JP3429341B2 - Active vitamin D intermediate - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to an intermediate for the synthesis of active vitamin D compounds having an excellent bone mass improving action, for example, 1α, 25-dihydroxy-2β- (3-hydroxypropoxy) vitamin D _{3 and the} like. The present invention relates to a steroid compound useful as a body and a method for producing the same.

[0002]

2. Description of the Related Art Up to now, no steroid compound has been known as an intermediate for the synthesis of active vitamin D derivatives having an alkoxy or hydroxyalkoxy group introduced at the 2β-position.

[0003]

[Problems to be Solved by the Invention] By introducing an alkoxy group or a hydroxyalkoxy group at the 2β-position of an active vitamin D compound, it is possible to exhibit an interesting pharmacological action not seen in conventional active vitamin D compounds. As it becomes known, there is a need for versatile intermediates for the synthesis of these compounds.

[0004]

Means for Solving the Problems As a result of intensive studies by the present inventors in order to solve the above-mentioned problems, as a result, the formulas (I), (II), (II
I) and (IV)

[Chemical 8] It was found that a steroid compound represented by the formula (wherein R ₂ represents a hydroxyl-protecting group, R ₃ represents an alkoxy group or a protected hydroxyalkoxy group) is a useful intermediate, and the present invention was completed. It was That is, the present invention relates to an intermediate for synthesizing the active vitamin D derivative represented by the above formulas (I), (II), (III) and (IV).

The steroid compounds of the formulas (I) and (III) of the present invention have the following formula (V) or (VI)

[Chemical 9] C-22 or C-24 alcohol derivative represented by (R
₂ , R ₃ is a protective group for hydroxyl group (Nikkei, 1992 , 53p)
p. By selectively epoxidizing the double bond at the 1-position thereof with the following formula (VII) or (VIII)

[Chemical 10] A 1α, 2α-epoxide compound represented by (wherein R ₂ and R ₃ are hydroxyl-protecting groups), and then the 3-position hydroxyl-protecting group of this compound is eliminated to give the following formula (IX) or (X):

[0006]

[Chemical 11] An epoxy alcohol represented by (R ₁ is a hydroxyl-protecting group), and then the epoxy alcohol is reacted with an alcohol such as methanol, ethanol, ethylene glycol, or 1,3-propanediol in the presence of an acid or alkali catalyst, The following formula (XI) or (XII)

[Chemical 12] (R ₂ is an alkoxy group or a hydroxyalkoxy group,
R ₃ is a compound represented by the following formula (XIII) or (XI).
V)

[Chemical 13] (Wherein R ₂ and R ₄ are hydroxyl-protecting groups, R ₃ is an alkoxy group or a protected hydroxyalkoxy group, respectively), and then the compound is a 5,7-diene-protecting group 4- Phenyl-1,2,4-triazoline-
It can be obtained by reductively removing 3,5-dione.

The steroid compounds of formulas (II) and (IV) of the present invention are compounds (I) obtained as described above.
Alternatively, it can be obtained by treating (III) with an oxidizing agent to convert a hydroxymethyl group into an aldehyde group.

In the above compounds (V) and (VI), 3
It is necessary to chemically distinguish the hydroxyl group at the 22-position and the hydroxyl group at the 22-position or the 24-position, and especially the protective group for the 3-position hydroxyl group is a selective α.
-It is necessary to use bulky ones to achieve the epoxidation. It is necessary to select a protective group for the 22-position or 24-position hydroxyl group that can be converted into an alcohol in the final step. From the above, t-butyldimethylsilyl, t-butyldiphenylsilyl group and the like are used as the protective group for the 3-position hydroxyl group, and ester bonds such as acetyl and benzoyl are used as the protective groups for the 22- and 24-position hydroxyl groups. Those that have are used.

Compounds (XIII) and (XIV) are required to be stable under these conditions because the side chains are bonded under basic conditions as described below. Further, since it is necessary to be stable even in the oxidation reaction, a tetrahydropyranyl group, a triethylsilyl group or the like is used as a protective group for the hydroxyl group at the 3-position.

The compound thus obtained is, for example, a phenyl sulfone derivative (XV) (R is a hydroxyl-protecting group)

[Chemical 14] (Bull. Chem. Soc. Jpn., 62 , 2599 (198
9)), and after several steps, 1α, 25-dihydroxy-2β- (3-hydroxypropoxy) vitamin D ₃ (ED-71) (Chem. Pharm. Bull., 46 , 11
11 (see 1993)).

In the above-mentioned specific reaction procedure of the present invention, the compound of the formula (V) or (VI) as the starting compound is first selectively epoxidized with the double bond at the 1-position. This epoxidation is carried out in a suitable organic solvent such as chloroform using peracetic acid or m-chloroperbenzoic acid as an epoxidizing agent. The preferred epoxidizing agent in this epoxidation is m-chloroperbenzoic acid (m-CPBA).

1α, 2 of the formula (VII) or (VIII) obtained
The α-epoxide compound is then eliminated by removing the protective group for the hydroxyl group at the 3-position to give a free hydroxyl group.
Since it is necessary to carry out without removing the protecting group R ₃ for the hydroxyl group in the side chain at the 7-position and to selectively achieve the epoxidation in the previous step, the hydroxyl group at the 3-position R ₂ is t
It may be a group such as -butyldimethylsilyl, t-butyldiphenylsilyl, etc., and each of these groups can be treated with a known agent for elimination, for example, in the case of a protecting group having a silyl bond, a tetrayl group. It is treated with butylammonium fluoride (n-Bu ₄ NF) or the like.

The epoxy ring of the obtained epoxy alcohol of the formula (IX) or (X) is composed of an alcohol such as methanol, ethanol, i- or n-propanol, ethylene glycol, 1,3-propanediol, etc. and an acid or alkali catalyst. The ring is opened in the presence of formula (XIII) or (XI
V), but the acid catalyst in this case is p
-Toluenesulfonic acid or the like is t as an alkali catalyst.
-Butoxy potassium and the like are used.

The compound of formula (XIII) or (XIV) obtained is then the protecting group for the 5,7-diene of this compound.
-Phenyl-1,2,4-triazoline-3,5-dione and a protective group R ₄ for the hydroxyl group are reductively removed. Examples of the reducing agent used in this case include alkali metal hydrides or alkali metal borohydrides such as LiAlH ₄ , NaAlH ₄ , KAlH ₄ , and L.
iBH _4, such as NaBH _4, KBH ₄ and the like, LiA
1H ₄ is preferably used.

When the compound (I) or (III) thus obtained is a compound (II) or (IV) which is a compound having an aldehyde group on its 17 side chain, it is treated with an oxidizing agent. The hydroxymethyl group can be converted to an aldehyde group. In this case, pyridinium chlorochromate (PCC), pyridinium dichlorochromate (PDC), Swern oxidant or the like is used as the oxidizing agent, and PCC is particularly preferable.

The synthetic route of the compounds ((I) to (IV)) having a 3-hydroxypropoxy group at the 2β-position of the present invention is as shown in the following scheme 1 when exemplified by a reaction using a specific reaction reagent. .

[0017]

[Chemical 15]

A synthetic example of ED-71 using compound (I) is illustrated by the following scheme 2 by a reaction using a specific reaction reagent.

[0019]

[Chemical 16]

The present invention will be described below with reference to examples.
It is not limited to these. In addition, the synthesis of an active vitamin D derivative, 1α, 25-dihydroxy-2β- (3-hydroxypropoxy) vitamin D ₃ (ED-71) using the compound of the present invention is shown as a reference example. Example 1 1α, 3β-Dihydroxy-2β- (3-hydroxypropoxy) -23,24-dinor-5,7-coradiene-
22-ol 1α, 2β (3-), 3β-tristetrahydropyranyl ether (Compound (I)) Compound (V) (R ₃ = Bz) (10.0 g) was dissolved in chloroform (200 ml) and m-CPBA ( 10.0 g)
Was added and stirred overnight at room temperature. The extract was washed with a 10% K ₂ CO ₃ aqueous solution and brine and dried. Chloroform was distilled off, and the compound (VII) obtained as a residue was treated with THF (1
(00 ml), n-Bu ₄ NF (1M solution, 20 m
l) was added, and the mixture was stirred at room temperature for 2 hours. It was extracted with ethyl acetate, washed with brine and then concentrated. The residue was purified by silica gel chromatography to obtain 6.7 g of compound (IX).

This compound (IX) (5.0 g) was added to THF.
Dissolve in (50 ml), 1,3-propanediol (50 m
l) and p-toluenesulfonic acid (200 mg) were added,
The mixture was heated under reflux for 5 hours. Extracted with ethyl acetate, NaHCO
₃ , washed with water and brine and then concentrated, and the residue was purified by silica gel chromatography to obtain 2.1 g of compound (XI). This compound (XI) (2.1 g) was added to dichloromethane (50 ml).
Dihydropyran (1.2 g), pyridinium and p-toluenesulfonate (150 mg) were added to the solution and the mixture was stirred overnight. After washing with brine and drying, the solvent was distilled off to obtain 2.5 g of compound (XIII). Compound (XIII) (2.5
g) was dissolved in THF (100 ml) and LiAlH ₄ (1.
0 g) was added and the mixture was heated under reflux for 1 hr. Water was added to decompose excess LiAlH ₄ and MgSO ₄ was added, and the THF layer was separated and concentrated to obtain 1.7 g of the title compound (I). ¹ H NMR (CDCl ₃ ) δ 0.85 (3H, s), 1.06 (3H, s), 1.15 (3
H, d, J = 6.0Hz), 5.31 (1H, m), 5.62 (1H, m). λ _max 282nm (ε = 10,800, EtOH)

Example 2 1α, 3β-dihydroxy-2β- (3-hydroxypropoxy) -5,7-coradien-24-ol 1α,
2β (3-), 3β-Trishydropyranyl ether (Compound (III)) Compound (VI) (R ₃ = Bz) (3.0 g) was treated in the same manner as in Example 1 to give the title compound (III). 580 mg was obtained. ¹ H NMR (CDCl ₃ ) δ 0.84 (3H, s), 1.05 (3H, s), 1.16 (3
H, d, J = 6.1Hz), 5.32 (1H, m), 5.61 (1H, m).

Example 3 1α, 3β-dihydroxy-2β- (3-hydroxypropoxy) -23,24-dinor-5,7-coradiene 2
2-ar 1α, 2β (3-), 3β-tristetrahydropyranyl ether (Compound (II)) The compound (I) (500 mg) obtained in Example 1 was dissolved in dichloromethane (10 ml), and PCC (500 mg) was added. ,
Stir at room temperature for 3 hours. Dichloromethane was distilled off, and the residue was purified by silica gel chromatography to obtain 380 mg of the title compound (II). ¹ H NMR (CDCl ₃ ) δ 0.87 (3H, s), 1.07 (3H, s), 1.16 (3
H, d, J = 6.0Hz), 5.34 (1H, m), 5.65 (1H, m), 9.64 (1H,
s).

Example 4 1α, 3β-dihydroxy-2β- (3-hydroxypropoxy) -5,7-coladiene-24-al 1α,
2β (3-), 3β-Tristetrahydropyranyl ether (Compound (IV)) The compound (II) (500 mg) obtained in Example 2 was treated in the same manner as in Example 3 to obtain 410 mg of the title compound (IV). . ¹ H NMR (CDCl ₃ ) δ 0.86 (3H, s), 1.07 (3H, s), 1.17 (3
H, d, J = 6.1Hz), 5.33 (1H, m), 5.64 (1H, m), 9.71 (1H,
s).

Example 5 1α, 3β-dihydroxy-2β-methoxy-23,24
-Dinor-5,7-coladiene-22-ol 1α, 3
β-bistetrahydropyranyl ether compound (IX) (1.0 g), methanol (10 ml), p
-Toluenesulfonic acid (50 mg) in THF (20 m
l) was treated as in Example 1 to give 170 mg of the title compound.
Got ¹ H NMR (CDCl ₃ ) δ 0.84 (3H, s), 1.06 (3H, s), 1.16 (3
H, d, J = 6.1Hz), 3.47 (3H, s), 5.33 (1H, m), 5.64 (1H,
m).

Reference Example The synthetic compound (I) (1.0 g) of ED-71 was dissolved in pyridine (10 ml), tosyl chloride (0.6 g) was added, and the mixture was stirred at 0 to 4 ° C. overnight. After extraction with ethyl acetate and washing with NaHCO ₃ water and brine, the solvent was evaporated. The residue was dissolved in acetone (10 ml), NaI (1.0 g) was added, and the mixture was heated under reflux for 2 hr. It was extracted with chloroform, washed with brine, dried, and concentrated to obtain 750 mg of compound (XVI).

Phenylsulfone (XV) (750 mg) was added to T
It was dissolved in HF (10 ml) and cooled to -20 ° C. n-B
uLi 1.6N (1.5 ml) and dimethyl-2-imidazolidinone (0.5 ml) were added, and the mixture was stirred at -20 ° C for 30 minutes. THF solution of compound (XVI) (750 mg) (10 m
l) was added dropwise and the mixture was stirred for 2 hours at -20 ° C. Aqueous NH ₄ Cl solution was added, the mixture was extracted with ethyl acetate, washed with brine, dried, and the solvent was evaporated. The residue (1.1 g) was dissolved in chloroform (5 ml), MeOH (20 ml) and p-toluenesulfonic acid (50 mg) were added, and the mixture was stirred at 50 ° C for 2 hr. It was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue (650 mg) was dissolved in methanol (20 ml), 5% Na-Hg (2.0 g) was added, and the mixture was stirred at room temperature overnight. The mercury was separated, the methanol was concentrated, the residue was extracted with ethyl acetate and washed with brine. The residue (460 mg) obtained by distilling off ethyl acetate was purified by silica gel chromatography and then crystallized to obtain 240 mg of tetraol (XVII). Melting point 155 ° C. (ethyl acetate) λ _max 282 nm (ε = 10,900, EtOH) ¹ H NMR (CDCl ₃ ) δ 0.64 (3H, s), 0.98 (3H, d, J = 6.1H
z), 1.08 (3H, s), 1.21 (6H, s), 3.65 ~ 4.00 (7H, m),
5.34 (1H, m), 5.66 (1H, m).

This tetraol (XVII) (50 mg) was added to T
It was dissolved in HF (500 ml) and irradiated with a high pressure mercury lamp (450 W) for 2 minutes (filter: 1.2% KNO ₃ aqueous solution). THF was concentrated, ethanol (5 ml) was added to the residue, and the mixture was heated under reflux for 1 hr. Ethanol was distilled off, the residue was purified by HPLC, and the title compound (XVIII) (= ED-
71 mg of 71) was obtained. ¹ H NMR (CDCl ₃ ) δ 0.56 (3H, s), 0.92 (3H, d, J = 6.0H
z), 1.22 (6H, s), 3.61 ~ 4.05 (5H, m), 4.15 ~ 4.40 (2H,
m), 5.10 (1H, s), 5.45 (1H, s), 6.04, 6.40 (2H, ABq,
J = 11.0Hz). λ _max 264nm (ε = 17,200, EtOH)

Front page continued (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07J 7/00 C07J 43/00 C07J 75/00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The following formulas (I), (II), (III) and (I
V) [Chemical 1] (In the formula, R ₂ represents a hydroxyl-protecting group, and R ₃ represents an alkoxy group or a protected hydroxyalkoxy group, respectively). 2. The following formula (V) or (VI): C-22 or C-24 alcohol derivative represented by (R
₂ , R ₃ is a hydroxyl-protecting group) and the double bond at the 1-position thereof is selectively epoxidized to give the following formula (VII) or (VIII) A 1α, 2α-epoxide compound represented by the formula (R ₂ and R ₃ are hydroxyl-protecting groups), and then the 3-position hydroxyl-protecting group of this compound is eliminated to give the following formula (IX) or (X): ] An epoxy alcohol represented by (R ₁ is a hydroxyl-protecting group), and then this epoxy alcohol is reacted with an alcohol such as methanol, ethanol, ethylene glycol, or 1,3-propanediol in the presence of an acid or alkali catalyst, The following formula (XI) or (XII) (R ₂ is an alkoxy group or a hydroxyalkoxy group,
R ₃ is a compound represented by the following formula (XIII) or (XI).
V) [Chemical 6] (Wherein R ₂ and R ₄ are hydroxyl-protecting groups, and R ₃ is an alkoxy group or a protected hydroxyalkoxy group, respectively), and then the protecting group for the 5,7-diene of this compound is 4- Phenyl-1,2,4-triazoline-
When R _4, which is a protecting group for 3,5-dione and a hydroxyl group, is reductively released, and a compound having an aldehyde group on the 17 side chain is desired, it is further treated with an oxidizing agent to convert the hydroxymethyl group to an aldehyde group. The following formula (I), which consists of converting:
(II), (III) and (IV) embedded image (Wherein R ₂ represents a hydroxyl-protecting group and R ₃ represents an alkoxy group or a protected hydroxyalkoxy group).