JPS59163364A - 6,19-ethylenevitamin d3 derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is H or OH-protecting group; R2 and R3 are H, arylsulfonyl, OH, lower alkoxycarbonyl, or hydroxymethyl; when one of R2 and R3 is arylsulfonyl or OH, the other group is H, when one of R2 and R3 is lower alkoxycarbonyl or hydroxymethyl, the other is the same group or one of R2 and R3 may form carbonyl together with C atom bonded thereto; R4 is H or OH). EXAMPLE:The compound of formula II. USE:It has physiological activity similar to vitamin D, and is useful as a synthetic intermediate of 6,19-ethylenevitamin D3. PREPARATION:The compound of formula I a is obtained by reacting the compound of formula II with SO2, and reacting the resultant compound of formula IIIwith aryl-SO2-CH=CH2. Reaction of the compound of formula I a with lithium diisopropylamide and molybdenum pentaoxide-pyridine-hexamethylphosphoric triamide complex in THF gives the compound of formula I b, which can be converted to the compound of formula I c by reduction.

Description

Detailed Description of the Invention The present invention is based on the general formula (I) (\where R1 means a hydrogen atom or a protecting group for a hydroxyl group, and R2 and R3 are each the same or different and represent a hydrogen atom, an arylsulfonyl group, a hydroxyl group, , lower alkoxycarbonyl group, hydroxymethyl group, provided that R2,'R
When one of 3 means an arylsulfonyl group or a hydroxyl group, the other means a hydrogen atom, and R2 and R
When one of 3 means a lower alkoxycarbonyl group or a hydroxymethyl group, the other also means the same group.

Note that either R2 or R3 may form a carbonyl group together with the substituted carbon atom. R4 means a hydrogen atom or a hydroxyl group. ) and relates to 6,19-ethylene vitamin D3 derivatives.

The 6,19-ethylene vitamin D3 derivative of the general formula (I) of the present invention is itself useful as a vitamin D-like material.

The compounds represented by the general formula (1) of the present invention are all new compounds, and can be produced, for example, by the method shown below using vitamin D3 or 25-hydroxyvitamin D3 as a starting material.

Method A) (lb) (I c) Method C) (1) (I) (In reaction formula A-0, R1 and R4 mean the same as above, and R means a lower alkyl group.) In the compound represented by the general formula (I) of the present invention, the protecting group for the hydroxyl group represented by R1 may be used in the reaction formula A-0, for example, the reaction for producing compound (Ib) from the compound (Ia) in the reaction formula A. There are no particular limitations as long as it is active, but ether protecting groups are preferred, and specific examples include 2-tetrahydropyranyl group and β-methoxyethoxymethyl group.

Further, the arylsulfonyl group in the compound of the present invention is a substituted or unsubstituted arylsulfonyl group, specifically a phenylsulfonyl group or a p-tolylsulfonyl group.

The compound of the present invention is isolated from the reaction mixture by a conventional method, for example, by distilling off the solvent and subjecting the mixture to column chromatography or the like.

(In the formula, THP means 2-tetrahydropyranyl group.) Vitamin D325 m'! and liquefied sulfur dioxide using a cold finger. Excess sulfur dioxide is removed by suction, the residue is bathed in a small amount of ethyl vinegar, and argon gas is blown to drive off the solvent, followed by drying. Then 7 enyl vinyl sulfone 21.9 m
? , sodium bicarbonate 197#g,) toluene 250
Add μμ, under argon gas flow, light shielding, stirring, 100
React in an oil bath for 14 hours and 35 minutes. The reaction solution was filtered to remove sodium bicarbonate, the solvent was distilled off, and the residue was subjected to column chromatography (5 grams of silica gel).

The mixture is purified using a solvent (ethyl acetate:hexane=1:2) to obtain a less polar compound (Ia-1) 22 vq and a more polar compound (I a'-1') 2■.

it) Compound (Ia-1) 1201n? 21 nI of methylene chloride! Dissolved in dihydrobilane 36.57
7ii1, pyridinium p-)luenesulfone, -)
Add 16.4 mg and stir at room temperature for 4 hours. After distilling off the solvent, the residue was purified by column chromatography (silica gel 2°?, solvent: ethyl acetate:hexane-1:9) to obtain compound (Ia-2) 102 mIi+.

NMR spectrum (CD0℃3) δ: 0.52 (3H
,S).

0.76 (3H, S), 3.88 (LH, m),
4.68 (LH.

m>, 5.00 (LH, d, J=7Hz), 7
．． 40-8.00 (5H, m) Mass spectrum # 'n3/: 636 (assistance, 552
, 354.410 Example 2゜1) Compound (Ia-2) obtained in Example 1 102 mg
was soaked in tetrahydrofuran and cooled at 78°C.
Add 3.4πg of 7M lithium diisopropylamide. After stirring for 3 minutes at -78°C, 278.47°C g of molybdenum pentaλkizydoviridine-hexamethyl 7-osulfuric triamide complex was added to 7 runs of 3rLe
Add the dissolved ingredients and stir for 1 minute. To the reaction solution, add 3π of sodium sulfite and 5 liters of water, and add 5'r of ether.
Extract 3 times with rtl. The ether layer was dried over sodium sulfate and filtered, and the solvent was distilled off, and the residue was purified by column chromatography (silica gel 40f, solvent: ethyl acetate A/:hexane-1:9) to obtain compound (Ib-1) 78 obtain.

NMR spectrum (CDCiL3) δ: 0.52 (3
H,s).

0.60 (3H, s), 3.50 (IH, m)
, 3.90 (IH.

m), 4.74 (IH, d, J = 10 Hz) mass spectrum -/, : 510 (fly), 426, 40
811) Compound (lb, -1) 24 mg was dissolved in two portions of methanol, 17.7 m7 of pyridinium p-)luenesulfonate was added, and the mixture was stirred at 50°C for 3 hours. After evaporating the solvent, the residue was purified by column chromatography (silica gel, 4?, solvent, ethyl acetate:hexane = 1:2) to obtain a less polar compound (Ib-2) with different coordination at the 6-position. ) 7.5 m'i and a more polar compound (1b-2') 8.5■ is obtained.

Compound ()b-2) NMR spectrum (CDCl2) δ: 0.52 (3H,
s).

3.52 (IH, d, J = 10Hz), 4.00 (I
H,ya).

4.75 (LH, d, J = 10Hz) Compound (lb-2') NMR spectrum (CDCl3) δ: 0.57 (3H
,s,).

3.52 (IH, d, J-10Hz), 4.00 (IH
9fn).

4.72 (IH, d, 10 Hz) Mass spectrum of compound (Ib-2) and (Ib=zl) "/,: 426 (M+), 408, 313, 2951)
5.3 mg of the compound (Ib-2) obtained in Example 2 was dissolved in 200 μL of tetrahydrofuran and dissolved in Li Et3 B.
Add H400μμ and react for 5 minutes. Water was added to the reaction solution and purified by column chromatography (silica gel, 42, solvent, ethyl acetate:hexane = 1:1) to obtain the compound (
lc-1) 1.8η is obtained as a single product.

NMR spectrum (CDCl3) δ: 0.56 (3H
', s).

2.70 (IH, d), 3.12 (IH,, emotion),
3.90 (2H.

@), 4.76 (IH, d) Mass spectrum “/,: 428 (M”), 416.3
8411) Compound (Ib-2') obtained in Example 2 8.
The compound (lc-
1') Obtain 47vry as a single item.

NMR spectrum (ODOfi3) δ: 0.60 (3H
,s).

2.78 (IH, d), 3.18 (IH, m), 3
．． 90 (2H.

愼), 4.78 (LH, d) Mass spectrum: t2g (#), 410.3841
) 25-Human tetraxyvitamin D3257q is reacted with liquefied sulfur dioxide under stirring. Excess sulfur dioxide was distilled off, and after suction drying, ethyl acetate was added to the residue to dissolve it.
After distilling off the solvent, it is dried. Next, 21 parts of phenylvinyl sulfone, 20 parts of sodium bicarbonate, 20 parts of toluene
Add 0 μλ and stir under argon gas flow, shielding from light, and stirring for 100 min.
React for 14 hours in a °C oil bath. After filtering the reaction solution and distilling off the solvent, the residue was purified by column chromatography (silica gel, 51. Solvent, ethyl acetate:hexane = 1:2) to obtain compound (Ia-3) as a mixture of two or more isomers. 29.77'g is obtained.

Massspect/I/lyt/: 56g (M+)
, 550, 426ii) Compound (Ia-s)
29.77'lli', 5% Na (H3 disodium hydrogen phosphate 73.4 mf/, methanol 4 m
1 was allowed to react at room temperature for 2 hours with stirring.

Next, 44171v of 5% Na (Hg) and 0.14r of disodium hydrogen phosphate were added for reaction. After filtering the reaction solution, column chromatography (silicage #5
F, solvent, purified with ethyl acetate dihexane = 1:2) to obtain a mixture of compound (Id-1) and (Id-I) (6.5 m
g and raw material compound 171! Obtain Ig. The raw material compound undergoes the same reaction again, and finally compounds (Id-1) and (Id
-17.7 ml of a mixture is obtained. This mixture was subjected to high performance liquid chromatography (Microporacil, solvent, 7%
A less polar compound (Id-1) (2.3 mV) and a more polar compound (Id-1') 3.3 mV were obtained by separation using isopropyl alcohol, Kuhexane).

Compound (■d-1) N M R7, hexyl (0DO42s) δ: 0.
56 (3H', s).

0.97 (3H, d, J=5Hz), 1.22 (
6H,s).

3.96 (IH, m), 4.82 (IH, d, J=
10Hz) Compound (Id-]/) NMR, ;<h) (CD0n3)δ: 0
．． 54 (3H, s).

0.97 (3H, d, 'J=5Hz), 1.
22 (6H, s).

3.92 (IH, m), 4.80 (IH, d, J=lO
Hz) Mass spectra of compound (1d-1) and (Id-10 -/,: 428 (M"), 410, 164
, 146 Example 5. - React vitamin D35007n9 with liquefied sulfur dioxide. Excess sulfur dioxide is distilled off and the remaining iG:)
Le! React for 35 dtJ [+, dimethyl maleate]. After filtering the reaction solution and distilling off the solvent, the residue was subjected to column chromatography (silica gel).

501, purified with solvent ethyl acetate S>-hexane = 1:4), a less polar compound (le-1) 342°5
7n? and a more polar compound (Ie i') 5
Obtain 1”f.

Compound (Ie-1) NMR spectrum (OD 013) δ? 0.55 (3H
,s).

3.60 (3H, s), 3.70 (3H, s)
, 4.76 (IH.

d, J=10Hz) Compound-(Ie-1Q NMR spectrum (CDCl2) δ: 0.57 (3H,
s).

3.60 (3H, s), 3.70 (3H, s), 4.7
5 (LH.

d, J=10Hz) Mass spectra Tn7. of compounds (Ie-1) and (Ie-1〆). ;528 (M+), 510,415,280
1) After stirring 15.4 μl of lithium aluminum hydride and 8 yrtl of tetrahydro7rane, 215 my of the compound (Ie-i) obtained in Example 5 in a 2rnl bath of tetrahydro7rane was added dropwise under ice cooling. . After stirring for 30 minutes at room temperature, 15.4 μ of lithium aluminum hydride was added. After 30 minutes, the reaction solution is cooled on ice, and aqueous tetrahydrofuran (water:tetrahydrofuran=1:2) is added to decompose excess lithium aluminum hydride, and inorganic substances are filtered off and washed with ethyl acetate. After drying with sodium sulfate, the solvent was distilled off and the residue was subjected to column chromatography (silica gel,
20? , solvent, ethyl acetate) to obtain the compound (If-1
) to obtain 777n9 as a single item.

NMR spectrum (CDO43) δ: 0.58 (3H,
s).

3.70 (4H, m), 3.85 (LH, m), 4
．． 78 (LH.

d, J=10Hz) Mass spectrum"/, : 472(M"),'45
4, 359.

341.224 11) Compound (Ie-Il) obtained in Example 5 51 mg
was treated in the same manner as in 1) above to obtain the compound (If-1
') as a single item for 17■.

NMR spectrum (CDCl3) δ: 0.58 (3H,
s).

3.70 (4H, m), 4.06 (IH, m), 4.
80 (LH.

d, J=lOHz) Mass hect IL/″rL/, ゛:472(M+), 4
54 Applicant Chugai Pharmaceutical Co., Ltd.

Claims (1)

[Scope of Claims] (In the formula, R1 means a hydrogen atom or a hydroxyl group, and R2 and R3 are each the same or different, and each represents a hydrogen atom, an arylsulfonyl group, a hydroxyl group, a lower alkoxycarbonyl group, a hydroxymethyl means a group, provided that R2, R3
When one of them means an arylsulfonyl group or a hydroxyl group, the other means a hydrogen atom, and R2 and R3
When one of them means a lower alkoxycarbonyl group or a hydroxymethyl group, the other also means the same group. Note that either R2 or 'fL3 may form a carbonyl group together with the substituted carbon atom. R4 means a hydrogen atom or a hydroxyl group. ) indicated by 6, 1
9-Ethylene vitamin D3 derivative.