JPS5982400A - Manufacture of epoxysteroid using noncyclic amine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for making epoxy steroids using acyclic amines.

Total of the invention Δ9(11) - The steroid is converted to the corresponding bromohydrin (
It is well known that the 9α-bromo-11β-hydroxysteroid), then the corresponding 9β,11β-epoxysteroid of 11, and then finally converted to the desired 9α-fluoro-11β-hydroxysteroid by reaction with hydrogen fluoride. There is. In Nuknol, a strong base such as methoxide, [-butoxide or sodium hydroxide (U.S. Pat. Nos. 2,838,493 and 3,725,392);
Potassium acetate in acetone [U.S. Pat. No. 3,980,778 and J, Am, Chem, Soc, Vol. 77
, p 4438 (1955)], potassium fluoride (US Pat. No. 3,255,185) and D
Cyclic amidine bases such as l'iU (U.S. Patent @42
No. 07235), and various reagents have been used in the epoxidation reaction.

The ring closure of the 9α-bromo-11β-hydroxybromohydrin to the corresponding 9β,11β-epoxide is a dehydrohalogenation reaction. H. Nibuiger et al. CIl, O
ediger, et al, 5yntlxesis 5
91 (1972)] compare the elimination of hydrogen chloride by various organic bases. It is shown that the 592 acyclic amidine does not perform as well as DBN in dehydrohalogenation reactions.

Therefore, the acyclic amidine is I) B N or DB
Equivalent to U, it is believed that it does not convert 9α-bromo-11β-hydroxybromohydrin to the corresponding 9β,11β-epoxide.

D.H.R. Burton (1), I (, R.

Barton, J, C9S, Chem, Comtn, l.
135, (1981)] reported on the preparation of many guanidines, which are strong organic radicals. but,
Burton does not report that these bases are useful in dehydrohalogenation reactions such as the conversion of bromohydrin to the corresponding epoxide.

The present invention relates to the corresponding 9β
, which encompass acyclic guanidines and amidines that are surprisingly and unexpectedly efficient in their conversion to 11β-epoxide (II). The guanidine C no If) Oyobiamidine (IV)
[J) 13 U Oyohi I) It is cheaper and easier to prepare than known dehydrohalogenation reagents such as BN, and does not cleave the 21-acyloxy group like most other bases.

SUMMARY OF THE INVENTION The present invention provides a 9α-substituted-11β-hydroxysteroid of formula (1) with a guanidine of formula (Jll) and a guanidine of formula (W
The present invention provides a method for producing an epoxide of formula (1), which comprises contacting the epoxide with an acyclic amine selected from the group consisting of three amidines, and isolating the epoxide (II).

DETAILED DESCRIPTION OF THE INVENTION The 9α-ft,-11β-hydroxystero-r-do(1
) The starting materials are well known in the art or can be readily prepared from compounds known in the art by methods known in the art.

The method of the present invention for converting the 9α-1a-11β-hydroxysteroid (■) to the epoxide (II) can be applied to a wide range of steroid A-rings. Δ4
-3-keto (,A), Δ1°4-3-ke) (13
) and 3β-hydroxy-Δ” (C) steroid A
Rings are preferred (see chart 13).

The fluorine atom or methyl group at the c-6 position does not cause any inconvenience to the method of the present invention at 6-+6.

The leaving group is chlorine, bromine or iodine, or hydroxy as tosylate, mesylate or trifuthoester. Preferably, the pigment is bromine. R1
6 is hydrogen, acyloxy or methyl of 2 to 6 hydroxyl groups. When R16 is a hydroxyl group and hydroxy is present at the C-17 position, these hydroxy may be present in the form of acetonide; R17 is hydrogen or -CO
In R17α, R17α is an alkyl group having 1 to 6 carbon atoms, and R17α is phenyl. When R17 is hydrogen and 1 (16 is hydroxy), the hydroxy may exist in the form of acetonide. R21 is alkyl having 1 to 6 carbon atoms, phenyl, or phenyl substituted with ρ-nitro or In-methoxy group The method of the present invention is equally applicable to Δ-3-ketosteroids and Δ1,4,3-ketosteroids.The preferred steroid ring is represented by the formula (C) in Chart C.
It is shown as D).

Acyclic amidines (1v) are known in the art or can be readily prepared from known compounds by methods known in the art. C.J., A11l.

Chem, Soc, Vol, 102. P7125 (1
980) and Mj3redereck eL al,
Chem, l5er,, 95°1350 (196
3) Reference] ka is alkyl having 1 to 7 carbon atoms, 5 to 7 carbon atoms
7 cycloalkyl still has 1 to 3 -k, -OR5g
or -N (R50)2 (two 1s of the amine (
5o may be the same or different and may be combined to form a secondary amine selected from the group consisting of piperidine, pyrrolidine or morpholine (tetrasubstituted phenyl), preferably: ka is t-butyl.

1 and R4 may be the same or different, and may be alkyl having 1 to 7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms/I
/ or 1 to 3 -k, -0R50 still -'(R5
0) 2-substituted phenyl. However, the number of carbon atoms in ~ and ~ is 14 or less in total, and ~ and Hq may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and morpholine.

Preferably, both katana and R4 are methyl.

Guanidines of formula (Jlf) are well known in the art or can be readily prepared from known compounds by methods well known in the art (see mtJ Parton et al.). Rg is hydrogen, phenyl or p
-) IJ Same as I(a) except that it also contains a group. Preferably, Rg is hydrogen. R1, ~, and R may be the same or different; Number 1~
7 alkyl, cycloalkyl having 5 to 7 carbon atoms, 0 to 3
-1(, -OR50 still -N (J,L 50
) phenyl substituted with 2 (the two R50's of the amine may be the same or different and may be combined to form a secondary amine selected from the group consisting of piperidine, pyrrolidine or morpoline). However, R1-R2
and the total number of carbon atoms in 顯-顯 is 14 or less, and 琯-R
2j, - and 1l-11,4 are combined to form piperidine,
A cyclic secondary amine selected from the group consisting of pyrrolidine and morpholine may also be formed. Preferably, R1, Lump, Lump, and 1M are all methyl or hydrogen.

Tables 1 and 2 below show the guanidines CIII) and amidines (1v) used in the process of the invention, some of which are particularly preferred.

9α-1it-11β-hydroxysteroid (I)
ethyl chloride/, acetone, ethyl acetate, 1) M S
O, l) MF, Tll F, '; 1st Lee, /
, acetonitrile, tonol/ene, and chloroform with either acyclic guanidine (Jlr) or acyclic amidine (1v) in a neutral polar organic solvent selected from the group consisting of , acetonitrile, tonol/ene, and chloroform. Preferred neutral polar organic solvents are 1)
MF.

1 to 2 equivalents of guanidine per 1 equivalent of steroid (
ill) 't: use amidine (1v).

Preferably, about 1.1 equivalents of guanidine (1+11) or amidine (1v) are used per equivalent of steroid.

The reaction is preferably, but not necessarily, carried out under a nitrogen atmosphere.

The reaction is carried out in the temperature range from 0 to 100°C, depending on the nature of the guanidine (nr) or amidine (1) used. When the acyclic amine is guanidine(III), the reaction is generally carried out within the temperature range from 0 to 40°C, preferably from 25 to 35°C.

When the acyclic amine is amidine (1v), the reaction is generally carried out within the temperature range of 70-100°C, preferably 80-90°C. The reaction can be carried out by heating in a sealed container, thereby shortening the reaction time. Generally, the reaction is carried out at the reflux temperature of the organic solvent used.

The reaction is monitored by TLC. Generally, about 1 hour for guanidine (III) and about 1 hour for guanidine (III);
v) indicates that the reaction is completed in about 4 to 5 hours.

When 1' L C indicates the reaction is complete, the reaction mixture is
Acids such as hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid or P-TS
Dilute with water containing A. Desired epoxide (II
) is extracted from the reaction solvent by methods well known in the art or isolated by water precipitation and p-filtration.

Epoxide (1■) is useful for reacting the epoxide with hydrogen fluoride and converting it to the corresponding 9α-fluoro-11β-hydroxysteroid, as is well known in the art, as described by Fleet et al. Fr1ed, eL
al,, J, Am, Cbem, Soc,, Vol.

76, P1455 (1954)] Hirschman et al. CI
lirschmann et al., J., Am., Ch.
em, Sac, 4957 (1956F); U.S. Patent Nos. 2,894,007, 3,049,556, 3,086
See No. 032, No. 3007923, No. 3211758υ and No. 3980778.

Thus, according to the method of the invention, D B U and D
Using a base that is cheaper and easier to produce than BN,
9α-substituted-11β-hydroxy 2]-ester to the corresponding 9β,11β-epoxide 21-ester (JT)
The 21 ester & can be converted to 'A' without opening.

Danmu Next, definitions of abbreviations and symbols used in this specification are shown.

■"IIF stands for tetrahydrofuran.

DMSO stands for dimethyl sulfoxide.

1) MF stands for dimethylformamide.

p-TsA is the monohydric jaw of p-)luenesulfonic acid.

When a mixed solvent is used, the ratio of the solvents is volume/volume (V/V).

D B U is 1,8-diazabi/chloro(5,4,O)
I'm talking about Lounssen-7.

1) BN is 1,5-diazabicyclo[5,4,0
] Nonene-5.

The alkyl, acetic acid, etc. that indicate the number of carbon atoms include isomers.

k is alkyl having 1 to 3 carbon atoms.

Ra is alkyl having 1.-7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, 1 to 3 -R, -0R50 or -N
(R5o)2 (Two 1's (50) of the amine may be the same or different and may still be combined to form a cyclic secondary amine selected from 1!T' consisting of piperidine, pyrrolidine and morpholine. phenyl substituted with

itg is the same as Ra, or hydrogen, phenyl or p-)lyl.

hydrogen, alkyl having 1 to 7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, 0 to 3 -P~, -〇R50- or -N (R5o)2 (two R50s of the amine are the same) phenyl substituted with a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine), provided that R1 and The total number of carbon atoms is 14 or less, and 1 (1 and R2 may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and morpholine.

The square is hydrogen, alkyl having 1 to 7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, 0 to 3 -k, -0R50 or -N
(R50)2('T Minno2-)+7J) R5g
may be the same or different and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine), with the proviso that R1 and the square carbon The total number is 14
1q and 1q may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and morpholine.

R3 is hydrogen, alkyl having 1 to 7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, 0 to 3 -1(, -OR5g is still -・N(iζ50)2 (two R5g of the amine are the same) or different, and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine), with the proviso that The total number is 14 or less, and the cylindrical and cylindrical amines are combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and morpholine [7 may also be used].

The width is alkyl having 1 to 7 carbon atoms, cycloargyl having 5 to 7 carbon atoms. (which may form a cyclic secondary amine selected from the group consisting of
Up to four of the groups may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine.

1q is hydrogen, carbon #j~7 a-lekyl, 1 major prime number 5~
7 cycloalkyl, 0 to 3 1R, -OR5
.

or -N(R50)2 (two R2Os of the amine
may be the same or different and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpoline), with the proviso that The sum of carbon numbers J1 is 1
With 4 concave or less, connect R3 Omahi 4- to piperidine,
A cyclic secondary amine selected from the group consisting of pyrrolidine and morpholine may also be formed.

The width is alkyl with 1 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, 0 to 3 -R, -OR5g and -N
(R50) 2 (The 5o groups on the amines may be different and may be bonded to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine) phenyl,
However, the total number of carbon atoms in I and I4 is 14 or less, and 1 and 14 are combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and O-morpholine. Good too.

Kinuta is hydrogen, fluorine, and methyl.

t4 is chlorine, bromine, iodine or hydroxy as a tosylate, mesylate, or triflate ester.

I (16 is hydrogen, hydroxy, acyloxy (the number of carbon atoms in the acyl group is 2 to G), or a F group, and R
When 16 is hydroxy and R17 is hydrogen, C-16
Hydroxy at position and C-17 may be present in acetonide form.

■(17 is hydrogen or d, -〇〇R 17α, but ■
(When 17 is hydrogen or 16 is hydroxy, C-1
Hydroxy at position 6 and C-17 may be present in the acetonide form.

R17α is alkyl)V having 1 to 6 carbon atoms or phenyl.

R21 is alkyl having 1 to 6 carbon atoms, phenyl or P
- phenyl substituted with a nitro or m-methoxy group.

5o is hydrogen or argyl having 1 to 3 carbon atoms.

"~" indicates that the bonded atom or group is in the alpha or beta configuration.

Two is one ton or double bond.

Example Next, the present invention will be explained in more detail with reference to Examples.

Example 1 9β. 11β-epoxy-1 α. 21-dihydroxypregna-1,4-diene-3,20-dione 21-acetic acid ester) v (,11) 1) 9α in 12 ml of MF
-Bromo-11β,17α,21-trihydroxypregna-1,4-diene-3.20-dione 21-acetic acid ester/l/2.4069 [(■), JACS77, 4
438, (1955)] in a 12°C water bath under a nitrogen atmosphere.

Tetramethylquanidine 0. 6 5 6 tri to j
Add to the mixture and stir overnight. lNli acid 10-
Add 20 - of water containing with stirring. During the water/hydrochloric acid addition, the mixture is cooled in an ice-water bath. water 137
Slowly add J to the mixture at -10°C with stirring. Stir the solution at 6"C for 20 minutes, remove the solids, wash with water three times, and then stir at 50-60°C for 3.5 minutes.
Dry under reduced pressure for an hour to obtain the title compound.

Example 2 9β. 11β-epoxy-17α,21-dihydroxypregna-4-ene-3,20-dione 21-acetic acid ester (1■) 9α-bromo-11β. 17α. 21-1-lihydroxypregnar 4-ene-3,20-dione 21-acetic acid ester zv2.00fl: (I), JAC577,443
8 (1955)) in DMF 5 ml K C8. Tetramethylguanidine 0.4759 wokat,
The mixture is stirred at 20-25°C. When TLC indicates completion of the reaction, 10% hydrochloric acid in water is added, the mixture is stirred, the solids are skimmed off, washed and then dried under vacuum to give the title compound.

Example 3 9β,11β-epoxy-17α,21-dihydroxy-16β-methylpregna-1,4-diene-3,20
-dione-benzoic acid ester (Il, ) 9α-bromo-11β, 17α, 2]-)lihydroxy-16β-methylprekner 1,4-diene-3,20-dione 21
- Benzoic acid ester 2.01: (i), U.S. Pat. No. 31
64618, Example 30] was slurried in 10-methylene chloride. [-butyldimethylamidine 0
．． 869 is added and the mixture is heated to reflux. 6 hours later,
-1-L Cr(J: indicates the reaction is 90% complete. The organic solvent is replaced with ethyl acetate, the mixture is filtered and the solid is dried under reduced pressure to give the title compound.

Example 4 9β,11β-epoxy-1phα,2]-dihydroxy-16α-methylpregna-1,4-diene-3,20
-dione 21-acetic acid ester (1■) 9α-bromo-1
1β, 17α, 21-1-lyhydroxy-16α-methylpregna-1,4-diene-3,20-dione 21
-Acetate ester 1.00g [(D), U.S. Patent No. 316
No. 4618, Example 40 (C)] in 5 m of methylene chloride.
Make a slurry with l. t-Butyldimethylamidine 0.
431 nl are added and the mixture is stirred overnight. The methylene chloride is replaced with ethyl acetate, the mixture is filtered and the solid is dried under reduced pressure to give the title compound.

Example 5 1) Ratio of epoxidation reaction with BU and tetramethylguanidine I) BU 9α-Bromo-11β, 17α, 21-)lihydroxypredi- ner 4-ene-3,20- Dione 21-acetic acid ester (i) 4.0i1' and I) M F 20
Mix 1 ml at 5°C. 1) BUI, 49. /(9,
94+nmole). After 15 minutes, 50 ml of water containing 10% aqueous hydrochloric acid was added, and the mixture was stirred.
9β, 11β-
Epoxy-17α, 21-dihydroac-pregna-4
-ene-3,20-acetic acid ester (11) in yield of 93.
Obtained with 2 shadows.

■3. Tetramethylguanidine 9α-bromo-11β,17α,21-1-dihydroxypregna-4-dic-3,20-dione 21-acetic acid ester (I) 4. OL deceased and I) M F20
ml at 5°C. Tetramethylguanidine 1.2
Add 4 ml (9, g4 mmole). After 15 minutes, add 5'Ornl of water containing 10% aqueous hydrochloric acid.

The mixture is stirred and filtered. The solid is washed with water and dried to obtain 9β,11β-epoxy-17α,2[-dihydroxypregna-4-ene-3,20-dione 21-acetic acid ester (n) in a yield of 92.3%.

Example 6 6α-fluoro-9β,11β-epoxy-16α,1
7α,21-)dihydroxypregna-1,4-diene-3,20-dione 16. '17-acedonido21-
Acetate ester (II) '9α-bromo 6α-fluoro 11β, 16α, 21-tetrahydroxypregna-
1,4-diene-3,20-dione 16.17-acedonide 21-acetic acid ester [(Ding), J, Am, CC
11e, Soc.

Vol. 77.4438 (1957)) 2.641 in 5 ml of DMFl at 20-25°C. 0.629 g of tetramethylguanidine(III) is added and the mixture is stirred for 15 minutes. 30 ml of water and a small amount of 10% phosphoric acid are added. The mixture is cooled and filtered.

The solid is washed with cold water and dried in an oven overnight to give the title compound.

Example 7 9β,11β-epoxy-J6α,17α,21-trihydroxypregna-4-ene-3,20-dione 16
．． 21-Diacetate (If)9α-bromo-11
β, 16α, 17α, 21-tetrahydroxypregnath-4-ene-3,20-dione 16,21-diacetic acid ester [(I), J, Am, Chem, Soc,, Vol.
, 81 , 1689) )) to give the title compound.

Example 8 9β,11β-epoxy-16α,17α,21-trihydroxypregna-1,4-diene-3,20-dione 16,21-diacetic acid ester/I/(■)9Cχ-brome-11β, 16α, 17α, 21-tetrahydroxypregna-1,4-die/-3°20-dione 16,2
1-diacetic acid ester [(■), J, Atn, CC11e
, Soc, , Vol. 81 , 1689 (1959)
The title compound is obtained by following the general method of Example 1, except that the starting material is .

Example 9 9β,11β-epoxy-17α,21-dihydroxypregna-4-ene-3,2o-dione 21-acetic acid ester (,U) Same as Example 5B except that guanidine is used instead of tetramethylguanidine. Following general procedures, the title compound is obtained.

Examples 10 to 20 The method of Example 4 was followed except that the 9α-substituted-11β-hydroxysteroid (I) listed in Column A below was used as the starting material to obtain the epoxide (1■) listed in Column 13.

Table 2 - Amidine bases -975 Chart A Chart B Chart C 3 N-R2 1

Claims (1)

[Claims] A 9α-substituted 11β-hydroxysteroid represented by 6 is brought into contact with an acyclic amine selected from the group consisting of compounds represented by the formula: The formula (
A method for producing the epoxide shown in II). [In the above formulas (I) to (IV), ka is alkyl having 1 to 7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, 1 to 3 -R, -0R50'J or -N(
R50) 2 (the two R50s of the amine may be the same or different and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine) phenyl, Rg is the same as ka, or hydrogen, phenyl or P
- Tril, 1? , 1 is hydrogen, alkyl having 1 to 7 carbon atoms, 5 to 7 carbon atoms
7 cycloalkyl, 0 to 3 -, -OR5g or -N(R50)2 (2 of the amines + 7)l'-5
phenyl substituted with a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpoline, which may be the same or different in size and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpoline, with the proviso that and the total number of carbon atoms is 14 or less, and R and R2 may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and morpholine; ! i1-7 alkyl, carbon number 5-7
cycloalkyl, 0 to 3 -I(, -'JR50 and -N(R50)2 (5o to the two ends of the amine may be the same or different, bonded to form piperidine, pyrrolidine and morpholine) (which may form a cyclic secondary amine selected from the group consisting of may form a cyclic secondary amine selected from the group consisting of , pyrrolidine and morpholine; (, -0R50 or -
N("50)2 (the amines may be the same or different and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpoline) is a phenyl substituted with , provided that the total number of carbon atoms in 顯 and 1q is 14 or less, and R 3 j, - and 键 are bonded to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpoline. may be formed, R3 is alkyl having 1 to 7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, 0 to 3 -R, -0R50 or 11 m(
R50)2 (The two R50s of the amine may be the same or different and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine) phenyl substituted with , provided that the total number of carbon atoms in and is 14 or less, and R and R are combined to form a cyclic secondary amine selected from 1iT consisting of piperidine, pyrrolidine and morpholine. - is hydrogen, alkyl having 1 to 7 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, or -N(R50)2 (two R50 of the amine)
may be the same or different and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine), with the proviso that The total number of carbons is 14
Equal and Il. 4(l-1: may be bonded to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and morpoline, ring is alkyl having 1 to 7 carbon atoms, cycloargyl having 5 to 7 carbon atoms, 0 to 3 1k, -0R50 or -N(R
5o) 2 (the two R50s of the amine may be the same or different and may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine and morpholine). However, the total number of carbon atoms in it3 and ume is 14 or less, and sho and ume may be combined to form a cyclic secondary amine selected from the group consisting of piperidine, pyrrolidine, and morpholine. Good, R6 is hydrogen, fluorine, or methyl; phase is halogen, bromine, iodine, or hydroxy as tosylate, mesylate, or triflate ester; technique is argyl having 1 to 3 carbon atoms; R50 is hydrogen; It means alkyl having 1 to 3 carbon atoms, and "~" indicates that the bonded atom or group is in α or β coordination]