JPH0224268B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to intermediates in the production of vitamin D analogues and methods for their production. In the past, modified vitamin D derivatives have been produced via modification of sterol precursors. These are then converted to vitamin D derivatives by a standard series of steps, usually initial conversion of the Δ5,7-diene followed by irradiation of the diene to produce vitamin D. First, Δ5,7
- All available methods for the synthesis of dienes tend to produce mixtures of products or require a large number of steps and proceed with relatively low yields. A second difficulty is that the few known conversions of 5,7-dienes to vitamins involve radiation followed by thermal equilibration. Radiation inherently produces a mixture of by-products. This limits the yield of the desired vitamin and further complicates its recovery in pure form. Previous attempts to modify the 17β-side chain of vitamin D compounds have been unsuccessful due to instability problems. The inventors have demonstrated that vitamin _D2 and related compounds are converted to a protected form that can withstand the reaction conditions necessary for oxidative cleavage of the 22,23-double bond to form 22-aldehydes. Yes, this 22-
It has been found that aldehydes can be converted to other derivatives as mentioned above. In particular, we show that vitamin _D2 compounds in either cis or trans configuration are stabilized by the formation of Deels-Alder dienophile adducts, which after side chain modification are reconverted to the trans form of the vitamin. I found out what I can do. These transvitamin analogs can then be efficiently converted to the active cis form by known reactions. According to one feature of the invention, the general formula [Wherein, R represents a hydrogen atom or a hydroxyl-protecting group, Y represents a hydrogen atom or an optionally protected hydroxyl group, and X represents -SO ₂
- or a residue of a diacylazo compound, and R ¹ is a halogen atom, a hydrocarbylsulfonyloxy group, or a formula -Z-R ³ (where Z is -O
-, -S-, -SO-, -NR ⁴ -or-CR ⁴ R ⁵
- and R ³ , R ⁴ and R ⁵ are the same or different and are hydrogen atoms or straight-chain or branched aliphatic groups having 1 to 12 carbon atoms, as the case may be. (which may have one or more substituents selected from halogen atoms and optionally protected hydroxyl groups), and R ² represents a hydrogen atom, or R ¹ and
R ² together represent an oxo group or an optionally substituted alkylidene group provided that R ¹ and R ² are the group to which they are bonded - CH (CH ₃ )
CH-, which together with CH- do not represent a group having a branched 17β-hydrocarbyl side chain skeleton of vitamin D ₂ or vitamin D ₃ . The above-mentioned compounds are vitamin _D3 analogues such as general formula and a

【formula】

[Method A]

Methyltriphenylphosphonium bromide (2.898g) suspended in THF (32ml) at 0°C
Butyllithium (2.03M, 4ml) was added to the solution. Add isobutylene epoxide (720 μl, 1 equivalent) to this.
was added gradually. After a further 15 minutes, butyllithium (4ml) was added. To 3 ml of this solution was added the aldehyde from Reference Example 2(f)(1) (300 mg) in benzene (10 ml). The red color quickly disappeared. Water was added and the mixture was extracted _{with CH2Cl2} . After acid work-up, the main product was isolated by PLC to give the title compound (105 mg, 31%). [Method B] Betaine (628 mg) from (h) above was suspended in ether (15 ml) and THF (10 ml). Butyllithium was added dropwise to obtain a stable color, followed by further addition of (0.75 ml, 2 equivalents for the steroid, 1 equivalent for the P compound). To this mixture was added (about 5 minutes) the aldehyde from Reference Example 2(f)(1) (400 mg) in benzene (6 ml).
After the addition, water was added and the mixture was extracted with CH ₂ Cl ₂ . Work-up as described above gave the title compound (155 mg, 34%). [Method C] The phosphonium salt from (h) above (280 mg, 1.5 eq.) was dissolved in THF (15 ml) at 0°C.
To this was added phenyllithium (3 equivalents). Aldehyde (206a) in benzene (6 ml)
(150 mg, 1 eq.) was added quickly. Tlc for 30 minutes
showed no change, so water was added. Work-up as described above and isolation by PLC gave the title product (80 mg, 47%). Crystalline material was obtained from CH ₂ Cl ₂ /ether. mp175-177℃;
[α] _D = +347° (c = 0.83); ¹ Hnmrδ8.3 (m, W =
12Hz, 2H, Aryl), 7.8 (m, W=10Hz, 2H,
aryl), 5.9 (d, J=10Hz, C-7H), 5.27
(m, W=10Hz, C-3H, 22H, 23H), 4.78 and 4.21 (AB system, J=18Hz, C-19H ₂ ), 4.75 (d,
J = 10Hz, C-6H), 2.03 (s, OAc), 1.15 (s,
C-26H ₃ , 27H ₃ ), 0.97 (d, J=7Hz, C-
21H ₃ ), 0.17 (s, C-18H ₃ ); IRνmax3800 (m),
2950(s), 2900(sh), 1750(s), 1650(s), 16
Ten
(m), 1370 (s), 1350 (s), 1240 (s), 965 (
m),
cm ^-1 ; mass spectrum molecular ion m/e = 600;
(Actual value in elemental analysis: %C, 73.94; H, 8.17;
N, 4.59; C ₃₇ H ₄₈ O ₅ N ₂ theoretical value: %C, 73.97; H,
8.05; N, 4.66). (m) 6(R),19-[N,N'-phthalhydrazide]-9,10-seco-3β-acetoxy-25
-Hydroxycholester-5(10), 7(E), 22(Z)
-Triene To the phosphonium salt from (i) above (1.9g) in THF (30ml) was added phenyllithium (1.5M solution, 1.7ml, 1 eq.). After a few minutes, the aldehyde (206a) (1
g) was added dropwise over about 1 minute. After an additional 3 minutes, water was added and the mixture was diluted with CH ₂ Cl ₂ followed by acid work-up. The reaction was repeated as above and the products were combined and chromatographed to give 2.12 g (78%) of crude yellow product. The above mixture (1.4 g) was mixed with AcOH/H ₂ O/ for 1.5 hours.
Treated with THF (8:1:1) (10ml). this
Diluted with CH ₂ Cl ₂ , aqueous workup and chromatography followed by crystallization to 1 g.
(85%) of product was obtained. Furthermore, when it was recrystallized from CH ₂ Cl ₂ /ether, it was pointed out that the main component had the following characteristics. mp182-184℃; [α]
_D = +339° (c = 0.84); ¹ Hnmrδ8.3 (m, W = 12Hz,
2H, aryl), 7.8 (m, W = 10Hz, 2H, aryl), 5.9 (d, J = 10Hz, C-7H), 5.27 (m,
W=12Hz, C-3H, 22H, 23H), 4.78 and
4.21 (AB system, J=18Hz, C-19H ₂ ), 4.75 (d, J
= 10Hz, C-6H), 2.03 (s, OAc), 1.17 (s, c
-26H ₃ , 27H ₃ ), 0.9 (d, J = 7Hz, C -
21H ₃ ), 0.17 (s, C-18H ₃ ); IRνmax3650 (m),
2950(s), 2900(sh), 1750(s), 1650(s), 16
Ten
(m), 1370 (s), 1350 (s), 1240 (s), cm ^-1 ;
Mass spectrum molecular ion m/e = 600; (actual value in elemental analysis: %C, 74.10; H, 8.15; N, 4.47;
C ₃₇ H ₄₈ O ₅ N ₂ Theoretical value: %C, 73.97; H, 8.05; N,
4.66). (n) 6(R),19-[N,N'-phthalhydrazide]-9,10-seco-3β,25-dihydroxy-cholester-5(10),7(E)-diene NaHCO ₃ (100mg) and 5% Pt/C (150mg)
The unsaturated side chain compound from (i) above (450 mg) in benzene (5 ml) and ethanol (5 ml) containing was stirred under an atmosphere of hydrogen for 24 hours.
The mixture was passed through Celite and the solvent was removed. To this residue in benzene (10ml) was added NaOH in methanol (1.25M solution, 2ml) and the mixture was stirred at room temperature for 20 minutes. Acid work-up followed by crystallization from CH ₂ Cl ₂ /ether.
380 mg (91%) of the title side chain saturated diol was obtained.
mp174−177℃; [α] _D = +408° (c = 0.825);
¹ Hnmrδ8.3 (m, W=12Hz, 2H, aryl), 7.8
(m, W=10Hz, 2H, aryl), 5.9 (d, J=
10Hz, C-7H), 4.78 and 4.22 (AB system, J=18
Hz, C-19H ₂ ), 4.75 (d, J=10Hz, C-6H),
4.11 (m, C-3H), 1.22 (s, C-26H ₃ , 27H ₃ ),
0.87 (wide single wire, C-21H ₃ ) 0.18 (s, C-
18H ₃ ); IRνmax3550(s), 2950(s), 2900(sh)
,
1650(s), 1610(m), 1370(s), 1350(s), cm
^-1 ; (actual value in elemental analysis: %C, 74.65; H,
8.66N, 5.06; C ₃₅ H ₄₈ O ₄ N ₂ theoretical value: %C,
74.96; H, 8.63; N, 5.00). Example 1 General method for converting phthalazine-1,4-dione adduct to the corresponding 5(E), 7(E), 10(19)-triene system of calciferol. ) to ethanol (10
ml) and hydrazine (3 ml) under argon overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the resulting solid was taken up in water (30ml) and CH ₂ Cl ₂ (30ml). 2 under argon
Dianisyl telluroxide (150-450 mg) in the phase system,
K ₂ CO ₃ (6 g) and 1,2-dibromotetrachloroethane (3 g) were added and the mixture was stirred for about 5 hours (tic control). After acid work-up, the mixture was chromatographed through silica gel (12 g) and the product was recovered from traces of tellurium oxidants by PLC to yield the desired vitamin D compound.
Obtained in 93% yield. 1 9,10-Seco-3β,25-dihydroxy-cholester-5(E),7(E),10(19)-triene Produced from adduct (240b) (200 mg) as described above to give 131 mg (92 %) was given. Obtained as a solid from ether/hexane. mp79-81℃; [α]
_D =+160゜(c=0.735); UVλmax273nm
(21500); ¹ Hnmrδ6.5 and 5.83 (ABq, J=11
Hz, C-6H, 7H), 4.97 (s, C-19H), 4.67
(s, C-19H), 3.85 (m, W=14Hz, C-3H),
1.22 (s, C-26H ₃ , 27H ₃ ), 0.95 (wide single wire, C
-21H ₃ ), 0.55 (s, C-18H ₃ ); IRνmax3400
(m), 2950 (s), 1620 (w); Mass spectrum molecular ion m/e = 400; (Actual value in elemental analysis: %
C, 77.50; H, 10.99; C ₂₇ H ₄₄ O ₂ theoretical value: %C,
80.94; H, 11.07; _{C27H44O2 ・ H2O} theoretical _value :%
C, 77.46; H, 11.075). 2 3β-(3′,5′-dinitrobenzoate) ester The above crude calciferol in pyridine (5 ml)
(1) (125 mg) was treated with 3,5-dinitrobenzoyl chloride (85 mg, 1.1 eq.). Water was added to this and the mixture was diluted with ether. After acid work-up, the ester was isolated by PLC (129 mg,
70%). Obtained as a crystalline material from ether/hexane. mp105-107℃: [α] _D = +168° (c =
0.97); ¹ Hnmrδ9.13 (m, 3H, aryl), 6.62 and 5.82 (ABq, J=11Hz, C-6H, 7H), 5.3
(m, W=14Hz, C-3H), 5.07 (s, C-19H),
4.77 (s, C-19H), 1.23 (s, C-26H ₃ ,
27H ₃ ), 0.93 (wide single line, C-21H ₃ ), 0.43 (s,
C-18H ₃ ); IRνmax3550 (m), 2950 (s), 2900
(sh), 1750 (s), 1640 (w), 1550 (s), 1350
(s), 1275 (s), cm ^-1 ; (actual value in elemental analysis:
%C, 68.62; H, 7.85; N, 46.5; C ₃₄ H ₄₆ N ₂ O ₇
Theoretical values: %C, 68.66; H, 7.80; N, 4.71). Example 2 (a) 9,10-Seco-3β,25-dihydroxy-cholester-5(Z),7(E),10(19)-triene Benzene containing triethylamine (2 drops) and anthracene (25 mg) The 5,6-trans compound (126
mg) solution was completely degassed. A Hanobia lamp (No. 654A36) was placed so that the outside of the water-cooled jacket was 15 cm from the reaction vessel. 25 to the mixture
and the title 5,6-cis compound.
Isolated by plc (93 mg, 74%). acetone/
Obtained as a crystalline material from water. mp98~100℃ (lit.
¹⁷⁴ 95~100℃); [α] _D = +77° (c = 0.26);
UVλ _nax 262nm (19060); ¹ Hnmrδ6.25 and 6.1
(AB system, J=11Hz, C-6H, 7H), 5.05(s, C
-19H), 4.83 (s, C-19H), 3.9 (m, W=18
Hz, C-3H), 1.27 (s, C-26H ₃ , 27H ₃ ), 0.95
(Wide single wire, C-21H ₃ ), 0.55 (s, C-18H ₃ );
IRνmax3500(s), 2950(s), 2900(sh), 1640
(m), 1480 (m), 1380 (m), 1055 (s), cm ^-1 ;
(Theoretical value _{of C27H44O2}・_H2O in elemental _analysis : %C,
77.46; H, 11.08; Actual value: %C, 77.29; H,
11.08). The contact did not degrade when mixed with the authentic sample supplied by Roussel Ukraf. (b) 3-(3',5-dinitrobenzoate) ester Produced as described in Example 1(2) above. Obtained as a crystalline material from ether/hexane. mp149~150℃ (lit. ¹⁷² 147~148℃); [α] _D
=+90° (c=0.6); (Theoretical value of C ₃₄ H ₄₆ N ₂ O ₇ in elemental analysis: %C, 68.66; H, 7.80; N, 4.71; Actual value: %C, 68.94; H, 7.80; N, 4.52). Reference example 8 9,10-seco-3β-hydroxy-ergoster-5(Z),7(E),10(19),22(E)-tetraene
_SO2 adduct Sulfur dioxide was passed slowly through a well-stirred mixture of benzene (100 ml) and water (50 ml) containing ergocalciferol (5 g) for a total of 3.5 hours. Air was then passed through the mixture for approximately 20 minutes. Ether and brine were added and the layers were separated. Aqueous work-up provided the known sulfur dioxide adducts (172a, 173a), which were used without further purification. Example 3 (a) 9,10-Seco-3β-(triethylsilyloxy)-ergostar-5(E), 7(E), 10(19), 22
(E)-Tetraene To the 3β-alcohol (4.3 g) corresponding to the title compound in CH ₂ Cl ₂ (50 ml), imidazole (4
g) Then triethylsilyl chloride (3 ml)
added. After a few minutes, add water and immerse the organic layer in water/
Washed with brine and dried. After chromatography, the required silyl ether was essentially quantitatively isolated as an oil.
UVλ _nax 274nm; ¹ Hnmrδ6.45 and 5.87 (ABq,
J=11Hz, C-6H, 7H), 5.2(m, W=9Hz,
C-22H, 23H), 4.92 (s, C-19H), 4.63 (s,
C-19H), 3.82 (m, W=18Hz, C-3H). (b) 9,10-seco-1α-hydroxy-3β-(triethylsilyloxy)-ergostar-5(E),
7(E), 10(19), 22(E)-tetraene N-methylmorpholine N-oxide (NMO)
(6.3 g) in anhydrous MgSO ₄ in CH ₂ Cl ₂ (50 ml) for 30 min.
and stirred together. Selenium dioxide (1.3 g) was stirred in methanol (50 ml) for 45 minutes and warmed to reflux, and the CH ₂ Cl ₂ mixture was dissolved in dichloroethane (50 ml) to form the 5,6-trans- It was filtered into a solution of ergocalciferol derivative (5.5 g). The mixture was warmed to reflux, then the hot methanol mixture was added and the total reflux continued for an additional 35 minutes. _The heat source was removed and the mixture was diluted with _CH2Cl2 . Perform aqueous post-treatment,
This was then chromatographed on silica gel (40 g) to give 2.66 g (47%) of the title compound as an oil. UVλ _nax 274nm; ¹ Hnmrδ6.57 and
5.90 (ABq, J=11Hz, C-6H, 7H), 5.25 (m,
W=9Hz, C-22, 23H), 5.08(s, C-19H),
4.98 (s, C-19H), 4.65-3.92 (m, C-1H,
3H). (c) 9,10-Seco-1α,3β-dihydroxy-ergoster-5(E),7(E),10(19),22(E)-tetraene from (b) above in THF (10 ml) Silyl ether (460 mg) was stirred with tetrabutylammonium fluoride (460 mg) for 30 minutes. After diluting the mixture with CH ₂ Cl ₂ and aqueous work-up, the title diol was purified by PLC to give 305 mg (84
%) was obtained. Obtained as a crystalline material from ether/hexane. mp103~105℃; [α] _D = +172° (c =
0.58); UVλ _nax 272nm (22600); ¹ Hnmrδ6.38 and 5.82 (ABq, J=11Hz, C-6H, 7H), 5.18
(m, W=9Hz, C-22H, 23H), 4.9 (m, W=
9Hz, C-19H ₂ ), 4.53-3.77 (m, C-1H,
3H), 0.57 (s, C-18H ₃ ); IRν _nax 3500 (s),
2950 (s), 2900 (sh), 1640 (w), 1460 (m), 13
75
(m), 1050 (s), 1030 (s), cm ^-1 ; Mass spectrum molecular ion m/e = 412; (Elemental analysis value, actual value: %C, 79.57; H, 10.71; C ₂₈ H ₄₄ O ₂ Theoretical value:
%C, 81.50; H, 10.79; _C28H44O2.1 / _2H2O theory: % _C , 79.76 _; H, 10.76). (d) 9,10-seco-1α-hydroxy-3β-triethylsilyloxy-ergostar-5 (Z),7
(E),10(19),22(E)-Tetraene 5,6-trans compound (600 mg) from above (b) in benzene (30 ml) containing phenazine (120 mg) and triethylamine (a few drops)
was photoisomerized for 30 minutes as described above, and then 400 mg of
(66%) of the title 5,6-cis vitamins were obtained.
UVλ _nax 263nm; ¹ Hnmrδ6.38 and 6.08 (ABq,
J=11Hz, C-6H, 7H), 5.23(m, W=10Hz,
C-19H, 22H, 23H), 5.0 (s, C-19H), 4.6
~3.92 (m, C-1H, 3H). (e) 9,10-Seco-1α,3β-dihydroxy-ergoster-5(Z),7(E),10(19),22(E)-tetraene Silyl ether derivative from (d) above (200 mg)
n-Bu ₄ NF (1M solution in THF, 2
ml) in THF (10 ml) at room temperature. Dilution with CH ₂ Cl ₂ and aqueous work-up followed by purification by PLC gave 129 mg (82%). Crystallization from ether/hexane gave the title compound. mp141~143℃ (lit. ¹⁰⁶ 138~140℃); [α] _D
=+34° (c=0.645); UVλ _nax 264nm (19100);
¹ Hnmrδ6.35 and 6.05 (ABq, J=11Hz, C-
6H, 7H), 5.16 (m, W = 14Hz, C-19H, 22H,
23H), 4.98 (s, C-19H), 4.6-3.85 (m, C-
1H, 3H), 0.55 (s, C-18H ₃ ); IRν _nax 3500
(s), 2950 (s), 2900 (sh), 1640 (w), 1460
(m), 1370 (m), 1060 (s), cm ^-1 ; mass spectrum molecular ion m/e = 412; (elemental analysis
C ₂₈ H ₄₄ O ₂ Theoretical value: %C, 81.50; H, 10.75; O,
7.76; Actual value: %C, 81.39; H, 10.60). Example 4 (a) 9,10-Seco-3β-acetoxy-1α-benzoyloxy-ergostar-5(E),7(E),10
(19),22(E)-Tetraene The 1α-hydroxy-3β-triethylsilyloxy compound (2 g) from Example 3(b) was treated with benzoyl chloride (2 ml) in pyridine (25 ml). After 30 minutes, water was added and the mixture was diluted with ether. After acid post-treatment, the solvent was removed and the resulting oil was treated with THF/H ₂ O/AcOH (8:1:3).
(36 ml) overnight. After dilution with ether and aqueous work-up, the crude benzoate/alcohol was taken up in benzene (40ml). To this were added triethylamine (7 ml), acetic anhydride (3 ml) and 4-dimethylaminopyridine (15 mg). After 30 minutes water was added and the mixture was diluted with ether. Acid work-up and chromatography through silica (10 g) yielded 1.76% (83
%) of the title acetate-benzoate as an oil. ¹ Hnmrδ8.05 (m, W=12Hz, 2H, aryl), 7.5 (m, W=10Hz, 3H, aryl), 6.58
(d, J = 11Hz, C-6H), 5.88 (m, W = 16Hz,
C-1H, 7H), 5.15 (m, W=10Hz, C-3H,
19H ₂ , 22H, 23H), 2.05 (s, OAc), 0.57 (s,
C-18H ₃ ). (b) 6(R),19-[N,N'-phthalhydrazide]
-9,10-seco-1α-benzoyloxy-3β
-Acetoxy-Ergostar-5(10), 7(E), 22(E)
-Triene To a well-stirred suspension of phthalhydrazide (2 g) in CH ₂ Cl ₂ (200 ml) at 0° C. containing the vitamin (2 g) from (a) above is added CH ₂ Cl ₂ (20
ml) and Pb(OAc) in acetic acid (1 ml) ₄
(4 g) was added dropwise. After consumption of starting material (checked by tic), excess phthalhydrazide was removed by filtration. 1.4 g (from 248b) was subjected to aqueous work-up and then chromatographed.
(52%) with the presumed (250) 6(S) isomer.
A 95:5 mixture was obtained. Crystallization from CH ₂ Cl ₂ /hexane gave the pure title compound. mp211~213
°C; [α] _D = +295° (c = 0.83); ¹ Hnmrδ8.5~7.3
(m, 9H, aryl), 5.95 (m, W=14Hz, C-
1H, 7H), 5.28 (m, C-3H), 5.17 (m, W=10
Hz, C-22H, 23H), 4.92 and 4.37 (AB series, J
=18Hz, C-19H ₂ ), 4.8 (m, C-6H), 2.05
(s, OAc), 0.17 (s, C-18H ₃ ): IRν _nax 2950
(s), 2900 (sh), 1750 (s), 1720 (s), 1640
(s), 1610 (m), 1265 (s), 1245 (s), cm ^-1 ;
Mass spectrum molecular ion m/e = 718; (elemental analysis value, actual value %C, 75.26; H, 7.54; N, 3.82;
C ₄₅ H ₅₄ O ₆ N ₂ ; Theoretical value: %C, 75.18; H, 7.57;
N, 3.90). Reference example 7 (a) 9,10-Seco-3β-(tertiary-butyldimethylsilyloxy)-ergostar-5(E), 7(E),
10(19),22(E)-SO ₂ adduct of tetraene CH ₂ Cl ₂ (40
A crude mixture of the sulfur dioxide adduct of ergocalciferol (prepared from 5 g of ergocalciferol as described above) in 3.5 g of tertiary-butyldimethylsilyl chloride was stirred with tertiary-butyldimethylsilyl chloride (3.5 g). After 1.5 h the reaction was worked up as previously described and
After chromatography, 4.8 g (66% from ergocalciferol) of the title compound was converted to C-
Obtained as an oily epimer in 6. ¹ Hnmrδ5.22
(m, W = 9Hz, C-22H, 23H), 4.64 (m, W
= 10Hz, C - 6H, 7H), 4.02 (m, W = 16Hz, C
-3H), 3.67 (wide s, C - 19Hz), 0.91 (s, t-
Bu), 0.68+0.59 (2xs, C-18H ₃ ), 0.07s, [(Si
-CH ₃ ) ₂ ]. (b) 9,10-seco-3β-triethylsilyloxy-ergostar-5(E), 7(E), 10(19), 22(E)-
SO ₂ adduct of tetraene CH ₂ Cl ₂ (40
A crude mixture of the sulfur dioxide adduct of ergocalciferol (prepared from 5 g of ergocalciferol as described above) in ml) was stirred with triethylsilyl chloride (3.5 ml). about
After 30 minutes, the reaction was worked up as before and after chromatography gave 5.3 g (74% from ergocalciferol) of (210b) as an oil. ¹ Hnmrδ5.22 (m, W=9Hz, C-22H,
23H), 4.64 (m, W=10Hz, C-6H, 7H), 4.02
(m, W=16Hz, C-3H), 3.67 (wide s, C-
_19H2 ). (c) 9,10-Seco-3β-(tertiary-butyldimethylsilyloxy)-20(S)-formyl-pregnator-5(E),7(E),10(19)-triene SO ₂
Adduct The vitamin D ₂ adduct (4.7 g) from (b) above was treated with ozone in a conventional manner as described above, yielding 3.25 g (78%) of the aldehyde (211a) after chromatography. Ta. ¹ Hnmrδ9.39(m,C-
22H), 4.66 (m, W=16Hz, C-6H, 7H), 4.0
(m, W=16Hz, C-3H), 3.66 (wide s, C-
19H ₂ ), 1.15 (d, J=6Hz, C-21H ₃ ), 0.89
(s, t-Bu), 0.71+0.62 (2xs, C-18H ₃ ),
0.05s, [(Si-CH ₃ ) ₂ ]; IRν _nax (thin film)
2950(s), 2900(sh), 1720(s), 1660(w), 14
60
(m), 1305 (s), 1250 (s), 1150 (m), cm ^-1 . (d) Similarly, 9,10-seco-3β-(triethylsilyloxy)-20 was prepared from the above (b) with a yield of 82%.
(s)-formyl-pregnathic-5(E), 7(E), 10
(19)-triene SO ₂ adduct was prepared.
¹ Hnmrδ9.57 (m, C-22H), 4.67 (m, W=12
Hz, C-6H, 7H), 3.97 (m, W=16Hz, C-
3H), 3.65 (wide s, C-19H ₂ ), 1.15 (d, J
=6Hz, C-21H ₃ ); IRν _nax (thin film)
2950(s), 2900(sh), 1735(s), 1660(w),
1460 (m), 1380 (m), 1310 (s), 1150 (m), cm
^-1 . Example 5 (a) 9,10-Seco-3β-(tert-butyldimethylsilyloxy)-20(S)-(hydroxymethyl)-pregnar-5(E), 7(E), 10(19) - SO ₂ adduct of triene The aldehyde corresponding to the title compound (3.1 g) was reduced as described in the general procedure to give the title compound in essentially quantitative yield. ¹ Hnmrδ4.63
(m, W=12Hz, C-6H, 7H), 4.02 (m, W=
16Hz, C-3H), 3.80~3.28(m, C-19H ₂ ,
22H ₂ ), 1.05 (d, J=6Hz, C-21H ₃ ), 0.87
(s, t-Bu), 0.68+0.58 (2xs, C-18H ₃ ),
0.05 [s, (Si-CH ₃ ) ₂ ]; IRν _nax (thin film)
3550 (br), 2950 (s), 2900 (sh), 1660 (w), 14
75
(m), 1350 (s), 1275 (s), 1155 (m), cm ^-1 . (1) Similarly, 9,10-Seco-
3β-(triethylsilyloxy)-20(S)-
(Hydroxymethyl)-Pregnar-5(E), 7(E),
The SO ₂ adduct of 10(19)-triene was prepared.
¹ Hnmrδ4.63 (m, W=12Hz, C-6H, 7H),
3.93 (m, W=16Hz, C-3H), 3.77~3.17 (m,
C-19H ₂ , 22H ₂ ); IRν _nax (thin film)
3550 (br), 2950 (s), 2900 (sh), 1660 (w),
1460 (m), 1380 (m), 1305 (s), 1240 (m),
1155 (m), cm ^-1 . (2) 9,10-Seco-3β-(tertiary-butyldimethylsilyloxy)-20(S)-(hydroxymethyl)-pregnare-5(E),7(E),10(19)-triene The above The adduct (3 g) of (1) was dissolved in NaHCO ₃ (3 g) for 2.5 hours.
g) in refluxing methanol (50ml). This was post-processed as described above and 2.36g (90g
%) of calciferol was obtained. UVλ _nax
274nm; ¹ Hnmrδ6.47 and 5.87 (ABq, J=11
Hz, C-6H, 7H), 4.92 (s, C-19H), 4.65
(s, C-19H), 4.1~3.15 (m, C-3H,
22H ₂ ), 1.06 (d, J=5Hz, C-21H ₃ ), 0.9
(s, t-Bu), 0.58 (s, C-18H ₃ ), 0.07s,
[(Si-CH ₃ ) ₂ ]. (3) In the same manner, 9,10-Seco-
3β-(triethylsilyloxy)-20(S),
(Hydroxymethyl)-Pregnar-5(E), 7(E),
10(19)-triene (267d) was produced.
UVλ _nax 273nm; ¹ Hnmrδ6.43 and 5.7 (ABq,
J=1Hz, C-6H, 7H), 4.9(s, C-19H),
4.6 (s, C-19H), 4.03~3.13 (m, C-3H,
_22H2 ). Example 6 9,10-seco-3β-hydroxy-20(S)-hydroxymethyl-pregnane-5(E),7(E),10
(19)-Triene [Method A] Phthalazine adduct from Reference Example 3 (1) (200 mg)
was treated with hydrazine followed by oxidation as described in General Methods to give the title product (105 mg, 85%). [Method B] Phthalazine adduct from Reference Example 3 (3) (250 mg)
was similarly converted to give the title product, tertiary-butyldimethylsilyl ether (166 mg, 90%). This material in refluxing THF (10 ml) was incubated for 1 h with n-
Stirred with Bu ₄ NF (1M solution in THF, 2 mg). This was diluted with CH ₂ Cl ₂ followed by aqueous work-up and purified by plc to give (267c) (107 mg,
87%). [Method C] The product of method B (160 mg) obtained via the corresponding SO ₂ adduct was similarly converted to the title compound. [Method D] The triedosilylether (160 mg) of the title compound obtained via the corresponding SO ₂ adduct in THF (10 ml) was dissolved in n-Bu ₄ NF (1M solution in THF, 2
ml) at room temperature. Approximately 30 minutes after the reaction
Post-processed as in (B) (267c) (101 mg, 85
%) was obtained. A crystalline material was obtained by crystallization from CH ₂ Cl ₂ /hexane. mp104~106℃; [α] _D = +
190° (c=0.37); UVλ _nax 273nm (22640);
¹ Hnmrδ6.5 and 5.83 (ABq, J=11Hz, C-
6H, 7H), 4.93 (s, C-19H), 4.62 (s, C-
19H), 4.08-3.12 (m, C-3H, 22H ₂ ), 1.05
(d, J=5Hz, C-21H ₃ ), 0.58(s, C-
18H ₃ ); IRν _nax 3450 (s), 2980 (s), 2950 (sh)
,
1635(w), 1450(m), 1050(s), 1030(s), cm
^-1 ; Mass spectrum molecular ion m/e = 330; (Elemental analysis value, actual value %C, 79.46; H, 9.94;
_C22H34O2 % _of theory C, _79.95 ; H, 10.37. Reference example 8 6(R),19-[N,N'-phthalhydrazide]
-9,10-Seco-3β-acetoxy-20(S)-
[p-Toluenesulfonyloxymethyl]-pregna-5(10),7(E)-diene The alcohol from Reference Example 3(1) (2.275 g) in pyridine was mixed with p-toluenesulfonyl chloride (6.25 g) at room temperature. and stirred overnight. Water was added to the ice-cold mixture and after about 20 minutes the mixture was extracted with CH ₂ Cl ₂ . This was acid worked up and crystallized from CH ₂ Cl ₂ /ether to yield 2.5 g (85
%) of the required tosylate (216) was obtained.
mp91~92℃; [α] _D = +308° (c = 1.26);
¹ Hnmrδ8.3 (m, W=12Hz, 2H, aryl), 7.8
(m, W=10Hz, 2H, aryl and d, J=7
Hz, 2H, Tosil), 7.33 (d, J = 7Hz, 2H, Tosil), 5.85 (d, J = 10Hz, C-7H), 5.06 (m,
C-3H), 4.78 and 4.2 (AB system J=18Hz, C-
19H ₂ ), 4.75 (d, J=10Hz, C-6H), 3.8 (m,
W=12Hz, C-22H ₂ ), 2.43 (s, Toshiru), 2.03
(s, OAc), 0.88 (d, J=5Hz, C-21H ₃ ),
0.13 (s, C-18H ₃ ); IRν _nax 2950 (s), 2900
(sh), 1750 (s), 1650 (s), 1610 (s), 1475
(s), 1240 (s), 1175 (s), cm ^-1 ; Mass spectrum molecular ion m/e = 686; (Elemental analysis value, actual value: %C, 68.09; H, 6.84; N, 4.00; S ，
4.90; C ₃₉ H ₄₆ O ₇ N ₂ S theoretical value: %C, 68.19; H,
6.75; N, 4.08; S, 4.67). Reference example 9 3-methyl-1-butyn-3-yltetrahydropyranyl ether 3-methyl-1-butyn-3-ol (25ml,
21.7g), dihydropyran (50ml) and p-toluenesulfonic acid (5mg) were mixed together at 0°C for 1 hour and stirred for a further 40 hours at room temperature. The mixture was concentrated and the residue was added to 5% aqueous NaHCO ₃ and extracted with benzene. The organic solution was dried to give 37.3 g (86%) of the title ether after distillation. bp47℃/0.8mmHg (lit30~33℃/0.5mm
⁵⁰ ; 57℃/3.5mm ¹⁷⁰ ); ¹ Hnmrδ5.6(m, THP C-
2'H), 2.45 (s, C-1H), 1.51 (s, CH ₃ ), 1.48
(s, CH ₃ ); IR (thin film) 3350 (s), 2950
(s), 2900 (sh), 1125 (s), 1070 (s), 1030
(s), cm ^-1 . Reference Example 10 1-Mercapto-2-methyl-2-hydroxy-propane Ethyl-2-mercaptoacetate (10ml) was added to dry ether (150ml). The solution was stirred well, cooled to 0°C and ethereal solution of methylmagnesium bromide (3M solution, 100°C)
ml, 3.3 eq.) was added dropwise over 1.5 hours. The mixture was removed from the ice bath and stirred for an additional 30 minutes. ammonium chloride in water (carefully add 18 g;
The mixture was neutralized with hydrochloric acid to produce two clear layers. The layers were separated and the ether layer was washed with water/brine and dried. The solvent was removed under reduced pressure and the product was distilled to yield 4.4 g of thiol. bp46℃/16mmHg (lit.64゜/26mm ^158a , 61゜/
22mm ^158b ); ¹ Hnmrδ2.6(d, J=9Hz, C-
1H ₂ ), 2.5 (s, exchange with D ₂ O, -OH), 1.38 (t,
J=9Hz, -SH), 1.28 (s, 6H, -( _CH3 ) ₂ );
Mass spectrum molecular ion m/e59(100), 73
(24), 91(14). Reference example 11 6(R),19-[N,N'-phthalhydrazide]
-23-thia-9,10-seco-3β-acetoxy-25-hydroxy-cholester-5(10),7(E)-diene Tosylate from Reference Example 8 in THF (125 ml) and HMPTA (3 ml) 1-Mercapto-2-methylpropan-2-ol (3 ml) from Reference Example 10 was added to 2.51 g). The mixture was degassed and NaH (50% dispersion in oil, 1.3 g) was added.
After 2 hours, water was added and the mixture was diluted with benzene/CH ₂ Cl ₂ . Acid work-up followed by chromatography and crystallization from CH ₂ Cl ₂ /ether afforded 1.71 g (77%) of the title sulfide. mp187~188℃; [α] _D = +348° (c =
0.62); ¹ Hnmrδ8.3 (m, W = 12Hz, 2H, aryl), 7.8 (m, W = 10Hz, 2H, aryl), 5.9
(d, J=10Hz, C-7H), 5.07 (m, C-3H),
4.78 and 4.18 (AB system, J=18Hz, C-19H ₂ ),
4.75 (d, J=10Hz, C-6H), 2.58 (s, C-
24H ₂ ), 2.03 (s, OAc), 1.23 (s, C-26H ₃ ,
27H ₃ ), 0.98 (d, J=6Hz, C-21H ₃ ), 0.15
(ss, C-18H ₃ ); IRν _nax 3600 (m), 2950 (s),
2900 (sh), 1740 (s), 1640 (s), 1610 (m), 13
70
(s), 1350 (s), 1240 (s), cm ^-1 ; Mass spectrum molecular ion m/e = 620; (Elemental analysis value, actual value: %C, 69.47; H, 7.63; N, 4.43; S ，
5.21; C ₃₆ H ₄₈ O ₅ N ₂ S theoretical value: %C, 69.64; H,
7.79; N, 4.51; S, 5.17). Example 7 23-thia-9,10-seco-3β,25-dihydroxy-cholester-5(E),7(E),10(19)-triene Addition of Reference Example 11 as described in General Methods Manufactured as an oil from a substance. UVλ _nax 273nm;
¹ Hnmrδ6.52 and 5.83 (ABq, J=11Hz, C-
6H, 7H), 4.95 (s, C-19H), 4.67 (s, C-
19H), 3.85 (m, W=14Hz, C-3H), 2.63 (s,
C-24H ₂ ), 1.3 (s, C-26H ₃ , 27H ₃ ), 1.1 (d,
J=6Hz, C-21H ₃ ), 0.58 (s, C-18H ₃ ). Reference Example 12 3-(3',5'-dinitrobenzoate)-ester Prepared from the adduct of Reference Example 11 in 67% yield as described for the compound of Reference Example 1(2). A crystalline material was obtained by crystallization from ether/hexane. mp108~110℃; [α] _D = +188° (c =
0.742); UVλ _nax 272nm (25400) and 262nm
(25400); ¹ Hnmrδ9.12 (m, 3H, aryl),
6.62 and 5.82 (ABq, J=11Hz, C-6H, 7H),
5.33 (m, W=12Hz, C-3H), 5.08 (s, C-
19H), 4.78 (s, C-19H), 2.63 (s, C-
24H ₂ ), 1.27 (s, C-29H ₃ , 27H ₃ ), 1.08 (d,
J=6Hz, C-21H ₃ ), 0.45(s, C-18H ₃ );
IRν _nax 3600 (m), 2950 (s), 2900 (sh), 1740
(s), 1640 (m), 1550 (s), 1350 (s), 1280
(s), 1170 (s), cm ^-1 ; Mass spectrum molecular ion m/e = 612; (Elemental analysis value, actual value: %C,
64.39; H, 7.26; N, 4.43; S, 5.11;
C ₃₃ H ₄₄ O ₇ N ₂ S theoretical value: %, 64.68; H, 7.24; N,
4.57; S, 5.23). Example 8 23-thia-9,10-seco-1α-hydroxy
3β,25-bis(triethylsilyloxy)-
Cholester-5(E),7(E),10(19) Triene To the diol of Example 7 (400 mg) in CH ₂ Cl ₂ (15 ml) was added imidazole followed by triethylsilyl chloride (450 μl). After 7 hours water was added and the mixture was diluted with CH ₂ Cl ₂ . This was acid worked up to give the crude bisTES derivative, which was used without further purification. Selenium dioxide (106 mg) was stirred in methanol (5 ml) for 45 minutes. N-methylmorpholine-
N-oxide (NMO) (528mg) anhydrous for 30 minutes
Stirred in CH ₂ Cl ₂ (5 ml) in the presence of MgSO ₄ . The NMO solution was filtered into a solution of the crude bisTES derivative in 1,2-dichloroethane (5 ml) and the mixture was warmed to reflux.
SeO ₂ /methanol was added to the reflux mixture.
After 35 minutes at reflux, the heating mantle was removed, the mixture was diluted with CH ₂ Cl ₂ and immediately washed with 5% aqueous NaHCO ₃ and dried. Purification by PLC gave 233 mg (35% from the adduct of Reference Example 11) of the title 1α-hydroxy compound as an oil.
UVλ _nax 274nm, ¹ Hnmrδ6.58 and 5.92 (ABq, J
= 12Hz, C-6H, 7H), 5.08 (s, C-19H),
4.97 (s, C-19H), 4.67-4.03 (m, C-1H,
3H), 2.58 (s, C-24H ₂ ), 1.32 (s, C-26H ₃ ,
_27H3 ). Reference example 9 23-thia-9,10-seco-1α,3β,25-trihydroxy-cholester-5(E),7(E),10(19)
-triene Bis from Example 8 in THF (5 ml)
The TES derivative (112 mg) was treated with anhydrous tetrabutylammonium fluoride (220 mg) in benzene (3 ml).
mg) was added. After 2.25 hours at reflux, the mixture was diluted with ethyl acetate, washed with water (3X)/brine and dried. Title triol (50 mg, 68
%) were isolated by plc. A crystalline material was obtained by crystallization from CH ₂ Cl ₂ /hexane. mp129~131
℃; [α] _D = +184゜ (c = 0.2175); UVλ _nax 273nm
(21860); ¹ Hnmrδ6.58 and 5.92 (ABq, J=11
Hz, C-6H, 7H), 5.12 (s, C-19H), 5.0
(s, C-19H), 4.65-4.0 (m, C-1H, 3H),
2.67 (s, C-24H ₂ ), 1.28 (s, C-26H ₃ ,
27H ₃ ), 1.12 (d, J=7Hz, C-21H ₃ ), 0.57
(s, C-18H ₃ ); IRν _nax 3550 (s), 2950 (s),
2900 (sh), 1640 (w), 1050 (m), 1030 (m), cm
^-1 ; Mass spectrum molecular ion m/e = 434; (Elemental analysis value, measured value: %C, 71.57; H, 9.57; S,
7.23; C ₂₆ H ₄₂ O ₃ S theoretical value: %C, 71.84; H,
9.74; S, 7.38). Example 10 23-thia-9,10-seco-3β,25-dihydroxy-cholester-5(Z),7(E),10(19)-triene Containing triethylamine (1 drop) and anthracene (15 mg) 5,6-transvitamin (64
mg) solution was completely degassed and photoisomerized as described in Example 1(1). The mixture was irradiated for 20 minutes and the required title vitamin (49 mg, 77
%) was isolated as an oil by PLC. UVλ _nax
262nm; ¹ Hnmrδ6.25 and 6.0 (ABq, J=11Hz,
C-6H, 7H), 5.03 (s, C-19H), 4.82 (s,
C-19H), 3.93 (m, W=18Hz, C-3H), 2.67
(s, C-24H ₂ ), 1.27 (s, C-26H ₃ , 27H ₃ ),
1.08 (d, J=6Hz, C-21H ₃ ), 0.55 (s, C-
_18H3 ). Example 11 The 3-(3',5'-dinitrobenzoate) ester of the product of Example 10 was prepared using the method of Example 1(2). A crystalline material was obtained by crystallization from ether/hexane. mp145~148℃; [α]
_D = +109° (c = 0.571); Shoulder at UVλ _nax 260nm (24900) and 235nm (30600); ¹ Hnmrδ9.08
(m, 3H, aryl), 6.33 and 6.06 (ABq, J
= 11Hz, C-6H, 7H), 5.33 (m, C-3H),
5.15 (s, C-19H), 4.93 (s, C-19H), 2.65
(s, C-24H ₂ ), 1.27 (s, C-26H ₃ , 27H ₃ ),
1.08 (d, J=6Hz, C-21H ₃ ), 0.57 (s, C-
18H ₃ ), IRν _nax 3750 (m), 2950 (s), 2900 (sh)
,
1750(s), 1640(s), 1550(s), 1345(s), 12
80
(s), 1170 (s), cm ^-1 ; Mass spectrum molecular ion m/e = 612; (Elemental analysis value, actual value: %C,
64.7; H, 7.24; O, 18.25; N, 4.36; S,
5.15; C ₃₃ H ₄₄ O ₇ N ₂ S theoretical value: %C, 64.68; H,
7.24; O, 18.28; N4.57; S, 5.23). Example 12 23-thia-9,10-seco-1α-hydroxy
3β,25-bis(triethylsilyloxy)-
Colestar-5(Z),7(E),10(19)-triene The corresponding 5(E) compound of Example 6 (40 mg) in benzene (35 ml) containing phenazine (40 mg) and triethylamine (4 drops) ) was completely degassed and irradiated as described above for 35 min. 137
mg (75%) of the less polar 5(2) compound is plc
isolated as an oil. UVλ _nax
263nm; ¹ Hnmrδ6.35 and 6.05 (ABq, J=11
Hz, C-6H, 7H), 5.27 (s, C-19H), 4.95
(s, C-19H), 4.6-3.93 (m, C-1H, 3H),
2.57 (s, C-24H ₂ ), 1.2 (s, C-26H ₃ ,
_27H3 ). Example 13 23-thia-9,10-seco-1α,3β,25-trihydroxy-cholester-5(Z),7(E),10(19)
-Triene To the corresponding bisTES derivative from Example 12 (185 mg) in THF (8 ml) was added tetrabutylammonium fluoride (1M solution in THF, 2
ml) was added. After 1.25 h at reflux the mixture
Diluted _{with CH2Cl2} . Aqueous work-up followed by PLC purification afforded 110 mg (90%) of the title triol. Crystallization from ether/hexane gave the crystalline material. mp124~126℃; [α] _D = +54゜(c
=0.37); UVλ _nax 264nm (17400); ¹ Hnmrδ6.35 and 6.05 (ABq, J=11Hz, C-6H, 7H), 5.33
(s, C-19H), 5.0 (s, C-19H), 4.65-4.0
(m, C-1H, 3H), 2.63 (s, C-24H ₃ ), 1.27
(s, C-26H ₃ , 27H ₃ ), 1.1 (d, J=6Hz, C
-21H ₃ ), 0.55 (s, C - 18H ₃ ); IRν _nax 3550
(s), 2950 (s), 2900 (sh), 1640 (w), 1050
(m), 1030 (m), cm ^-1 ; Mass spectrum molecular ion m/e = 434; (Elemental analysis value, actual value: %C,
71.63; H, 9.61; S, 7.34; C ₂₆ H ₄₂ O ₃ S theoretical value:
%C, 71.84; H, 9.74; S, 7.38). Example 14 23-thia-9,10-seco-1α,3β-bis(3′,
5'-Dinitrobenzoyloxy)-25-hydroxy-cholester-5(Z),7(E),10(19)-triene Triol from Example 13 (75 ml) in pyridine (3 ml) and benzene (5 ml) 3,
5-Dinitrobenzoyl chloride (85 mg) was added. Water was added to this and the mixture was diluted with ether. After post-treatment as in Example 1 (2)
Purification by PLC yielded 97 mg (68%) of unstable bis(dinitrobenzoate). ¹ Hnmrδ9.8(m,
6H, aryl), 6.62 (d, J=11Hz, C-6H),
6.12-5.42 (m, C-1H, 3H, 7H, 19H), 5.32
(s, C-19H), 2.63 (s, C-24H ₂ ), 1.27 (s,
C-26H ₃ , 27H ₃ ), 1.08 (wide single line, C-21H ₃ ),
0.22 (s, C-18H ₃ ). Example 15 23-thia-9,10-seco-1α,3β,25-trihydroxy-cholester-5(Z),7(E),10(19)
-Triene-23,S-oxides Methanol (10ml), ether and water (2ml)
Sulfide from Example 13 (100 mg) in
was stirred with sodium metaperiodate (50 mg) at room temperature. After 3 hours, add an oxidizing agent (20
mg) was added. After a total of 5 hours, pour the mixture into
Diluted _{with CH2Cl2} . Aqueous work-up followed by PLC to yield 92 mg (89%) of the title sulfoxide mixture. It was obtained as a solid by crystallization from acetone, methanol/hexane, and ether. mp148~155℃;
[α] _D = +77° (c = 0.691); UVλ _nax 263nm
(18150); ¹ Hnmrδ6.35 and 6.05 (ABq, J=11
Hz, C-6H, 7H), 5.33 (s, C-19H), 5.0
(s, C-19H), 4.62-3.72 (m, C-1H, 3H,
-OH, D ₂ O exchange), 2.83 and 2.75 (wide solid wire, C-24H ₂ ), 1.52 and 1.38 (C-26H ₃ ,
27H ₃ ), 1.23 (wide single wire, C-21H ₃ ), 0.6 (s, C
-18H ₃ ); IRν _nax 3500 (s), 3300 (s), 2950
(s), 2900 (sh), 1620 (w), 1320 (s), 1220
(s), 1070(s), 1050(s), 1030(s), 1000
(s), cm ^-1 ; mass spectrum molecular ion m/e=
450; (Elemental analysis value, actual value: %C, 69.05; H,
9.44; S, 7.13; C ₂₆ H ₄₂ O ₄ S theoretical value: %C,
69.29; H, 9.39; S, 7.12). Example 16 23-oxa-9,10-seco-3β,25-dihydroxy-cholester-5(E),7(E),10(19)-triene The silyl ether (160 mg) from Example 38 was added to 40
Stirred with n-Bu ₄ NF (1M solution in THF, 1 ml) in refluxing THF (5 ml) for minutes. this
Dilution with CH ₂ Cl ₂ followed by aqueous work-up and purification by plc gave the title compound (102 mg, 82%).
UVλ _nax 274nm; ¹ Hnmrδ6.47 and 5.85 (ABq,
J = 11Hz, C-6H, 7H), 4.9 (s, C-19H),
4.63 (s, C-19H), 3.83 (m, W=18Hz, C-
3H), 3.58-3.07 (m, C-22H ₂ ), 3.18 (s, C-
24H ₂ ), 1.2 (s, C-26H ₃ , 27H ₃ ), 1.03 (d, J
=6Hz, C-21H ₃ ), 0.58(s, C-18H ₃ ). Example 17 The 3-(3',5'-dinitrobenzoate) ester of the product of Example 16 was prepared in a manner similar to that described above for Example 1(2). Crystallization from ether/hexane gave a crystalline material. mp75～
77℃; [α] _D = +176° (c = 0.58); ¹ Hnmrδ9.15
(m, 3H, aryl), 6.58 and 5.78 (ABq, J
= 11Hz, C - 6H, 7H), 5.3 (m, W = 12Hz, C
-3H), 5.03 (s, C-19H), 4.73 (s, C-
19H), 3.57-3.07 (am, C-22H ₂ ), 3.2 (s, C
-24H ₂ ), 1.22 (s, C - 26H ₃ , 27H ₃ ), 1.02 (d,
J = 6Hz, C-21H ₃ ), 0.47 (s, C-18H ₃ );
IRν _nax 3500 (m), 2950 (s), 2900 (sh), 1730
(s), 1640 (m), 1550 (s), 1460 (m), 1340
(s), 1270 (s), 1165 (m), cm ^-1 ; Mass spectrum molecular ion m/e = 596; (Elemental analysis value, actual value: %C, 66.31; H, 7.55; N, 4.56;
C ₃₃ H ₄₄ O ₈ N ₂ Theoretical value: %C, 66.42; H, 7.43; N,
4.70). Example 18 23-oxa-9,10-seco-3β (tert-butyldimethylsilyloxy)-25-hydroxy-collector-5(Z),7(E),10(19)-triene phenazine (35mg) Benzene containing (30
ml) and the corresponding 5(E) compound from Example 38 (160 mg) in triethylamine (3 drops) were thoroughly degassed and irradiated as above for 30 minutes. This was purified by PLC (273a) (138 mg,
86%). UVλ _nax = 263nm; ¹ Hnmrδ6.25 and 6.0 (ABq, J = 11Hz, C-6H, 7H), 5.05
(s, C-19H), 4.82 (s, C-19H), 3.92 (m,
W=18Hz, C-3H), 3.62~3.10(m, C-
22H ₂ ), 3.20 (s, C-24H ₂ ), 1.23 (s, C-
26H ₃ , 27H ₃ ), 1.03 (d, J=6Hz, C-21H ₃ ),
0.91 (s, t-Bu), 0.58 (s, C-18H ₃ ), 0.05
[s, (Si—CH ₃ ) ₂ ]. Example 19 23-oxa-9,10-seco-3β,25-dihydroxy-cholester-5(Z),7(E),10(19)-
Triene The corresponding 3-tert-butyldimethylsilyl ether (138 mg) from Example 18 was dissolved in refluxing THF (5 ml).
and n-Bu ₄ NF (1M solution in THF, 2 ml). After 45 minutes the mixture was diluted _{with CH2Cl2} . This was aqueous worked up and purified by PLC to give diol (273b) (91 mg, 85%) as an oil. UVλ _nax 263nm; ¹ Hnmrδ6.24 and 6.04
(ABq, J=11Hz, C-6H, 7H), 5.03(s, C
-19H), 4.83 (s, C-19H), 3.92 (m, W-18
Hz, C-3H), 3.57-3.12 (m, C-22H ₂ ), 3.25
(s, C-24H ₂ ), 1.22 (s, C-26H ₃ , 27H ₃ ),
1.03 (d, J=6Hz, C-21H ₃ ), 0.57 (s, C-
_18H3 ). Example 20 The 3-(3',5'-dinitrobenzoate) ester of the product of Example 19 was prepared as in Example 1(2). Obtained in crystalline form by crystallization from ether/hexane. mp136~138℃; [α] _D = +
101° (c=0.615); ¹ Hnmrδ9.12 (m, 3H, aryl), 6.22 and 6.01 (ABq, J==11Hz, C-
6H, 7H), 5.23 (m, W=18Hz, C-3H), 5.1
(s, C-19H), 4.92 (s, C-19H), 3.57-3.1
(m, C-22H ₂ ), 3.2 (s, C-24H ₂ ), 1.22 (s,
C-26H ₃ , 27H ₃ ), 1.05 (d, J=6Hz, C-
21H ₃ ), 0.53 (s, C-18H ₃ ); IRν _nax 3550 (m),
2950 (s), 2900 (sh), 1750 (s), 1650 (m), 15
55
(s), 1470 (m), 1350 (s), 1280 (s), cm ^-1 ;
Mass spectrum molecular ion m/e = 596; (elemental analysis value, actual value: %C, 66.34; H, 7.37; N, 4.61;
C ₃₃ H ₄₄ O ₈ N ₂ Theoretical value: %C, 66.42; H, 7.43; N,
4.70). Example 21 23-oxa-9,10-seco-3β-(tert-butylmethylsilyloxy)-25-(triethylsilyloxy)-cholester-5(E),7(E),10
(19) - 25 from Example 38 in triene CH ₂ Cl ₂ (10 ml) -
The hydroxy compound (300 mg) was treated with triethylsilyl chloride (130 μl) in the presence of imidazole (200 mg) for 16 hours. Acid work-up of this gave the title bissilylated calciferol (274), which was used in the next step without further purification. Example 22 23-oxa-9,10-seco-1α-hydroxy-3β-(tertiary-butyldimethylsilyloxy)
-25-(triethylsilyloxy)-cholester-5(E),7(E),10(19)-triene Selenium dioxide (60mg) was mixed with methanol (40mg) for 45 minutes.
ml). NMO (300mg) anhydrous for 30 min
Stirred in CH ₂ Cl ₂ (4 ml) in the presence of MgSO ₄ . The NMO solution was filtered into a solution of the bissilyl ether from Example 21 in 1,2-dichloroethane and the mixture was warmed to reflux. SeO ₂ /methanol mixture was added to this reflux mixture. After 23 minutes, the heating mantle was removed and the product was worked up and isolated as described above.
190 mg (51% based on the product of Example 38) of the title 1α-hydroxylated product were obtained. UVλ _nax
274nm; ¹ Hnmrδ6.55 and 5.88 (ABq, J=12
Hz, C-6H, 7H), 5.1 (s, C-19H), 5.0 (s,
C-19H), 4.75-4.02 (m, C-1H, 3H), 3.65
~3.12 (m, C-22H ₂ ), 3.25 (s, C-24H ₂ ). Example 23 23-oxa-9,10-seco-1α,3β,25-trihydroxy-cholester-5(E),7(E),10(19)
-Triene The bissilyl ether from Example 22 (190 mg) in THF (6 ml) was dissolved in nBu ₄ NF for 1 hour.
(1M solution in THF, 2 ml). The mixture was diluted _{with CH2Cl2} . This gave the title triol (103 mg, 84%) after aqueous work-up and purification by PLC. Crystalline material was obtained by crystallization from chloroform/hexane. mp141
~144℃: [α] _D = +144゜ (c = 0.355); UVλ _nax
272nm (20554); ¹ Hnmr (400MHz) δ6.58 (d, J
= 12Hz), 5.89 (d, J = 12Hz), 5.13 (s, C-
19H), 4.98 (s, C-19H), 4.50 (m, W) 12Hz,
C-1H), 4.26 (m, W=20Hz, C-3H), 3.43
(m, 1H), 3.30-3.15 (m, C-22H ₂ , 24H ₂ ),
1.20 (s, C-26H ₃ , 27H ₃ ), 1.02 (d, J=6
Hz, C-21H ₃ ), 0.58 (s, C-18H ₃ ); IRν _nax
3500(s), 2950(s), 2900(sh), 1640(w), 14
50
(m), 1380 (m), 1360 (m), 1045 (s), cm ^-1 ;
Mass spectrum molecular ion m/e = 418; (elemental analysis value, actual value: %C, 74.76; H, 10.33; C ₂₆ H ₄ O ₄
Theoretical value: %C, 74.60; H, 10.11). Example 24 23-oxa-9,10-seco-1α-hydroxy-3β-(tertiary-butyldimethylsilyloxy)
-25-(triethylsilyloxy)-cholester-5(Z),7(E),10(19)-triene from Example 23 in benzene (35 ml) containing phenazine (40 mg) and triethylamine (4 drops) of the corresponding 5(E) compound (200 mg)
After irradiation with a Hanobia lamp for 35 minutes as above and purification by PLC, 155 mg (78%) of the title compound was obtained as a less polar oil.
UVλ _nax 263nm; ¹ Hnmrδ6.30 and 6.01 (ABq,
J=12Hz, C-6H, 7H), 5.23(s, C-19H),
4.97 (s, C-19H), 4.67-3.9 (m, C-1H,
3H), 3.53-3.07 (m, C-22H ₂ ), 3.17 (s, C-
_24H2 ). Example 25 23-oxa-9,10-seco-1α,3β,25-trihydroxy-cholester-5(Z),7(E),10
(19)—Triene Bissilyl ether from Example 24 (155 mg)
and n-Bu ₄ NF (1M solution in THF, 2 ml) were stirred together in refluxing THF (5 ml) for 1 hour. This was diluted with CH ₂ Cl ₂ and aqueous work-up and
The title triol (252a) (77) was purified by PLC.
mg, 77%). It was obtained in crystalline form by crystallization from ether/hexane. mp121~123℃: [α] _D =
+47° (c=0.6); UVλ _nax 264nm (17200);
¹ Hnmrδ6.37 and 6.05 (ABq, J=11Hz, C-
6H, 7H), 5.33 (s, C-19H), 5.0 (s, C-
19H), 4.57-3.87 (m, C-1H, 3H), 3.6-3.1
(m, C-22H ₂ ), 3.23 (s, C-24H ₂ ), 1.23
(s, C-26H ₃ , 27H ₃ ), 1.05 (d, J=6Hz, C
-21H ₃ ), 0.58 (s, C - 18H ₃ ); IRν _nax 3500
(s), 2950 (s), 2900 (sh), 1640 (w), 1450
(m), 1380 (m), 1360 (m), 1045 (s), cm ^-1 ;
Mass spectrum molecular ion m/e = 418; (elemental analysis value, measured value: %C, 74.47; H, 9.97; C ₂₆ H ₄₂ O ₄
Theoretical value: %C, 74.60; H, 10.11). Example 26 9,10-Seco-3β-(triethylsilyloxy)-20(S)-(p-toluenesulfonyloxymethyl)-pregna-5(E), 7(E), 10(19)
-Triene [Method A] To the hydroxy compound from Example 6 (D) (400 mg) in pyridine (5 ml) was added tosyl chloride (350 mg) and the mixture was stirred at room temperature overnight. Water was added to this and the mixture was diluted with ether. 310 after acid post-treatment and purification by PLC.
mg (58%) of the title tosylate was obtained. ¹ Hnmrδ7.73
(d, J=8Hz, 2H, aryl), 7.28 (d, J=
8Hz, 2H, Aryl), 6.43 and 5.81 (ABq,
J = 11Hz, C-6H, 7H), 4.92 (s, C-19H),
4.63 (s, C-19H), 4.2-3.57 (m, C-3H,
22H ₂ ), 2.48 (s, aryl-CH ₃ ); IRν _nax (thin film) 2960 (s), 2900 (sh), 1600 (w), 1460
(m), 1360 (s), 1190 (s), 1175 (s), 1090
(s), cm ^-1 . [Method B] Crude 9,10-Seco-3β-triethylsilyloxy-20(S)- from Example 5(1) at 5°C.
(Hydroxymethyl)-Pregnar-5(E), 7(E),
10(19) - SO ₂ adduct of triene (3.2g) p-
Stirred overnight in pyridine (40ml) with toluenesulfonyl chloride (4g). The reaction was cooled to 0 °C, water was added and after a few minutes the mixture was diluted with _Et2O .
diluted with Crude oily product after work-up with acid (281)
in ethanol (100ml) for 1 hour.
Refluxed in the presence of NaHCO ₃ (4 g). The mixture was concentrated and partitioned between CH ₂ Cl ₂ /water/brine. The organic solution was dried and chromatographed to give the same nmr as the product obtained in method A.
Obtained 2.64 g (70%) of the required vitamin (278c) with and IR. Example 27 9,10-Seco-3β-hydroxy-20(S)-
[Fluoromethyl]-Pregnar-5(E), 7(E),
10(19)-triene The tosylate from Example 26 (200 mg) in THF (5 ml) was mixed with n- _Bu4NF (1M solution in THF,
1 ml) for 45 minutes. this mixture
Diluted _{with CH2Cl2} . After aqueous post-treatment of this
Purification by plc gave 70 mg (63%) of the title fluoride (279). ¹ Hnmrδ6.5 and 5.83 (ABq,
J = 11Hz, C-6H, 7H), 4.97 (s, C-19H),
4.7 (br, s, C-19H, 22H), 4.2-3.6 (m, C
-3H, 22H), 1.1 (d, J=6Hz, C 21H ₃ ),
0.6 (s, C-18H ₃ ). Example 28 9,10-Seco-1α-hydroxy-3β-(triethylsilyloxy)-20(S)-(p-toluenesulfonyloxymethyl)-Pregnar-5
(E),7(E),10(19)-Triene Selenium dioxide (56 mg) was stirred in acetonitrile (3.5 ml) for 45 minutes. NMO (280 mg) was stirred in CH ₂ Cl ₂ (3.5 ml) in the presence of anhydrous MgSO ₄ for 30 min. This NMO solution was prepared using the 1-
It was filtered into a solution of desoxy compound (308 mg) and the mixture was warmed to reflux. SeO ₂ /
A CH ₃ CN mixture was added and reflux continued for an additional 5.5 minutes. The reaction mixture was cooled in an ice bath and CH ₂ Cl ₂
and post-processed as described above to give 180 mg
(57%) of the title 1-hydroxy compound was obtained.
¹ Hnmrδ7.73 (d, J=8Hz, 2H, aryl),
7.28 (d, J=8Hz, 2H, aryl), 6.43 and
5.81 (ABq, J=11Hz, C-6H, 7H), 5.03 (s,
C-19H), 4.93 (s, C-19H), 4.63-3.6 (m,
C-1H, 3H, 22H ₂ ), 2.48(s, aryl-
_CH3 ). Example 29 9,10-Seco-1α,3β-dihydroxy-20
THF containing (S)-(p-toluenesulfonyloxymethyl)-pregnar-5(E),7(E),10(19)-triene n-Bu ₄ NF (1M solution in THF, 0.4 ml) 3 from Example 28 in (5 ml)
Triethylsilyl ether derivative (180mg) 15
Stir for a minute. The mixture was diluted _{with CH2Cl2} . After aqueous post-treatment, this was purified by PLC to 118 mg.
(81%) of the title diol was obtained. Obtained as a solid by crystallization from CH ₂ Cl ₂ /hexane. mp97~99℃;
[α] _D = +132° (c = 0.57); UVλ _nax 272nm (23360
)
and 218nm (15920); ¹ Hnmrδ7.73 (d, J=8
Hz, 2H, aryl), 7.28 (d, J=8Hz, 2H,
aryl), 6.43 and 5.81 (ABq, J=11Hz, C
-6H, 7H), 5.03 (s, C - 19H), 4.93 (s, C
-19H), 4.63-3.53 (m, C-1H, 3H, 22H ₂ ),
2.5 (s, aryl-CH ₃ ), 1.02 (d, J=6Hz,
C-21H ₃ ), 0.57 (s, C-18H ₃ ); IRν _nax 3500
(s), 2950 (s), 2900 (sh), 1600 (w), 1450
(m), 1355 (s), 1190 (s), 1175 (s), cm ^-1 . Example 30 9,10-Seco-1α-hydroxy-3β-(triethylsilyloxy)-20(S)-(p-toluenesulfonyloxymethyl)-Pregnar-5
(Z),7(E),10(19)-triene The corresponding 5(E) from Example 28 in benzene (35 ml) containing triethylamine (3 drops)
185 mg (82%) of the title compound was obtained after irradiation and PLC of the compound (225 mg) for 30 min with anthracene (45 mg) as a triple sensitizer as described above. UVλ _nax 263nm and 216nm; ¹ Hnmrδ7.73
(d, J=8Hz, 2H, aryl), 7.3(d, J=
8Hz, 2H, Aryl), 6.28 and 5.98 (ABq,
J = 11Hz, C-6H, 7H), 5.28 (s, C-19H),
4.92 (s, C-19H), 4.55-3.58 (m, C-1H,
3H, 22H ₂ ), 2.45 (s, aryl-CH ₃ ). Example 31 9,10-Seco-1α,3β-dihydroxy-20
THF containing (S)-(p-toluenesulfonyloxymethyl)-pregna-5(Z),7(E),10(19)-triene n- _Bu4NF (1M solution in THF, 0.32 ml) The silyl ether from Example 31 (185 mg) in (5 ml) was stirred at room temperature for 15 minutes.
This was diluted with CH ₂ Cl ₂ and aqueous work-up followed by plc
Purified by to give the title diol (110 mg, 73%)
I got it. UVλ _nax 263nm (17427) and 216nm
(18672); ¹ Hnmrδ7.68 (d, J=8Hz, 2H, aryl), 7.23 (d, J=8Hz, 2H, aryl),
6.28 and 5.97 (ABq, J=11Hz, C-6H, 7H),
5.27 (s, C-19H), 4.93 (s, C-19H), 4.57
~3.6 (m, C-1H, 3H, 22H ₂ ), 2.45 (s, aryl-CH ₃ ), 1.05 (d, J=6Hz, C-21H ₃ ),
0.52 (s, C-18H ₃ ). Reference Example 13 1-Amino-2-methyl-2-hydroxy-propane Acetone cyanohydrin in ether (50 ml) was added to a well-stirred mixture of lithium aluminum hydride (12 g) in ether (200 ml) at 0°C for 1 hour. (11.2g, 12ml) was added dropwise. The mixture was stirred overnight at room temperature.
After cooling to 0°C, water (24ml) was carefully added dropwise. After quenching, anhydrous Na ₂ SO ₄ (65 g) was added and stirring at room temperature was continued for an additional 2.5 hours. Remove the solid and evaporate the ether, distilling
4.8 g (41%) of the title compound was obtained as a viscous colorless liquid. bp74~76℃/14mmHg (lit ¹⁶⁹ 62~64
°C/13mmHg) n ²⁰ _D = 1.4463 (lit ¹⁶⁹ n ²⁰ _D = 1.44667);
¹ Hnmrδ2.6 (s, 2H), 1.87 (s, 3H, exchange with D ₂ O), 1.2 (s, 6H); IRν _nax (thin film) 3400
(s), 3000 (m), 1600 (m), 1475 (m), 1380
(m), 1360 (m), 1220 (m), 1170 (m), 1110
(m), 960 (m), cm ^-1 . Example 38 23-Aza-9,10-Seco-1α,3β,25-trihydroxy-cholester-5(Z),7(E),10(19)
-Triene A solution of the tosylate (100 mg) from Reference Example 13 in 1-amino-2-methyl-2-hydroxy-propane (0.5 ml) was degassed for 6 hours 50
Stir at ˜55° C. and an additional 12 hours at room temperature under argon. Dilute the solution _{with CH2Cl2} ,
Washed with water/brine then dried and purified by PLC to give 44 mg (53%) of the title triol. [α] _D = +24°; UVλ _nax 264nm (15400);
¹ Hnmrδ6.38 and 6.07 (ABq, J=11Hz, C-
6H, 7H), 5.35 (s, C-19H), 5.02 (s, C-
19H), 4.67-3.93 (m, C-1H, 3H), 2.5 (s-
C-24H ₂ ), 1.2 (s, C-26H ₃ , 27H ₃ ), 1.02
(d, J=6Hz, C-21H ₃ ), 0.57(s, C-
18H ₃ ); IRν _nax 3500 (s), 2950 (s), 2900 (sh)
,
1640 (w), 1460 (m), 1380 (m), 1055 (m), cm
^-1 ; Mass measurement, actual value: 417.3242; _{C26H43O3N theoretical value} : 417.3243. Example 33 23-Aza-9,10-Seco-1α,3β,25-trihydroxy-cholester-5(Z),7(E),10(19)
Methanol (5 ml) containing -triene-23-acetyl K ₂ CO ₃ (500 mg)
The crude amine from Example 32 derived from the above tosylate in was treated with acetic anhydride (0.2ml). The mixture was diluted with _CH2Cl2 , washed with brine _, dried and applied to the plc to give 50 mg
The title amide was obtained [55% from tosylate].
Obtained as a solid by crystallization from CH ₂ Cl ₂ /hexane.
mp107~109℃; [α] _D = -14° (c = 0.49);
UVλ _nax 263nm (16275); ¹ Hnmrδ6.37 and 6.05
(ABq, J=11Hz, C-6H, 7H), 5.33(s, C
-19H), 5.0 (s, C -19H), 4.65~4.02 (m, C
-1H, 3H), 3.4 (s, C-24H ₂ ), 2.17 (s, acetyl), 1.22 (s, C-26H ₃ , 27H ₃ ), 0.95 (d,
J=7Hz, C-21H ₃ ), 0.6(s, C-18H ₃ );
IRν _nax 3550(s), 2950(s), 2900(sh), 1640
(s), 1460 (m), 1380 (m), 1055 (m), cm ^-1 ;
(Elemental analysis value, actual value: %C, 70.80; H,
10.12; N, 2.77; C ₂₈ H ₄₅ O ₄ N theoretical value: C,
73.16; H, 9.87; N, _{3.05; C28H45O4N.H2O theory} : %C, _70.40 ; H, 9.92; _N , 2.93). Example 34 9,10-Seco-3β,25-dihydroxy-cholester-5(E),7(E),10(19)-triene Magnesium particles were washed with diluted HCl/water/acetone/ether and then washed with diluted HCl/water/acetone/ether. It was vacuum dried for 24 hours. 1- in freshly distilled (from _LiAlH ) THF (10) containing magnesium metal (82 mg)
Bromo-4-methyl-4-triethylsilylbutane (1 g) was refluxed for 2 hours. Place cuprous iodide (100mg) in a flask and heat to 0°C.
Purged with argon while cooling to . To this was added the Grignard solution (5 ml) and the purple mixture was stirred for an additional 30 minutes at 0°C. Tosylate (278C) (200
mg) solution was added and the mixture was stirred at room temperature for 40 minutes. Water was added and the reaction mixture was extracted with ether. After acid work-up, a non-polar product contaminated with large amounts of low molecular weight alkyl residues was isolated by PLC. This mixture was refluxed for 2 hours in THF (5 ml).
and n-Bu ₄ NF (1M solution in THF, 2 ml). This was diluted with CH ₂ Cl ₂ cm ² followed by aqueous work-up and purified by PLC to yield 110 mg [82% from tosylate (278c)] of the title diol. The physical and spectroscopic properties of this material corresponded in all respects to the product obtained from the phthalazine adduct. Example 35 9,10-Seco-3β,25-dihydroxy-cholester-52,7(E),10(19)-triene
The product from Example 34 (100 mg) in triethylamine (3 drops) was thoroughly degassed and irradiated for 1 hour as described above and purified by PLC to give the title 5(Z) compound (90 mg , 82%). The physical and spectroscopic properties of this material were in all respects consistent with the product obtained via the phthalazine adduct. Melting point measurements mixed with this material and an authentic sample kindly supplied by Rousselle Ukraf did not decrease. Example 36 9,10-Seco-1α,3β-bis(triethylsilyloxy)-20(S)-(p-toluenesulfonyloxymethyl)-pregnar-5(Z),7
Tosylate (276b) (105 mg) in CH ₂ Cl ₂ (5 ml) containing (E), 10(19)-triene imidazole (75 mg) and triethylsilyl chloride (45 μl) was stirred at room temperature for approximately 15 minutes. To this water was added and the mixture was diluted with CH ₂ Cl ₂ . Acid work-up of this gave the non-polar title bissilyl ether, which was used without further purification. Example 37 9,10-Seco-1α,3β,25-trihydroxy-cholester-5(Z),7(E),10(19)-triene Alkyl copper reagent prepared as described above at 0°C A solution of the above tosylate (276c) in THF (3 ml) was added to the solution and the mixture was stirred for 25 minutes at room temperature. This was worked up and purified as in Example 1(1) to give a tristriethylsilyl derivative contaminated with large amounts of low molecular weight alkyl residues. This mixture was diluted with n-Bu4NF (1M solution in THF, ₄ ml) in THF (5 ml) for 20 min at room temperature.
The iso-isomer was treated with
Title steroid triol [38 mg, (276b) to 63] contaminated with pentanediol (10 mg)
%] mixture was obtained. This material was dissolved in CHCl ₃ to give the required product as its crystalline CHCl ₂ solvate (25 mg). mp99~105℃(lit106~112
℃ ¹⁴² , 103~106℃ ¹³⁸ ; [α] _D [Et ₂ O) = +35゜(c
= 0.86); UVλ _nax 264nm (16820); ¹ Hnmrδ (acetone-d ₆ ) 8.07 (s, CHCl ₃ ), 6.35 and 6.18
(ABq, J=12Hz, C-6H, 7H), 5.38(s, C
-19H), 4.93 (s, C -19H), 4.7~4.07 (m, C
-1H, 3H), 1.2 (s, C-26H ₃ , 27H ₃ ), 1.0 (wide single wire C-21H ₃ ), 0.6 (s, C-18H ₃ ); IRν _nax
3500(s), 2950(s), 2900(sh), 1640(w), 14
80
(m), 1440 (m), 1380 (m), 1360 (m), 1140
(m), 1050 (s). Example 38 23-oxa-9,10-seco-3β-(tert-butyldimethylsilyloxy)-25-hydroxy-cholester-5(E),7(E),10(19)-triene Benzene (5 ml) The 22-hydroxy compound (167b) in ) was refluxed with isobutylene epoxide (1 ml) in the presence of dibenzo-18-crown-6 (100 mg) and potassium tert-butoxide (500 mg) for 55 minutes. To this water was added and the mixture was diluted with CH ₂ Cl ₂ . aqueous organic layer
Washed with K ₃ PO ₄ /water/5% aqueous NaHCO ₃ /brine and dried. Purify this using PLC
330 mg (67%) of a slightly less polar oil product was obtained. ¹ Hnmrδ6.45 and 5.85 (ABq, J=
12Hz, C-6H, 7H), 4.9 (s, C-19H), 4.63
(s, C-19H), 3.92 (m, W=18Hz, C-3H),
3.63~3.12 (m, C-22H ₂ ), 3.22 (s, C-
24H ₂ ), 1.23 (s, C-26H ₃ , 27H ₃ ), 1.05 (d,
J=6Hz, C-21H ₃ ), 0.92 (s, t-Bu), 0.6
(s, C-18H ₃ ), 0.05s, [(Si-CH ₃ ) ₂ ]. For reference, Table 1 shows the relationship between example compounds, formulas, and a.

【table】

【table】

【table】

Claims (1)

[Claims] 1 General formula or a [Formula] [Formula] [In the formula, R represents a hydrogen atom or a hydroxyl protecting functional group, Y represents a hydrogen atom or an optionally protected hydroxyl group, and R ¹
is a halogen atom, a hydrocarbylsulfonyloxy group, or a formula -Z-R ³ (where Z is -O-, -S
-, -SO- or -NR ⁴ -, and R ³ and R ⁴ are the same or different and are hydrogen atoms or straight-chain or branched aliphatic groups having 1 to 12 carbon atoms. R ² represents a hydrogen atom or R ¹ and R ² together represent an oxo group or an alkylidene group optionally substituted with a substituent selected from a halogen atom and an optionally protected hydroxyl group. 2 In the formula, R ¹ is a halogen atom, hydroxyl or tosyloxy group, or a formula (In the formula, Z' is -O-, -S-, -NH- or -
SO— and R ⁶ is a hydrogen atom or a hydroxyl protecting group), and
R ² represents a hydrogen atom or R ¹ and R ² together may be optionally substituted by one or more substituents selected from halogen atoms and optionally protected hydroxyl groups. A compound of the general formula or a according to claim 1, which represents an alkylidene group having 1 to 8 carbon atoms. 3 General formula [Wherein, R represents a hydrogen atom or a hydroxyl-protecting group, Y represents a hydrogen atom or an optionally protected hydroxyl group, and X represents -SO ₂
- or a residue of a diacylazo compound, and R ¹ is a halogen atom, a hydrocarbylsulfonyloxy group, or a formula -Z-R ³ (where Z is -O
-, -S-, -SO- or -NR ⁴ -, and R ³ and R ⁴ are the same or different and are hydrogen atoms or a straight-chain or branched chain having 1 to 12 carbon atoms. represents an aliphatic group which may optionally bear one or more substituents chosen from halogen atoms and optionally protected hydroxyl groups, and R ² represents a hydrogen atom; or R ¹ and R ² together represent an oxo group or an alkylidene group optionally substituted with a substituent selected from a halogen atom and an optionally protected hydroxyl group]
The general formula consisting of deprotecting the compound of by removing X and then optionally converting the group R ¹ to another group R ¹ and isomerizing the resulting compound of formula to a compound of formula a or a [Formula] [Formula] (wherein R, Y, R ¹ and R ² have the same meanings as described above). 4. A process according to claim 3, wherein the product obtained has a hydroxyl group as R ¹ and this hydroxyl group is converted into a halogen atom or a hydrocarbylsulfonyloxy group. 5 The product obtained has a halogen atom or a hydroxyl or hydrocarbylsulfonyloxy group as R ¹ in the formula
A process according to claim 3 or 4, wherein R ¹ is converted into a product representing a group of the formula - ZR ³ as defined in claim 1 other than a hydroxyl group. .