Method for prepn. of 1 alpha, 25-dihydroxy vitamin Da medicine and anologue

The invention relates to 1α, 25-dihydroxy vitamin D₃ and 1 α-hydroxy vitamin D₃ preparation method. 1 α, 25-dihydroxy vitamin D₃ is a molecular formula with the following three-dimensional structure of the steroid compound. It exists in other animal body and in the human body, and can be separated from it. 1 α-hydroxy vitamin D₃ analogs of is, after entering the human body, after liver , kidney, the role of the small intestine, can be converted to 1α, 25-dihydroxy vitamin D₃.

1 α, 25-dihydroxy vitamin D₃   1 α-hydroxy vitamin D₃

Laboratory-scale production is completed, the amount of each time 0.5 micrograms, clinical demonstrate that 1α, 25-dihydroxy vitamin D₃ vivo active metabolites is, play a very good in vivo clinical effect of the, shown in the following respects: 1. the kidney of the metabolism of the necessary material, inhibitors of osteoporosis bone mass reduction 2 ., 3. the treatment of chronic kidney, parathyroid function is low, rickets, osteomalacia, metabolic abnormalities VD bone caused by the lesion, with 4. were secreted hyperspienism inhibition of thyroid, 5. regulating serum calcium concentration.

A purpose of this invention is to provide a synthetic preparation of 1α, 25-dihydroxy vitamin D₃ and 1 α-hydroxy vitamin D₃ method of the medicament.

After long-term and careful study, the present inventors developed a more simple and convenient, the method of synthesis through the short. Than danske Leo Company, Corporation of Japan pharmaceutical emperor person method is more simple and more convenient, with a route short, high yield and the like. The United States, Japan sold on the market the hydroxy vitamin D₃ types of medicament is 2 a, a to 1α, 25-dihydroxy vitamin D₃, another kind is the 1 α-hydroxy vitamin D₃

According to the invention, the reaction process of the II and I through the reaction process can be easily make the above-mentioned two kinds of vitamin D₃ kinds of medicament.

I reaction process (and the reaction procedure II)

Type used in the solid-line-arrow is disposed above the plane of the paper to key, dashed-line arrow means is located below the paper plane of the key.

R is a protecting group for hydroxyl group SiMe₃, SiMe₂ Bu-t, SiPh₂ Bu-t, CO₂ Me,

MOM, THP, MEM, such as EE;

R ' for OR, H;

For ' R C₁-C₆ alkyl;

X is CH₂ Cl, CH₂ Br, CH₂ I, CH₂ OMs, CH₂ OTs, CHO;

Y is H, PhSO₂;

Z is H, =O;

X ' as OH, H;

Y ' is H, PhSO₂;

Z ' for =O, H;

X 'to OCS₂ R'

According to the method provided by the invention, the compound 3 (substituted steroid part) with compound 4 in the reaction is performed in the presence of an alkali reagent, branched chain extension compound prepared surface 5.

Alkali reagent can be sodium methoxide, sodium ethoxide, lithium hydride , sodium hydride, potassium hydride, n-BuLi, diisopropylamine based lithium, wherein two isopropylamines based lithium is preferred.

This reaction may be the in -80 under to [...] such as hexane, at room temperature, anhydrous ether, cyclohexane, anhydrous ethanol, anhydrous methanol, dichloromethane, carbon tetrachloride, tetrahydrofuran or dioxane in organic solvent for five minutes to 48 hours.

Furthermore, the reducing agent for compound 5 for reaction. The reduction reaction can be room temperature to the reflux temperature of the solvent, in the routine in the aforementioned organic solvent stirring five minutes to 48 hours, the reaction is complete, to make structured compound 6 or compound 7.

Compound 7 with the 1-substituted imidazole thioester (compound 8) in the presence of alkali agent or alkali-free reagent for the reaction to prepare the compound 9.

Alkali reagent can be sodium methoxide, sodium ethoxide, lithium hydride , sodium hydride, potassium hydride, wherein the sodium hydride is preferred.

This reaction may be in the 0 to [...] under the reflux temperature of the solvent, such as hexane, anhydrous ethyl ether, cyclohexane, anhydrous ethanol, benzene, anhydrous methanol, dichloromethane, carbon tetrachloride, tetrahydrofuran or dioxane in organic solvent for five minutes to 48 hours.

Furthermore, using Bu₃ SnH/AIBN reagent the steroid compound 9 to free radical reaction.

The free radical reaction may be the room temperature to the reflux temperature of the solvent in the conventional organic solvent is hexane, anhydrous ethyl ether, cyclohexane, anhydrous ethanol, anhydrous methanol, dichloromethane, tetrahydrofuran or dioxane, benzene, toluene for five minutes to 48 hours. Thus make the compound 6.

The compound 6 with Lewis acid in conventional organic solvent is hexane, anhydrous ethyl ether, cyclohexane, anhydrous ethanol, anhydrous methanol, dichloromethane, carbon tetrachloride, tetrahydrofuran or dioxane, benzene, toluene, the hydrolysis reaction, so as to prepare compound 10. This reaction may be the in -80 to [...] carried out under reflux temperature of the solvent 1 minutes to 48 hours. Lewis acid can be Bu₄ NF, HF, HCl, AeOH, CF₃ CO₃ H, TsOH, HF·Py, PPTs, BF₃ ·Et₂ O.

Finally, the presence of the organic solvent, compound 10 carries on the actinic reaction. but is the benzene of the organic solvent, ethanol, toluene, acetonitrile. The in -40 [...] to the solvent reflux temperature of the reduction reaction is carried on under 1 minutes to 24 hours.

Necessary, by chromatography to separate hydroxy vitamin D₃ and impurity. The chromatography can use the silica gel column chromatography or Sephadex column chromatography, can be used the eluent chloroform/hexane/methanol mixed liquid.

This invention adopts the existing technology with the synthesis of 1α, 25-dihydroxy vitamin D₃ or 1 α-hydroxy vitamin D₃ different synthetic pathway, so as to synthesize the International market for sale of expensive hydroxy vitamin D₃ kinds of medicament. Furthermore, the preparation method of this invention also has the advantages of low cost, mild reaction conditions, notably the synthetic pathway the characteristics of short, and the like.