JPS58135855A - Cyclovitamin d derivative - 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 Technical Field This invention concerns cyclovitamin D# conductors, which are important intermediate compounds in the preparation of compounds with vitamin D-like activity.

More specifically, the invention relates to cyclovitamin D derivatives which are used to prepare compounds with vitamin D-like activity, having one oxygen function at the carbon 10 position of the molecule.

It is well known that vitamin D exhibits certain biological effects such as stimulation of calcium absorption in the intestine, stimulation of bone mineral resorption, and prevention of rickets.

It is also a well-known fact that such biological activity is due to the fact that these vitamins are converted into hydroxylated derivatives in vivo, that is, undergo metabolic changes. For example, according to recent evidence, 1α, 25-
Dihydrokilevitamin D.

is the active form of vitamin D in vivo, and it has been pointed out that this compound is involved in the biological effects mentioned above.

Synthetic lα-hydroxyvitamin D analogs, such as lα-hydroxyvitamin D1.1α-hydroxyvitamin D, also exhibit significant biological efficacy, and such compounds, including natural metabolites, have been shown to improve calcium metabolism and It has great potential as a therapeutic agent for bone diseases such as osteodystrophy, osteomalacia, and osteoporosis.

BACKGROUND OF THE INVENTION Because 1α-hydroxylation is an essential element in making vitamin D compounds and their derivatives biologically active, there is great interest in how to chemically achieve such hydroxylation. I was approached. One method proposed for the global synthesis of lα-hydroxyvitamin D (L7thgoe et al. + J, C
hem, Soc, , PerkinTrans I
, p. 2654. 1974), the synthesis of 1α-hydroxylated vitamin D compounds involved the preparation of 1α-hydroxylated steroids from which the corresponding 1α- After conversion to hydroxy-5,7 difactorysterol derivatives, the desired vitamin D compounds were usually obtained by well-known photochemical methods. As a result, effective synthetic methods involve multiple steps, which are often inefficient and laborious.

Other synthetic examples involving 1α-hydroxylation of vitamin D-related compounds can be found below. 1), Method for preparing steroid derivatives, Ishikawa et al., U.S. Patent Nos. 3 and 9
No. 29,770, published December 30, 1957. 2),
Method for preparing 1α,25-dihydroxycholecalciferol, Matsunaga et al., U.S. Patent No. 4,022,768
No., published May 10, 1977. 3).

1α-hydroxycholecalciferol, DaLuea
Also, U.S. Patent No. 3,741,996, issued June 26, 1973. 4), 1α-hydroxyergocalciferol and method for preparing the same compound, DaLuea
Yu, U.S. Pat. No. 3,907,843, September 23, 1975.

5), Selenium dioxide oxidation of colcalciferol, Bo
Humil Pe1e, Stayed, Volume 30, Mu2.
August 1977.

DISCLOSURE OF THE INVENTION The compounds of this invention can be used to treat vitamin D or vitamin D.
We have discovered a new method for introducing a hydroxyl group at the carbon atom 1 (C-, 1) position of a derivative molecule, which is fundamentally different from conventional synthetic methods both conceptually and in terms of implementation. This method, which will be explained in detail later, is a method of directly attaching one oxygen function to the C-1 position by allyl oxidation.

Generally, in preparing the 1α-hydroxylated compound represented by the general formula, this method allylicates the compound of the present invention represented by the following general formula (hereinafter generally referred to as silleropitamine D),
Collecting the 1α-hydroxylated cyclovitamin D compound from the allyl oxidation reaction mixture, acylating the recovered compound, recovering the product 1α-0-acyl derivative, and performing acid-catalyzed solvolysis of the derivative; The desired 1α-O-acyl vitamin D compound is recovered and 1α
The -0-acylated product is hydrolyzed (or reduced with a hydrogenating agent) to obtain a 1α-hydroxyvitamin D compound.

In the method described above, 8 in the formula represents a steroid side chain, most commonly substituted or unsubstituted,
There are also saturated or unsaturated or substituted unsaturated cholesterol side groups, in the formula 211 hydrogen atoms, lower alkyl groups, lower acyl groups, or aromatic acyl groups.

Preferably, R is a tosulcholesterol or ergosterol side chain group characterized by having a hydrogen atom or a hydroxyl group at the 25th carbon atom (C-25) in the target molecule.

*"Lower" is used here and in the following claims as a modifier of alkyl or acyl to mean a hydrocarbon chain having from 1 to about 4 carbon atoms; Includes both stranded or branched stranded sequences. Aromatic acyl groups include benzoyl groups and substituted benzoyl groups. Also, in the various formulas, a wavy line to a substituent indicates that the substituent is in the α or β stereoisomeric form. It is desired that R in all of the above and the formulas in the claims is a cholesterol side chain having the following structural formula.

Here, each of RlR and R1 is selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a 〇-lower alkyl group, a substituted 〇-lower alkyl group, and fluorine.

The most preferred side chain groups having the above structure are R1 and R.
Examples include those in which 1 is a hydrogen atom and R2 is a hydroxyl group. Other preferred side chain groups include those in which R1, R1 and R1 are hydrogen atoms, or R1 is a hydroxyl group and R
Examples include those in which 2 and R3 are hydrogen atoms, or those in which R1 and 82 are hydroxyl groups and R1 is a hydrogen atom.

Another preferred side group represented by R is an ergosterol side group characterized by the formula:

Here, each R1, R, and R8 are a hydrogen atom,
It is selected from the group consisting of hydroxyl group, lower alkyl group, substituted lower alkyl group, 〇-lower alkyl group, substituted 〇-lower alkyl group and fluorine, and R4 is selected from the group consisting of hydrogen atom and lower alkyl group.

The most desirable side chain group having the above-mentioned ergosterol side chain arrangement is that R1 and R1 are hydrogen atoms, R- is a hydroxyl group, and R
4 is a methyl group, or R, R, and R1 are hydrogen atoms, R4 is a methyl group, and R4 is stereochemically similar to ergoste-4.

If a hydroxyl group is present in the side group R of the cyclovitamin D starting material, this group can be acylated in any case to a lower acyl group, such as an acetyl group, a substituted lower acyl group, or to a benzoyl group, a substituted benzoyl group, etc. This acylation is not necessarily required in this method, although it is clear that it can be changed to

The cyclovitamin starting material for the oxidation process can be easily prepared from vitamin D compounds in two steps. That is, a vitamin D compound having a 3β-hydroxyl group is converted to the corresponding 3β-tosylated derivative, and this tosylated product is then subjected to norpolysis in a suitable buffer solution such as a methanol/acetone mixture containing sodium acetate. to obtain the cyclovitamin product. 5heves and Mazur (J, Am, Ch@os, Soe
, 97.6249 (1975)) applied this technique to vitamin D, and obtained cyclovitamin D3 as the main product. They gave this compound the following structural formula. In other words, 6R-methoxy-3,5-cyclovitamin D,
It is.

The cyclovitamin by-product formed in this step was confirmed to be a metal compound with a 68-methoxy sequence.

Here, the solvolysis reaction mentioned earlier is changed if N
It has been found that when run in methanol using aHCO, buffer, a better yield of the cyclovitamin product can be obtained than the methods of 5heves and Mazur.

In addition to this, it has been found that vitamin D compounds bearing other chemically reactive substituents (such as side chain hydroxyl groups) can also be efficiently converted to their cyclovitamin Dll conductors. For example, if 25-hydroxyvitamin D3 is used as a starting material in the above process, 25-hydroxy-6-medoxy3.5-cyclovitamin D3
can be seen. The structure of this compound is as follows, where R represents the 25-hydroxycholesterol side chain. Similarly, when 24.25-dihydroxyvitamin D is used as the starting material in step 1 above, 24.25-dihydroxy-6-methyl-3,5-cyclovitamin D as shown below is produced. Here 10124, 25-
Represents dihydroxycholesterol side chain. Using vitamin D as a starting material, a similar procedure yields cyclovitamin D2, which also has the structure shown below, where R represents the ergosterol side chain. These cyclovitamin D compounds are new compounds.

By analogy with the results of 5haves and Mazur cited above, the 6R-methoxy stereochemistry corresponds to the major vitamin D product obtained in these reactions, and the 6S-methoxy configuration represents a minor component of the cyclovitamin-forming mixture. component (
5-10%). Leg 11 of the 1α-hydroxyvitamin D compound according to the method described above does not require separation of these stereoisomers.

However, if necessary, these separations can be carried out by conventional methods, and either C-(6)-epimer can be used, although the production efficiency is not necessarily the same.

For the above reasons, the stereochemical arrangement (structure) at C-6 of the cyclovitamin D compound is not specified in Book #4IIA and the claims.

By appropriately selecting a mouse reagent or conditions, a cyclovitamin D analog represented by the following general formula can be obtained.

Here 2 represents a hydrogen atom, an alkyl group or an acyl group, and R represents any type of side chain structure defined above. For example, if ethanol is used instead of methanol as the medium for solvolysis, a cyclovitamin having the above structure in which 2 represents an ethyl group is obtained. It is evident that other O-alkylated cyclovitamin D products can be obtained by using appropriate alcohols in the reaction medium.

Similarly, solvolysis reaction media consisting of H,0-containing solvents such as acetone/H20 mixtures, dioxane/H,0 mixtures, in the presence of acetate or other buffer solutions, are yields the corresponding cyclovitamin D compound of structural formula that is atomic.

5haves and Mazur (Tetrahedr
on Letters (Mu34) pp, 2987-
29990 (1976)) in fact prepared 6-hydroxycyclovitamin D3.

In other words, vitamin D is treated with aqueous acetone buffered with KHCO3, which is a silyl compound, and in the above structural formula, 2 is water W.
A compound was prepared in which AN child, R, is a cholesterol side chain.

Here, the 6-hydroxy cyclovitamin can be converted into the corresponding acyl derivative (i.e. where 2 is an acyl group such as acetyl or benzoyl) by acylation under standard conditions (acetic anhydride/pyridine) if necessary. was discovered.

In addition, 1. When the above solvolysis is carried out using dry methanol containing sodium acetate as a medium, acylated cyclovitamin D, in which 2 is an acetyl group in the above structural formula, is produced as a by-product. Cyclovitamin D compounds in which 2 is a methyl group are preferred starting materials for the subsequent reactions.

The compounds of the present invention are then allyloxidized to the corresponding 1α-hydroxy compounds, the 1α-hydroxy compounds are acylated to give 1α-0-acylcyclovitamin D compounds, the derivatives are subjected to solvolysis, and the solvolysis products are obtained. is converted into the corresponding hydroxy compound to obtain the 1α-hydroxylated compound represented by the general formula (I).

Allyl oxidation is commonly carried out using selenium dioxide as the oxidizing reagent in a suitable solvent such as, for example, CH, Ct, CHCt, dioxane, tetrahydroctane, and the like. Due to the nature of this oxidation reaction, it is desirable to conduct the reaction at room temperature or at low temperature.

This oxidation reaction is also most advantageously carried out in the presence of a hydroperoxide such as tert-butyl-hydroperoxide. The oxidation product, the 1α-hydroxycyclovitamin D compound, can be easily recovered from the reaction mixture by solvent extraction (such as ether). It is easily further purified by chromatography. Other allyl oxides can be used if desired. Naturally, if other oxides are used, the yield of the product will be different, and the oxidation conditions will need to be changed, but this will be obvious to those skilled in the art. The product resulting from the allyl oxidation of a cyclovitamin D compound in which 2 is a lower alkyl group (eg, methyl group) in the above structural formula can be easily explained by the following 2.

Here, R is any of the side chain groups specified above, and 2 represents lower alkyl (such as a methyl group).

Oxidation of cyclovitamins by this method of preparation can yield l-hydroxycyclopitami/ with the desired lα-stereochemistry. In other words, this 1α-stereochemistry is the biologically active 1-hydroxylated vitamin D.
Biologically active metabolite. The regio- and stereochemical selectivity and remarkable high efficiency of this oxidation method are both novel and completely unexpected;
Furthermore, all of the 1α-hydroxycyclovitamin D compounds disclosed herein are novel compounds.

A by-product of selenium dioxide oxidation of a cyclovitamin D compound is a 1-oxocyclovitamin D derivative having the following structure.

Here, 2 represents a lower allyl group, and R consists of any of the side chain groups defined above. These 1-oxocyclovitamin D derivatives are hydrogenating agents (e.g., LiAlH4+ N
It is easily reduced with aBH45 (and other equivalent reagents) and mainly produces 1α-hydroxycyclovitamin D derivatives having the formulas already explained. The facile reduction of lα-oxocyclovitamin D compounds and the preferential production of lα-hydroxycyclovitamin D compounds, especially those with lα-stereochemistry, are unexpected findings. From a mechanistic argument, 1-oxocyclovitamin D
The hydrogenation-reducing agent approaches the compound from the side with less hindrance in terms of molecular space, and in that case, it is expected that 1β-hydroxycyclovitamin evimer will have a preferential effect. This is because that.

Acylation of the recovered 1α-hydroxycyclovitamin D compound is easily accomplished by standard methods using well-known acylating agents such as acetic anhydride in a suitable solvent such as pyridine. This is usually done in a room mttc for several hours, e.g. overnight. The product of acylation is the corresponding 1α-0-acylcyclovitamin D compound. In preparation for the next reaction, this is recovered in a sufficiently pure KN form by solvent (e.g., ether) extraction and solvent evaporation from the medium.

Side chain (R) of 1α-hydroxycyclovitamin D compound
Any primary or secondary hydroxyl groups present therein are also acylated under such conditions. If complete acylation of tertiary hydroxyl groups (eg 25-hydroxy groups) is required, stronger acylation conditions are usually required. For example, acylation is performed at high temperature (75 to 100°C). In such cases, it is preferable to carry out the reaction in a nitrogen atmosphere to avoid decomposition of unstable compounds. The product of such acylation is described by the following formula.

Here, Y represents a lower acyl group or an aromatic acyl group, 2 represents a lower alkyl group, and R represents any of the steroid side chains defined earlier in this specification. Here, the initially present primary or secondary hydroxyl group is now present as the corresponding O"-acyl substituent, and the initially present tertiary hydroxyl group is now present as a hydroxyl group or as an O"-acyl substituent, depending on the conditions selected. By acid-catalyzed solvolysis of the cyclovitamin present as
1α-0-acyl cyclovitamins can be converted to lα-0-acyl vitamin D derivatives. Therefore, 1α-0-acyl cyclovitamin D (p-) in a suitable solvent mixture (e.g. dioxin/H2O)
When heated with luenesulfonic acid, a 1α-O-acyl vitamin D compound is produced. 5heves and Mazur utilized this reaction for the conversion of cyclovitamin D to vitamin D (J.

Am, Chem, Soe, 97.6249 (1
975)).

In a new and surprising discovery, neither obvious nor plausible from the prior art, 1α-0-acyl cyclovitamin D compounds can be converted to the corresponding 1α-0-acyl vitamins in very high yields by acid solvolysis. That's what it means.

This result was completely unexpected since the allylic 1α-oxygen function of the 1α-hydroxycyclovitamin D compound was expected to be very unstable under such solvolysis conditions.

1α- in the presence of organic carboxylic acids such as acetic acid, formic acid, etc.
Hydroxycyclovitamin D can also be directly solvolyzed to recover the corresponding civitamin D derivative in 3-0-acyl 1α-hydro, and such derivative can be converted to the corresponding hydroxy compound and recovered.

It is also important to protect the tertiary or allyl-alcohol functions present in the side chains by converting them to the corresponding acylates or other suitable acid-stable protecting groups. The product, 1α-0-acyl vitamin D, can be easily extracted from the sorbosone mixture with a solvent and further purified by chromatography. Due to this solvolysis reaction, the natural 5°6-
Both the 1α-0-acyl vitamin D1 with the Z3 double bond geometric isomer and the corresponding 1α-0-acyl vitamin D with the 5,6-trans geometric isomer contain approximately 5:
Obtained in a ratio of 1. These products can be easily separated by solvent extraction and chromatography, resulting in pure lα-O-acyl vitamin D products with the general formula as explained below (as well as If necessary, the corresponding 5,6-) lance-isomer can be obtained).

Here, Y represents a lower acyl group (eg, acetyl group) or an aromatic acyl group (eg, benzoyl group), and R represents any of the steroid side chains defined above. It will be understood that all hydroxyl functions herein are present as their corresponding 0-acyl derivatives.

Removal of the acyl protecting group by hydrolysis or reduction converts the 1α-0-acylvitamin Da conductor into 111JILK.
It can be converted to the desired 1α- and droxyvitamin D compounds. The selection of individual methods is 1, the nature of the compound, %
It varies depending on the nature of the side chain R group and its substituents. For example, if functional groups susceptible to reduction such as ketones and esters are to be avoided from being simultaneously reduced, reduction with hydrides should not be performed. In this case, it is also possible to convert such functional groups into a suitable form before the reductive removal of the acyl groups. Thus, by treatment of the acylate with a suitable hydrogenation reducing agent (e.g. lithium aluminum hydride),
The corresponding 1α-hydroxyvitamin D compounds can be obtained. Similarly, the desired 1
It is also possible to obtain α-hydroxy derivatives. In this case, it will be understood that stronger conditions (high temperature, long reaction time) are required when the side chain has an 0-acyl group with large steric hindrance (for example, tertiary). 1α-Hydroxyvitamin D compounds prepared by either method can be obtained in pure form by solvent extraction (e.g. ether) and chromatography and/or crystallization from a suitable solvent.

Another new method for converting 1α-0-acyl cyclovitamin D compounds to the corresponding vitamin D products is
There is a method of acid-catalyzed solvolysis of tecyclovitamin compounds in a medium consisting of an acid (eg acetic acid, formic acid). In this case, if it is necessary to dissolve the cyclovitamin in %, acetone or dioxane may be used as a co-solvent. This method is particularly advantageous if the side chains contain tertiary hydroxyl groups (for example 25-hydroxyl groups), since there is no need to protect such functionalities as their acyl derivatives. For example, when solborinsing lα-acetoxyvitamin D, in glacial acetic acid, 1α-acetoxyvitamin D, 3β acetate and the corresponding 5
, 6 trans compounds are produced in a ratio of about 3:1. These products can be separated by chromatography. These mixtures can also be hydrolyzed under basic (such as KOH/MeOH) conditions to yield 1α- and droxyvitamin D, and the corresponding 1α-hydroxy-5,6-)lancevitamin D.

K conversion, which can then be separated chromatographically. This method can be applied to any of the 1α-0-acyl cyclovitamin D compounds having any of the side groups R defined previously in this manual.

Even more advantageously, the solvolysis of the 1α-0-acylcyclovitamins can be carried out in formic acid or in formic acid with a suitable co-solvent such as dioxane. In this method, a derivative of lα-〇-acyl-vitamin D3β-formate as shown in the following formula is prepared, where Y is a lower acyl group (preferably not a formyl group) or an aromatic acyl group, and 8 is a Any of the side chain groups already defined. Here too, the corresponding 5,6-) lanced metals are produced as by-products. The 3β-0-formyl group is easily hydrolyzed under conditions such that the lα-0-acyl group is not affected (2-3 min treatment with potassium carbonate II, as shown in the example below). Therefore, the 3-0-formyl product is easily converted into 1α-〇-
Acyl vitamin D and its corresponding 5,6-) lance isomer can be converted. This mixture can be easily separated at this stage by chromatographic methods to provide pure lα-0-acylvitamin D and the corresponding 5
, 6-) Lance 1α-〇-acyl vitamin D can be obtained. This can now be separately subjected to alkaline hydrolysis or reductive R-cleavage of the acyl group to yield the 1α-hydroxyvitamin D compound and the 5.6-) lance-1α-hydroxyvitamin D compound.

Another novel method for converting lα-0-acyl cyclovitamin derivatives into lα-0-acyl-3β-formi^vitamin D compounds having the structural formula described above is
1 crown ether" catalyst. For example, an appropriate crown ether (e.g. 15-crown 5
Aldrich CherniealCo, Milw
aukee) and formite ion, lα-0-
Acylcyclovitamin D hydrocarbon (fl.

According to a two-phase reaction system consisting of a hexane/benzene) solution and formic acid, a high yield of lα-0-acylcyclovitamin D
can be converted into lα-O-acyl-3β-〇-formyl vitamin D derivatives.

At this time, the corresponding 5,6-) lance isomer is also produced as a by-product, but it can be conveniently separated by chromatography.

Another variation of the above method is to convert the lα-hydroxycyclovitamin D compound (with mixed acetic acid-formic acid anhydride in piriline) to the lα-formyl derivative represented by the following structural formula: It is the law.

Here, R is any of the side chain groups mentioned above, and 2 represents a lower alkyl group. This intermediate product is solvolysed in glacial acetic acid as described above to yield 1α-formyloxyvitamin D3β-acetate and the corresponding 5,6-trans isomer as a by-product. As explained above, removal of the formyl group yields 1α-hydroxyvitamin D3-acetate and its 5.6-) lance isomer. This can be easily separated by chromatography at this stage and then the individual k.

The acetate is hydrolyzed or cleaved by reduction to produce pure 1α-hydroxyvitamin D product and its 5.6
-) the lance isomer can be obtained.

The allyl oxidation process of this invention can also be applied to cyclovitamin D compounds having a 6-hydroxyl group or a 6-0-acyl group. Therefore, in the following structural formula, a vitamin compound in which 2 has a hydrogen atom and R has any of the side chain groups mentioned above has 1 carbon atom in the allyl oxidation of this invention.
is oxidized at the position to yield 1α-hydroxy-6-bitroxycyclovitamin D compounds and 1-oxo-6-hydroxycyclovitamin D compounds.

Under the previously mentioned oxidative conditions, the 5,6-ciso, lα-hydroxy-6-bitroxycyclovitamin D compound
:1lJ5.6-) A ring conversion to the lance-1α-hydroxyvitamin D product occurs. All products can be easily removed from the oxidized mixture by chromatography. The lα-hydroxy-6-bitroxycyclovitamin D compound obtained by allyl oxidation can be acylated (e.g., acetylated) by standard procedures described above. The resulting 1,6 diacyl cyclovitamin D intermediate can be easily converted to 5,6-cis and 5,6-trans-1α-0-acyl vitamin D compounds by acid norpolysis. This product can be easily separated by chromatography.

Hydrolysis (by known methods) of the 1-0-acyl derivatives yields the desired 1α-hydroxyvitamin D products and their 5,6-)lance isomers, respectively.

The 1-oxo-6-bitroxycyclovitamin D product can be easily reduced with hydrogenating agents to yield 1α-hydroxycyclovitamin derivatives.

Similarly, cyclovitamin D compounds in the above structural formula in which 2 is an acyl group (e.g., acetyl, benzoyl group) or R is any of the previously defined side groups can also be used for 6- and droxy analogs. As described, allyl oxidation,
By acylation, acid solvolysis and finally hydrolysis of the acyl group, the 1α-hydroxyvitamin D products and their corresponding 5,6-)lance isomers can be converted.

5 Remarkable and unexpected results obtained before making this invention
One discovery was that by solvolysis of 3β-tosylation (or mesylation) of lα-hydroxy or 1α-〇-acyl vitamin D # conductors, 1α-hydrocypitane D compounds can be easily and efficiently converted to lα-hydroxy. It can be converted into a fucrovitamin D compound. For example, solvolysis of 1α-acetoxyvitamin D, 3-tosylate by heating under the conditions described above, such as in a methanol solvent containing NaHCO3, yields 1α-hydroxy-6-medoxy-3,5-cyclovitamin D. Oxidation of this product (e.g. with MnO2 in CH, CL, solvent) results in the formation of the corresponding 1-oxo-6-medoxy 3.
5-cyclovitamin D.

Analogs are obtained.

As described above, the cyclovitamin D# conductor wire of the present invention is extremely suitable as a starting material for preparing a 1α-hydroxylated compound having vitamin D-like activity.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are for illustrative purposes only;
-Hydroxycyclovitamin D.

The digits indicating 4 correspond to the numbers listed below indicating the various structural formulas of the products.
5 6' 8Z=H1
0 9Z=:Ac ti 12 Example 1 1α-Hydroxycyclovitamin D, (3m) O and l-oxo-cyclovitamin D, (7m): 1.4'1F ( 1,2X
701 tert-butyl hydroperoxide (t-
Add 7 μt (5,1×1025 moles) of BuooH).

After stirring for 25 minutes, the solution was injected with 0.5 mA of CH.
, CL, K, 9N (2,3X 10'mol) (
1) 3.5-cyclovitamin, D, (compound 2a,
Vitamin D.

(1a) by the method of She ves and Mazur, J. Am. Chem. Soe.
97.6249-(1975) Drop the dissolved solution. The mixture is stirred for an additional 25 minutes at room temperature. Next, 2.0 ml of K 101 NaOH is added and the resulting mixture is diluted with 15 ml of diethyl ether. Separate the organic phase and add ton NaOH (2X 1
0mA), H2O (2X 1GmA), saturated FeSO
4 (3xlOmA) and saturated Nacz (tsmL)
and then drying with MgSO4. Removal of the solvent in vacuo yields a crude oily product. This product was dissolved in 30% ethyl acetate: Skell
Silica gel thin plate (1
When expanded at 0X 20nx, 750Jn), 1
α-Hydroxy-3,5-cyclovitamin D.

(King 3) is produced in a yield of 4.5 q (431 G″f). The product exhibits the following properties: Mass spectrum; (m/
e) 41'4 (30), 382' (70), 341 (
35).

269 (20), 247 (45), 174 (25), 1
65 (3G), 135 (65); NMR, δ, 0.53
(3HI 118-H3), 0.61 (2H,m,
4-H2), 0.87 (6H.

d, 26-H, and 27-H,), 0.92 (3H
,d, 2l-H3), 3.26(3H,l, 6-
0CH3), 4.18 (IH.

d, J=9.0)h, 6-H), 4.22(l
H, m, 1-H).

4.95 (IH, d, J=9Hz, 7-H),
5.17 (IH, d.

J=2.2Hz, 19(Z)-H), a25(I
H, d, J=2.2Hz, 19(E)-H).

As a secondary component, 2HIg (yield 19
-) of 1-oxo-Schiff vitamin D, (7m) was isolated. Massbek) Lut (m/e) 412(
40), 38G (50), 267 (15), 247 (2
3).

Ml mt 18-H,), 0.58 (2H, ml
4-H,), 0.87(6H,d, 26-H,),
0.93 (3H, d, 21·~H1).

3.30 (3H, a, 6-0CH3), 4.07 (
IH, d, J=9.0Hz, 6-H), 5.02(I
H, d, J=kai, OHz, 7-H), 5.62 (IH,
s, '19(Z)-H), 6.04 (IH.

s, 19(E)-H); UV 248 (4,000)
.

Example 2 Compound 3m (1,5q) was dissolved in 200nt dry pyridine and 50μt acetic anhydride and reacted overnight at room temperature, then diluted with 5mA saturated NaHCO3 solution. The solution is washed three times with 6 mt of ether and the organic extract is washed with H2O (2 x 10 nnA).

Next, drying over KMgSO, followed by removal of the solvent under reduced pressure, yields compound 4a.

NMR, δ, 0.53 (3H,s, 18-H,,0
, 69 (2H.

fllll+ 4-H2)w O,87(6Hw do
2'6-H3 and 27-H3), 0.92 (3H, d
, 2l-Hs), 2.10 (31°s=10Ac)
-3,26(3H,m,60CH3)-4,18(I
H, d, J = 9.2Hz, 6-H), 4.98 (IH,
d, J=9.2Hz, 7-H), 4.98(IH, d,
J=2.1Hz, 19(Z)-H), &23(IH, m
, 1-H), 5.25 (IH.

d, J-2, 1Hz, 19 (E)-H).

Snoring lα-Hydroxyvitamin D3 (6m): Add 1.3q of (4aNII solution) to 0.5mt of a 3:1 mixture of 1,4-dioxane and H, O, and heat for 55'aK.

A solution of 0.2"f of p-)luenesulfonic acid in 4 .mu.t of water is added to this and heating is continued for 30 minutes. The reaction is then quenched with saturated NaHCO@2 mA and extracted with 21 parts of 10 mA of ether. This organic extract was combined with MgSO2
Dry and remove the solvent in vacuo. This product is 3.0 *
EtOAc: 1 in 5 kellysolve B
Developed on a 0x20 scratched silica gel plate. By the above method, 400 μg of product 5a having the following properties was obtained. UV
.

λm&! 64nm; mass spectrum, m/a 442
(Ml, 75), 382 (70), 269 (15), 1
34(100)iNMR, δ, 0.52(3Ht 89
18-H2CO, 86 (6H, d, J- & 5Hz,
26-H3 and 27-H3), 0.91 (3H,
d, J=5.9Hz, 21-H3), 2.03(
3H,a, 10COCH1), 4.19 (I
H-m, 3-H) -5,04(IH,' d,
J=1.5Hz, 19 (Z) -H), 5.31
(IH* m, (1+-p), 19 (E)-H), &
49 (IH.

m, 1-H), 5.93 (IH, d, J=11.4Hz
, 7-H).

6.37 (IH, d, J=11.4Hz, 6-H)
.

Product 5a was taken up in 0.5 mA ether and excess Li
Treat with AlH4. The reaction is quenched with saturated N; CL, the product is filtered and separated by evaporation of the solvent in vacuo.

This isolated product (6a) was converted into 1α-hydroxyvitamin D.
Standard sample of , CHCA, :OH,0R=97:3 solvent tacochromatography j! I'm concerned. (1a-hi)'
o-? Shipitami/D, Rf = 0.10゜1β-hydroxyvitamin D3Rf70.1 s, product (6a
) Rf=0.10). This product is λm&X=264
The mass spectrum and nmr spectrum also show the same results as pure 1α-hydroxyvitamin Ds. , 25-hydroxyvitamin D in 0.5mt of dry pyridine
, (lb) 100 kg and p-toluene-sulfonyl chloride 150 q were reacted at 3 t for 24 hours, and then the reaction was quenched with 5 ml of saturated NaHcOs.

The aqueous phase was extracted with ether (2X10mt) and the ethereal extract was extracted with saturated NaHCO3 (axt).

mA), 3sHCL (2X10mt), and Hl0
(2X10mt) and then dried over MgSO4. The solvent was removed in vacuo and the crude residue (25- and droxyvitamin D, 3-) silates) t1. s mt
of anhydrous methanol-λ and 0.3 mt of anhydrous acetone. Na0Ae 1701F (8 eq, Washed three times with )K and develop. This yields 48"f (ib < vs. 1 part Lte45 *f) yield)
17) (2b) was obtained. Characteristics of 2b; Mass spectrum s tn/・: 414 (M”, 40), 399
(10), 382 (8G).

253 (50), 59 (100); NMR, δ, 0
．． 53 (3H.

m-18Hl)-0,74(2H-m-4-H2)-
0,94(3H,d, J=6.2Hz, 2l-Hl
), 1.21 (6H, l, 26-H, o and 27-
H3), 3.25 (3H,s, 6-OCH3).

4.16 (IH, d, J=9.2Hz, 6-H)
, 4.89 (IH.

m (Sharp), 19 (Z)-H), 4.99 (IH,
d, J=9.3Hz, 7-H), 5.04(IH, m
(Sharp), 19(E)-H).

Example 5 1α-25-dihydroxycyclovitamin D.

(3b) and l-oxo-hydroxycyclovitamin D, (7b): 8e02@1 of 2.4511II (0,5eq, )
A mixture of 4 sL (2 eq, ) of t-BuOOH, and 1.2 mA of dry 0HICL was added at room temperature to
Let it react for a few minutes. In this oxidizing medium, 0.5 m
l's cu, cz? pc dissolved cyclovitamin (2b
) Add the ill solution dropwise and continue the reaction for 15 minutes.

Next K 2. The reaction is quenched with 10% NaOH in OmA and diluted with 20at in diethyl ether. Separate the organic phase and add 1011G NaOH, H2O-saturated FeSO
4# solution and saturated NaHCO1, and then washed again with H,0
After washing with water, dry with Mg5O. The solvent was removed in vacuo and the crude residue was deposited on a thin layer of silica gel (20aI
IX20m.

5kellyaolve B at a thickness of 750 pm)
:Develop with ethyl acetate (,6:4) system. According to this method, (3b) with the following properties is 11q (yield 53-
)can get. -r SX spectrum l' e m/e 4
30 (M e 15) *412 (12), 3゛8
0 (35), 269 (10), 59 (100); NMR
, δ, 0.53 (3H,s, 18-H,)10.6
1 (2H, m, 4-H2), 0.93 (3H, d,
J=6.2Hz, 2l-Hl), 1.21(6H
*8.26 Hl and 27 Ha) = 3.25
(3H-m-60CHI), 4-17 (IH, d, J
=9.2Hz, 6-H), 4.20 (IH, m,
1-H).

4.95 (LH, d, J=9.2Hz, 7-H), 5.
19 (IH.

d, J=1.9Hz, 19(Z)-H), 5.
22 (LH, d, J=1.9Hz, 19 (E)-
H). As a by-product, 1-oxo-25-hydroxycyclovitamin D, (7b) was obtained from the product mixture (1
5Ls). Mass spectrum: m/e 428 (M).

Kan 1 1α 25-dihydroxycyclovitamin D, -200
A solution of 7q of (3b) in dry pyridine of aA is treated with 10 μt of acetic anhydride. The system is then flushed with N and heated for 16 hours at 97". After cooling, the mixture is diluted with 5 mt of saturated NaHCOs. The aqueous mixture is extracted with 2 parts of 10 ml of ether and the organic phase is 2 parts of 10at saturated NaHCO3 and 10at
H! Wash sequentially with O.

After drying over Mg5O, the solvent and residual pyridine were removed by azeotropic distillation in vacuo using benzine. Next, this coarse star product was deposited on a thin layer of silica gel.

(10mX 20aa, thickness 750JIm) K applied,
5kel-1y Hatakeo1ve B: Ethyl acetate (8:2
).

As a result, diacetate) (4b, 25'0Ac)
61111 (729) and 1.2q of the corresponding 3-acetoxy-25-hydroxy rust conductor are obtained.

Example 7 1α-25-dihydroxyvitamin D, -1,25-diacetate (5b, 25-OAe): 400 μt of dioxane: H, O (a: i) mixture was added with 3.8 q of (
4b, 25-OAe) and heat for 55 minutes. Add 8 μt of p-1 toluenesulfonic acid solution dissolved in water and continue heating for 10 minutes. The reaction is quenched with 1 saturated NaHCO and extracted with 2 portions of 10 mA ether. The ether solution was washed with 2 parts of 10 mA H2O and MgSO4
Dry at. The solvent was removed in vacuo and the residue was washed with a thin layer of silica gel (5 x 20 mm, thickness 250 m).
@1lysolve B: Develop with ethyl acetate (8:2). Thus 1.8q (45%) of (5b, 25-
OAe) was obtained. It exhibited the following properties. UV:
λmaz265nmi mass spectrum; m/e 5
00(M”, 25), 440(55), 422(
15), 398 (10), 380 (45), 134 (1
00); NMR, δ, 0.52 (3H, s, 18-
Hl), 0.92 (3H, d, J=6.2Hz,
2l-Hl), 1.42 (6H,I, 26-H
, and 27-Hl )t 1.97 (3H,a,
25-0COCH3) -2,03(3H-s-10C
OCHs) -4,18(IH,m,3-H), 5
．． 03 (IH, d, J=1.1Hz, 19(Z)-H)
, 5.31 (IH, m (Sharp), 19 (E)-H
), &49(IH, m, 1-H),! L93 (IH, d
, J=11.4Hz, 7-H), 6.37(IH,d,
J=11.4Hz.

6-H).

Example 8 Diacetate, (5b, 25
-OAe) 1q solution K L 1AIH
Add 0.5 mA of an ether solution saturated with 4. After standing for 10 minutes at room temperature, the reaction is quenched with saturated NaCj solution. Next, add K39IHC1 to dissolve this salt. The aqueous phase is extracted with ether, washed with ethereal H,0 and dried over Mg804. 51G MeOH: CH
Thin layer chromatography using CLs (5X20a+
treated with a silica gel plate (250 μm thick). As a result, 1α showing λmax 265nn* in the UV-spectrum
.

25-dihydroxyvitamin D, (6b), is 0.6q
(701) Obtained. The identification of 6b as 1α,25-dihydroxyvitamin D is determined by the mass of the product.
and nmr spectra directly compared to pure or 6
This was demonstrated by chromatography simultaneously with authentic 1α,25-dihydroxyvitamin D.

Example 9 Cyclovitamin D2 (2c): Dissolved in 0.3 mL of pyridine. 100q of vitamin Dx(le) and 100g of p-)rue/sulfonyl chloride solution were reacted for 24 hours in 3 shots, then 1
Stop the reaction with saturated NaHCO at 0 mA.

The aqueous mixture was extracted with 2 parts of 10 mA water and the ethereal extract was dissolved in saturated NaHCO3 (3X 10 mA) -3*H
C1 (2X 1GmA) and H2O (2X 10 mA
) and then dried with MgSO4. The solvent is removed in vacuo and the crude vitamin ]), -3-) sylated product is taken up in a mixture of 1.5 mA absolute methanol and 0.3 mA absolute acetone. Then add 17 oz of sodium acetate and heat the solution at 55 colors for 20 hours.

After cooling, the solution was diluted with 10 mA H,0 and 10 mA
Extract with 3 parts of ether. Organic extract at 10mA
H! Wash with 3 parts of Mg5O, dry with 3 parts of Mg5O, and remove the solvent under vacuum. The residue was removed using a silica gel thin plate (20
5kelly -5 on X20a11.750J1m)
Olve B: Separate by chromatography using ethyl acetate (8:2) as a developing agent. 6 oq (591
) (2e) is obtained. The characteristics of (g) are as follows; mass spectrum; m/e410 (M", 15L378 (
40), 253(40), 119(60); NMR.

δI O, 55 (3HI so 18-Hs) I O,
74 (2HI m, 4-H,), 0.82 and 0.84 (6H, dd, J=4.1Hz.

26-H, and 27H1), 0.91(3H, d
, J=7.0Hz, 21-Hl), 1.02(
3H, d, J=6.6Hz, 28H1)-3,26
(3H-s-60CHi)-4,13(IH-d, J
=9.6Hz, 6-H), 4.89(IH, m,
19 (Z)-H), 5.00 (IH, d, J=
9.4Hz, 7-H), ! LO4 (IH, m (Sharp), 19 (E)-H), &2G (2H, m, 22-
H and 23-H).

Example 10 1α-Hydroxycyclovitamin D! (3c) O1
．． Mix 2.7q of 5eO1 and 13.4sL of 70% t-BuOOH to 5sL of dry cH,ct,
Let it react for a minute. Next, compound 2c (aoq) was dissolved in 0.5 sL of CH2CL, and this was added dropwise to the above mixture, and the reaction was continued for 15 minutes. Next 2. Omt's 1onNa
Stop the reaction with OH. Dilute the solution with 15 sL of ether, separate the ether phase, and add 10% NaOH.

Wash sequentially with u, Ot saturated F@SO4 solution, saturated NaHCO3 and again with H,0. After drying over Mg5O, the solvent was removed under vacuum and the residue was deposited on a silica gel thin plate (20x20aw, 7504m).
lysolve B: Develop in ethyl acetate (8:2) system. (±ヱ) of 9.54 (451) is obtained.

The characteristics of (3c) are as follows. Mass spectrum; m/e4
．． 26 (M”, 55), 394 (75), 353 (30
).

269 (40), 135 (95); NMR, a, 0.5
3(3H,It 18-H,)IO,63(2HI
m, 4-H,)IO,82 and 0.84(6H,
dd, '26-H, and 27-Ha).

0.92 (3H, d, J=6.0Hz, 21-H
, ) , 1.02 (3H, d, J=6.4Hz,
28-H3) 13.26 (3H9s, 6OCH3)
= 4.18 (IH, d, J=9.6Hz, 6H)-4
,21(IH,m,,1-H),4.94(in,d,
J=9.6Hz, 7-H)', 5.17(IH,m (
sharp), 19(Z)-H), 5.19(2H, m
, 22-H and 23-H).

Fh, 24 (IH, m (Sharp), 19 (E)-H)
. The second most common compound isolated from the mixture was identified as 1-oxocyclopitaquine Dz (7e). Mass spectrum, m/e 424 (M).

Example 11 1α-Hydroxycyclovitamin D, -1-ace300
Dissolve 6.5ay of (3c) in dry pyridine of xj,
To this is added 150 μt of acetic anhydride. 55% of this solution
Heat with Th for 1 hour, then dilute with 5 sL of saturated NaHCOs and extract with 2 parts of 10 mA ether. The organic extracts were washed with saturated NaHCO, and H,O, and MgSO
Dry at step 4. Residual pyridine and solvent are azeotropically distilled off with benzene in vacuo. This results in compound 4c. Mass spectrum; m□ I++'' ~ /e 468 (M'', 4G), 408 (20), 376
(65).

251(60), 135(100).

Example 12 1α-hydroxyvitamin 1) 2-1-acetate (5
c) Knee □ 400m of mixed solution consisting of dioxane:H,O (3:1)
tK5. Add (4C) and heat to 55'<K.

This Kp-) luenesulfonic acid aqueous solution (50 parts g/μt
) and continue heating for 10 minutes. Quench the reaction with saturated NaHCO3 and extract with two portions of 10 mA ether.

The separated ether phase is washed with 10 sL of saturated NaHCO3 and 2 parts of 10 mAf)H2O and dried over Mg5O. The solvent is removed under vacuum. Silica gel (S
k@1lysolve B: ethyl acetate A/, 8:2)
Apply to thin layer chromatography. As a result, 5C is 1
．． 6 drops (32-yield) obtained. Characteristics: Uvλm&
X265nm; Mass spectrum: m/s 454 (M+
1,80) s394 (80), 376 (2G), 269
(40), 135(100)iNMR,a, 0.53(
3H,s, 18-Hl).

0.81 and 0.84 (6H, d, J=4.4Hz
, 26-H3 and 27-■3), 0.91 (3H,
d, J=7.0Hz, 2l-Hs) = 1.01
(3H1d, J=6.7Hz, 28 H3) -2,0
3(3H,s, 30COCHs)-4,18(IH
, m, 319(Z)-H).

, -H and 23-4), 5.3 (1'H.

m (Sharp), 19 (E)-H), 5.48 (IH,
m, 1-H), 5.92 (IH, d, J=11.0
Hz, ? -H), 6.37 (IH, d, J=11
．． 0Hz, 6-H').

Example 13 1α-Hydroxyvitamin D, (6e): Ether 1.
5mAK (5c) dissolved in 11wII** is LiA
Treat with 2 parts 0.5 mt of ether saturated with lH4. The reaction was allowed to proceed for 10 minutes at room temperature, then the reaction was stopped with saturated NaCl and the salt was dissolved in 3*HCl K. The aqueous solution was extracted with ether, the organic extracts were washed with water, and MgSO
Dry at step 4. 5% methanol: in chloroform,
TLC (thin layer chromatography) was performed using a 5×203 plate with a thickness of 250 μm. As a result, 1α-hydroxyvitamin D2 is obtained in o, gq (ys yield). Some characteristics are as follows a UVIIλmaz2'65nm;
r soot vector: m/a 412' (M+),
394.376, 287.269.251.152°134 (B-x peak) iNMR: δ, 0.56
(3H.

s e 18- H3) e O, 82 and 0.84
(6H, dd, J=4.4Hz, 26-Hs and 27-H3), 0.92 (3H, d.

J=6.6Hz 21 H3) -1,02(3H
-dlJ=6.6Hz-28-H3), 4.23(IH
, m, 3-H), 4.42 (IH.

m, 1-H), 5.00 (IH, m (Sharp), 19
(Z)-H), 5.20 (2H,m, 22-H and 23-H).

! i32 (IH, dd, J=14Hz, 19(E
) -H), 6.02 (IH, d, J=11.1Hz
, 7-H), 6.38 (IH, d.

J=11.6Hz, 6-H).

These spectral values can be obtained using completely different methods (Lam et al.
5science, baby, 1038-1040 (1974
) 1α-hydroxyvitamin D2 and complete K prepared in
Match.

Example 14 Solvolysis of 1α-acetoxycyclovitamin D in acetic acid: A solution of a,0q of 1α-hydroxycyclovitamin D, -1-acetate (4m) in 200 at of glacial acetic acid was heated at 55 t for 15 minutes. Afterwards, the reaction is stopped with ice-cooled saturated NaHCO3. The aqueous mixture is extracted with diethyl ether and the organic phase is washed with saturated NaHCO3 and water and dried over MgSO4.

When this is filtered, 5.6-cis and 5.6 trans-1α-acetoxyvitamin D, 3-acetate) (
A solution of UV: λmaw 267-269 nm) is obtained. Add a small amount of this dry (water-free) ether solution (1
, OMf) Lithium treated with aluminum hydride, quenched with saturated N-Ct, filtered and the solvent removed in vacuo. Crude oil was transferred to a chromatography plate (thickness: 250 μm) coated with a thin layer of 5×2051 silica gel.
i Methanol: Develop in chloroform. Product N
From the results of MR analysis, 1α-hydroxyvitamin Da (
6m) and the corresponding 5,6-) lance isomer (5,6
-) lance-1α-hydroxyvitamin D,) mixture (UV.

λmax 267-269 nm) was found to be 1.6 kg. The characteristic resonance values of the cis isomer (6a) are: δ, 6.38 and 6.01 (d, J=1
1.4Hz, '6-H and ? -H), ! L33(
dd, J=1.5Hz, 19(E)-H), 5.
01 (sharp m, 19 (Z,)-H), 0
．． 54(1,18-H,): Characteristics of s, 6-) lance isomer? :6.5 & and 5.88 (d, J=11.4Hz
, 6-H and 7-H), 5.13(d, J=1
．． 4Hz, 19(E)-H).

4.98 (sharp m, 19(Z)H), 0.560
11s-H,).

Cyclopranering of other cyclovitamins or their C-1-oxygenated congeners
) can also be converted to 1M (cycloconversion) using the same method. Therefore, if 1α-acetoxy-25-hydroxyvitamin D, (compound 4b, no protecting group is required for the 25-OH function) is heated as described above in glacial acetic acid, 1α-acetoxy- 25-Hydroxyvitamin D, 3-acetate (and some corresponding 5,6-) lance isomer as a by-product) is produced and this mixture can be directly hydrolyzed (MeOH/KOH) or as described in step 5 above. When reduced with hydride, 1α is the main product.
.

25-dihydroxyvitamin D3 as a by-product
．． 6-) Lance 1α, 25-dihydroxyvitamin D1
occurs.

Example 15 1α-acetoxycyclovitamin D using formic acid catalyst,
Solvolysis: A solution of 1α-acetoxylic acid vitamin YD (4 m) in dry dioxane is heated to 55'eK and treated with a 1:1 solution of 98 thiformic acid to dioxane (50 μt/ql cucrovitamin) for 15 cycles. . The reaction is then stopped with ice water and extracted with ether. Ether extract with water, saturated NIL
Wash with HCO3 + saturated Na(J), dry with MgSO4 and remove the solvent in vacuo.The crude product (lα-acetoxy-3β-formylvitamin D3 and its 5.6-
) lance isomer) in a 1:1 dioxane:methanol solution, and 2CO3 (10q/100
*j) is added. After standing for 5 minutes at room temperature, the solution is diluted with water and extracted repeatedly with ether. The ether extract is washed with water, dried over MgSO4 and the solvent is removed in vacuo. This crude l-acetoxy-3-hydroxyvitamin cis and trans mixture was dissolved in 1:3 ethyl acetate:5 kellysolve B at 101
Chromatography on a 0x20° 750μm thick silica gel plate yields pure cis-1α-acetoxyvitamin D. After hydrolysis with a base (NaOH in methanolic solution), it is chromatographed with a standard reagent for 1α-hydroxyvitamin D3. The same product is obtained from both the graph and the spectrum.

Example 16 Vitamin D, -cyclovitamin DB by NaHCOs-buffered solvolysis of tosylate, (2m):
170q of Vitasan D in anhydrous methanol 6, OmA,
-) 213q (8,O
Add eq.) of NaHCOs. The system (solution) is flushed with N and heated to 58t' for 20 hours.

The reaction is then diluted with saturated NaCt solution, transferred to a separatory funnel, and extracted with 2 portions of 10 mt Etto. The organic extracts are washed with 10 sL of saturated NaCl and dried over MgSO4. After removing the solvent in vacuo, the oily residue was removed with a 750 μm + 20×20 m silica gel plate.
Ethyl acetate: 5kellysolve B2:
Separate using Chroma Dog 2 Fee in 8. 94q (751G) of cyclovitamin Ds (2m) is obtained.

Example 17 Low hydroxy-cyclovitamin D, (8m): 100
A mixture of q of Vitamin Ds, 100 q') TsCA and 500 aj of dry pyridine is held for 24 hours for 5 puffs, then diluted with ether and washed several times with saturated NaHCOs. The organic phase is dried with MgSO4 and the solvent is removed in vacuo. Coarsely, --) the silide is co-suspended with xysq (8 eq,) of NaHCO, in a 4.0 mA acetate:H,09:2 mixture.

The above product mixture was heated to 55°6″Q overnight and saturated NaC
1 and then extracted twice with ether. The ether extract is washed again with water, dried over Mg5O, and the solvent is removed in vacuo. For separation (prepa-rativ
e) TLC (20X 20m, 750Jsm, 8
: 2 Skallysolve B : Treatment with ethyl acetate yields 55 Da of 6-hydroxy-3,5-cyclovitamin D3 (8 m). Characteristics of this substance; mass spectrum: m/e 384 (M L 366.2
53,247゜Example 18 6-Acedoxycyclobitane D, (9m): In a solution consisting of 300 μt of dry pyridine and 20200 At of AC,
6q 6-hydroxy- dissolved in 200 μt pyridine
, Kukuropitami yD, (8m) is added. The reaction is heated at 55δ for 2 hours in the presence of N, then diluted with a large excess of toluene. Evaporate and dry toluene under vacuum to obtain crude 6-acetoxycyclovitamin D, (
9m) is obtained. The mass spectrum of this substance e m/
e 426 (M+).

Example 19 3a ether of 1-oxo-cyclovitamin D3 (7m) 500 μt K1-oxo-cyclovitamin D, 2.
Treat the dissolved solution with 300 sL of ether saturated with LiAlH4. After 30 minutes, saturated NaCl
dropwise and carefully stop the reaction. Insoluble salts are removed by filtration and the filtrate is dried over MgSO4. When the solvent is removed in vacuo, 1α-hydroxycyclovitamin Da
(3m) and the corresponding 1β-hydroxycyclovitamin D, 1.7q of a mixture of isomers in a ratio of 95:5 are obtained. This can be separated by chromatography. Na
100-ethanol saturated with BH4 1- at 300 t
When oxo-cyclovitamin D is treated in the same way, 1α
-Hydroxy and lβ-hydroxycyclovitamin Ds compounds (3m and its 1β-isomer) in a ratio of 8:2.

Example 20 1, 5 of 6-hydroxycyclovitamin DB (8m)
Add 70*t-BuooH10s to the well-stirred suspension by adding ml of dry CH2C'4K 5e012.04.
Add L. After becoming uniform, 500jlIt of dry CM, (6-hydroxycyclovitamin D of JK14q)
A solution of 3 (8 m) was added dropwise, and the mixture was heated at room temperature for 1 hour 30 minutes.
Continue the reaction for minutes. The reaction was stopped with 101s NaOH, diluted with ether, washed with 10% NaOH and water,
Dry over MgSO4 and remove the solvent under vacuum. The crude oily residue was chromatographed (10X20a+,
750μm, 1:1 ethyl acetate:5kellysolv
e B ) K When expanded, it becomes 1.5ay (10%
) of 1-oxo-6-hydroxy-7 chlorohitamine D
, : Mass spectrum, (ml.).

398 (35), 380 (25), 247 (25), 1
35 (40) = 133 (100); 2.0 Jv (1
5%) of 1α.

6-cyhydroxycyclovitamin D, (10m): Mass spectrum; (mle)e 400 (50), 38
2 (80), 269 (20), 247 (40), 135
(80).

133 (40); and 2.0 wg<15%) (1) 1
α-hydroxyvitamin Dl (6m) and the corresponding 1α-hydroxy-5,6-to)/su isomer are obtained.

Example 21 1α,6-hydroxycyclovitamin D3 (10m
) to 1α-hydroxyvitamin D, (6m): 400 μt dry pyridine, 200 μt glacial acetic acid and 1α
, 6-hydroxycyclovitamin D3 (1m)2.
Heat the solution consisting of 0ay for 2 hours. Next, the reaction solution is diluted with toluene and dried. Produced oil (1
α,6-dihydrocyclovitamin Ds) at 100 m
For 1 of THF, 200 nt of 971 GHCO! Treat at 55'IC'C for 15 minutes. Saturated NaC
Diluted with L, extracted with ether, saturated NaHCO3
Washing with MgSO4, drying with MgSO4 and removal of the ether in vacuo gives the crude 1-acetoxy-3-formate-cis and trans-vitamin derivatives. K, Co
Selective hydrolysis of the formic acid ester with , followed by chromatography yields pure 1α-acetoxyvitamin D.

(51) is obtained. This is lα-hydroxyvitamin D by simple hydrolysis with KOH/MeOHK.

(6a).

Example 22 24 (R), 25-dihydroxycyclovitami 150
10.4 cape of 24R125-(
OH), D, and 7.13 mg (1,5 q,) of T
Add sCl. React for O'N-72 hours, then dilute with saturated NaHCO3 and extract with ether. The ether extract was washed with saturated NaHCO, dried over MgSO4, and the solvent removed under vacuum, followed by the crude tosylate (TL
~7G%) with 25wt NaHCO, 2
ml of anhydrous MeOHKI! 2 at 58 °C in N2.
Heat for 0 hours. The reaction is then diluted with saturated NJLct and extracted with ether. Wash the ether extract with water,
Dry with MgSO4 and remove the solvent in vacuo. Separate TL
C (10X 20cI1.750am silica gel*
6: 45kellysolve B: ethyl acetate) to generate 2.5q of 24R,25-(OH)! D, and 24R,25-dihydroxycyclovitamin D (2d) of 4411I can be changed. Characteristics of (2d): mass spectrum, (ml・)t 430(15), 398(6
5).

253(40), 159(45), 119(55), 5
9 (100); NMR, a, o, ss (3H9a
-18-Hl) -0,74(2H,m, 4-Hl)
e O,94(3H,d, J=6.2Hz, 21-
H,), 1.17(3H,s, 26-[3), 1
．． 22(3H+s*27Hl)s3.
26 (3He !l, 6 (X:Hl L3.3
4 (IH, m, 24-H), 4.17 (IH, d, J=
9.0Hz, 6-H), 4.88 (IH, m
(Sharp), 19(Z)-H), 5.00 (1-
H, d, J=9.0Hz, 7-H), 5.04
(IH, m (Sharp), 19(K)-H).

Example 23 1α-24(R),25-)rihydroxycyclo previously prepared solution, i.e. dried CH,CL.

1.12g of S e Oz and 12μt of 75* in
4.2q of 24R,
Dissolve 25-dihydroxycyclovitamin D in 500 μL of CH, CL and add. After 30 minutes, 1.12qS
50 701Gt-BuOOH of e02 and 12at
0 μtll) CHzCLz K solution was added and the reaction was continued for an additional hour. Quench with 101 NaOH, dilute with ether, wash twice with 101 NaOH, then water. The organic solution is dried over Mg5O, and the solvent is removed under vacuum. The resulting oil is purified by chromatography using 5×20 am, 250 μm silica gel plates with ethyl acetate:5kellyaolve B 1:1. As a result, 1 of 16q
α, 24(R), 25-trihydroxycyclovitamin D, (3d); mass spectrum, (ax/e).

446(30), 414(50), 396(40), 2
69 (30), 135 (80), 59 (100); NM
R, δ.

0.55 (3H=a, 18-Hz)-0,65
(2H1m-4-Hz), 0.96(3H,d, J
=6.0Hz, 21Hz)-1,19(3H,
Dew, 26-Hz), 1.24 (3H, a, 27
-H,), 3.28 (3H,I, 6-OCH,)
, 3.35 (IH.

m, 24-H), 4.20 (IH, d, J=9
．． 0Hz, 6-H).

4.22 (IH, m, 1-H), 4.97 (IH
, d, J=9.0Hz, 7-H), 5.18(I
H, m (sharp), 19 (Z)-H), 5.26 (I
H, d, J=2.2Hz, 19(E)-H) is obtained. As a by-product, 1-oxo-24(R), 25-dihydroxycincrovitamin D, (7i) is also isolated (20- and below).

Example 24 1α, 24 (R), 25-)rihydroxyvitamin D, (6d): 200 Jt dry pyridine and 150 μt AC,O
1.4wII of 1α,24R,25-trihydroxy-cyclovitamin D, (3d) is added to. This system is N
Cook for 20 hours at 2 to 7 degrees and 95 degrees. Thereafter, the reaction solution is diluted with dry toluene and azeotropically distilled to dryness. Oily product, 1α, 24(R), 25-triacetoxy-
Dissolve cyclovitamin D, (4d-24,25-diacetate) in 200μt THF, 97HCO,H:
Add a solution of THFl:1 at 500 tK and heat at 55 tK for 15 minutes. The cooled reaction solution was diluted with ether, washed with water, saturated NaHe03 m saturated NaCl, and MgS
Dry with O4. After removing the solvent in vacuo, the crude lα
, 24R,25-) diacetoxy-3β-formate vitamin D intermediate is dissolved in 200 μt of THF. stop【
, 1.0 in 10 μt water and 90 fit MeOH
Treat with a solution containing qKCO for 5 minutes at room temperature. Diluted with saturated NaCl, extracted with ether, 5 x 20
αw, 250Jme□ Using a silica gel plate, perform purification by chromatography with a solution of ethyl acetate: 5kelly-Hatake o1ve B4: 6, 1α, 24R, 25-) Riacetoki Patent Applicant Rice Consin Alumni Page 1 Continued Priority claim June 12, 1978■United States (US)■
633 East Gorham Street, Nshin Madison 914796

Claims (1)

[Claims] (Here, 2 is selected from the group consisting of a hydrogen atom, a lower alkyl group, a lower acyl group, and an aromatic acyl group, and each RIR. and 8. is hydrogen Atom, hydroxyl group, lower alkyl group, substituted lower alkyl group, 〇-lower alkyl group, benzoate group, substituted benzoate group, and fluorine.Provided that 2 is a hydrogen atom or a methyl group, and (If both R1 and Rs are hydrogen atoms, R3 is not a hydrogen atom.) (2) The compound according to claim 1, wherein R1 and R1 are water bulk atoms, and R8 is a hydroxyl group. (a) The compound according to claim 1 or 2, wherein Z is a methyl group. (4) A compound having the following formula. (Here, 2 is selected from the group consisting of a hydrogen atom, a lower alkyl group, a lower acyl group, and an aromatic acyl group, and each R1, R1, and R1 is a hydrogen atom, a hydroxyl group, a lower alkyl group) , substituted lower alkyl, kyl group, 〇-lower alkyl group, substituted 0-lower alkyl group, 〇-lower acyl group, substituted 〇-lower acyl group, Henzoe) L l
It is selected from the group consisting of an it-substituted benzoate group and fluorine, and R4 is selected from the group consisting of a hydrogen atom and a lower alkyl group. (5) The compound according to claim 4, wherein R1, R, and R1 are hydrogen atoms, R4 is a methyl group, and has a stereochemical ergosterol side chain. (@) R1 and R8 are hydrogen atoms, R2 is hydroxyl group, R4
is a methyl group and is a stereochemical ergostero-compound.