JPS58172388A - Novel vitamin d3 derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is aromatic or lower aliphatic acyl; R2 and R3 are H, OH or protected OH). EXAMPLE:Adduct of vitamin D3-acetate the sulfur dioxide. USE:Synthetic intermediate of hapten of formula II (R2' and R3' are H or OH; n is 2-4) useful for the preparation of an antibody necessary in the determination of vitamin D3 compound (e.g. 25-hydroxyvitamin D3) in blood by the antigen-antibody reaction. Also useful as a synthetic intermediate of vitamin D3 derivative. PROCESS:The compound of formula I can be prepared either by reacting the corresponding vitamin D3 compound (vitamin D3, 25-hydroxyvitamin D3, 24,25- dihydroxyvitamin D3, etc.) with sulfur dioxide, and reacting the resultant compound of formula III with an acid halide or acid anhydride and an organic base, or by acylating the 3-position of the vitamin D3 compound, and then reacting with sulfur dioxide.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a vitamin I) 34 conductor represented by the general formula ('I).

(In the formula, R1 means an aromatic or lower aliphatic acyl group, and R2 and R3 are the same or different and mean a hydrogen atom, a hydroxyl group, or a protected hydroxyl group.) The compounds of the invention improve blood vitamin D3, e.g.
As a synthetic intermediate for hapte/ represented by the general formula (IJ) for producing antibodies necessary when measuring 5-hydrobixvitami7 D3, la, 25-dihydroxyvitamin D3, etc. using an antigen-antibody reaction. It is also extremely useful as an intermediate for producing various other vitamin D3 derivatives.

(In the formula, R'2S R'l are the same or different and mean a hydrogen atom or a hydroxyl group, and n means an integer of 2 to 4.) As a conventionally known adduct of vitamin D3 with sulfur dioxide. has a hydroxyl group at the 3-position or a hydroxyl group protected with an ether-based protecting group such as a tetrahydropyranyl group. However, these compounds are extremely unstable to acids and cannot be used in synthetic reactions using oxidizing agents.

In view of these circumstances, the inventor conducted research and found that the compound of the present invention in which the 3-position is protected by an aromatic or aliphatic acyl group is extremely stable against acids, and is suitable for various syntheses using acids. It has been found that the compounds of the present invention are useful as raw materials for reactions such as alkylation reactions at the 6- or 19-position under acidic conditions.Furthermore, surprisingly, the compounds of the present invention are themselves extremely stable and can be stored for long periods of time. It has optimal physical properties as a synthetic raw material, such as being resistant to

The compound of the present invention is a new compound, for example, the general formula (Il
The compound represented by l) is produced by a conventional method, for example, by reacting an acid halide or acid anhydride with an organic base, or by first acylating the 3-position of the vitamin D3, and then reacting with sulfur dioxide. Manufactured by forcing.

(In the formula, R2 and R3 have the same meanings as in Koki.) The acyl group in the compound of the present invention is an aromatic acyl group or a lower aliphatic acyl group. Examples of the aromatic acyl group include a benzoyl group, p-nitrobenzoyl group, and naphthoyl group, and examples of the lower aliphatic acyl group include an acetyl group, a propanoyl group, and a butyryl group. There are no particular restrictions on the protecting group for the hydroxyl group in the side chain at position 17, but aromatic or lower aliphatic acyl groups are preferred.

Example 1 32.1 g of vitamin D was dissolved in 10 ml of pyridine,
Add 10 ml of acetic anhydride. Stir in Murogata for about 2 hours and pour into ice water. Extract with ethyl acetate, wash sequentially with dilute hydrochloric acid and water, and dry with magnesium sulfate. Distilling off the ethyl acetate yields 2.3 g of an oily residue of vitamin D3 acetate.

The residue was dissolved in 73 ml of diluted water and a cold finger cooled with Tri-ice was attached to the reaction vessel.

After purging the inside of the reaction vessel with dry argon, sulfur dioxide gas was added to the reaction solution until it reached approximately 3' Om +. 3
Reflux with cane moe for 0 minutes to 1 hour. The cold finger is removed and excess sulfur dioxide is removed under reduced pressure. The product was then subjected to column chromatography using linica gel and eluted with hexa/ethyl acetate (2:1). Collecting the 7 Raksi:I/ containing the target product and distilling off the solvent, the vitamin D3 acetate sulfur dioxide adduct of oil V2.
Obtain 24g.

This substance is a mixture of 6g isomer and 6H isomer (1:1).

6H isomer Melting point: 123-125°C (decomposed) (recrystallized from dichloromethane-isopropyl ether) NMRδ: 5.22-4.87 (IH, m)
, 4.69 (2H, m) , 3.69 (2H,
m), 2.05 (311,s), 0.55 (3H
,5) 6S isomer NMRδ: 5.22-4.90 (ill, m)
, 4.04 (2H, m), 3. E35 (2t
l, m), 2.03 (31j s), 0.64
(3H,s>Example 2 3.6g of a vitamin D3-sulfur dioxide adduct prepared from vitamin D3 and sulfur dioxide by a conventional method was added to 20% of pyridine.
ml and add 20 ml of acetic anhydride. At room temperature 1~
After stirring for 2 hours, pour into ice water. Extract with chloroform, wash the chloroform layer sequentially with dilute hydrochloric acid and water, and dry with magnesium sulfate.

When chloroform is distilled off, 3.8 g of vitamin D3 acetate sulfur dioxide adduct is obtained.

Procedural amendment (formality) %formula% 1.Display of the incident 1981 Patent Application No. 53686 2. Name of the invention Novel vitamin D3 derivative 3. Person who makes corrections Relationship to the case Patent applicant 5-5-1 Ukima, Kita-ku, Tokyo (331) Chugai Pharmaceutical Co., Ltd. Representative Kimio Ueno 3-41-8 Takada, Todori-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 6. Subject of correction Specification 7. Contents of correction As per attached sheet Engraving of the detailed statement (no changes to the contents) 669

Claims (1)

[Claims] In the general formula (wherein R1 means an aromatic or lower aliphatic acyl group, R2 and R3 are the same or different and mean a hydrogen atom, a hydroxyl group or a protected hydroxyl group) Compounds shown.