JPS5945674B2 - 1α-hydroxycyclovitamin D derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field This invention relates to important intermediate compounds used in the preparation of compounds with vitamin D-like activity.

More particularly, this invention relates to 1α-hydroxycyclovitamin D derivatives having one oxygen functionality at carbon 1 of the molecule and useful for preparing compounds with vitamin D-like activity.

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, recent evidence suggests that 1α,25−
It has been pointed out that dihydroxyvitamin D3 is the in vivo active form of vitamin D, and that this compound is involved in the biological effects mentioned above. Synthetic 1α-hydroxyvitamin D analogs, such as 1α-hydroxyvitamin D3 and lα-hydroxyvitamin D2, also exhibit significant biological efficacy, and such compounds, including their natural metabolites, have been shown to improve calcium metabolism and bone. dystrophy, osteomalacia,
It has great potential as a therapeutic drug for bone diseases such as osteoporosis.

BACKGROUND OF THE INVENTION Because 1α-hydroxylation is an essential element in rendering vitamin D compounds and their derivatives biologically active, there is great interest in how to achieve such hydroxylation chemically. I came here.

One method proposed for the global synthesis of 1α-hydroxyvitamin D (LythgOe et al., J. Chem.
．． SOc・, PerkinTransl, p. 2654
, 1974), all conventional ones are 1α
- The synthesis of hydroxylated vitamin D compounds involves the preparation of 1α-hydroxylated steroids, from which the corresponding 1α-hydroxy-5,7 diene styrene derivatives are converted and then processed by well-known photochemical methods. of vitamin D compounds were usually obtained.

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. Pat. No. 3,929,770, issued December 30, 1957.

2), Method for preparing 1α,25-dihydroxycholecalciferol, Matsunaga et al., U.S. Patent No. 4,022.7
No. 68, published May 10, 1977.

3), 1α-hydroxycholecalciferol, DeL
uca et al., U.S. Pat. No. 3,741,996, 19
Published June 26, 1973.

4), 1α-Hydroxyergocalciferol and Process for Preparing Same Compounds, DeLuca et al., U.S. Pat. No. 3,9
No. 07,843, September 23, 1975.

5), Selenium dioxide oxidation of colcalciferol, BO
humilPelcl steroids, volume 30, rot 2, 19
August 1977.

Disclosure of the Invention A new method for introducing a hydroxyl group at the carbon atom 1 (C-1) position of a vitamin D or vitamin D derivative molecule, which is fundamentally different from previous synthetic methods both conceptually and in terms of implementation. I found out.

This method, which will be explained in detail later, provides a method for directly attaching one oxygen function to the C-1 position by allyl oxidation. The 1α-hydroxycyclovitamin D derivatives of the present invention are intermediate compounds produced in this new method. Next, the 1α-hydroxycyclovitamin D derivative of the present invention was added to the final compound 1α-
This will be explained along with a method for preparing a hydroxyvitamin D compound (hereinafter referred to as this preparation method). That is, in preparing the 1α-hydroxyvitamin D compound represented by the general formula, this preparation method involves allyl oxidation of the compound represented by the following general formula (hereinafter generally referred to as cyclovitamin D), and an allyl oxidation reaction mixture. Collect the 1α-hydroxylated cyclovitamin D compound (the compound of the present invention) from Perform catalytic solpolysis to recover the desired 1α-0-acyl vitamin D compound, and hydrolyze the 1α-0-acylated product (or reduce it with a hydrogenating agent) to obtain the 1α-hydroxyvitamin D compound. It's a method.

In this preparation method, R in the formula represents a steroid side chain,
The most common of these are substituted or unsubstituted, saturated or unsaturated, or substituted unsaturated cholesterol side groups, where Z is a hydrogen atom, a lower alkyl group, a lower acyl group, or It is an aromatic acyl group.

Preferably, R is a cholesterol or ergosterol side chain group characterized by having a hydrogen atom or a hydroxyl group at the 25th carbon atom position (C-25) in the target molecule. Here, the term lower 7, used as a modifier of alkyl or acyl, refers to a hydrocarbon chain having from 1 to about 4 carbon atoms, and includes both straight chain and branched chain arrangements. include.

Aromatic acyl groups include benzoyl groups and substituted benzoyl groups. Also, in various formulas, a wavy line to a substituent is
Indicates that the substituent is in alpha or beta stereoisomeric form.
The compound of the present invention is represented by the following formula (1).
(Here, Z1 is selected from the group consisting of a hydrogen atom and a lower alkyl group, R1 is a hydrogen atom, a lower alkyl group, or a hydroxyl group, and R2 is a group consisting of a hydrogen atom, a hydroxyl group, and a lower acyl group. Y, is selected from a hydrogen atom and a lower acyl group, and R3 and R4 represent a hydrogen atom or are taken together to form a double bond.

) When R3 and R4 are combined to form a double bond, the side chain is preferably stereochemically similar to ergosterol.

Next, the compound of the present invention is used as an intermediate. 1α-
A method for preparing a hydroxyvitamin D compound will be explained in detail.

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, converting a vitamin D compound having a 3β-hydroxyl group into the corresponding 3β-tosylated derivative, and then
This tosylated product was mixed with methanol containing sodium acetate/
Solpolysis in a suitable buffer solution such as an acetone mixture yields the cyclovitamin product. Sheve
s and Mazur (J. Am. Chem. SOc. 9
7,6249 (1975)) applied this method to vitamin D.
3 and obtained cyclovitamin D3 as the main product. They gave this compound the following structural formula. That is 6R
-methoxy-3,5-cyclovitamin D. The cyclovitamin byproduct formed in this step contains 6 methoxy
It was confirmed that the compound corresponds to the S sequence.

Here, the solpolysis reaction mentioned earlier is changed if N
It has been found that when run in methanol using aHCO, buffer, the cyclovitamin product can be obtained in better yield than the method of Sheves and Mazur. It has been found that vitamin D compounds with other chemically reactive substituents can also be efficiently converted to their cyclovitamin D derivatives.

For example, when 25-hydroxyvitamin D is used as a starting material in the above-mentioned process, the formation of 25-hydroxy-6-methoxy-3,5-cyclovitamin D3 is observed. The structure of this compound is as follows, where R represents the 25-hydroxycholesterol side chain. Similarly, in the above step, 24,25-mono-dihydroxyvitamin D
3 as a starting material, 24,25-dihydroxy-6-methyl-3,5-cyclovitamin D3 as shown below.
occurs. Here R represents a 24,25-dihydroxycholesterol side chain. When vitamin 8 is used as a starting material, cyclovitamin D, which is produced in a similar manner, is also represented by the following structure, where R represents the ergosterol side chain. These cyclovitamin D compounds are new compounds. By analogy with the results of Sheves and Mazur cited above, the 6R-methoxy stereochemistry corresponds to the major vitamin D product obtained in these reactions, while the 6S-methoxy configuration represents a minor component of the cyclovitamin product mixture. This corresponds to a commercial component (5-10%).

This method of preparation does not require separation of these stereoisomers. However, if necessary, these can be separated by conventional methods, and any 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 the specification and claims. By appropriately selecting reagents or conditions, a cyclovitamin D analog represented by the following general formula can be obtained according to this preparation method.

Z here 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 solpolysis, a cyclovitamin having the above structure in which Z represents an ethyl group can be obtained. It is clear that other 0-alkylated cyclovitamin D products can be obtained by using appropriate alcohols in the reaction medium. Similarly, acetone/H
Solpolysis reaction medium consisting of a H2O-containing solvent such as 2O mixture, dioxane/H2O mixture, in the presence of acetate or other buffer solution, reacts with the corresponding cyclosiloxane of the above formula in which Z is a hydrogen atom. Produces vitamin D compounds.

Sheves and Mazur (Tetrahedr
OnLe-Tters (7f634) Pp. 2987-
29990 (1976)) in fact prepared 6-hydroxycyclovitamin D3. That is, a compound having the above structural formula in which Z is a hydrogen atom and R is a cholesterol side chain was prepared by treating tosylated vitamin D3 with aqueous acetone buffered with KHCO3. Here, 6-hydroxycyclovitamin is added under standard conditions (acetic anhydride/
It has been found that the corresponding acyl derivatives (i.e. Z is an acyl group such as acetyl or benzoyl) can be converted by acylation under pyridine.

Furthermore, when the above solpolysis is carried out using dry methanol containing sodium acetate as a medium, acylated cyclovitamin D, in which Z is an acethyl group in the above structural formula, is produced as a by-product. Cyclovitamin D compounds in which Z is a methyl group are preferred starting materials for the subsequent reactions. In this preparation method, allyl oxidation is carried out, for example, by CH2C22, C
This is commonly done using selenium dioxide as the oxidizing reagent in a suitable solvent such as HC23, dioxane, tetrahydrofuran, etc.

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. Oxidation products, i.e. 1α-
Hydroxycyclovitamin D compounds can be easily recovered from the reaction mixture by solvent extraction (such as ether). This 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 1α-hydroxycyclovitamin D derivative of the present invention can be obtained by this allyl oxidation or by further acylating the product of this allyl oxidation. The product resulting from allylic oxidation of a cyclovitamin D compound in the above structural formula where Z is a lower alkyl group (eg, methyl group) can be easily explained by the following formula.

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

In this preparation method, oxidizing cyclovitamins results in
1-Hydroxycyclovitamin with the desired 1α stereochemistry can be produced. In other words, this 1α-stereochemistry is a biologically active 1-hydroxylated vitamin D metabolite. The regio- and stereochemical selectivity and exceptionally high efficiency of this oxidation method are both novel and entirely unexpected; furthermore, all of the 1α-hydroxycyclovitamin D compounds disclosed herein are It is a new compound. A by-product of selenium dioxide oxidation of a vitamin D compound is a 1-oxocyclovitamin derivative having the following structure.
Here, Z represents a lower alkyl group, and R consists of any of the side chain groups defined above.

These 1-oxocyclovitamin D derivatives are hydrogenating agents (
e.g., LiAlH, NaBH4, and other equivalent reagents) and has the formula already explained.
-Mainly produces hydroxycyclovitamin D derivatives. 1
The facile reduction of α-oxocyclovitamin D compounds and the preferential production of 1α-hydroxycyclovitamin D compounds, especially those with 1α monostereochemistry, are unexpected and unexpected findings.

This is because, from a mechanistic argument, it is predicted that the hydrogenation reducing agent will approach from the side of the 1-oxocyclovitamin D compound that is less hindered in terms of molecular space, and in that case, the 1β-hydroxy It is expected that cyclovitamin epimers will lead to preferential effects. 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 at room temperature for several hours, for example overnight. The product of acylation is the corresponding 1α-0-acylcyclovitamin D compound. Prepare this for the next reaction,
It is recovered in sufficiently pure form, such as by solvent (eg ether) extraction and solvent evaporation from the medium. Any primary or secondary hydroxyl groups present in the side chains (R) of the 1α-hydroxycyclovitamin D compound 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, Z represents a lower alkyl group, and R is any of the steroid side chains defined earlier in this specification.

Here, the originally present primary or secondary hydroxyl group is now present as the corresponding O-acyl substituent, and the originally present tertiary hydroxyl group is now present as a hydroxyl group or as an O-acyl substituent, depending on the conditions selected. Exists as a base. The 1α-0-acylcyclovitamin can then be converted to the 1α-0-acylvitamin D derivative by acid-catalyzed solpolysis.

Therefore, warming 1α-0-acylcyclovitamin D with p-toluenesulfonic acid in a suitable solvent mixture (eg dioxane/H2O) yields the 1α-0-acylvitamin D compound. Sheves and Mazur utilized this reaction for the conversion of cyclovitamin D, to vitamin D3 (J. Am. Chem. SOc. 97.6249
(1975)). A new and surprising discovery, which was neither obvious nor inferable from the prior art, is that 1α-0-acylcyclovitamin D compounds are converted to the corresponding 1α-0-acylvitamins in consistently high yields by acid solpolysis. It means that it can be done. This result was completely unexpected since the allylic 1α monooxygen function of the 1α-hydroxycyclovitamin D compound was expected to be very unstable under such solpolysis conditions.

1α- in the presence of organic carboxylic acids such as acetic acid, formic acid, etc.
It is also possible to directly solpolyze hydroxycyclovitamin D to recover the corresponding 3-0-acyl 1α-hydroxyvitamin D derivative, and to convert such derivative to the corresponding hydroxy compound and recover it. It is also important to protect the tertiary or allyl-alcohol functions present in the side chains by converting them into corresponding acylated compounds or other suitable acid-stable protecting groups.

The product, 1α-0-acylvitamin D, can be easily extracted from the solpolysis mixture with a solvent and further purified by chromatography. Through this solpolysis reaction, 1α with a natural 5,6-cis double bond geometric isomer
Both the -0-acylvitamin Ds and the corresponding 1α-0-acylvitamin D with the 5,6-trans geometric isomer are obtained in a ratio of approximately 5:1. These products can be easily separated by solvent extraction and chromatography.
The result is 1α− with the general formula as explained below.
The 0-acylvitamin D product can be obtained in pure form (as well as the corresponding 5,6-trans-isomer, if desired). 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 O-acyl derivatives. If the acyl protecting group is removed by hydrolysis or reduction, 1α-0
-Acylvitamin D derivatives can be easily converted into desired 1α-hydroxyvitamin D compounds.

Another new method for converting 1α-0-acylcyclovitamin D compounds to the corresponding vitamin D derivatives involves the use of organic acids (
For example, there is a method of acid-catalyzed solpolysis of cyclovitamin compounds in a medium consisting of acetic acid, formic acid).

In this case, especially when it is necessary to dissolve the cyclovitamin, acetone or dioxane may be used as a co-solvent. Side chain R is a tertiary hydroxyl group (for example, 25 monohydroxyl group)
, this method is particularly advantageous since there is no need to protect such functionality as their acyl derivatives. Even more advantageously, the solpolysis of 1α-0-acylcyclovitamins can be carried out in formic acid or in formic acid with a suitable co-solvent such as dioxane.

This method leads to derivatives of 1α-0-acylvitamin D3β-formate as shown below. Here, Y is a lower acyl group (preferably not a formyl group),
Alternatively, it is an aromatic acyl group, and R is any of the side chain groups defined above.

Here too, the corresponding 5,6-trans compound is produced as a by-product. The 3β-0-formyl group is easily hydrolyzed under conditions such that the 1α-0-acyl group is not affected (2-3 min treatment with potassium carbonate, as shown in the example below). Because of the
, 6-tran z isomer.

This mixture can be easily separated at this stage by chromatographic methods, producing pure 1α-0-acylvitamin D and the corresponding 5,6-trans 1α-0-
Acyl vitamin D can be obtained. This is now separately subjected to alkaline hydrolysis or reductive cleavage of the acyl groups to form the 1α-hydroxyvitamin D compound and the 5,
A 6-trans-1α-hydroxyvitamin D compound can be obtained. The 1α-0-acylcyclovitamin derivative has the structural formula explained above.
Another novel method of converting to β-formyl vitamin D compounds involves the use of a crown ether 2 catalyst.

For example, a suitable crown ether (e.g., 15-crown 5, A1drichChemica1C0.Mi1wa
According to a two-phase reaction system consisting of a hydrocarbon (e.g., hexane/benzene) solution of 1α-0-acylcyclovitamin D containing formate ions and formic acid, 1α-0-acylcyclovitamin D can be produced in high yield. Vitamin D can be converted to 1α-0-acyl-3β-0-formyl vitamin D derivatives. At this time, the corresponding 5,6-
Trans isomers also occur, but can be conveniently separated by chromatography. Another variation of the above method is 1
This is a method of converting an α-hydroxycyclovitamin D compound (with mixed acetic acid-formic acid anhydride in pyridine) into a 1α-0-formyl derivative represented by the following structural formula.

Here, R is any of the side chain groups mentioned above, and z represents a lower alkyl group.

This intermediate product was obtained by solpolysis in glacial acetic acid as described above, and 1α-formyloxyvitamin D3 was obtained.
It produces β-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-trans isomer. This can be easily separated at this stage by chromatography and then the acetate can be individually hydrolyzed or cleaved by reduction to yield the pure 1α-hydroxyvitamin D compound and its 5,6-trans isomer. You can get a body. The allyl oxidation process which produces the compounds of the invention as products is also applicable to cyclovitamin D compounds having 6-hydroxyl or 6-0-acyl groups. Therefore, in the following structural formula, a cyclovitamin compound in which Z has a hydrogen atom and R has any of the side groups mentioned above is oxidized at the carbon atom 1 position by the allyl oxidation of this preparation method. This yields 1α-hydroxy-6-hydroxycyclovitamin D compounds and 1-oxo-6-hydroxycyclovitamin D compounds. Under the oxidizing conditions mentioned earlier, 1α-
A ring conversion of the hydroxy-6-hydroxycyclovitamin D compound to a mixture of 5,6-cis and 5,6-trans-1α-hydroxyvitamin D occurs.

All products can be easily removed from the oxidized mixture by chromatography. The 1α-hydroxy-6-hydroxycyclovitamin D compound obtained by allyl oxidation can be acylated (e.g., acetylated) by standard procedures described above. The resulting 1,6-diacylcyclovitamin D intermediates are easily accessible by acid solpolysis to 5,6-cis and 5,6-trans-1α-0-
Can be converted to acyl vitamin D compounds. This product can be easily separated by chromatography. 1-0-
By hydrolysis (by known methods) of acyl derivatives,
The desired 1α-hydroxyvitamin D products and their 5,6-trans isomers are produced, respectively.

The 1-oxo-6-hydroxycyclovitamin D product can be easily reduced with a hydrogenating agent to yield the 1α-hydroxycyclovitamin derivative.

Similarly, cyclovitamin D compounds in the above structural formula in which Z is an acyl group (e.g., acetyl, benzoyl group) and R is any of the side groups defined above may also be considered as described for the 6-hydroxy analogs. Similarly, allyl oxidation,
The 1α-hydroxyvitamin D products and their corresponding 5,6-trans isomers can be converted by acylation, acid solpolysis and finally hydrolysis of the acyl group.

Another remarkable and unexpected discovery that led to this invention was that 1α-hydroxy It is possible to easily and efficiently convert a vitamin D compound into a 1α-hydroxycyclovitamin D compound.

For example, when 1α-acetoxyvitamin D33-tosylated product is heated and solpolysed under the conditions described above, for example in a methanol solvent containing NaHCO3, 1α-hydroxy-6-methoxy-3,5-cyclovitamin D3 is produced. Oxidation of this product (e.g. with MnO2 in CH2Cl2 solvent) results in the corresponding 1-oxo6-methoxy-3,5 as illustrated in the individual examples.
- A cyclovitamin D3 analogue is obtained. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are for illustrative purposes only, but in each case a number, e.g. 1α, is used to identify the particular product.
-Hydroxycyclovitamin D3 3a corresponds to the numbers listed below indicating the various structural formulas of the products.

The production examples of the compounds of the present invention in the following examples are shown in the following table using the above numbers indicating the compounds. Examples other than those listed in the table are examples of preparing the target 1α-hydroxylated compound from the compound of the present invention or producing raw materials for the compound of the present invention, as indicated in each example. Example 1 1α-Hydroxycyclovitamin D3 (3a) and 1-oxocyclovitamin D3 (7a): Dried 1
m10) 1.4 instant (1.2 x 10-5
Add SeO2 of mono(c) and mix it with 7
0% tert-butyl hydroperoxide (t-BuO
Add 7 μl (5.1×10 −5 mol) of OH).

After stirring for 25 minutes, add 0.5a of CH2 to this solution.
Cl2, 9 mol (2.3 x 10-5 mol) of 3,5-cyclovitamin D3 (compound Otsu), vitamin D3 (±a)
Prepared by the method of Sheves and Mazur, J. Arll. Chem. SOc. 97,6249 (
(1975) Drop the dissolved solution.

The mixture is stirred for an additional 25 minutes at room temperature. Then 2.0 ml of 10% NaOH are added and the resulting mixture is diluted with 15r1Le diethyl ether. The organic phase was separated and diluted with 10% NaOH (2 x 10a), H2O (
2 x 10' ml), washed successively with saturated FeSO4 (3 x 10 m0) and saturated NaCl (15 ml), then dried over MgSO4. Removal of the solvent in vacuo yielded a crude oily product. This product is
Silica gel thin plate (10 x 200 fn, 750 μm) using 0% ethyl acetate:SkellysOlveB solvent
Development at 1α-hydroxy-3,5-cyclovitamin D3 (3a) yields 4.57f9 (43% yield). This product exhibits the following properties: Mass spectrum; (m/e) 414 (30), 382 (70), 341
(35), 269 (20), 247 (45), 174 (
25), 165 (30), 135 (65); NMR, δ
,0.53(3H,a,18H3),0.61(2H,
m, 4-H2), 0.87 (6H, d, 26-H3 and 27-H3), 0.92 (3H, d, 21.H3),
3.26 (3H.s, 6-0CH3), 4.18 (1H.s
．． d, J = 9.0Hz, 6-H), 4.22 (1H, m
, 1-H), 4.95 (1H, d, J=9Hz, 7-H
), 5.17 (1H, d, J=2.2Hz, 19(Z)
-H), 5.25(1H, d, J=2.2Hz, 19(
E) One width. As a secondary component, 2 mg (
1-oxocyclovitamin D3 ('I
A. ) was separated. Mask vector; (m/e)41
2 (40), 380 (50), 267 (15), 247
(23), 135 (50), 133 (100):Nll
S4R, δ, 0.49 (3H, s, 18-H3), 0.
58 (2H, m, 4-H2), 0.87 (6H, d, 2
6-H3), 0.93 (3H, d, 21-H3), 3.
30 (3H, s, 6-0CH3), 4.07 (1H, d
, J=9.0Hz. 6-H), 5.02 (1H, d, J
=9.0Hz, 7-H), 5.62(1H, s, 19(
Z)-H), 6.04(1H,s,19(E)-H):
U248 (4,000).

Example 2 1α-acetoxy-cyclovitamin D3 (4a): Compound 3a (1.5W9) was dissolved in 200μ2 of dry pyridine and 50μl of acetic anhydride and reacted overnight at room temperature, followed by 5ml of saturated NaHCO3 solution. Diluted.

The solution is washed three times with ether of 5a and the organic extract is washed with H2O (2x10ml). Next, Mg
Drying over SO4 followed by removal of the solvent under reduced pressure yields the compound Siandan. NMR, δ, 0.53 (3H, s
, 18-H3, O. 69 (2H, m, 4-H2), 0.
87 (6H, d, 26-H3 and 27-H3), 0.
92 (3H, d, 21-H3), 2.10 (3H, s,
1-0AC), 3.26 (3H, s, 6-0CH3),
4.18 (1H, d, J=9.2Hz, 6-H), 4.
98 (1H, d, J=9.2Hz, 7-H), 4.98
(1H, d, J=2.1Hz, 19(Z)-H),5.
23 (1H, m, 1-H), 5.25 (1H, d, J-
2.1Hz, 19(E)-H). Example 3 1α-Hydroxyvitamin D3 (6a): 1.3 w (
Add the solution and heat to 55°C.

A solution of 0.2η of p-toluenesulfonic acid added to 4μ2 of water was added to this, and heating was continued for 30 minutes. The reaction is then quenched with saturated NaHCO32a and extracted with 2 portions of 10d ether. The organic extract is dried over MgSO4 and the solvent is removed in vacuo. This product was dissolved in 30% EtOAc:Sk
10×20cr in ellysOlveB! Develop on a silica gel plate. By the above method, 400 ttg of product 5a having the following properties was obtained. UV, λMax264
nm; mass spectrum, m/E442 (M+, 75),
382 (70), 269 (15), 134 (100);
NMR, δ, 0.52 (3H, s, 18-H3), 0.
86 (6H, d, J = 5.5Hz, 26-H3 and 2
7-H3), 0.91 (3H, d, J=5.9Hz, 2
1-H3), 2.03 (3H, s, 1-0C0CH3)
, 4.19 (1H, m, 3-H), 5.04 (1H, d
, J=1.5Hz, 19(Z)-H), 5,31(1H
, m (sharp), 19 (E)-H, 5.49 (1H,
m, 1-H), 5.93 (1H, d, J-11.4Hz
, 7-H), 6.37 (1H, d, J=11.4Hz,
6 Ichikame product D was taken up in 0.5 ether and excess L
Process with ialH. The reaction is quenched with saturated NaCl, the product is filtered and separated by evaporation of the solvent in vacuo. This isolated product (6a) was mixed with a standard sample of 1α-hydroxyvitamin D3 using CHCl3:CH3OH 97:3.
Develop cochromatography in a solvent. (1α-hydroxyvitamin D3Rf = 0.10, .1β-hydroxyvitamin D3Rf = 0,15, Rf of product (6a)
=0.10). Is this product λMax? 264 nm, and the mass spectrum and Nmr spectrum are also pure 1
Shows the same results as α-hydroxyvitamin D3. Example 4 25-hydroxycyclovitamin D3 (2b): 25-hydroxycyclovitamin D3 (1b) in 0.5d dry pyridine
) 100Tf9, p-toluene-sulfonyl chloride 1
After reacting the solution to which 50η was added at 3°C for 24 hours, the reaction was quenched with 5 lnl of saturated NaHCO3.

The aqueous phase was extracted with ether (2 x 10 ml) and the ether extract was combined with saturated NaHCO3 (3 x 10 mt), 3
%HCI (2 x 10a), and H2O (2 x 10'M
1,) and then dried over MgSO4. The solvent was removed in vacuo and the residue (25-hydroxyvitamin D33-tosylated) was dissolved in 1.5 d of anhydrous methanol and 0.5 d of anhydrous methanol.
．． 3d in anhydrous acetone. Then NaOAcl7O
Add η (8 eq.) and heat this at 55° C. for 20 hours. Cool the mixture, dilute with 10d water, 3X10m
Extract with 1 ether. The organic extract is washed three times with 10 ml of water, dried over MgSO4 and the solvent is removed in vacuo. SkellysOlve this crude residue:
In a dry acetic acid (8:2) system, 20 (177!×20?
Developed on a Silica Genol/TLC plate (thickness 7.50 μm). This gave 48~ (45% overall yield based on TO) of (tango). Reciprocal characteristics: Mass vector, m/e: 414 (M+, 40), 399 (10)
, 382 (80), 253 (50), 59 (100):
NMR, δ, 0.53 (3H, s, 18-H3), 0.
74 (2H, m, 4-H2), 0.94 (3H, d, J
=6.2Hz,21-H3),1.21(6H,s,2
6-H3 and 27-H3), 3.25 (3H, s.6
-0CH3), 4.16 (1H, d, J=9.2Hz,
6-H), 4.89 (1H, m (sharp), 19 (Z
)-H), 4.99 (1H, d, J-9.3Hz, 7-
H), 5.04 (1H, m (sharp), 19 (E) -
H). Example 5 1α-25-dihydroxycyclovitamin D3 (3b)
and 1-oxohydroxycyclovitamin D3 (7
b): 2.45W1f (0.5eq.) of SeO2,l
4 μm1 (2 eq.) of t-BuOOH. and 1.2
d mixture of dry CH2C22 is reacted for 3''0 minutes at room temperature.

A solution of cyclovitamin (2b) in 0.5a0 CH2C2 is added dropwise to this oxidizing medium and the reaction is continued for 15 minutes. The reaction is then quenched with 2.0 ml of 10% NaOH and diluted with 201 rL of diethyl ether. The organic phase is separated and washed successively with 10% NaOH, H2O, saturated FesO4 solution, saturated NaHCO3, again with H2O and dried over MgSO4. The solvent was removed in vacuo and the crude residue was deposited on a thin silica gel plate (20 cTn
SkellysOl at 20crn, thickness 750μm)
Develop with veB:ethyl acetate (6:4) system. According to this method, 11 mfi (yield 53%) of (minor) having the following characteristics can be obtained. Mass spectrum; m/E43O (
M+, 15), 412 (12), 380 (35), 26
9 (10), 59 (100), NMR, δ, 0.53 (
3H, s, 18-H3), 0.61 (2H, m, 4-H
2), 0.93 (3H, d, J = 6.2Hz, 21-H
3), 1.21 (6H, s, 26-H3 and 27-H
3), 3.25 (3H, s, 6-0CH3), 4.17
(1H, d, J = 9.2Hz6-H), 4.20 (1H
, m, 1-H), 4.95 (1H, d, J=9.2Hz
,7-}1),5.19(1H,d,J=1.9Hz,
19(Y)-H), 5.22(1H, d, J=1.9H
z, 19-(E)-H). As a by-product, 1-oxo-25-hydroxycyclovitamin D3 (Otoyama) was obtained from the product mixture (15%). Mass spectrum: m/E4
28 (M+). Example 6 1α 25-dihydroxycytalvitamin D3-1,2
5-diacetate (4b-25-0Ac): 200 μl
A solution of 7Tf19 (3b) in dry pyridine is treated with 10μ2 of acetic anhydride.

The system was flushed with N2 and heated at 97°C for 16 hours. After cooling, the mixture was dissolved in 5 ml of saturated NaHCO3.
Dilute with 10m of aqueous mixture! , of ether, and the organic phase is washed successively with 2 parts of 10'ml of saturated NaHCO3 and 10ml of 10H20. After drying over MgSO4, the solvent and residual pyridine were removed by azeotropic distillation using benzine in vacuo. Next, this crude product was transferred to a thin silica gel plate (10CfL×20C7rL,
750μm) and SkellysO-1ve
B: Treat with ethyl acetate (8:2). This resulted in diacetate (4b,25-0Ac) 6η (72%) and the corresponding 3-acetoxy-25-hydroxy derivative 1
．． 2 instants are obtained. Example 7 1α-25-dihydroxyvitamin D3-1,25-diacetate (5b,25-0Ac): 3.8Tn9 (4
b, 25-0Ac) and heated to 55°C.

A solution of 8μ10p-toluenesulfonic acid dissolved in water was added to this and heating was continued for 10 minutes. Saturate the reaction with NaHCO
The mixture was quenched at 3° C. and extracted with 2 portions of 10 ml of ether. The ether solution was washed with 10 d of H2O, and the M
Dry with gSO4. The solvent was removed in vacuo and the residue was deposited on a thin silica gel plate (5 x 20 cm, 250 μm thick).
Then, SkellysO-1veB:ethyl acetate (8:2
) to expand. In this way, 1.8η (45?) of (5b,
25-0Ac) was obtained. It exhibited the following properties.
U; λMax265nm; mass spectrum; m/E5O
O (M+, 25), 440 (55), 422 (15),
398 (10), 380 (45), 134 (100),
NMR, δ, 0.52 (3H, s, 18-H3), 0.
92 (3H, d, J=6.2Hz, 21-H3), 1.
42 (6H, s, 26-H3) and 27-H3), 1
．． 97 (3H, s, 25-0C0CH3), 2.03 (
3H, s, 1-0C0CH3), 4.18 (1H, m,
3-H), 5.03 (1H, d, J=1.1Hz, 19
(Z)-H), 5.31 (1H, m (sharp), 19
(E)-H), 5.49 (1H, m, 1-H), 5.9
3 (1H, d, J = 11.4Hz, 7-H), 6.37
(1H, d, J=11.4Hz, 6-H).

Example 8 1α-25-dihydroxyvitamin D3 (6b): 1.
Diacetate, (5b, 25-0
Ac) LiAlH4 is added to the stirred solution of 1Tfi9.
Add 0.5 rILe of an ethereal solution saturated with .

After standing for 10 minutes at room temperature, saturated NaCl! Stop the reaction with solution. Then add 3% HC2 to dissolve the salt. The aqueous phase is extracted with ether and the ether extracts are washed with H2O and dried over MgSO4. 5% MeOH:CH
Treat with thin layer chromatography (5 x 20 square silica gel plates, 250 μm thick) using Cl3.

As a result, 0.6 mg (70?) of 1α,25-dihydroxyvitamin D3, which exhibits λMax 265 nm in the UV spectrum, is obtained. Identification of 6b as 1α,25-dihydroxyvitamin D3 can be made by directly comparing the mass and Nmr mass vector of the product with the pure product, or by simultaneously comparing 6b with authentic 1α,25-dihydroxyvitamin D3. I was able to prove this by subjecting it to chromatography. Example 9 Cyclovitamin D2 (2c): 100η of vitamin D dissolved in 0.3d of pyridine.
2q”) and 100f! p-toluenesulfonyl chloride solution was reacted at 3°C for 24 hours, and then 10-
The reaction was stopped with saturated NaHCO.

The aqueous mixture was extracted with 2 parts 10a of water and the ethereal extracts were combined with saturated NaHCO3 (3x10a), 3% HCI (2x
10mt) and H2O (2X10) and then dried with MgSO4. Remove the solvent in vacuo,
1.5 mI of crude vitamin D2-3-tosylated product! , of anhydrous methanol and 0.3 d of anhydrous acetone. Next, 170η of sodium acetate was added and the solution was
Heat at 5°C for 20 hours. After cooling, add 10d0 of this solution
) Dilute with H2O and extract with 3 parts of 10 d of ether. The organic extract was washed with 3 parts of 10d0) H2O and MgS
Dry with O4 and remove solvent under vacuum. The residue is chromatographed on a thin silica gel plate (20×20C!Nl 750 μm) using SkellysOlveB:ethyl acetate (8:2) as the developing agent. 60m
g (59%) of (2c) is obtained.

The properties of (2c) are as follows; mass spectrum; m/E4
lO (M+, 15), 378 (40), 253 (40)
, 119 (60); NMR, δ, 0.55 (3H, s.
18-H,), 0.74 (2H, m, 4-H2), 0.
82 and 0.84 (6H, dd. J=4,1Hz, 2
6-H, $3 and 27H3), 0.91 (3H, d, J
? 7.011z, 21-HJ), 1.02 (3H, d,
J? 6.6h,28-H,),3.26(3H,s,6
10CH,). 4.13 (1H, d, J=9.6Hz,
61H). 4.89(1H,m,19(Z)-H),5
．． 00 (1H, d, J=9.4Hz, 7-H), 5.0
4 (1H, m (sharp), 19 (E)-H), 5.2
0 (2H, m, 22-H and 23-H). Example 101α
- Hydroxycyclovitamin D2 (3c) and 1-oxocyclovitamin D2 (7c): 1.5d dry C
H,C! i 2.7η of SeO2 and 13Aμ4 of 7
Mix 0% t-BuOOH and react for 30 minutes: +E.
Ru.

Then add the compound to 0.5-CH2Cl2 (30mf)
was dissolved, and this was added dropwise to the above mixed solution, and the reaction was continued for 15 minutes. The reaction is then stopped with 2.0 d of 10% NaOH.
The solution was diluted with ether of 15a, the ether phase was separated and 61070NaOH, saturated FesO4 solution, saturated NaH
Wash sequentially with CO, and again with H2O. MgS
After drying with O4, the solvent was removed under vacuum, and the residue was transferred to a thin silica gel plate (20×20CT!L, 75Oμm
), Ske-11ys01veB: ethyl acetate (8
:2) Expand within the system. 9.5 wa (45%) of (1 day)
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, δ, 0
．． 53 (3H, s, 18-H,), 0.63 (2H, m
, 4-H2), 0.82 and 0.84 (6H, dd,
26-H3 $3 and 27-H3), 0.92 (3H, d
, J=6.0Hz, 21-H, ), 1.02 (3H.d
, J=6.4z,28-H,),3.26(3H,s,
6-0CH3), 4.18 (1H, d, J=9.6Hz
, 6H), 4.21 (1H, m, 1-H), 4.94 (
1H, d, J = 9.6Hz, 7-H), 5.17 (1H
, m (sharp), 19 (Z)-H), 5.19 (2H
, m, 22-H and 23-H), 5.24 (1H, m
(Sharp), 19(E)-H The second most abundant compound isolated from the rabbit mixture was 1-oxocyclovitamin D2.
It was identified as (1s). Mass spectrum, m/E424
(M+). Example 11 1α-Hydroxycyclovitamin D2-1-acetate (4c): 6.57f1f in 300μ2 dry pyridine
Dissolve step 7 (3c) and add 150It1 of acetic anhydride to it.

The solution was heated at 55 °C for 1 h, then 5 mt saturated N
Dilute with aHCO, and extract with 2 parts of 10 ml ether. The organic extracts are washed with saturated NaHCO, and H2O, and dried over MgSO4. Residual pyridine and solvent are azeotropically distilled with benzene in vacuo. This results in the compound tip s. Mass spectrum; m/E468 (M+
, 40), 408 (20), 376 (65), 251 (
60), 135(100). Example 12 1α-Hydroxyvitamin D2-1-acetate (5c
): Dioxane:H2O (3:1) mixed solution 40
5.0WII in 0m1! Add (s) above and heat to 55°C.

To this was added p-toluenesulfonic acid aqueous solution (50μg/μl
) and continue heating for 10 minutes. Quench the reaction with saturated NaHCO, and extract with 2 portions of 10 d ether. The separated ether phase was dissolved in 10 ml of saturated NaHCO3 and 10 a
0) Wash with 2 parts of H2O and dry with MgSO4.
The solvent is removed under vacuum. Silica gel (Skellys)
OlveB: ethyl acetate, 8:2) by thin layer chromatography. As a result, 1.6 times (32% yield) of 5c is obtained. Characteristics of 5c: U; λMax 265 nm; Mass spectrum: m/E454 (M+, 80), 394
(80), 376 (20), 269 (40), 135 (
100); NMR, δ, 0.53 (3H, s, 18-H
3), 0.81 and 0.84 (6H, d, J = 4.4
Hz, 26-H3 and 27-H3), 0.91 (3H
, d, J=7.0Hz, 21-H3), 1.01(3H
, d, J=6.7z, 28-H3), 2.03(3H,
s, 3-0C0CH3), 4.18 (1H, m, 3-H
), 5.03 (1H, d, J=1.5Hz, 19(Z)
-H), 5.19 (2H, m, 22-H and 23-H
), 5.3 (1H, m (sharp), 19(E)-H)
, 5.48 (1H, m, 1-H), 5.92 (1H, d
, J=11.0Hz, 7-H), 6.37(1H, d,
J=11.0Hz, 6-H).

Example 131α-Hydroxyvitamin D2 (6c): A solution of 1.1η of (5c) dissolved in 1.5Tn1 of ether
Treat with 0.5 ml of an ether solution saturated with iAlH4.

After reacting for 10 minutes at room temperature, the reaction is quenched with saturated NaCl and the salt is dissolved in 3% HCI. The aqueous solution is extracted with ether and the organic extracts are washed with water and dried over MgSO4. In 5% methanol-lichloroform, thickness 250
μ, 5×20? It is subjected to TLC (thin layer chromatography) using a plate.

As a result, 1α-hydroxyvitamin D2 is 0.8η
(75? yield) is obtained. Its properties are as follows: UV:
λMax265nm; Mass spectrum: m/E4l2(
M+), 394, 376, 287, 269, 251, 1
52,134 (base peak); NMR: δ, 0.56
(3H,s,18-H3), 0.82 and 0.84(
6H, dd, J=4.4Hz, 26-H3 and 27-
H3), 0.92 (3H, d, J=6.6Hz, 21-
H3), 4.23 (1H, m, 3-H), 4.42 (1
H, m, 1-H), 5.00 (1H, m (sharp),
19(Z)-H), 5.20 (2H, m, 22-H and 23-H), 5.23 (1H, dd, J = 1.4Hz
, 19(E)-H), 6.02 (1H, d, J=11.
1z, 7-H), 6.38 (1H, d, J=11.6H
z, 6-H). These spectral values can be obtained in a completely different way (
Lam et al., Science, l86, lO38-1
040 (1974). Example 14 Solpolysis of 1α-acetoxycyclovitamin D in acetic acid: 3.0 mg of 1α-hydroxycyclovitamin D (raw) in 200 tt1 of glacial acetic acid
After heating the solution at 55°C for 15 minutes, the reaction is quenched 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, a solution of 5,6-cis and 5,6-trans-1α-acetoxyvitamin D33-acetate (UV: λMax 267-269 nm) is obtained. Add a small amount of this dry (water-free) ether solution (
1.0Tf19) Treat with lithium aluminum hydride, quench with saturated NaCl, filter and remove solvent in vacuo. Crude oil was analyzed using a 5X20Cr1L silica gel thin layer chromatography plate (thickness 250μm).
Develop in 5% methanol-lichloroform. From the results of NMR analysis of the product, 1α-hydroxyvitamin D,
(6a) and the corresponding 5,6-trans isomer (5,
It was found that a mixture of 6-trans-1α-hydroxyvitamin D3 (U, λMax 267-269 nm) was obtained from 1.6. The characteristic resonance values of the cis isomer (?ball) are as follows: δ, 6.38 and 6.01 (D, J = 1
1.4Hz, 6-H and 7-H), 5.33(Dd,
J = 1.5Hz, 19(E)-H), 5.01 (sharp M, l9(Z)-H); 0.54 (S, l8-H3
); properties of the 5,6-trans isomer: 6.58 and 5
．． 88 (D, J=11.4Hz, 6-H and 7-H)
, 5.13 (D, J = 1.4Z, 19(E)-H),
4.98 (sharp M, l9(Z)-H), 0.56
(S, l8-H,). The cyclopuran ring (Cycloprane) of other cyclovitamins or their C-1-oxygenated homologs
Opening (cycloconversion) of Oprane-Ring can be done in the same way. Therefore, 1α-acetoxy-25
-Hydroxyvitamin D3 (compound failure, no protecting group required for the 25-0H functionality) is heated as described above in glacial acetic acid to produce 1α-acetoxy-2 as the main product.
5-Hydroxyvitamin D,3-acetate (and some corresponding 5,6-trans isomer as a by-product) is produced and this mixture is subjected to direct hydrolysis (MeOH/K
OH) or reduced with a hydride as described above, the main product is 1α. 25-dihydroxyvitamin D, and 5,6-trans-1α,25-dihydroxyvitamin D3 are produced as by-products. Example 15 1α-acetoxycyclovitamin D using formic acid catalyst,
Solpolysis: A solution of 1α-acetoxycyclovitamin D3(Ia) in dry dioxane was warmed to 55°C and dissolved in a 1:1 solution of 98% formic acid to dioxane (50 μm/
ηcyclovitamin) for 15 minutes.

The reaction is then stopped with ice water and extracted with ether. The extract is washed with water, saturated NaHCO3, saturated NaCl, dried over MgSO4 and the solvent is removed in vacuo.
The crude product (1α-acetoxy-3β-formylvitamin D3 and its 5,6-trans isomer) was dissolved in a 1:1 solution of dioxanerimethanol and an equal volume of aqueous K2C.
Add O3 (10mg/100μl). After standing for 5 minutes at room temperature, the solution is diluted with water and extracted repeatedly with ether. The ether extract was washed with water and MgSO
4 and remove the solvent in vacuo. This crude 1-acetoxy-3-hydroxyvitamin cis and trans mixture was mixed with 1:3 ethyl acetate:SkellysOlve.
10×20C in B! Chromatography was carried out on a silica gel plate with a thickness of 750 μm to obtain pure cis-1α-acetoxyvitamin D. Hydrolysis with a base (NaO
(H in methanol) yields a product that is chromatographically and spectrally identical to the standard reagent for 1α-hydroxyvitamin D. Example 16 Vitamin D, monotosylated cyclovitamin D by NaHCO3 monobuffered solpolysis, (2a): anhydrous methanol 6.01
213W9 (8.0eq.) of Na was added to a suspension of 170W9 of vitamin D, monotosylated in 1tt.
Add HCO.

The system (solution) is flushed with N2 and heated to 58°C for 20 hours. The reactants were then saturated with NaC! diluted with solution,
Transfer to a separatory funnel and extract with 101 ILe of Et2O2 parts. The organic extract was washed with 10 d of saturated NaCl and
Dry with gSO. After removing the solvent in vacuum,
The oily residue was added to 750 μM. 2O×20CTfL
On a silica gel plate, ethyl acetate: Skelly-SOlv
Separate by chromatography in eB2:8. 94T19 (75%) of cyclovitamin D3 (2a) is obtained. Example 17 6-hydroxy-cyclovitamin D, (8a): 100
mg of vitamin D,, lOOmf7 of TsCl and 5
The mixture of dry pyridine of 00It1 is kept at 5° C. for 24 hours, then diluted with ether and washed several times with saturated NaHCO.

The organic phase is dried with MgSO4 and the solvent is removed in vacuo.
The crude D3-tosylated product was dissolved in 4.0 d of acetone:H2O9:
2 with 175 w (8 eq.) of NaHCO. The resulting mixture is heated at 55° C. overnight, diluted with saturated NaCt, and then extracted twice with ether. The ether extract is washed again with water, dried over MgSO4 and the solvent is removed in vacuo. Separation (Prepara-Tive) TLC (20x20mm, 750μM, 8:2
Ske11ys01veB: upon treatment with ethyl acetate,
55T19 of 6-hydroxy-3,5-cyclovitamin D3 (8A) is obtained. Characteristics of this substance: Mass vector, m/E384 (M+), 366, 253, 247
. Example 18 6-acetoxycyclovitamin D3 (9a): In a solution consisting of 300μj dry pyridine and AC2O2OOμl,
Add 6711f 6-hydroxy-cyclovitamin D, (8A) dissolved in 200μ of pyridine.

The reaction solution was heated at 55°C for 2 hours in the presence of N,
Then dilute with a large excess of toluene. The toluene is evaporated to dryness at 40° C. under vacuum to yield crude 6-acetoxycyclovitamin D3 (9A). Mass spectrum of this substance, m/E426 (M+). Example 19 Reduction of 1-oxocyclovitamin D3 (7a) to 3a with hydride: ether 500μ! 1-oxocyclovitamin D32. The OWfWlOS solution was
Treat with 300 μj of ether saturated with iAlH.

After 30 minutes, the reaction is carefully quenched by dropwise addition of saturated NaCl.

Insoluble salts are removed by filtration and the filtrate is dried over MgSO4. Removal of the solvent in vacuo yields a mixture of 1α-hydroxycyclovitamin D3 (3a) and the corresponding 1β-hydroxycyclovitamin D3 isomer in a ratio of 1.7 to 95:5. This can be separated by chromatography. Similar treatment of 1-oxocyclovitamin D3 with 300 μl of 100% ethanol saturated with NaBH4 yields a mixture of 1α monohydroxy and 1β-hydroxycyclovitamin D3 compounds (3a and its 1β monoisomer) in a ratio of 8:2. occurs. Example 20 SeO2 of 6-hydroxycyclovitamin D3 (8a)
/t-BuOOH oxidation: 1.5 ml dry CH2Cl2
SeO22. Add Oη and stir well. Add 10 μl of 70% t-BuOOH to the suspension.

After becoming homogeneous, add 14 ml to 500 μl of dry CH2Cl.
A solution dissolved in mg of 6-hydroxycyclovitamin D3 (8a) was added dropwise, and the reaction was continued for 1 hour and 30 minutes at room temperature. The reaction was quenched with 10% NaOH, diluted with ether, and diluted with 10% NaOH.
Wash with 0% NaOH and water, dry over MgSO4 and remove the solvent under vacuum. The crude oily residue was chromatographed (10 x 20 (1-JMoV!, 750 μM,
Developing with 1:1 ethyl acetate (SkellysOlveB) yields 1.5η (10%) of 1-oxo-6-
Hydroxy-cyclovitamin D3: mass vector, (
m/e), 398(35), 380(25). 247(
25), 135 (40), 133 (100); 20η(
15%) of 1α,6-dihydroxycyclovitamin D3
(Utan'): Mass vector; (m/e), 400 (5
0), 382 (80), 269 (20) 247 (40)
, 135(80), 133(40): and 2.0Tr
9 (15%) of 1α-hydroxyvitamin D3 (6A)
, and the corresponding 1α-hydroxy-5,6-trans isomer are obtained. Example 21 1α,6-dihydroxy-cyclovitamin D3 (10a
) to 1α-hydroxyvitamin D3 (6a) 400μ1 of dry pyridine, 200μ2 of glacial acetic acid and 1α,
6-dihydroxy-cyclovitamin D3 (1a) 2.0
The solution consisting of η is heated at 55° C. for 2 hours.

Next, the reaction solution is diluted with toluene and dried. The produced oil (1α,6-diacetoxycyclovitamin D3) was taken up in 100a(7) THF, and 200 μl of 97% HC was added.
Treat with O2H for 15 minutes. Dilution with saturated NaCl, extraction with ether, washing with saturated NaHCO3, drying over MgSO4, and removal of ether in vacuo yields the crude 1-acetoxy-3-formatosis and trans-vitamin derivatives. Selective hydrolysis of the formate ester with K2CO3 and chromatographic treatment yields pure 1α-acetoxyvitamin D3 (5A). This is 1α-hydroxyvitamin D3 (6
A). Example Otsu 24 (R), 25-dihydroxycyclovitamin D3 (
2d): 10.4 mg of 2 in 150 μl of dry pyridine
4R,25-(0H)2D3 and 7.13W1f(1
．． 5eq. ) of TsCl is added.

React for 72 hours at 0°C, then dilute with saturated NaHCO3 and extract with ether.

The ether extract was washed with saturated NaHCO3 and MgSO
After drying at 4 and removing the solvent under vacuum, the crude tosylate (~70% by TLC) was suspended in 2 ml of anhydrous MeOH with 25 η of NaHCO and purified at 58 °C in N2 for 2 min.
Heat for 0 hours. The reaction was then diluted with saturated NaCl,
Extract with ether. The ether extract was washed with water and M
Dry with gSO4 and remove the solvent in vacuo. Separation TLC
(10 x 20 cm, 750 μm silica gel, 6:4 Sk
e11ys01veB: ethyl acetate), 2.5T
24R,25-(0H)2D3 and 4.4 of I19
24R,25-dihydroxycyclovitamin D (2d
) can be obtained. Characteristics of (2d): mass vector, (m
/e), 430 (15), 398 (65), 253 (4
0), 159 (45), 119 (55), 59 (100
): NMR, δ, 0.55 (3H, s, 18-H3),
0.74 (2H, m, 4-H2), 0.94 (3H, d
, J=6.2Hz, 21-H3), 1.17(3H,s
, 26-H3), 1.22 (3H.s, 27-H3),
3.26 (3H, s, 6-0CH3), 3.34 (1H
, m, 24-10, 4.17 (1H, d, J = 9.0H
z, 6-H), 4.88 (1H, m (sharp), 19
(Z)-H), 5.00 (1-H, d, J=9.0Hz
, 7-H), 5.04 (1H, m (Shayab) 19 (E
)-H). Example 231α-24(R),25-trihydroxycyclovitamin D3 (3d): previously prepared solution,
i.e. 1.127!9 S in dry CH2Cl2
To a solution containing eO2 and 12 μl of 75% t-BuOOH, add 4.2 to 24R,25-dihydroxycyclovitamin D3 dissolved in 500 It11 of CH2CI1.

After 30 minutes, 70 of 1.12mgse02 and 12μ2
A solution of 500 μl (!) of %t-BuOOH in CH2Cl2 is added and the reaction is continued for an additional hour.

The reaction was quenched with 10% NaOH, diluted with ether and diluted with 10% NaOH.
% NaOH twice, then water.

The organic solution is dried with MgSO4 and the solvent is removed under vacuum. The resulting oil is processed into acetic acid: Skelly.
5×20cTn, 2501t using sOlveBl:1
Purify by chromatography using a silica gel plate. As a result, 1α, 24(R), 25 of 1.6η
-Trihydroxycyclovitamin D3 (Akira A): Mass spectrum, (m/e), 446 (30), 414 (5
0), 396 (40), 269 (30), 135 (80
), 59 (100); NMR, δ, 0.55 (3H, s
,18-H3),0.65(2H,m,4-H2),0
．． 96 (3H, d, J=6.0Hz, 21-H,), 1
．． 19 (3H, s, 26-H3), 1.24 (3H, s
,27-H,),3.28(3H,s,6-0Cdan,)
, 3.35 (1H, m, 24-H), 4.20 (1H,
d. J=9.0Hz, 6-H), 4.22(1H, m,
1-H), 4.97 (1H, d,.J?9.0z, 7-
H), 5.18 (1H, m (sharp), 19 (Z)-
H), 5.26 (1H, d, J-2.2Bz, 19 (E
)-H) is obtained. As a by-product, 1-oxo-2
4(R),25-dihydroxycyclovitamin D3(L
A) is also isolated (less than 20%). Example 24 1α,24(R),25-trihydroxyvitamin D,
(6d): 200μl dry pyridine and 150μl
of AC2O with 1.4η of 1α. Add 24R,25-trihydroxy-cyclovitamin D, (3d).

The system is flushed with N2 and heated at 95°C for 20 hours. Thereafter, the reaction solution is diluted with dry toluene and azeotropically distilled to dryness. Oily product, 1α,24(R),25-triacetoxy-cyclovitamin D3 (Id-24,25-
diacetate) in 200μ2 THF',
%HcO2H: 'RHFl: Add to 500μ of a solution of 1 and heat at 55°C for 15 minutes. The cooled reaction was diluted with ether, washed with water, saturated NaHCO3, saturated NaCl, and dried over MgSO4. After removing the solvent in vacuo, the crude 1α,24R,25-triacetoxy-3β-
Dissolve the formate vitamin D intermediate in 200 μ2 THF. It is then treated with a solution containing 1.0~KCO3 in 10 μl of water and 90 tt1Me0H for 5 minutes at room temperature. Dilute with saturated NaCl, extract with ether, 5X
20 crn, 250 μM, purified by chromatography using a silica gel plate with ethyl acetate:SkellysOlveB 4:6 solution, 1α, 24R, 25-
Obtain triacetoxy-vitamin D3. Treatment of this triacetate with LiAlH4 yields 1α,24R,25-trihydroxyvitamin D3, which is identical in all respects to the standard reagent. Example 25 1-Hydroxycyclovitamin D, (Tudan) was converted into 1α-formyl intermediate (11a
) and converted to 1α-monohydroxyvitamin D3 (6a,
Gradually add 100 μl of formic acid.

The solution is heated briefly (15 minutes) to 50°C and then cooled to 0°C. This acetic-formic anhydride is then added to 5 mg of 1α-hydroxy-cyclovitamin D3 (3!) dissolved in pyridine at 0°C. After 2 hours, the reaction is diluted with saturated NaC2, extracted with ether, washed with H2O, and dried over MgSO4.

The solvent is removed under vacuum and the resulting crude 1α-formyl-cyclovitamin D3 is dissolved in glacial acetic acid and heated at 55° C. for 15 minutes. Saturated NaC! Dilution with ether, extraction with ether and separation of the organic products yield a crude product consisting of 1-formyloxyvitamin D,3-acetate (Lldan) and the corresponding 5,6-trans isomer. The crude mixture was treated with K2CO3 in H2O/MeOH and chromatographed (5 x 20C
T! L, 25OμM, silica gel, 3:7 ethyl acetate:
When purified with SkellysOlveB), pure 1α
-Hydroxyvitamin D,3-acetate and 5,6
- trans-1α monohydroxyvitamin D33-acetate is obtained. By hydrolysis (KOH/MeOH), the corresponding 1α-hydroxyvitamin D3
(6A) and its 5,6-trans isomer. Example 26 Crown ether-catalyzed cycloreversion of 1α-acetoxycyclovitamin D3 (jig neck reversal): 15-crown-5 in 0.5M hexanelivenzene (1:1) solution (Aldrich Chemical
O. , Milwaukee) with finely ground anhydrous sodium acetate.

600 for 3001t1 of this solution! Add 11.0η of 1α-acetoxy-cyclovitamin D3 (4A) dissolved in tl dry hexane, then add 97? Add formic acid 2001t2. The two-phase mixture is stirred vigorously from time to time for 30 minutes or more, then diluted with hexane to remove the acid layer.

The organic phase was washed with saturated NaHCO3, saturated NaCl, and M
Dry with gSO4 and then remove the solvent under vacuum.
300p, 10THF and 300μl of this crude oil
10mg taken in methanol and dissolved in 100μ2 of water
Treat with K2CO3. After standing at room temperature for 5 minutes, the reaction is diluted with saturated NaCl and extracted with 2 parts of ether.

The organic phase is washed with H2O, dried over MgSO4 and then the solvent is removed in vacuo. The resulting mixture was separated by TLC (750 μM, 10 x 2001 TL, 75:
Treatment with 25Ske11ys01veB: ethyl acetate) yielded 5.7η (54%) of 1α-acetoxyvitamin D3 (DanA) and 2.1η (20%) of 5,6-trans-1α-acetoxy-vitamin D3. It will be done. Example 27 Conversion of 1α-hydroxyvitamin D3 (6a) to 1α-hydroxycyclovitamin D3 (3a): 0.2ml
of pyridine, 3,01T19 of 1α-acetoxyvitamin D3 (Σ main), ((5A) is selective acetylation of 1α-hydroxyvitamin D3 (1) (dissolve 2 moles of excess acetic anhydride in pyridine, room temperature Leave it for 4 hours at
The desired 1α-acetoxyvitamin D3 derivative (or obtained from Example 2) and 6.0η of tosyl were separated by preparative silica gel thin layer chromatography using a 3:1 mixture of ellysOlveB:ethyl acetate. Add chloride.

After reacting at 3°C for 18 hours, the reaction was quenched with saturated NaCl solution, extracted with ether, and the ether extract was diluted with saturated NaCl solution.
Wash repeatedly with HCO3 solution.

After drying over MgSO4 and removing the solvent under vacuum, the crude 1α-acetoxyvitamin D33-tosylated
Anhydrous MeOH3 buffered with 2.0 mg NaHCO3
, taken in Oa. The reaction mixture is heated at 55° C. overnight, quenched with saturated NaCl solution, extracted with ether and then the solvent is removed in vacuo. This crude product was prepared by thin layer chromatography (5X20cTn, 250μ
m silica gel, SkellysOlveB:ethyl acetate, 3:1). As a result, 2.2η of 1α-hydroxycyclovitamin D3 (3a), which is identical in all respects to that obtained in Example 1, is obtained. Example 28 1α- of 1α-hydroxycyclovitamin D3 (3a)
MnO2 oxidation to oxy-cyclovitamin D3(7a): 3.0η of 1α-hydroxycyclovitamin D3(3a) and 35Tf1y in 1.0a of dry CH2Cl2
Add crushed MnO2 of 0 (e.g. Paare
nOther J. Chem. SOc. , Chem. COmm
．． 89O (1977)).

After 2 hours, the reaction is filtered through Celite and treated with preparative thin layer chromatography (5 x 20 CTIL, 250 μM, silica gel, Skellys Olve B: ethyl acetate).

This results in 1-oxocyclovitamin D3(7a)2.6, which is identical in all respects to the product described in Example 1. Example 29 Direct solpolysis of 1α-hydroxycyclovitamin D compounds 380η of 1α-hydroxycyclovitamin D3
Add 3.8a of glacial acetic acid to and warm the solution at 60°C for 10 minutes.

After cooling, add this mixture to the ice/NaHCO3 mixed stirred solution. This neutralized (neutral) aqueous solution is extracted with diethyl ether, and the combined organic extracts are washed once more with water and dried over MgSO4.

After removing the solvent, the crude product was heated to 1.5×60C
50f with TIL column! Using neutral silica gel of E
4% solution of tOAc/SkelIysOlvB mixture 100
a, 8% liquid 1001ni3,12? liquid 100ml1,16
Elute with 400d of % solution. Through this operation, the desired 1α-hydroxyvitamin D33 monoacetate isomer is converted to 1α-hydroxyvitamin D33 monoacetate isomer.
Elutes before hydroxy-5,6-trans-vitamin D,3-acetate. As a result, 1α-hydroxyvitamin D,3-acetate of 175W9 is obtained. The properties of this compound are: UV: λMax 264 nm: Mass vector (m/e) 442 (M+, 8), 382 (70)
, 364 (15), 269 (20), 134 (100)
It is. Hydrolysis of 1α-hydroxyvitamin D,3-acetate (10% NaOH/MeOH, 2 hours, room temperature) yields 1α-hydroxyvitamin D,.

Claims (1)

[Claims] 1. A compound having the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼... (I) (where Z_1 is selected from the group consisting of a hydrogen atom and a lower alkyl group) , R_1 is a hydrogen atom, a lower alkyl group, or a hydroxyl group, R_2 is selected from the group consisting of a hydrogen atom, a hydroxyl group, and a lower acyl group, and Y_1 is selected from a hydrogen atom and a lower acyl group. and R_3 and R_4 represent a hydrogen atom or form a double bond together.)2 The compound according to claim 1, wherein Z_1 is a methyl group and Y_1 is a hydrogen atom. . 3. The compound according to claim 1, wherein Z_1 is a methyl group and Y_1 is an acetyl group.