JPH04211051A - Process for producing 25-hydroxyvitamin d2 compound and corresponding 1alpha-hydroxylated derivative - Google Patents

Abstract

PURPOSE: To obtain vitamin D2 compounds useful as food supplement and medicament with an effective and simplified procedure by condensing steroidaldehyde with arylsulphone, followed by reduction and transformation.

CONSTITUTION: A steroidaldehyde of formula I (X₁ is hydroxy-protecting group) and an arylsulfone of formula II (X₂ is hydroxy-protecting group) are condensed to form a hydroxy-sulfonyl adduct of formula III. Then, after, if needed, the C-22-hydroxy group of said adduct is acylated or sulfonated, the adduct is reduced to an intermediate of formula IV (X₁ and X₂ are H or hydroxy-protecting group.), which is then transformed to a compound of formula V.

COPYRIGHT: (C)1992,JPO

Description

[Detailed description of the invention]

[00011

FIELD OF INDUSTRIAL APPLICATION This invention relates to biologically active vitamin D compounds. More particularly, the present invention relates to a method for producing hydroxylated derivatives of vitamin D2. [0002] Vitamin D is a very important agent for the control of calcium and phosphate metabolism in animals and humans, and is essential for proper bone growth and development. It has long been used in clinical practice to ensure safety and as a dietary supplement. It is known that the in vivo activity of these vitamins, in particular of vitamins D2 and D3, depends on their metabolism to hydroxylated forms. In this way, vitamin D3
undergoes two consecutive hydroxylation reactions in vivo,
It first becomes 25-hydroxyvitamin D3 and then 1°25-dihydroxyvitamin D3, the latter of which is thought to be the compound responsible for vitamin D3's well-known beneficial effects. Vitamin D2, commonly used as a dietary supplement, undergoes a similar hydroxylation sequence to its active form, where it is first converted to 25-hydroxyvitamin D2 (250H-D2) and then to 1,25-dihydroxyvitamin D2. Vitamin D2 (
L25(OH)2D3). These facts are well established and well known in the field [
For example, the biochemistry of Sudha et al.
Biochemistry) 8.3515 (1969) and Jones et al.
iochemi st ry) 14.1250 (1
975)]. [0003] Like the vitamin D3 series of metabolites, the hydroxylated version of vitamin D2 listed above is of interest for the healing or prevention of bone or related diseases due to its effectiveness and other beneficial properties. As pharmaceuticals or highly desirable dietary supplements, their value and possible uses are recognized in patents related to these compounds [U.S. Pat. Nos. 3,585,221 and 3,8
No. 80.894]. [0004] While many metabolites of vitamin D3 are produced by chemical synthesis, there is little research on the production of vitamin D2 metabolites. The known synthetic methods for metabolites of the D3 series (especially insofar as they concern the production of side-chain hydroxylated compounds) are of course usually not suitable for the production of the corresponding vitamin D2 metabolites, since the latter This is because it features a side chain structure (ie, the presence of a double bond and an extra methyl group) that requires a different synthetic approach than that applicable to chain hydroxylated 3 compounds. [0005] Various approaches to the production of vitamin D2 metabolites are known and described in US Pat. No. 4,448,721.
No. 4,847,012 and No. 4,769°181. [0006]

SUMMARY OF THE INVENTION A novel and convenient synthesis of 25-hydroxyvitamin D2 compounds has been developed and is described herein. This synthesis provides 25-hydroxyvitamin D2 (250H-D2) and the 24-epimer of 25-hydroxyvitamin D2, i.e. 25-hydroxy-24-shrimpvitamin D2), which have the structure shown below. Features:

embedded image (where Xl and X2 are hydrogen and the wavy line at carbon 24 indicates R or S stereochemistry), and the protection of the hydroxy of these compounds characterized by the above structure. derivatives (either XI or X2 or X
both l and X2 are selected from the group consisting of acyl, alkylsilyl or alkoxyalkyl). [0007] Additionally, the methods of the invention provide the 5,6-trans isomer of the above compound. Furthermore, the above compounds can be 1α-hydroxylated by known methods to obtain the corresponding 1α-hydroxyvitamin D derivatives. Particularly preferred examples of the latter are 1α,25-dihydroxyvitamin D2 and 1α,25-dihydroxy-24
Epi-vitamin D2. [00081 As used herein or in the claims, the term "acyl" refers to an aliphatic acyl group in all possible isomeric forms having from 1 to about 6 carbons (e.g., formyl,
acetyl, propionyl, butyryl, isobutyryl, valeryl, etc.) or aromatic acyl groups (aroyl groups) such as benzoyl, isomeric methyl-benzoyl, isomeric nitro- or halobenzoyl, etc., or dicarboxylic a with a chain length of 2 to 6 atoms.
cyl) group, i.e. an acyl group of the form ROOC(CH2)CO- or ROCCH20CH2Co-, where n has a value from 0 to 4 and R is hydrogen or an alkyl group such as oxalyl, malonyl, succinoyl,
glutaryl, adipyr, diglycolyl). The term "alkyl" refers to lower alkyl groups in all possible isomeric forms having 1 to 6 carbons, for example methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, 5ec-butyl, pentyl, etc., and the term "aryl" refers to phenyl or substituted phenyl groups such as alkylphenyl, methoxyphenyl, etc. The term "alkylsilyl" refers to a trialkylsilicone group (where the alkyl groups may be the same or different, e.g., trimethylsilyl, triethylsilyl,
dimethyl-tert-butylsilyl, etc.). The term "alkoxyalkyl" refers to protecting groups such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl and similar alkoxymethyl groups as well as related cyclic structures such as tetrahydropyronyl or tetrahydrofuranyl. [0009] The overall process developed for the production of the above compounds can be divided into two general steps, namely: (a) converting the completed preformed side chain fragment to a suitable steroid; addition to the precursor to yield the 5,7-diene steroid as a central intermediate;
(b) converting this 5,7-diene to the vitamin D structure to obtain the desired 25-hydroxylated compound, and, if desired, (c) converting the latter compound to the corresponding 1α-hydroxyvitamin D compound. . This process avoids the relatively difficult step of isomer separation required after conversion in the method of US Pat. No. 4,448,721. In addition, the methods of the present invention eliminate the need for additional side chain modifications as required by the method of 4,448,721. These advantages of the method of the invention significantly simplify the method of producing vitamin D compounds. These advantages also allow the yield of the final product to be increased because one obtains the desired final product rather than a mixture of side chain isomers as in U.S. Pat. No. 4,448,721. This is because preformed pure isomeric side chain fragments completed for the purpose are used. [00101-Inside the shell, the method of the invention creates the following structure:

[Formula 17] (wherein,
comprises reacting an alkyl or substituted alkyl selected from the group consisting of hydroxy, protected hydroxy and fluorine with a sulfone derivative. [00111 The coupling reaction carried out in a basic medium between the aldehyde and the sulfone derivative described above is expressed by the formula [1]
8], which gives a condensation product of the formula 22,
Reduction (as 22-hydroxy or as the corresponding 22-O-acylated derivative) using metal amalgams (Na, Al, Zn amalgams) or associated dissolved metal reduction systems to obtain 23-unsaturated steroids. Let them do it. This steroid intermediate can be further converted to the desired vitamin D compound by known reactions. [0012] It is readily apparent that by appropriate variation of R in the aryl sulfone derivative used in the above coupling step, a variety of vitamin D compounds can be produced. The reaction sequence shown by process scheme ■ is
Illustrating a specific example of the overall process, Process Scheme II is a steroid-22-
The preparation of suitable side chain units for addition to aldehydes is shown. [00131 The starting material for the present invention is steroid 2
2-aldehyde, such as the PTAD diene-protected-22-aldehyde (4) shown in Scheme 2, where PTA
D represents the indicated phenyltriazoline-3,5-dione protecting group), which can be prepared from ergosterol in a known manner (Scheme ■). [0014] The first step of the method involves the addition of an appropriate side chain fragment. Condensation of the sulfonyl-side chain fragment shown in Scheme II (sulfone (21), discussed further below), present in its anionic form in an ether or hydrocarbon solvent, with an aldehyde (4) produces a hydroxysulfone intermediate (5). give. The anion of the sulfone (21) side chain fragment is generated by treatment of the sulfone with a strong base such as lithium diethylamide, n-butyllithium or methyl or ethylmagnesium bromide (or similar Grignard reagent) in an ether or hydrocarbon solvent, forming the sulfone. To this solution of anions is added steroid aldehyde (compound 4) as a hydrocarbon solution or ether. The reaction is best conducted under an inert atmosphere. [0015] The next step involves removal of the side chain hydroxy- and phenylsulfonyl groups with the formation of a 22(23)-trans-double bond. Treatment of compound (5) with sodium amalgam under an inert atmosphere in a methanol solution saturated with N a HP 04 gives compound (6) characterized by the desired trans-22-double bond in the side chain. . If desired, the 22-hydroxy group of compound (5) may also be acylated or sulfonylated (eg, mesylated) prior to the Na/Hg reduction step, although this is usually not necessary. [0016] As shown in Process Scheme ■, the addition of the side chain fragment, sulfone (21), to aldehyde (4) does not cause shrimping at the asymmetric center of carbon 20,
That is, it should be noted that the stereochemistry at this center is preserved as desired. If desired, carbon 20
Preservation of stereochemistry at may be ensured at this stage of the synthesis by conversion of the type (6) intermediate to the initial aldehyde starting material. For example, ozonolysis of compound (6) by reduction treatment using completely conventional standard conditions yields the corresponding C-22 aldehyde, i.e. the structure (
4) produces the aldehyde. Spectroscopic and chromatographic comparisons of the aldehyde obtained from ozonolysis with the original starting material demonstrate retention of C-22 stereochemistry. [0017] The next step in the process is to generate the desired 5,7-diene intermediate (7) of these ring B-protected steroids.
Including conversion to . In the case of PTAD-diene-protected compounds (6), this transformation is achieved in a single step, i.e. treatment of (6) with a strong hydride reducing agent (e.g. LiAlH4) in an ethereal solvent at reflux temperature. , gives diene (7). The diene (7) is then converted to its 25-hydroxylated form (8) by known procedures according to Scheme 1. [0018] Final vitamin D product (10) or (1
The conversion of 5,7-diene to 5) involves a series of several steps. The sequence shown in the process scheme involves first irradiating an ether or hydrocarbon solution of 5,7-diene (8) with ultraviolet light to yield the previtamin analog (9), which can be dissolved in a suitable solvent (e.g. It undergoes isomerization by heating (50-90°C) in ethanol, hexane) to form 25-hydroxyvitamin D2 compound (10). [0019] Next, compound (10) is converted into 1,25-dihydroxyvitamin D2 by a known step shown in the scheme
It may be converted to compound (15). A suitable prior art for these conversions is U.S. Pat. 260.
No. 549 and No. 4,554,106 may be cited. [00201 The side chain fragment sulfone (21) as used in Scheme 2 is specifically the (R) enantiomer. Therefore, compound (10) or (15)
are the C-24-R-epimer, 25-hydroxy-24-epi-vitamin D2 (10) or 1, respectively.
25dihydroxy-24-epi-vitamin D2 (1
5). Thus, compound (10) or (
15) is obtained in enantiomerically pure form and does not require separation of the C-24-epimer as required in the method disclosed in US Pat. No. 4,448.721. The use of the (S)-epimer of sulfone (21) in the process of the invention is particularly useful for 250HD2 and, of course, for the respective 1,25-dihydroxyvitamin D2 compounds, i.e. Structure (10)
and yields the compound (15). [0021] 5.7-Diene (7) can be used as a free hydroxy compound or in its hydroxy protected form, with hydroxy protecting groups (C-3 and/or
or C-25 position) is an acyl group as described above,
It may be an alkylsilyl group or an alkoxyalkyl group. The 250HD2 products are thus obtained as free hydroxy compounds or optionally as C-3 or C-25-hydroxy-protected or 3,25-dihydroxy-protected derivatives. Synthesis according to Scheme ■ gives the 250HD2 product as a free hydroxy compound, but not as a 3- or 25-protected or 3,25-di-protected derivative of 5.7-
Analogous transformation of diene intermediate (7) can yield the corresponding hydroxy-protected derivative of the 250HD2 product. [0022] Individual 250HD2 epimers, i.e., 250HD2 or 25-0H-24-shrimp-D2 (10) obtained in the free hydroxy form, can be reacted with C-3 or 25-0H-24-shrimp-D2 (10) by conventional reactions known in the art. C-2
Conveniently hydroxy protected at 5 or both positions. 250HD2 can be acylated, e.g. 25-0HD23-acetate or the corresponding 3,2
5-diacetate may be produced. Similarly, the 3-monoacetate can be converted to C-2 by treatment with different acylating reagents.
5 may be further acylated, or 3.25-
The diacetate may be selectively hydrolyzed with mild base (KOH/MeOH) to yield the 25-monoacetate, which can be reacylated with a different acyl group at C-3 if desired. Other hydroxy protecting groups can also be introduced by similar known reactions. [0023] In addition to the hydroxy-protected derivatives, 2
The 5,6-trans isomer and 1,25-dihydroxy compound of 5-0H-24-epi-D2 is a compound with potential medical utility due to its important vitamin D-like activity. . These 5. 6-) Lance compounds include Lek, Trub, such as Verloop,
Chim, Pace Bass (Rec, Trav,
Ch im. The 5,6-
The corresponding 3- and/or 25-hydroxy protected derivatives obtained from the cis isomer (i.e. 10 or 15) can be obtained by analogous isomerization of the corresponding 5,6-cis-acylate or from the 5,6- trans-25-OH
A similar result is obtained by hydroxy protection of the D2 compound. [0024] The desired side chain fragment sulfone (
21) itself is obtained according to the method shown in the process scheme. The synthesis is simple and the first step involves reaction of ester (16) with methylmagnesium bromide in anhydrous tetrahydrofuran (THF) to yield diol (17). Diol (17) is dissolved in anhydrous pyridine and reacted with p-toluenesulfonyl chloride to yield tosylate (18). Tosylate (18
) is dissolved in a solution of anhydrous dimethylformamide and reacted with thiophenol and t-BuOK to yield the sulfide (19). The sulfide (19) was then dissolved in dichloromethane and then reacted with 3-chloroperoxybenzoic acid to form the hydroxysulfone compound (20
). Pyridinium p-)luenesulfonate is then added to a solution containing compound (20) in anhydrous dichloromethane and reacted with dihydropyran to form the hydroxy-protected tetrahydropyranyl sulfone (21a).
get. The corresponding (S)-epimer of sulfone (21) corresponds to (16) as starting material and has (S) at carbon-2.
) is prepared in the same way using an ester with the configuration. [0025]

EXAMPLES The invention will be further explained by way of illustration. In this illustration, a number of specified specific products such as compound 1
．． 2.3 etc. indicates structures so numbered in Process Schemes ■ or II. [00261 Example 1 Ergosterol method 50 g of ergosterol 1 (
0.13 mol). The mixture was stirred at room temperature overnight and then 600 ml of water were added. The precipitate was filtered, washed several times with 200 ml of water, and then recrystallized from ethanol to yield 42.0 g (76%) of 2 (yellow-white crystals). [0027] 33g of 2 in 500ml of chloroform
(0,075 mol) of 4-phenyl-1゜2
．． 13.2 g of 4-triazolyl-3,5-dione (0,
075 mol) was added. The solution was stirred at room temperature for 30 minutes and then 5 ml of pyridine was added. The solution was cooled to -78°C and then treated with an ozone-oxygen mixture for 30 minutes (TCL control) and then thoroughly purged with nitrogen. 50 ml of dimethyl sulfide was added and the mixture was diluted with 3
Washed with 00 ml of water, 200 ml of 2N HCI (2 times) and a further 300 ml of water. The organic layer was separated and each wash was extracted with 400ml and 200ml of chloroform. -The combined extracts were dried over Na2SO4 and concentrated under vacuum. The residue was purified using a silica gel column (5, Ox 63 cm, 550 g of 150-42
5 μm silica gel). 20.5g (50%)
4 was eluted with 30% ethyl acetate in hexane. To increase the yield, the recovered 3 (eluted with 15% ethyl acetate in hexanes) was treated with the ozone-oxygen mixture described above. [0028] At -78°C, 12.1g (
37.1 mmol) of sulfone 21.5.10 m1 (3
6,4 mmol) of diisopropylamine and 100
ml of anhydrous tetrahydrofuran (containing 1,10-phenanthroline as indicator),
22.7 ml (36.3 mm1) of n-BuLi (
1.6M in hexane) was added. The solution was heated under nitrogen for 7
Stirred for 30 minutes at 8°C, then 10.0 g (18.3 mmol) of 4 in 40 ml of anhydrous tetrahydrofuran were added. The mixture was stirred at -78° C. for 1 hour, then decomposed by adding 100 ml of saturated NH4Cl solution, warmed to 0° C. and then extracted three times with 100 ml of ethyl acetate. Each extract was added to 1 part of saturated NaCl solution.
00ml, then dried over Na2SO4 and then concentrated in vacuo. The residue was filtered through a silica gel column (3,
2x60cm, 75-150μm silica gel 150g)
It was purified with Unreacted sulfone 21 was eluted with benzene and 14.7 g (92%) of 5 was eluted with ethyl acetate. [0029] Methanol 4 saturated with Na2HPO4
00ml 110g of 5% sodium amalgam and 5 hydroxysulfones 14. A mixture consisting of 7 g (16.9 mmol) was stirred at 5° C. for 20 hours under nitrogen atmosphere. The reaction solution was decanted and then concentrated in vacuo. Dissolve the residue in 200ml of ethyl acetate and add 400ml of water.
Washed with ml and 200ml. The ethyl acetate extracts were separated and each wash was extracted twice with 200 ml of ethyl acetate. - The combined extracts were dried over Na2SO3 and then concentrated in vacuo. 10.5 g (91%) of 6 was obtained. [00301 10.5 to 400ml of tetrahydrofuran
g (15.4 mmol) of a solution containing 6, 11.5 g
(303.0 mmol) of L i A I H4. The mixture was heated under reflux under a nitrogen atmosphere for 3 hours, then cooled with ice water and then decomposed by dropwise addition of 40 ml of ethyl acetate and 60 ml of water. next,
The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 200 ml of ethyl acetate and then saturated NaC.
Washed twice with 200ml of 1 solution. The ethyl acetate extracts were separated and each wash was extracted with 200ml of ethyl acetate. - Dry the combined extracts with Na2SO4 and then
Concentrated in vacuo. Next, the residue was transferred to a silica gel column (
3.2x25cm, 75-150μm silica gel 80g
) and 4.8 g (63%) of 7 was eluted with benzene containing 5% ether as eluent [yellow foam]. (00311) To a solution of 4.4 g (8.9 mmol) of 7 in 200 ml of methanol and 130 ml of dichloromethane was added 2.0 g (7.9 mmol) of pyridinium p-toluenesulfonate. After stirring overnight at room temperature, it was dissolved in 300 ml of saturated NaCl solution and then extracted three times with 400 ml of dichloromethane. Each extract was dissolved in 4 ml of saturated NaCl solution.
00ml and then combined, dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from ethanol to yield 2.5 g (68%) of 8 [white crystals]. To increase the yield, the mother liquor was concentrated in vacuo and then purified by chromatography before recrystallization from ethanol. [0032] 1.50 g (3.6 mmol) of 8
, 500 m of a mixture of ethanol and benzene (4:1)
water-cooled quartz immersion well with an ozone-free filter.
Eikosha (E well) with stirring under nitrogen.
i ko 5 ha) Irradiated with a high pressure UV lamp for 25 minutes. The reaction is Lichrosorb
Monitored by HPLC at 268 nm using a Si60 (5 μm) column and 3% 2-propanol in hexane. [0033] The solution was concentrated in vacuo and then redissolved in 100 ml of ethanol before heating under reflux and nitrogen for 3 hours. The solution was then concentrated in vacuo and the residue was purified using a silica gel column (3.2 x 50 cm,
75-150 μm silica gel (170 g). 0.74 g (50%) of 10 was eluted with 20% ethyl acetate in hexanes [white foam]. [0034] To a solution of 50 g (3.6 mmol) of 10 in 15 ml of anhydrous pyridine,
1.50 g (7.9 mmol) of tosyl chloride was added. The mixture was stirred at 5°C under nitrogen for 20 hours. next,
This solution was poured into 200 ml of cold saturated NaHCO3 solution. The mixture was allowed to stand for 30 minutes and then extracted three times with 150 ml of a mixture of ether and dichloromethane (4:1). Each extract was prepared using 150 ml of saturated NaCl solution. Cold rare HC
2 x 150 ml of 1 solution, 150 ml of saturated NaCl solution
, 150 ml of saturated Na HCOs solution and saturated Na
Washed with 150 ml of C1 solution. -The combined extracts are
Dry over Na2SO4 and concentrate in vacuo. 11
1.90 g (92%) of was obtained and converted to 12 without further purification [white form]. [0035] 40 g of anhydrous KHCO 3 was dissolved in 200 ml of anhydrous methanol at 50° C. under nitrogen. To this solution was added 1.90 ml of 11 in 30 ml of anhydrous dichloromethane.
A solution containing g (3.4 mmol) was added dropwise. The mixture was stirred for 21 hours at 50° C. under nitrogen. The solution was then concentrated in vacuo and the residue was dissolved in 200 ml of a mixture of ether and dichloromethane (4:1) and washed twice with 100 ml of water. Separate the organic extract and mix each wash with 100ml of the same mixture of ether and dichloromethane.
Extracted twice with 1. - Combined extracts with Na2 S04
1.50 g (
105%) obtained [yellow oil]. (0036) 2.7 ml (8.1 mmol) of t
ertbutyl hydroperoxide (3.0M in 2,2-4-trimethylpentane) was dissolved in anhydrous dichloromethane 7.
220mg of selenium dioxide contained in 5ml (2
,0 mmol) was added to the suspension. The mixture was stirred for 30 minutes at room temperature under nitrogen and 0.3 ml of anhydrous pyridine was added, followed by a solution of 50 g (3.5 mmol) of 121 in 30 ml of anhydrous dichloromethane. The mixture was stirred at room temperature under nitrogen for 30 minutes and heated under reflux for an additional 10 minutes. Next, 50 ml of 10% NaOH solution is added and the mixture is dissolved in ether 200.100 ml.
and extracted with 100ml. Each extract was added to 10% NaO
Washed with 50 ml of H solution and 50 ml of saturated NaCl solution. - The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column (3.2 cm x 15 cm, 50 g of 75-150 μm silica gel) using a mixture of ethyl acetate in hexane as eluent. 581mg (37%) of 1
3 was eluted with 30% ethyl acetate in hexanes [yellow oil]. (00371581 mg (1,3 mmol) of 13 was dissolved in acetic acid and heated at 50 °C under nitrogen for 1 h. The solution was poured onto ice and then neutralized with saturated Na HCO3 solution. The mixture was dissolved in ether and dichloromethane (4:
Extracted three times with 150 ml of the mixture of 1). Each extract was washed with 100 ml of saturated NaHcO3 solution and 100 ml of saturated NaCl solution. - Combined extracts with Na2S
Dry with O4 and concentrate in vacuo. 120 mg of maleic anhydride were then added to a solution of this residue in 10 ml of ethyl acetate, and the mixture was left for 2 hours at room temperature under nitrogen. The solution was then concentrated in vacuo and the residue was redissolved in 50 ml of ether. 50m of 0, IN KOH contained in methanol
1 was added and the solution was stirred at room temperature for 1.5 hours before being concentrated in vacuo. The residue was dissolved in 100 ml of a mixture of ether and dichloromethane (4:1) and 10%
twice for 2 hours with 50 ml of NaOH solution, then saturated NaC
Washed with 50ml of 1 solution. The organic extracts were separated and each wash was extracted twice with 100 ml of the same mixture of ether and dichloroethane. - The combined extracts were dried over Na2SO4 and then concentrated in vacuo. The residue was purified on a silica gel column (2.3 x 8.0 cm, 10 g of 45-75 μm silica gel) using a mixture of hexane and ethyl acetate as eluent. 310 mg of 15 was eluted with 30% ethyl acetate in hexane and another 15 3
37 mg and recrystallized from methyl formate. [00381 Example 2 20 g (0,169 mol) of intermediate for side chain methyl (R) -(-)
-3 Hydroxy-2-methylpropionate 16 is dissolved in 60 ml of anhydrous tetrahydrofuran and 245 ml of methylmagnesium bromide (0,
735 mol) to a stirred solution. At the end of the addition, 100 ml of anhydrous tetrahydrofuran was added to facilitate stirring. The mixture was stirred for 2 hours at room temperature, then decomposed with careful addition of 1150 ml of 5N HC while cooling with ice, and then extracted three times with 200 ml of ether. Each extract was washed with 150 ml of saturated NaCl solution, then combined and dried over Na2SO4. 16.4 by evaporation
g (82%) of 17 was obtained as a yellow oil. [0039] A mixture consisting of 16.4 g (0,139 mol) of 17, 26.5 g (0,139 mol) of tosyl chloride and 30 ml of pyridine was stirred at 4° C. overnight. The reaction mixture was then dissolved in 300 ml of ether, followed by 200 ml of water, 200 ml of dilute HCI, 2
00 ml of water and then 200 ml of saturated NaHCO3 solution. The ether extracts were separated and each wash was extracted twice with 200 ml of ether. - The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was filtered onto a silica gel column (5.5 x 20 cm, 150
425m silica gel (200 g), 32. 1
g (85%) of tosylate (18) was eluted with 1020% ethyl acetate in hexane [red oil].

To a stirred solution of 14.4 g (0.131 mol) of thiophenol in 70 ml of anhydrous dimethylformamide was added 14.4 g (0.131 mol) of t.
-Add BuOK and then anhydrous dimethylformamide 9
32.1 g (0,118 mol) of 18 in 0 ml were added. This mixture was stirred overnight and then heated to 300 ml of ice water.
ml of 300.200 ml of ethyl acetate, then 2
00ml was extracted sequentially. Each extract was washed with 200 ml of saturated NHCO3 solution and water before being combined and N
Dry with a2SO4 and then concentrate in vacuo. 2
8.0g (113%, including dimethylformamide)
19 was obtained and was oxidized without further purification [
red oil]. [0041] 28. og (o, 118 mol) of 19 was dissolved in 400 ml of dichloromethane and cooled with ice water. To this solution was added 51.7 g of m-chloroperbenzoic acid (0
, 300 mol) was added slowly and the mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was diluted twice with 300 ml of saturated NaHCO3 solution and 3 times with 300 ml of saturated NaHCO3 solution.
twice with 2SO3 solution and further 300 ml of saturated NaHC
Washed with O3 solution. Separate the organic phase and add each wash to 300 m
1 and extracted twice with dichloromethane. - The combined extracts were dried over Na2SO4, then concentrated in vacuo and recrystallized from a mixture of ethyl acetate and hexane to give 25
2g (88%) of 20 was obtained [white crystals]. (0042) 20g of 20 in 50ml of dichloromethane
20 ml (0.22 mol) of freshly distilled 2,3-dihydrofuran were added to the stirred solution containing (0.083 mol) and a further 0.8 g of pyridinium p-toluenesulfonate. The mixture was stirred for 2 hours at room temperature and then washed twice with saturated NaCl solution. The organic phase was separated and each wash was extracted twice with 50 ml of dichloromethane. - The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was transferred to a silica gel column (3
゜2x45cm, 75-150μm silica gel 150
g) and 26. og (96%) of 21a was eluted with benzene as eluent [colorless oil]. [0043]

Effect of the invention: According to the present invention, 25-hydroxy-24
Epi-vitamin D2 is obtained by an effective and simplified process to produce vitamin D2 compounds of importance as dietary supplements or medicines. [0044]

[C20] Ototsuji Fυnitoyu

[C21] Process scheme [0045]

[Chemical formula 22] Process scheme II

Claims (10)

[Claims] Claim 1: In producing 25-hydroxy-24-epi-vitamin D2 represented by the following formula [1], a steroid aldehyde of the formula [2] (wherein, Xl is a hydroxy protecting group) is converted into a steroid aldehyde of the formula [2] (wherein, Xl is a hydroxy protecting group) 3) (wherein X2 is a hydroxy protecting group) is condensed with an aryl sulfone to obtain a sulfonyl adduct of the formula [4] (wherein C of Xl hydroxyduct and X2 have the above meanings), Optionally, the adduct is acylated or sulfonylated before the adduct is reduced to form an intermediate of formula [5], where Xl and X2 are hydrogen or hydroxy protecting groups. and converting the intermediate into 2
A method for producing 25-hydroxy-24-epi-vitamin D2, which comprises obtaining 5-hydroxy-24-epi-vitamin D2. 2. Process according to claim 1, characterized in that the 25-hydroxy-epi-vitamin D2 is further 1α hydroxylated to obtain the corresponding 1α hydroxymo2 compound. 3. To produce 25-hydroxy-vitamin D2 having the following formula [6], a steroid aldehyde of the formula [7] (wherein, Xl is a hydroxy protecting group) is converted to a steroid aldehyde of the formula [8] (wherein , X2 is a hydroxy protecting group) and condensed with an aryl sulfone of the formula:
Optionally, the C-22-hydroxy group of the adduct is acylated or sulfonylated to obtain a hydroxy-sulfonyl adduct of the formula or a hydroxy protecting group), and converting the intermediate to obtain 25-hydroxy-vitamin D2. 4. Process according to claim 3, characterized in that the 25-hydroxy-vitamin D2 is further 1α hydroxylated to obtain the corresponding 1α hydroxymo2 compound. 5. In producing 25-hydroxy-vitamin D2 having the following formula [11], a steroid aldehyde of the formula [12] (wherein, Xl is a hydroxy protecting group) is converted to a steroid aldehyde of the formula [13] (formula (wherein, X2 is a hydroxy protecting group) is condensed with an aryl sulfone of the formula [14] (wherein, Xl and X2 have the above-mentioned meanings)
Optionally, the C-22-hydroxy group of the adduct is acylated or sulfonylated to obtain a hydroxy-sulfonyl adduct of the formula A method for producing 25-hydroxy-vitamin D2, which comprises obtaining an intermediate of 25-hydroxy-vitamin D2 or a hydroxy-protecting group, and converting the intermediate to obtain the desired 25-hydroxy-vitamin D2. 6. Process according to claim 5, characterized in that the 25-hydroxy-shrimp-vitamin D2 is further 1α-hydroxylated to obtain the corresponding 1α-hydrokymo2 compound. [Claim 7] The compound is 25-hydroxyvitamin D2.
The manufacturing method according to claim 5, characterized in that: 8. The method according to claim 5, wherein the compound is 25-hydroxy-24-shrimp vitamin D2. 9. The method according to claim 6, wherein the compound is 1α,25-dihydroxyvitamin D2. 10. The method of claim 6, wherein the compound is 1α,25-dihydroxy 24-epi-vitamin D2.