JPS58103400A - 6alpha-methylpredonisolone derivative - Google Patents

Abstract

NEW MATERIAL:A 6alpha-methylpredonisolone 17-ester, 21-chloride compound of the formula (R is lower alkyl or aryl). EXAMPLE:6alpha-Methylpredonisolone 17-butyrate, 21-chloride. USE:An adrenocortical hormone, having the powerful anti-inflammatory action (2.5-3.5 times or more that of 6alpha-methylpredonisolone), effective for dermatopathy, asthma, allergies, etc., and easily preparable. PROCESS:6alpha-Methylpredonisolone is reacted with an orthoester reagent of the formula RC(OR')3 to give 6alpha-methylpredonisolone 17,21-cyclic orthoester derivative, which is then reacted with xanthene-9-carbonyl chloride and subjected to the cleavage reaction to esterify the hydroxyl group at the 17-position and chlorinate the hydroxyl group at the 21-position simultaneously to prepare the compound of the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel derivatives of 6α-methylprednisolone, namely 6α-methylprednisolone 17-ester, 21-chloride compounds.

Recently, many adrenocortical hormones (corticosteroids) have been used clinically for the purposes of anti-rheumatic, anti-inflammatory, anti-allergic, and anti-shock effects, among others, they have been used as topical skin drugs. The number of topical corticosteroids available is now on the market. There are a wide variety of types, and from the perspective of the most basic structure, hydrocortisone, the chemical structure has been considerably designed and modified. Among these, corticosteroids in which a fluorine atom has been introduced into the 6th or 9th position or both of the steroid nucleus are currently in widespread clinical use. On the other hand, although such corticosteroids are drugs with strong effects, they have problems in terms of in vivo metabolism, and safety issues must also be taken into account, especially for those with fluorine atoms introduced. It is believed that there is.

The present inventors have searched for a new substance that has a structure similar to naturally occurring corticosteroids and can be manufactured more easily, and as a result, as a 6α-methylprednisolone derivative,
It has been discovered that a group of compounds with a structure in which the hydroxyl group at position 17 is esterified and the hydroxyl group at position 21 is replaced with a chlorine atom has a strong anti-inflammatory effect. The present invention provides such novel compounds. The structure is shown below using the general formula.

♂H3 (In the formula, R represents a lower alkyl group or an aryl group) Among the 6α-methylprednisolone derivatives represented by the general formula, R in the formula is particularly methyl, ethyl, propyl, isopropyl, or butyl. In the anti-inflammatory effect test using the vasoconstriction test (patch test) described below, compounds such as 6α-methylprednisolone, isobutyl group, and phenyl group were 2.5% lower than the starting material 6α-methylprednisolone. ~3.5
The effect was more than twice as strong.

Such a highly active and useful novel 6α-methylprednisolone derivative can be produced by various methods, and one method of production by Ton et al. is shown below.

6α-methylprednisolone has the general formula RC(OR')3
Reacting an orthoester reagent of the type represented by
The resulting 6α-methylprednisolone 17.21-cyclic orthoester derivative is subjected to a cleavage reaction in which xanthine-9-carbonyl chloride is applied to the 6α-methylprednisolone 17.
Esterification of the 17th position and chlorination of the 21st position of α-methylprednisolone are carried out simultaneously.

To explain this in more detail, 6α-methylprednisolone 17.21-Cyclic orthoester derivatives are generally prepared by dissolving 6α-methylprednisolone in dimethylamide, and adding a small amount of the above-mentioned orthoester reagent to the cyclic orthoester derivative.
It can be easily produced by adding luenesulfonic acid and heating at 70 to 110° C. for several hours in a stream of argon or nitrogen. Then, a small amount of pyridine or diluted sodium carbonate solution is injected into the reaction solution, and then the reaction product is extracted with ethyl acetate or methylene chloride or the like. The addition of the alkali solution described above is an important operation that is necessary for stabilizing the produced 6α-methylprednisolone 17.21-cyclic orthoester derivative and leads to improved yield. The extract is then washed in the usual way,
By drying and concentrating, a 6α-methylprednisolone 17.21-cyclic orthoester derivative is obtained as a crude product, which can be used as is in the next reaction. This product can be purified, if necessary, by operations such as recrystallization, column chromatography (silica gel), or preparative thin layer chromatography on silica gel.

Next, the thus obtained 6α-methylprednisolone 1
7.21-I Dissolve the i-type orthoester a conductor in sufficiently dried dinotylformamide, 1,2-dichloroethane, etc., and in a stream of argon or nitrogen,
Heat and stir to 0°C.

This is 1.0~ of xanthine-9-carbonyl chloride.
Add 3.0 equivalents at once and react at the same temperature for 30 minutes to 1 hour. Next, ethyl acetate, methylene chloride, or the like is added to this reaction solution at room temperature to extract the product. The obtained extract is washed with dilute carbonic acid solution, then thoroughly washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography or silica gel preparative thin layer chromatography, and then recrystallized.
The desired 6α-methylprednisolone 17-ester, 21-10-ester compound can be obtained purely in high yield.

The method described above is an excellent method that allows the production of a target compound from a starting material in only two steps, and is extremely simple. Furthermore, the reagent used, xanthine-9-carbonyl chloride, is itself crystalline, so it is stable enough to be purified by recrystallization, and is extremely easy to handle. Furthermore, since there is almost no decomposition due to moisture absorption, etc., the yield of the reaction product is high. In addition, this type of reaction using other carboxylic acid chlorides is very susceptible to the influence of moisture, leading to decomposition of the reagent, and in some cases, the formation of the target compound is hardly observed. Moreover, the presence of a primary amide such as dimethylformamide or dimethyl sulfoxide is an essential requirement;
If the tertiary amide t or dimethyl sulfoxide is not present, the result is similar to the conventional method of cleavage of the orthoester ring with acid, and a mixture of 17-ester and 21-ester is produced. It is said that 21-chloride is not produced (see Japanese Patent Publication No. 55-21759).

Thus, methods using other carboxylic acid chlorides include
This method has many problems in its implementation due to restrictions on operation and handling.

The above-mentioned method using xanthine-9-carbonylchloride IJF"i does not particularly require the presence of tertiary amide or dimethyl nulphoxylate as mentioned above, but uses 1,2-dichloroethane etc. alone as mentioned above. This is an excellent method that provides the desired 6α-methylprednisolone 17-ester, 21-chloride compound in good yield even when used as a solvent.This method is extremely useful especially as an industrial production method. It is something.

6α-Methylprednisolone 17-ester.

The 21-chloride compound can also be produced by other methods. For example, 11β, 17ff, 21-
A method is already known in which the 21st position of trihydroxycorticosteroid F (7) is converted to 7-tane sulfonate, and the 21st position is chlorinated with cyclized lithium.
-Producing the methylprednisolone 17-ester 21-chloride adduct requires a large number of steps and has a low yield, which is disadvantageous for industrial implementation.

The 6α-methylprednisolone 17-ester, 21-10+) compound provided by the present invention can be used clinically for various skin diseases because of its strong and potent local anti-inflammatory action, and can also be used for other skin diseases. It is an extremely excellent compound because it can be used adversely for diseases such as asthma and allergies.

6α-Methylprednisolone 1 provided by the present invention
7-Ester 21- Kuro! The results of a vasoconstriction test (patch test) of the compounds J) are described below, which will help to understand the potent anti-inflammatory action of these compounds provided by the present invention.

Local anti-inflammatory effect test (vasoconstriction test) The 6α-methylprednisolone 17-ester, 21-10 lido compound and control test substance listed in Table 1 below were each tested on a white petrolatum base. 0
, was prepared into an ointment with a concentration of 0.01%. This ointment was randomly applied to the sides of both hands and forearms of 10 healthy male adults, sealed for 16 hours (ODT), the drug was removed, and evaluation was made 2 hours later. Judgment is based on the degree of pallor ++ (
(pronounced), + (moderate), ± (slight pallor), - (ineffective)
The results were divided into 4 stages, and scores of 3 points, 2 points, 1 point, and 0 points were given to each child, and the results of the 10 test subjects were totaled, and then the average value of the results by the two judges was calculated. The results are shown in Table 1.

Table 1 (Control) 1.6α-Methylprednisolone 0. ol
7.0 12. Hydrocortisone
0.1 9.53, Placebo ointment (Peichizuke) 3.0 -4, No treatment (
Control) -3,5- As shown in Table 1, the f'16α-methylprednisolone 17-ester 21-chloride compound provided by the present invention is 6
Compared to α-methylprednisolone, Izugaku has a stronger anti-inflammatory effect.

Next, examples will be given to specifically describe the novel compound of the present invention and its production example.

Practical Example 1 6α-Methylprednisolone 17-butyrate 21-chloride 374 g of 6α-methylprednisolone was dissolved in dimethylformava draw, and ethyl ordobutyrate was added to n)
5' 80 II? was added, and further 9 Fr of p-toluenesulfonic acid was added, and the mixture was heated and stirred at 80° C. for 1 hour and 30 minutes in an argon stream. Next, pour the reaction solution into 50ml of ethyl acetate, and immediately add 1ml of 10% sodium carbonate solution, followed by 30ml of water. This solution was thoroughly shaken, and the ethyl acetate layer was separated, washed twice with 30 g of water, and then dried over anhydrous sodium sulfate.

Next, after filtration, the crude crystals obtained by distilling off the P liquid are A-1=)
Recrystallization from -hexane gave 6α-methylprednisolone 17.21-ethyl orthobutyrate as colorless needles in the form of 45089 (yield 9o, 9%).

m, p, 164.0~166.0℃ (min pp#) Engineering Rv
KB"ca-1: 3340.1720.1645ax MSm/e: 473 (M +1), 472 (M), 4
27,356. ．． 311,297°279.161,1
36.135 (Base Beak), 121 elemental analysis value (0
28H4006) Calculated value ('/cJ C; 7
1.16 H; 8.53 actual value (%l O; 71
．． 03 H; 8.71 then 1 this 6α-methylprednisolone 17.21-ethylordobutere-1-18
The solution was dissolved in dimethylformamide 3-, which had been dried with a molecular sieve, and heated and stirred at 75 to 80°C under an argon stream. 140ml of xanthine-9-carbonyl chloride? % was added all at once and heating and stirring was continued for 30 minutes. Next, the reaction solution was returned to room temperature, and 80 mg of ethyl acetate was added thereto, followed by 10% sodium carbonate and 30 mg of water, and the mixture was shaken. The ethyl acetate layer was separated, washed twice with 3°C of water, and then dried over anhydrous sulfuric acid. After filtration, the crude product obtained by concentrating the p solution was subjected to preparative thin layer chromatography (silica gel) to yield 6α-methylprednisolone 17-
Butyrate 21-(OIJ) 101011I (yield 57.4%) was obtained.

The physical properties and chemical data of this compound are as follows.

m, p, 120.0-123.0°C Peilstein reaction: positive thin layer chromatography (silica gel): RfO,
40 (single spot, benzene:ethanol = 7:1) Br Engineering R1/ml: 3400. Ding 720.1715
．． 1645ax NMRδcDct5: 0.93 (3H, m; CuH2C
) + 3), 1.0O (3H, s, 18th position CH3), 1
．． 13 (3H, d, J = 9Hz, 06a-CuJ),
1.46 (3H, s.

19th place OH5), 4.15 (2H, d, J"1.5H
2, C21-0H2), 4.48 (IH, br,
(31'1-Cu),'6.03CIH,m,C4
-(!H), 6.26(IH, (1.

J=10H2,C2-C1), 7.53(IH,d,
J=10Hz, cl-cH)Msm/e:463(M
++2), 462.461 (M+), 374,297,
279°161, 137.136 (base beak), 1
35,121 elemental analysis value (as 026H55czo5) calculated value (□□□ O; 67.46 H; 7.62
cz; y, b6 actual value 1 0; 67.53 H;
7.81 0t; 7.47 Example 26 α-Methylprednisolone 17-parerate 21-chloride 6α-Methylprednisolone 57-4 Q was dissolved in dimethylformamide 3-, and 3241 g of methyl orthoparerate was added to the solution, and further p -Toluenesulfonic acid 17Q is added and heated and stirred at 90°C for 5 hours in an argon stream. Next, 50-50% of ethyl acetate was added to the reaction solution at room temperature.
Add 0.5 ml of 10% sodium carbonate solution, and then add 30 ml of water and shake. Next, the ethyl acetate layer is separated, the filter is further washed with water, and then dried over anhydrous sodium sulfate. Next, after filtration, the crude product obtained by concentrating the P solution was separated by column chromatography using silica gel impregnated with triethylabane. 6α-Methylprednisolone 17.21-methylorthovalerate 43389 as a colorless amorphous solid (yield 91.7
%) Obtained ◎ IRvKBrCIPI: 5400, 1720,
1645ax MSrrv/e: 475CM +1), 472
(M”), 441 (M”-11), ! 156
゜297.161, 136.135 (base beak),
121 elemental analysis value (as 028H4006) calculated value (
4 C; 71.16 H; 8. ．． 55 Actual value (%l
O; 71.23 n; C69 then this 6α-methylprednisolone 17.21-methylorthopare)
220 m9 was thoroughly dried with molecular sieves, dissolved in Tashimethylformamide 6-, and heated in an argon stream.
The mixture was heated and stirred at 0 to 82°C. Xanthine-9-carbonyl chloride 17611 in this? was added all at once, and after continued heating and stirring for 30 minutes, 80-110% ethyl acetate was added at room temperature.
Add 1-1 of sodium carbonate and 3-3 of water (lWd) and shake well. Next, separate the ethyl acetate layer, wash the 8-layer twice with 30-mL of water, and then dry with anhydrous sulfuric acid. After filtration, the crude product obtained by concentrating the P solution was subjected to preparative thin layer chromatography (silica gel).
6α-Methylprednisolone 17-valerate, 21-chloride 92 (41.1%) was obtained. The physical properties of this compound and the respective structural data are as follows.

m, p, 109.0-111.5°C Peilstein reaction: positive thin layer chromatography (silica gel): RfO, 41
(Single spot, benzene:ethanol = 7:1) Engineering RvKBrc+++-1:3400,1720,17
15.1650ax NMRδcncz3:0.93(3H,m,0H2(3
H3), 1.02 (3H, s, 18th position CH3), 1.1
6 (6H9d, J=6H2, C6α-CH5), 1.4
8 (3H2S.

19 Yu CH3), 4.20 (2H, d, J=:2H
z, 021-C! H2), 4.63 (IH, br
, 101 j −0H), 6.03(IH,s, C
4-0H), 6.28 (IH,'d.

J = 10Hz, 02-CH), 7.30 (IH, d
, J=10Hz', C1-C! , H) MSm/e
: 478(M++2), 477, 476(M+
), 475, 297, 279.

161.136 (Base Beak), 135.121 Elemental analysis value (as C27H570t○5) Calculated value (Regular c
; 6Z98 H; 7.82 C1; 7.45 actual value (stomach C; 67, B2 H; 7.93 C1; 7.5
7 Example 66 α-Methylprednisolone 17-isobutyrate 21-chloride 6 α-methylprednisolone 749 Genus 9 was dissolved in dimethylformamide 6-, and methyl orthoisobutyrate 889 and p-toluenesulfonic acid 64 were added.
The mixture was heated and stirred at 80° C. for 1 hour in an argon stream. Then, at room temperature, 80- and 10-ethyl acetate were added to the reaction solution.
Add 2% sodium carbonate solution and 50% water. Shake this mixture well and separate the ethyl acetate layer.

After further washing with water and f, drying with anhydrous sodium sulfate. After filtration, the crystalline crude product obtained by concentrating the p solution was recrystallized from chloroform-hexane, and 6α-methylprednisolone 17.21-methylorthoisobutyrate was obtained as colorless needle crystals and 1, te 862. If? ”(yield 95
．． 9%) obtained-f17'c.

The physical properties and analytical data of this compound are as follows.

mops 172.0-175.0℃ (decomposition) Br Engineering Rv cIn-': 3320, 1715.1645
ax MSrrVe: 459 (M +1), 458
(M+), 427 (M+-31), 325.

297.279.161, 136 (base beak),
135.121 elemental analysis value (as 027H3806)
Calculated value f % l O; 70.71 H; Exactly the same substance was obtained even after the same treatment.

The thus obtained 6α-methylprednisolone 17.2
250 mg of 1-methylorthoisovaleret is dissolved in dry dimethylformamide 3dK and heated and stirred at a temperature of 85 to 87°C. Add to this xanthine-9-carbonylchloride IJ)'200m+1l--IF and stir at the above temperature for 30 minutes! ffru. Next, by treating the reaction solution after heating with xanthine-9-carbonyl chloride in Example 1, 130 g (yield 51.0%) of 6α-methylprednisolone 17-isobutyrate 21-chloride was obtained. I got it.

The physical properties and temperature data of this compound are as follows.
, 39 (single spot, benzene:ethanol-7:1
) Br Engineering Rν α-1: 3400, 1720, 1715.16
45ax NMRδ0Dcz3 21.02 (3H, s, 18
Rank C! H3), 1.16(6H+d* J=(3H
I8119th place C! H3), 4.12(2H,8,C2
1-C! H), 4.50 (IH.

br, C11-CH), 6-03 (I H*S
, C' 4-OH) +6-27 (I H, d
, J"' 10H2,02-0H), 7.35(IH
, d, J=1QHz, 01-C! H) MSm/e: 46
3 (M++2), 462.461 (M), 374,2
97,279°161.136 (base beak), 1
35.121 elemental analysis value (5 total as C26H35Ct05 [iIn(9'ql O; 67.46
H; 7.62 0 t; 7.66 actual value F,)
O; 67.58 H; 7.79 C1;
7.51 Example 46 α-Methylprednisolone 17-isovalerate, 21-chloride 6α-Methylprednisolone 749 my was dissolved in 6 dK of dimethylformamide, and to this was added 973 ■ of methyl orthoisovalerate and 34 ■ of p-)luenesulfonic acid. Heat and stir at 80° C. for 1 hour in an argon stream. Then, at room temperature, 80 ml of ethyl acetate and 0.5 at of 10% sodium carbonate solution were added to the reaction solution, and 3 at of water was added.
Add 0mj and shake well. The ethyl acetate layer is separated, washed twice with 30ml of water, and then dried over anhydrous sodium sulfate. After filtration, the Oki liquid was concentrated and the resulting crude product was recrystallized from benzene-hexane to yield 783 mg of 6α-methylprednisolone-17,21-methylorthoisovalerate as colorless needle crystals (yield: 82.8%
) was obtained.

m, p, 168.0-1.71.0°C (decomposed).

IRν 3-1: 3400, 1715.1650ax MSm/e: 473(M+1), 472(
M+), 441 (M±-31), 356,297
°, 161, 136, 135 (base beak), 121
Elemental analysis value (as 028H4006) Calculated value (%l
O; 71.16 H; 8.53 actual value e', J
O;71.01 H;C41 6α thus obtained
-Methylprednisolone 17.21-Methyl orthoisovalerate 941 Ig is dissolved in dry dimethylformamide 3 and heated and stirred at 87 to 90°C. Next, xanthine-9-carbonyl chloride 741
1? Add at once and continue stirring at this temperature for 60 minutes.

Next, ethyl acetate 80410% was added to this reaction solution at room temperature.
Add 1 g of sodium carbonate solution and 30 mj of water, shake well, and separate the ethyl acetate layer. After washing this product twice with 30 g of water, drying with anhydrous sodium sulfate, filtering and concentrating the P solution, the obtained crude product (preparative thin layer) is obtained. 47 g (yield: 496%) of 6α-methylprednisolone 17-invalerate 21-chloride was obtained.

The physical properties and vector data of this compound are as follows.

m, p, 119.0-122.0°C Peilstein reaction: positive thin layer chromatography (silica gel): RfO,
40 (single spot, benzene:ethanol = 7:1) 1.14 (3H, d, J = 6Hz, C6,y-CH5)
, 6 (3H, 8, 1, 9th CHs) +416 (2
H181C21-CH2), 4. so(IH, br
, cll-OH).

6.07 (IH,s, 04-CH), 6.30 (1
H, J = 10H2, C2-0H).

7.35 (IH, d, J = 10H2,01-CH) MS
nme: 478 (M++2), 477, 47
6(M+), 574, 297, 279.

161.136 (base peak), 135.121 elemental analysis value (as C27H37ct05) for calculation
C! ; 67.98・H; 7.82 C1; 7.45 actual value (death 0; 68.13 H; 7.59 0t; 7
．． 5B Example 56 α-Methylprednisolone 17-propionate 21-chloride (al, 6α-methylprednisolone 74 qmyt was dissolved in dimethylformamide 4-, and 705 mg of ether orthopropionate and 17 m9 of p-toluenesulfonic acid were added thereto in a nitrogen stream. at 80-85℃ for 1 hour 30
Heat and stir for 1 minute. Then, 50% ethyl acetate was added to the reaction solution at room temperature.
m, 0.5 ml of 10% sodium carbonate and 30 ml of water.
Add and shake well. Separate the ethyl acetate layer and add 30 ml of water.
- and then dried over anhydrous sodium sulfate.

After filtration, the crude product obtained by concentrating the P solution was mixed with acetone.
Recrystallization from hexane yielded 6''-methylprednisolone 17.21-ethyl orthofluorobionate as colorless needle crystals (yield 91.2%) at 83619 (yield: 91.2%). 0℃ (decomposition) engineering RvK
Brffi-1: 3350, 1720, 1645
ax MSm/e: 459 (M +1), 458 (M ), 4
13,356,297,279゜161.136,15
5 (pace peak), 121 elemental analysis value (027H3
806) total 'R' value - C! ;70.71 H;
a35 actual value N Cs 70.59 Hp a 4
7 Next, this 6α-methylprednisolone 17.21-
3m7 of dimethylformamide dried from 229g of ethyl orthopropionate! 184 g of xanthine-9-carbonyl chloride was added at once to the solution, which was heated and stirred at 90° C. under an argon stream, and stirring was continued at that temperature for 60 minutes. Next, by treating the reaction solution with xanthine-9-carbonyl chloride in Example 1, 6α-methylprednisolone 17-propionate, 21-chloride was converted into 19 y
my (yield 87.6%) was obtained at rt.

The physical properties of this compound and the vector data for each are as follows.

m, p, 147.0-1495°C Peilstein reaction: positive thin layer chromatography (silica gel): RfO, 39
(Single spot, benzene:ethanol = 7:1) IRI/KBrC1fi-': 3360, 1720.
1710.1645ax NMRδcDO63' 1.00-1.20 (9H, m
, CH2CH3, CH3 at position 113 and C6a-CHs>
, 1.47 (3H, s, 19th C!H3), 4.14
(2H, s.

Cat-CH2), 4.50 (IH, br, 01
1-C! H), 6.00 (IH, s, C4-CH
).

6.25 (IH, a, , T=10Hz, C2-
CH), 7.37(I H,a, J=1(E,'
Qt-Gl) MSm/e: 449 (M +2), 448
,447(M),374,297,279°161
, 136 (Base Beak), 135.121 Yuan Cumulative Analysis Value (as C25H35C405) Calculation Value (Death 0; 6
6.89 H; 7.41 Ct near, 90 actual subvalue (
%IO; 66.95 H; 7.66 Ct; 7
．． 8"1(1)l 6α-methylprednisolone obtained in (a) above 17.21-Ethyl orthopropionate 92m+11-dried L7'c1,2-dichloroethane 4
- and heat and stir at 85°C. To this, 981 g of xanthine-9-carbonyl chloride was added at once, and the mixture was stirred at that temperature for 1 hour. Next, 80 sd of ethyl acetate, 0.5 sd of 10% sodium carbonate, and 30 sd of water were added to this reaction solution at room temperature, and the mixture was thoroughly shaken, and the ethyl acetate layer was separated. Thereafter, when the reaction solution of xanthine-9-carbonyl chloride was treated in the same manner as in Example 1, 6α-
44 g (yield: 4a, 9%) of methylprednisolone 1 propionate, 21-chloride were obtained. The physical properties and spectral data of this compound all agreed with those obtained with (al) above.

Example 6 6α-Methylprednisolone 17-acetate 21-chloride 6α-Methylprednisolone 749Qt was dissolved in dimethylformamide 3-, and ethyl orthoacetate 6
Add 491 g and 17 mg of p-)luenesulfonic acid, and heat and stir at 75° C. for 1 hour and 30 minutes. Next, 80 ad of ethyl acetate and 0.5 of 10% sodium carbonate are added to this reaction solution at room temperature, followed by 30 of water and shaken well. The ethyl acetate layer was separated, washed twice with 30 ml of water, and dried over anhydrous sodium sulfate. After filtration, the P solution is concentrated to obtain a crude product as a crystalline solid. When this t is recrystallized from acetone-hexane, 6α-
8228g of methylprednisolone 17.21-ethyl orthoacetate as colorless needle crystals (yield 92.5%)
) Obtained.

m, p, 134.0-136.0°C (decomposition) MSrIv
e: 445 (M +1), 444 (M ), 399,
556,297,279°237,161.166,1
35C base peak), 121 elemental analysis value (C26H3
606) Calculated value <”14 (!;70.24
H; 8.16 actual value (o4JO; 70.13 H
; 8.08 Next, this 6α-methylprednisolone 1
7.21-Ethyl orthoacetate 225N was dissolved in dry dimethylformamide 3- and heated and stirred at 80-90°C in an argon stream. Konni xanthine-9
-Carbonyl chloride 184J14F was added all at once, and heating and stirring was continued at that temperature for 30 minutes. Later, when the reaction solution was treated in the same manner as in Example 1 after the reaction with xanthine-9-carbonyl chloride, 6α-methylprednisolone 17-acetate, 21-chloride 95my.
(yield 43.6%) was obtained. The physical properties and each phase data of this compound are as follows.

m-1), 242°0 to 245.0°C Peilstein reaction: positive Thin layer chromatography (silica gel): RtO,
37 (single spot, benzene:ethanol = 7:1) Engineering RvcIn-1: 3300.1725.1715.1
645ax IJMR'CDCl3: 0.98 (3H, a,
18th CH3) +1.12 (3H, JJ = 6H2,06
(y-OJ), 1.47 (3H,s, 199
position CH3,2,05 (3H.

s, cocH3), 4.18(2H,B,C
! 2l-CH2),'4.50(IH,br,C1
1-cH).

6.04(1)1. s, 04-C) (), 6.28 (I
H, d, J-10Hz, C! 2-cH).

7.37(IH, d, J=1DH,O,-(1!H)M
8m/e: 455 (M +2), 434.433 (M
), 374,297,279°161, 136 (ba-
Speak), 135.121 elemental analysis value (024H51
Calculated value (as C105) (4 C; 66.28 H;
7.19 at;s, 1s actual measurement value (to) C! ;66
．． 23 H; 7.26 0t; 8.07 Example 76α
-, ethylprednisolone 17-(inzoate, 21-
Chloride 6α-methylprednisolone, 2. Of, methyl,
Orthobenzoate 2.02 and p-toluenesulfone tlIO,09t were dissolved in dimethylformazde,
The mixture was heated and stirred at 80° C. for 5 hours in an argon stream. Next, 4-10% aqueous sodium carbonate solution was added to this reaction solution at room temperature, and 40-40% of water and 100% of ethyl vinegar were added.
stl was added and shaken, and the ethyl acetate layer was separated. The mixture was washed twice with 30ml of water, dried over anhydrous sodium sulfate, allowed to pass, and concentrated under reduced pressure.

When the obtained crude product was subjected to column chromatography on silica gel impregnated with triethylamine, 6α
-Methylprednisolone 17.21-methylorthobenzony) 1.75f (yield 66.4%) was obtained.This substance is a colorless amorphous substance, but based on the physical properties and spectra shown below. Its structure was confirmed.

IRA/KBrffi-1: 3350.1715.1
645M8m/e: 493(M++1), 4
92 (λ4+), 475 (M+-17), 461 (M+
-31), 356,297,279,161.136,
135,105C base peak), 77 Next, 298 IIg of this 6α-methylprednisolone 17.21-methylorthobenzoate was dissolved in dry dimethylformamide 4- and heated and stirred at 90°C in an argon stream. Next, add 220 xanthine-9-carbonyl chloride and 9 ounces of xanthine-9-carbonyl chloride at once, and heat at that temperature for 30 minutes.
Stirring was continued for 0 minutes. Xanthine-9- in Example 1
When the reaction solution was treated in the same manner as after the reaction with carbonyl chloride, 6α-methylprednisolone 17-benzoate 21-chloride 1451Ig (yield 4a7%) was obtained.

The physical properties and spectral data of this compound are as follows.

m, p, 157.0-159.0°C Peilstein reaction: positive thin layer chromatography (silica gel): RrO,
40 (single spot, benzene:ethanol = 7:1) IRI/KBr[-1:3400,1715,1700
．． 1650ax NMRδCDCl3” 1.08 (5H, s*1
8th position aH3), 1.23 (3H, m, 06α-0J
), 1.53 (3H,s, 19th cJ), 4.18 (2
H,s,021-CH2)+4.61(IH,t)r,
C11-CH), 6.09 (IH,s, C4-CH)
, 6.29 (IH, d, J=10H2, C2-CH
), 7.35 (I H, d, J=10Hz tCl
-CH) MSm/e: 498 (M +2), 497.496
(M+), 401, 374, 297.

279.161,136 (base peak), 135,1
22,105.77 elemental analysis value (929H33CtO5
) Calculated value (1) C; 70.08 H: 6.6
9 Ct near, 13 actual measurement @ C near 0.12
H; 6.80 C/, Near, 00 Patent Applicant Ota Pharmaceutical Co., Ltd. Procedure Amendment 7
Month/Day, 1980, Commissioner of the Japan Patent Office Shima 1) Haruki Tono 1, Indication of the case 1967 Patent Application No. 3 2, Title of the invention 6 Be-metherprednisolone derivative 3, Person making the amendment Relationship Patent applicant address: Kamijujo A-2g, Kita-ku, Tokyo Name: Ota Pharmaceutical Co., Ltd. 4, Agent address: 6, Sogo Daiichi Building, 3-chome, Kojimachi, Chiyoda-ku, Tokyo, Subject of amendment Description □, Contents of the amendment (1) Page 75, line 7 of the specification and page 20, line 76 (total number (M+), corrected as J. - (2) Same page θ, line 73, “G, /2 ( ,2H,s
, C□-CH), J is written as r'1. /2 (
JH, s, Ct heat - CHt), correct it as J.

(3) Same page 26 line and! r 7.37 (/H, d, J=/θH, C, - on page 9, line 10 (total places)
CH) Write the description of J as r 7.37 (/H, d, J =
Correct it as 10Hz, C, -CH)J.

(Page 4126, line 3 (D rM8m/e:'/-'1
9 (M+-1-J), 'I'1g.

4tlI? (M10)', write J as r MSm/e
:'IA;0 (M++2).

Correct it as 1Iyq, 114tza (M+), J.

(phrase same 29 negative//line r MSm/e: 4Uj(
M++2).

1I31I, ll,? 3(M+), the description of J is r
MS m/e: IIJA (M++, 2), lI3
! ;, Da3da (M”), J.

(61 same 32 negative 2-3 lines [ri, 3S...CH) J
After the description, , 2! ; -g, 10 (!;
H, m, Ph).

V top

Claims (1)

[Claims] 1) 6α-methylprednisolone 17-ester % + 21-chloro! represented by the general formula H3 (wherein R represents a lower alkyl group and an aryl group). j Compound 0 2) R is a methyl group, an ethyl group, a propyl group, an iso-
Claim 1, which is a group selected from the group consisting of 10 pyr groups, butyl groups, isobutyl groups, and phenyl groups.
6α-methylprednisolone 1-phoester as described in
21-Chloride compound.