. 23. A method of forming an epoxy compound comprising contacting a host compound having an olefinic double bond with a peroxide compound in the presence of a peroxide activator, wherein the peroxide activator is chlorodifluoroethane Indoleamine or equivalent to a compound of the formula: 16- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1248443 A8 B8 C8 D8 々, patent application scope X1 0 X2-C-Rp- C-NH; X3 wherein Rp is -(CX4X5)2-; χΐ, X2, X3, X4 and X5 are halogen. 24. The method of claim 23, wherein the peroxide activator is selected from the group consisting of chlorodifluoroacetamide and heptafluorobutanamine. 25. The method according to claim 23, wherein the substrate is equivalent to formula II: R3 R8 Wherein -Α·Α- represents a -CH2_CH2- group; R3 is hydrogen; R1 represents -C02Me; -B-B- represents a group of -CH2-CH2-; R8 and R9 are the representatives. 26. The method of claim 23, wherein the substrate is selected from the group consisting of: The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 8 8 8 A BCD 1248443 Patent range 0 〇 C 0 MeO And the epoxidation reaction product is selected from the following: 0 0 〇 0 〇 〇 -18- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 8 8 8 8 A BCD 1248443 VI. Patent application scope 〇 27. The method of claim 23, wherein the substrate is selected from the group consisting of: c/CH3 And the epoxidation reaction product is selected from the following: -19- This paper scale is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1248443 - C8 D8 VI. Patent application scope 0 0 Η 卜 CH3 Ό Ο Η 28. A compound of the formula 301, wherein the compound is hydrazine -20- The paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1248443 as B8 C8 D8 VI. Patent application scope 29. Compound of formula 302A, wherein the compound is 〇 30. A compound of formula 303A, wherein the compound is hydrazine 31. A compound of the formula 3 0 4 A, wherein the compound is 〇 -21 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1248443 8 8 8 8 A BCD VI. Patent application scope 32. Compound of formula 305A, wherein the compound is 〇 33. A compound of formula 306, wherein the compound is hydrazine 34. a compound of the formula wherein the compound is -22- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1248443 8 8 8 8 A B c D 々, 专利 patent scope 35. A compound of the formula wherein the compound is 36. A compound of the formula 307A, wherein the compound is 〇 37. A compound of formula 308A, wherein the compound is -23- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 8 8 8 A BCD 1248443 VI. Scope of Application 38. A compound of the formula 309A, wherein the compound is 〇 -24- This paper size is applicable to China National Standard (CNS) A4 specification (210x 297 mm)