JPS58126861A - Novel compound and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

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 into vitamin D by a standard series of steps, usually an initial conversion of the Δ5,7-diene and subsequent irradiation of the diene.
is converted into vitamin D derivatives by the production of First, all of the available methods for the synthesis of 5,7-dienes tend to produce mixtures of products, require multiple steps, and proceed with relatively low yields. Second
The 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. We have demonstrated that vitamin D2 and related compounds can be converted to protected forms that can withstand the reaction conditions necessary for oxidative cleavage of the 22,23-double bond to form 22-aldehydes. It was discovered that this 22-aldehyde can be converted into other derivatives as mentioned above. In particular, the inventors demonstrated that either cis or trans structure nohitamine D2
It has been found that the compound is stabilized by the formation of a Diels-Aldergenophile adduct, which can be reconverted to the trans form of the vitamin after modification of the side chain. These transvitamin analogs are then processed by known reactions.
It can be efficiently converted to the active cis form. According to one feature of the invention, compounds of the general formula I [wherein R represents a hydrogen atom or a hydroxyl protecting functional group,
i hydrogen atom represents an optionally protected hydroxyl group; is 10-1-s-1
-so-1-NR4- or -CR4R,5- and R3, R4 and R51j are the same or different hydrogen atoms; -so-1-NR4- or -CR4R,5-; group group, which may optionally be 1
and R2 represents a hydrogen atom or R1 and R2 together represent an oxo group or an optionally substituted alkylidene group, provided that R1 and R2 shall not represent a group having a branched 17β-hydrocarbyl side chain skeleton of vitamin D2 or vitamin D3 together with the group to which they are bonded -CH(CH3)C'H-]
A compound is provided. The above-mentioned compounds are vitamin D3 analogues such as the general formulas ■ and 1Va F/a (cis) ■ (trans) (wherein R
, Y, R1 and R2 are as defined above). The use of compounds of general formula 1 in the preparation of new compounds of formula 1 and lVa is illustrated in the following reaction scheme. Fa (cis) ■(trans)
1 In the above formula, R, Y%X, R1 and R2 are as defined above. The compounds of formulas i to (2) may further carry groups. Note that Diels-Alder adducts formed from either 5.6-cis or 5.6-)lance vitamin starting materials exist as a mixture of two possible isomers at the 6-position. It is possible. However, the final removal of the Diels-Alder residue is always 5.6-)
Since it generates a compound with lance configuration, such 6
- There is no need to distinguish between the isomers or to carry out their separation. The inventors have found that a wide range of groups R1 can be introduced into the vitamin D structure using the procedures described above. That is, as mentioned earlier, R1d formula Z-R5 (in the formula 2 is 10-1-8-1-8O-1-NR4- or -0R4R
5-, and R5, R4 and R5 are the same or different and are each a hydrogen atom or a straight or branched aliphatic group having 1 to 12 carbon atoms, such as a halogen It may be a group of atoms (which may bear one or more substituents, such as fluorine or an optionally protected hydroxyl group). In general, the group R5 in the final product should be of the formula described above with the following substitution possibilities. This is to provide the 17β-side chain in the approximate form present in natural vitamin D compounds. The heteroatom, if present, does not change the overall shape of the side chain. In particular, the present invention enables the preparation of compounds of formula 1 and IVa, in which R1 is of the formula. In the formula, 2' is 10-1-s-1-NH-'? 7'(
K-5o- and R6Jd represent a hydrogen atom or a hydroxyl-retaining functional group, the 1α-position optionally carrying a hydroxyl or a protected hydroxyl group, which are analogs of the active metabolite 25-hydroxyvitamin D5. be. Protected hydroxyl groups are, for example, acyl groups such as alkanoyl groups (preferably of #-11 to 6 carbon atoms), aralcamyl groups (preferably of 7 to 15 carbon atoms), aroyl groups (preferably 1-< of 6 to 12 carbon atoms), a cyclic ether group or a trihydrocarbylsilyl group. Examples of such groups include acetyl,
propionyl, hendiyl and tetrahydropyranyl groups, and up to 3 01-6-alkyl, c6-12
- includes trihydrocarbylsilyl groups with aryl and/or c7-15-aralkyl groups. The novel synthetic analogues of the present invention have modified vitamin D properties that are of interest from a pharmaceutical point of view. Compounds of the formula (1) and Wa in which R1 has the above-mentioned meaning are used, inter alia, if R1 is a halogen atom such as chlorine, bromine or iodine or a leaving group flLt, a hydrocarbylsulfonyloxy group 0-8O2R7 (in the formula R7 is preferably an alkyl group of 1 to 6 carbon atoms, preferably an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 15 carbon atoms) It can be produced by a nucleophilic substitution reaction on a compound. Tosyloxy group is preferred R1. Alternatively, said compound is of formula I. and the genophile group X
may then be removed. However, since nucleophilic substitution reactions are often carried out in the presence of a base, and the protected compound of formula I is less stable towards base than the original triene of formula ■ and Wa, the latter is usually the preferred substrate. In the production of 22-thia compounds (ZFi-8-), the nucleophile is conveniently a non-nucleophilic base such as an inorganic base (e.g. hydrogenated IJium) or an organic base (e.g. Example t was reacted in an inert solvent such as tetrahydrofuran in the presence of pyridine).
It is a thiol of H. By oxidation of the corresponding sulfoxides (2 is -SO-) of thia compounds (2 is -8-) using for example peracids or salts such as periodates (bermiodates) as oxidizing agents. can be manufactured. (Mixtures of sulfoxides and (8) sulfoxides are commonly formed and the present invention encompasses each of these sulfoxides and mixtures thereof. 22-oxa compounds of formula 1 or lVa can be prepared in combination with an alkylating agent. , V or fVa (wherein R1 is OH) by reaction of an alcohol or alternatively by reaction of a reactive derivative with an alcoholate.When, after these reactions, a compound of formula 1 is used, The above-mentioned reactive derivatives may be halides such as iodide, the first order may be hydrocarbylsulfonyloxy derivatives such as tosyloxy-conductors, and the above-mentioned alcoholates may be e.g. an alkali metal or thallium alcoholate.However, it is preferred to react a compound of formula 1.Fi' or Wa, in which R1 is OH, with an epoxide, which carries a hydroxyl group derived from the epoxide oxygen. When it is desired to make a 25-hydroxy-22-oxavitamin D5 derivative, a suitable reactant is imbutylene epoxide.The reaction is advantageously carried out in a carbonized inert solvent such as benzene. This is accomplished in the presence of a non-nucleophilic base in a hydrogen solvent, conveniently an alkali metal t-alkoxide, and a phase transfer agent such as a crown ether. It is preferable to use the starting compound of formula 1.IV or F/ because, as mentioned above, trienes are more stable under these conditions than the genophilic layered compound of formula 1.IV or F/ The 22-aza compound of a is R1 in the formula
Formula 1, where is OH. (2) or a reactive derivative of the alcohol of IVa, such as a halide (eg, iodite) or a hydrocarbylsulfonyloxy derivative (eg, tosyloxy derivative), prepared by reaction with an amine of (2) FlSR4NH. 2 or IV due to the basicity of the reactant
The substrate of a is preferred. When the amine is in liquid form, it is preferable to carry out the reaction without additional solvent. 22-Aza derivatives are often conveniently isolated as N-acylates, such as N-acetate. This can be formed by reaction with a suitable acid anhydride. Equation 1 used in the above reaction. If/and 0:
22-Hydrocarbylsulfonyloxy derivatives of IVa may be produced by reacting the corresponding alcohol with the appropriate hydrocarbylsulfonyloxybaryl chloride in the presence of a base such as pyridine. The result is obtained by carrying out this reaction on a compound of formula 1 in which X is so2 and removing the 802 residue by thermal decomposition as described below.
can be prepared by reacting a compound of formula i, ■ or lVa having a hahydrocarbylsulfonyloxy group R1, for example a tosyl group, with a carbon nucleophile. Suitable carbon nucleophiles are Grignard reagents which are reacted in the presence of a copper catalyst such as a cuprous salt. For example, 25-hydroxyvitamin D3 and its 1α
Monohydroxy derivative is the formula! , IV or F/a, a suitable hydrocarbylsulfonyloxy derivative of the formula (wherein R6
(as described above) in tetrahydrofuran in the presence of cuprous iodide. For the production of alcohols of formula I, in which R1 is OH, used for the preparation of the above novel vitamin D derivatives,
The formyl group in the corresponding aldehyde of formula (1) (where R1 and R2 together represent oxo) must be reduced. We have found that this can be easily accomplished, often in quantitative yields, by reaction with metal hydride reducing agents such as alkali metal borohydrides such as sodium borohydride. It is noteworthy that this reduction retains the original configuration at the 20th carbon atom. Such alcohols are at the same time new compounds. Formula 1, I, in which R1 is a divalent alkylidene group (which may have a substituent as described above for 1iR5)
Compounds V or ■a may also be prepared. That is, for example, an aldehyde of the formula I (wherein R1 and R2 taken together represent oxo) is a ylide, for example, a ylide of the general formula % [wherein the groups Ra1d are the same or different and alkyl (clamped or C1-5), Aralkyl (preferably C7-15)
or an aryl (preferably 06-12) group and RIA is an alkylidene group (preferably 1 to 8 carbon atoms).
) which may have substituents as described above for R5].
agent). The Witteig reagent will normally be produced in situ by reacting its quaternary salt with a strong base in an inert solvent. Suitable bases are for example phenyllithium and n
- includes hydrocarbyllithium compounds such as butyllithium. Suitable solvents include, for example, ethereal solvents such as tetrahydrobilane and diethyl ether. The aldehyde of formula (1) is preferably added immediately after the Howitig reagent is formed. A suitable phos7onium salt precursor of Wittig's reagent for the formation of the correct 17β-side chain of 25-hydroxyvitamin D3 can be prepared, for example, by reaction of inbutylene epoxide with methylenetriphenylphosphorane. The initially formed product in which R5 is H can be preserved if desired, for example by formation of a tetrahydropyranyl t*H)IJ hydrocarbylsilyl derivative. This phosphorane can be prepared in a cyclic ether solvent such as tetrahydrofuran in the presence of a strong base such as phenyl or n-butyllithium! Preferably, it is produced by reaction of onium bromide. The inbutylene epoxide is then reacted in situ with two equivalents of base. The inventors have discovered that although the phosphonium bromide initially produced is difficult to isolate and purify, it is possible to obtain a relatively pure product by converting it into a tetraphenylporate salt. If it is desired to form a saturated side chain, selective reduction of the newly formed 22,25-double bond is necessary. Unexpectedly, this was found to be possible using hydrogenation with 5% U radium on charcoal. It is noteworthy that this reduction retains the desired "natural" configuration at carbon atoms at positions 22 and 23. Therefore, this route is expressed by the formula 1 in which R1 is -CR5R4R5 as described above.
The present invention provides another method for producing compounds of 1.1 or Na. It will be appreciated that the compound of formula (1) in the above reaction scheme is a key intermediate in the preparation of the novel vitamin D analogs according to the present invention. For illustrative purposes, their manufacture is based on vitamin D.
2 or its 5,6 to trans isomer. Compound 2) is produced by reacting the vitamin D2 compound of formula 11a or Ilb with genonyl to introduce the desired divalent group X. This genophile is, for example, so2 or a diacylazo compound. Preferred azogenophile t-ta
Formula t azo compounds, such as tazinediones or triazolinediones, are generally represented by the formula (2). In the formula, an aromatic carbocyclic group having a WijZ valence, such as a 1,2-phenylene group, or a group J-R9 (in the formula, R91
d is an aryl group such as phenyl group). This divalent aromatic group or aryl group R9d may have substituents such as 01-6-alkyl, or an alkoxy group, a halogen atom or a nitro group. Derivatives of formula m in which X is of formula (2) are also novel compounds. If the genophile is SO2, it can be prepared with vitamin D in a suitable solvent such as an aqueous medium that dissolves the vitamin.
It can be simply reacted with two compounds. A well-stirred mixture of water and a hydrocarbon solvent (eg, benzene) is particularly useful. Preferably, basic conditions are used, for example inorganic bases such as alkali metal bicarbonates. If Genophile is a cyclic azo compound of the formula 1, in which W is a group ';It's coming. However, W is phthalazine-1
, 2-dione, this is preferably formed in situ by oxidation of the corresponding cyclic hydrazide, such as phthalhydrazide. Thus, the vitamin D2 compound can be reacted with a cyclic hydrazide in solution in an inert solvent such as a halogenated hydrocarbon in the presence of an oxidizing agent such as lead monoacetate/acetic acid. After the formation of the adduct of formula 2, the 22.25-double bond can be removed by e.g. permanganate/periodate, osmate/periodate or even preferably ozonolysis
22- of formula I by known oxidation techniques such as
cleaved to form formyl derivatives. The reaction proceeds selectively with high yield, with the 7,8-bond being #1
It is hardly cleaved and does not cause any trouble to the stereochemistry, especially at the 20-position. Ozonolysis is preferably carried out by passing ozone diluted with another gas, such as oxygen, through a solution of compound 2 in a solvent to form osinide, which is then reductively decomposed by a suitable reducing agent. tear it apart Suitable solvents are, for example, logenated hydrocarbons such as dichloromethane, ketones such as methyl ethyl ketone or acetone or alcohols such as methanol/ethanol. A mixture of dichloromethane and methanol gave particularly good yields. The reducing agent may be present during the reaction or may be added after ocinide formation is complete. Thus, for example, tetracyanoethylene can be present in solution in acetone during ozonolysis. Although reducing agents such as dimethyl sulfide can be used to reduce the ocinide after its formation, the preferred reactants are Fis phosphorus compounds such as triphenylphosphine. If an alcoholic solvent is used, the aldehyde product of Formula 1 may form an acetal contactor with the alcohol. However, this may be true for example with aqueous bases such as bicarbonate) I
It is easily hydrolytically decomposed using Jum. Preferably, the reaction is carried out at a low temperature, for example -78°C. After the 17-9 change, the genophile residue X is removed to produce the 5,6-transvitamin of general formula (1) as described above. Removal of residue X may be done in various ways depending on its nature. When X is so2 it may be treated under basic conditions in the presence of a hydroxyl solvent such as an alcohol (e.g. ethanol) containing a base such as an alkali metal bicarbonate (e.g. sodium bicarbonate). Conveniently it is removed by thermal decomposition (tlertoo], ysiθ). When X is a group of formula V, removal is carried out, for example, by basic hydrolysis or treatment with hydrazine to remove the -Co-W-Co moiety. The corresponding azotization of the unsubstituted vitamin hydrazide thus produced is easily accomplished by mild oxidation of the azo compound, which decomposes spontaneously to form the required 5.6-transvitamin. Basic hydrolysis is accomplished by using a strong alkali such as hydroxide or potassium in solution in an alcohol such as methanol or by treatment with an amine such as triethylamine. be done. However, the preferred method is treatment with hydrazine which yields the required hydrazide in high yield. This reaction has not previously been described for the decomposition of such Diels-Mulder adducts. Oxidation is accomplished using a reactant capable of oxidizing the hydrazo compound to an azo compound. Such reactants are, for example, ceric salts, cuprous salts, ferrous salts ferricyanates or periodates" or air. However, suitable mild reactants are, for example, dianisyl telluroxides. diaryl telluroxides such as 1,2-dibromotetrachloroethane, preferably used in conjunction with a reoxidizing agent such as 1,2-dibromotetrachloroethane and a base such as 2co5 (UK Patent No. 2).
058758 (see specification A). 1α-Hydroxyvitamin D compounds are optionally protected if required and then modified with the desired 17-side chain. can be subjected to 1α-hydroxylation using That is, the 5.6-) lance vitamin II compound can be reacted with a selenite ester which is preferably formed in situ by the reaction of selenium dioxide with an alcohol (eg methanol). The amount of selenium compound can be reduced if reoxidizing agents such as periodate or N-methylmorpholine 1-oxide are used. Alternatively, the reactive derivatives of the 22-hydroxy spinners of the above formulas l''l! or 2 may be 1α-hydroxylated by the operations described above and the desired side chains then formed. 5,6-) The lance vitamin D compound is prepared by a known procedure such as iodine' or diphenylselenide or preferably 45±5 per mole after transformation operations as described above.
Irradiation in the presence of triplet photosensitizers with triplet energies on the order of Kcal allows isomerization to the required active cis-vitaminated metals in high yields. Undesirable tachysterol
) To avoid isomerization to derivatives, acidic conditions should be avoided and photoisomerization is preferably carried out in the presence of a base, such as triethylamine. If protected hydroxyl groups are present in the vitamin product, these are removed by conventional methods. In general, the structure of vitamins is somewhat sensitive to acids but resistant to basic conditions, so the latter is used advantageously. Acyloxy groups are removed using, for example, an alkali metal hydroxide in an alcoholic solvent such as methanol. Silyl groups are removed, for example, by treatment with a quaternary ammonium fluoride, such as tetra-n-butylammonium fluoride. Since many of the reactions described above can be applied to compounds with unprotected hydroxyl groups, the protecting groups can be removed at various stages if desired. Although vitamins are base resistant (and acid sensitive), genophile adducts tend to be base sensitive and relatively acid resistant. Therefore, at the stage where the genophile residue X is present, the protecting group for the hydroxyl group may be removed or acidic conditions may be used. Generally, the majority of the steps described above proceed with excellent yields. Yields of better than 80 or more were achieved at each step when conditions were optimized. This means that vitamin D2
The overall yield of modified vitamins starting from is significantly better than using many conventional methods. Examples of leprosy are described below to explain the present invention. Trace analysis and mass spectra were performed using French G1 f-
Sur-Yvette In 5titut de Ch.
emie dessubstances nautur
Obtained by CNR8. @ Bara is a Kotsuhura block, mel-Temp
) or Fisher-Jones apparatus and are uncorrected. Latitudes were measured at room temperature using a Rudolph Photopolation 1 Model 70 and are reported for chloroform solutions unless otherwise noted. UVs is kutle is carey 1
1 spectrophotometer and reported for ethanol solutions. The molar absorptivity (g) for these absorbances is shown in parentheses! IL. The IFt spectrum is Perkin-Elmer 157 [
Infracord Recorded using a J spectrophotometer, 9xBr unless otherwise noted.
It has been reported about H plate. The absorbance characteristics are expressed by Jds = strong, m = moderate, v = weak, 5h = shoulder, and br = wide. 1 Hnmr spectroscopy, 1 barrier y (Varian) 60 on a T-60 spectrometer
Measured at MHz. NMRtK! + character is 8 = single line, d = double vertical line, tr = triple line, q = quartet, m - multi-3
1 line, expressed as W = half-width value and, unless otherwise specified, the value of δ (ppm, lower cutoff of TMS)

[7
CDCl3 solution using tetramethylsilane internal standard.
has been reported. ml-ri 0? Togerahui (tic) Vi250μshi
Rikagel GHLF [Uniplates J (Analtec
h company product) and pre-baratip layer chromatograph
PLC is 11Io1 silica gel GF'-25
On 41 Unibrate J (Analtech product)
It was implemented. "Chromatography" is Merck's silica
Medium pressure liquid chromatography performed using gel 60H
means fee. High performance liquid chromatography (H
PLC) consists of two 2-foot x % inch stainless steel
Waters Anciates Co., Ltd. was blessed by Calum.
Lycagel "Voracil A" and 6000 psi pump
and a Waters Ancillator equipped with a differential refractometer detector.
The experiments were carried out using a Yates chromatography system. O
Tovvers ozone equipment GE-
Generated from 150. Selective ozonolysis is dissolved
intensive mixing of the substrate and the oxygen-ozone gas mixture is required.
It is essential. For this purpose, stainless steel gas inlet/stirring
[Vibromixar
) j (product of Chemapag, Switzerland) is particularly popular.
It is for use. This device also contains 7 talazin-1 of vitamin D.
, 4 ~ for the formation of diondiels-Alder adducts
It was also used. 200W Novia medium pressure mercury vapor lamp (654A36
) as the irradiation source for the 5.6-double bond photoisomerization reaction.
was used. Reactions on calciferol substrates are carried out under an inert argon atmosphere.
It was carried out inside. Calciferols as crystalline solids
or (#-1 if possible) as an ether solution.
and stored at -20°C in the dark under argon. use
Solvents used were reagent grade unless otherwise noted. The essential work-up consists of partitioning between organic solvent and water, followed by 5
Aqueous sodium bicarbonate solution and saturated sodium chloride
means a series of washes with an aqueous solution. The organic m-liquid is anhydrous Mg
Dry using either 804 or anhydrous Na2804.
It was dried and the solvent was removed on a rotary evaporator. with acid
Post-treatment consisted of partitioning between organic MW and water, followed by (4%
HC1 aqueous solution, 5% bicarbonate as for aqueous work-up
This means a series of washings with sodium aqueous F6 solution, etc. Example 1 (a) 6(R), 19-[a'-Fue = Roux
1', 2', 4'-triacylidine-vl,
5/-dione-1',2'-yl]-9.10-seco
3β-hydroxy-ergosta-5(10), 7(E)
, 22(E)-triene Ethyl acetate (150+
+J) to ergocalciferol (51) in ethyl acetate.
4-phenyl-1,2,4-tria in (150d)
45 zolin-3,5-dione (24?, 1.1 equivalents)
I added it over a period of time. After another hour, some of the title adduct was
It precipitated. mixture . The liquid was passed through a neutral alumina column.
. The remaining product was obtained by stripping with hexane/ethyl acetate.
Ta. 6. Crystallize from alcohol. :zr(a6%)
Obtained. mp 99℃; [α] Wa=+208°(c=(L
76) ;'Hnmrδ7.48(a, 5H, Ally
), 5.22 (m, W=10Hz, C-22H, 25
1(), 4.98 and 4.73 (AB system, J=10H
2, C-6H17H), 42 and 5.85 (AB series,
, r=15H C-19H, l, 4.1(m, C-AH
), 0.55 (8,0-18H3). IRνmaw(C
HC/=3) 3700 (br), 2950 (s), 17
75 (m), 1710 (s), 1A25 (s) cm-
1B mass is a cuttle molecular ion, m/e=571 +
(Actual value in elemental analysis: 'i C, 75, 63i H
,862+N, 7.56 +C3eH4,OsNm
im era value: 4 C, 75, 62;) (, 8, 6
4; N, 7.55). Similarly, from ergocalciferol acetate, 85
The yield of the corresponding acetate i.e. 6(l(), 19
-[4'-phenyl-1', 2', 4'-thoria
syldine-sl, sl-dione-1',2'-yl]
-9゜10-seco-3β-acetoxy-ergostar-5
(10), 7(E), 22(K)-) dione was produced.
Ta. Crystallized from ethanol. +o, p, 85℃↓[α]
D=+183°(c=0.82)11Hnmra
7.48 (a, 5H+aryl), 5.22 (m,
W=1211z+C-5H+22H*23H), 4.9
8 and 4.73CAB system, J=10H7,C-6H,
7H), 4.2 and 585 (AB 4'= J=1
6) 1z. 019Hi), 2.0(ε, o*c), 0.53(s,
C-18]T3)+IRνmaw (CHCmu)295
0 (s), 2900 (sh). 1725(8), 1420(to)cIn-”; mass scale
Hactor molecular ion m/e=613; (elemental analysis
Actual value: Chi C, 7・4.18 i H* B11 r
No 665 i C3thHb□04N3 i Ri
Logical value 2%c, 74.35; H, 8,38+N, 6
．． 85). (b) Tetracyanoethylene (55η, 1 equivalent) in ozonolysis at -78°C.
k) from the above (at) in acetone (10 m) containing
adduct (25011v)'i3 minutes Osin (approximately 1.5
Mlt). Alkaline the system while warming to room temperature.
I purged it with Gon. Separate the product mixture by PLC
The starting material (nmr') of 130 and white Φ
The corresponding 20(8)-hole conductor (9o
IIIq, 84 excellent), 2Hnmrδ9.55
cd, J=3.75Hz, c-22H), 7.45(s
, 5H, aryl), 515 (m, W = 12Hz
+C-3) (), 492 and 4.82 (AB system HJ-
10Hz +C-6H, 7H), 4,18 and 4.7
0 (16Fiz, C-19HIl in AB system), 2.0
(8,OAc), 1.12 (d, J = 7H
lc-2In3), 0.57(s, C-18H3). Example 2 fat ergocalci 7 erolace f-) and 7 cod
Reaction with diene-1,4-dione I* in CHQC42 (200xt4)
lugocalciferol acetate) (10f) liquid nip
Talhydrazide (10f, 2.5 eq.) was suspended. The well mixed mixture was cooled to 0 °C and dried at dC.
HIICt, (fOOstation1) and acetic acid (1ttt
A solution of lead acetate (2or) in
Ta. The reaction was checked by ttc. It will remain after completion
The phthalhydrazide was removed (7). Aqueous work-up followed by
7.49 (54
6 (R), 19-rN, N'-phthalhydra
Dino 1-9,10-seco-3β-acetoxy-ergos
Tar-5 (10), 7 (E). 22(g)-triene was obtained. m, p, 202-203
°C;ra〕I)=+345°(c=1.02) ;U
V2max2. '+8nm (3B250) and 31
2nm (11300)i1Hnmrδ8.5 (m,
W=12Hz, 2H, aryl), 7.8(m
. W = 10 Hz + 2 H, aryl), s, 9
(d + J = 10 Hz + C-7H), 5.0
8 (m, W=10)17. C-5H, 22H, 23
H), 4.78 and 4.22 (AB system + J = 18Hz
, 0 19H1), 4.75 (d, J””10Hz
, C-6H), 2.0 (s, OAc), 013
(s, C-18H5)+IRνmax2950(s),
2900 (sh), 1750 (8), 1660 (s),
1610 (m), 1380 (m), 1355 (m), 1
250 (s) crn-1 + mass
m/e = 598; (actual value in elemental analysis: chi c
,7592;);,8.30;N,461+C7BH6
oO#N? Theory I 1 ((: - Warm t C, 76
, 2'), H, 842; N. 468). Chromatography of mother liquor on silica gel
Essentially a swab 6 (S) of 3.69 (26%)
), 19-(N,N'-phthalhydrazino]-9,10
- seco-5β-acetoxy-ergosta-5 (10),
7(F),22(E)-triene was obtained. A solid was obtained from CH Mayuzumi C42/hexane. m, p,
114-116°C; [αID=-306' (c=0.
64 ); 1Hnmrδ83(m+ ”” 12H
2l 2 Hl aryl), 7.8(m, W=10,
2H, aryl), 6.0 (d* J=10Hz+
C-7H), 5.2(+n, W=10Hz, C-4H,
22H, 25H), 4.85 (d, J = 10Hz,
c 6H), 4.78 and 4.25 (AB series +
J=I EHlz, c-19) I, ), 2.17
(a, OAc ), 0.65 (s, c 18H,
5) iIRνmaw 2950 (a), 2900 (
sh), 1660(s), 1610(m), 1380(
m), 1355 (m), 1250 (S) crn-'
;'! l1it souctor molecular ion m/e =
598゜fbl 6(R), 1q-Cx, N'-F
talhydrazide]-9,10-seco-3β-hydroxy
-Ergostar-5(10), 7/E), 22(E)-)
A from above (a) in lienbenzene (100 m/)
Acetate (5v) to NaOH/CH30H (1,25
M solution, 121Lt was added. After 20 minutes, pour the mixture into water and
and diluted with CH2CtQ. rs post-processing 12 is essentially
of the title 3β-hydroxy compound in quantitative yield (4,sp)
was crystallized from CH2Ct2/ether to obtain crystals. m, p, 169-171℃; [α] L1 = +39g (c
=0.775) ; Hn+nrδ8.3 (m,
W=12Hz, 2H, aryl), 7.8 (m +
W” 10 Hz + 2 H+Return), 5.9
(d, J=10H2,C-7H), s, 12 (m
r W = 91 [1z r C-22H, 23H), 4.
78 and 4.22 (AB system, J=18Hz, C-
19H, lL 4.75 (d, J=1011z,
C-6H), 41 (m, C-3H), 0.18 (s, C
18'H3). IRνmaw3550(br'), 29
50(B), 29011(sh), 1650(s), 1
610cm), 1. s7s(m), 1350(+n)α
−1; mass s and ctor molecular ion m, /e = 556
; (Actual value in elemental analysis: 俤c, 77.76
+H, 8,78; N, 5.17+C, q6H4B0
3N2 theoretical value: ChiC, 77, 66iH, 869iN, 5
．． (]3),. (c) 6 (R), 19-(N,N'-phthal
hydrazinoco-9,10-seco-3β-tetrahydropi
Ranyloxy-Ergosta-5 (10), 7 (g). 22(E)-) from above (b) in lienebenzene (100me)
alcohol (4,5M) to dihydrobilane (10tie
) and (mep-)luenesulfonoic acid (10).
Stirred overnight. After aqueous work-up, the title THP ether (
204c) (5v, 96 excellent) was obtained. Crystalline material was obtained from aH2cz, /ether. m,
p. 151-154°C; [α1p=+331(c=1.7
5) i1Hnmrδ8.3 (m + W-12Hz
+ 2 H + aryl), Z8 (m, W-10Hz
+ 2 H + aryl), 5.9 (d, J = 10Hz
, C-7H), 507 (m, W=9Flz, C-2
2H. 23H), 478 and 4.22 (AB series, J-18H
z. C-19H,), 4.75 (d, J = 10Hz,
C-6H), 47(m, THP, C-2'H), 4
．． 02 (m, C-3H), 3.5 (m. W"' 20 Hz l THP + C6' Hg
), 017(S, C-18H,,)i1Rνmax2
950(S), 2900(sh), 1650(s), 1
610(on), 1370(a), 1350(s), 1
050(B)m-1; Mass R structor molecular ion m/
e=640°. (at 6(R), 1q-Cu, N'-7 talhydra
dino]-9,10-seco-5β-[tert-butyldimethy
lucilyloxy]-ergosta-5 (10). 7(E), 22(g)-) Liene CH, Ct, (b) in (20xl)
(4,59) at room temperature for 1.5 hours.
tertiary butyldimethylsilyl chloride (1,9f)
and imidazole (2,71). while adding water
acid workup and crystallization from CI, CtR/hexane.
This gave 51f (94%) of the silyl ether. m,
p, 203-205°C; [α1p=+331r), 7
．． 8 (m + W = 10F4zH2H + aryl),
59 (d, J=10Hz,,C-7H), 5.08 (
m, W = 9Hz, C-22H, 23H), 478
and 4.22 (AB system, J=18To, , C19Ha
), 4.75 (d, J=1011Z+C-6H), 4
．． 05 (m, C-AH), 0.88 (s, 5th class block)
chill), 0.17 (s, C-18H3), 0.07 (
s, 5i-CH3), 0.05(s, Si CH3
) r IRνmax2950(s), 2900(8h
), 1650(8), 1610(m), 1370(s)
, 1350 (s), 1090 (s) crn-”;
Quality M spectrum molecular ion m/e=670i (original
Actual fence value in elementary analysis: %C274,98iH,9,26i
N, 4.15iCt*H6□03I4□S1 theoretical value:
C, 75, 18; H, 9, 31; N, 418). tel 6 (R), 19-4 N,N'-phthal
hydrazino]9.10-seco-3β-methoxyethoxy
Methoxy-ergostar-5(10), 7(E'). 22(F, )-triene (fb) in CH2Ct2 (100 Ml)
Alcohol (4,59)t) inopropylethyl from
Methoxyethoxymethylene in the presence of amine (20 e')
overnight at room temperature with luchloride (8tILg).
Stirred. #I Post-treatment and then chromatography?
4. followed by crystallization from CH, C1l/hexane.
39 (8q1%) of MgM ether was obtained. m, p, 123-125'Ci [α] p = +52 da
(c=1.295)+1Hnmrδ85 (m, W=
12Hz+ 2 H+ aryl), Z8(m, W=
10H7I 2Hl aryl), 5.9((1,J-1
0H2, C-7H), 5.15 (rn, W=9Hz
, C-22H. 25H), 4.82 (a, -QC) (20-), 4
78 and 4.22 (p, B system, J=18) +7. C-
19H, ), 4.75 (cl, J=1011z, C-6
H), 4.0 (m, C-3H'), 5.67 (m
, W=6Ell, -ocH,cH,O-),5. a
5 (S, 0CR1!I), 01B (s. 18H3) iIRνmax2950 (s), 2900
(sh), 1650 (s), 1610 (m), 1470
(m), 1450 (m), 1!170 (8), 1540
(s), 1100(a), ('m=;)iiil spec.
vector molecular ion m/e=644; (actual in elemental analysis
Measured value: %C, 7472:H, 8,57;N, 4.1
5 i C40H! 16011Nl Rimft
&: %C, 74,50k H. 8.75iN, 4.34). (r) Ergostane [- general ozone decomposition tank
method (εH*Cl2 (180 ml) and methanol (6
(a), (C), (al 4
or adduct (4-5f) from (el) was cooled to -78°C.
Rejected. This efficiently mixed solution is mixed with ozone and oxygen.
For 8 to 12 minutes, process with
(tLc control) and then completely evaporated with dry argon for approximately 5 minutes.
The page was edited. Triphenylphosphine (2,5-59)
and held the mixture at -78°C for about 30 minutes (
Depicting the destruction of the methoxyhydroperoxide intermediate with ttc.
54 Gravel with rlaHcO3 aqueous solution (
(to prevent dimethyl acetal formation) and leave it alone.
and warmed to room temperature. Separate each 1- and make the organic solution
Dry. Closure with silica gel (40-50t)
By matography, j C-20 (R) shrimp? −(n
aldehydes containing no mr) (75-86%>'
Got t-'. The following compounds were purified using this method. 1) 6(R), 19-[N,N'-phthalhydradinoco
-9,10-seco-5β-acetoxy-20 (Sl-photo)
Lumyl-Pregna-5(10),7(E)-Diene CH,C1,/Crystalline material made from ether. m, o, 192 195 °C; [α1r, =+
38 2° (c=1.235)i'Hnmrδ9.5
5 ('d, J = 3h, C-22H), F3.
5 (m, W=12 h + 2 H*aryl),
7.8 (rn, W=10Hy. 2H, aryl), 5.9 (d, J=10)17. C-
7H), 5.17(m, c-3H), 478 and 4
．． 22 (AH series. J-18BZ+ C19H2), 4.75 (d, J
=10Hz, C-6)]), 2.07 (s, OA
c ), 1.07 (d r J =7 Hz r C
-21H, ), 0.22 (81C-18H3) i I
Rvmax15 (CHCt32950(m), 2900
(sh), 1740(s), 1645(s), 1610
(m), 1370 (m), 1350 (m), a "1; electric
Electron spectrum molecular ion m/e = 530; (in elemental analysis
Median measurement 11ji: Chi C, 72, 13iH, 7, 12i
N, 5.20; C3@H3eO+Na sedimentation value: Chi
C, 72, 45; H. 7.22 iN, 5.28). 2) 6(R), 19-(u,rq'-phthalhydrazi)
]-9,10-seco-3β-tetrahydrohyranyl
xy-20(S)-formyl-pregna-5(10),
7(E)-Crystalline product from diene cH, cz,/ether? Obtained with. m, p, 154 156°C; [α1D=+156'
(C=0.84)il)(nmrδ9.4S (d,
J:=3Hz, C22)('), s, s(m+W=
12uz, 2H, aryl), 7.8 (m, W
= 10H712H, aryl), 5°9 (d, J=1
0Hz, C-7H), 478 and 4.22 (AH system,
J=18H), C-19H11), ) 4.75(d
,,y==10Hz,C-6H),4.69(III,
THPIC-2'H), 4.0 (m, C-AH), 5.
5 (m+ W=18HzITHP, C-6' H2
), 0.95 (d, J=6Hz, C-21H3'), [
3,25 (8,0-1883). IRVmax 295
0 (s), 2900 (sh), 1725 (8),
1640 (s), 1610 (m), 1370 (m)
, 1350 (m), 1025 (s), ('m-"; quality
Spectrum molecular ion m/e=572; (7C1f=
Analytical analysis method [: 4 C, 72, 89 IH, 7,
58i N, 4.783'35H4405N2 theory value:
Excellent C+73.40; H+7.74+N. 4.89). , 5) 6(R)+19-[N,N'-phthalhydra
Zinoco-9,b methylsilyloxy 1-20(S)-formyl-preg
Na-5(10), 7(is, )-diene CH2
Obtained as a crystalline material from CL,/hexane. m, n, 195-197°C; [α]I-, = ten! +! +
5° (C=1°64);'Hnmrδ9.52 (d,
J = 5H7, C-22H), 83 (m. W" 12Hz, 2H, aryl), 7.8 (
m + w ~10 B2 +2H, aryl), 5.
9 (d, J=10Hz, C-7H), 478 and 4.
22 (AB series, J=181'lz, C19J), 47
5 (do J=10tlz, 0 6H), 4.07
(m, 0 3H), 1.07 (d, J=7Hz,
C-21Hs), 0.88 (a, 5th-butyl), 0
．． 22 (13, c 18H, t), 0.07 (so
8l-CH, ), 0.03 (s, sx -CH3
); IRνmax295(](s), 2900(s
h), 1740(8), 1650(s), 1610(
a), 1350 (s), 1090 (8'), cnr';
'i parable takukuriru molecular ion m/e = 602;
(Actual measurement value in 7C elementary analysis: 'IC, 71, 57+H,
849FN, 451 iC*6H5r+04N23
i Theoretical value: % C', 71.72; H, 856
iN, 4.65). a) 6(R), 1q-CN, N'-phthalhydrazino
Co-9,10-Seco-20(S)-formyl-5β-methane
Thioxyethoxymethoxy-pregna-5(10), 7
(g)-Diene cH,ct, obtained from /hexane with crystallinity @negative. m, p, 136-137℃; [α': ID=+327''
(c=0.62)i1Hnmrδ9.49 (d, J
~5 Hz + C22H), 8.3 (m, W”12
Hz, 2H, aryl), 7.8 (m, W= 10
f(Zl 21(1■ aryl), 5.9 (d, J=10Flz, C-
7H), 4.87(s, -0CRIO), 4.78
and 4.22 (AB system, J=1Bh, C-19Ha)
, 4.75 (a, J=10Hz, C=6H), 4, Q3
(m, C-3H), 5.7 (m, W=iz, -0
CH2CH20), 3.47 (11,0C1i3)
, 1.07 ((1, J=7Elz, C2113), 0.
22 (a, C-18H3): IRνmax29
50 (m), 2900 (8h), 1740 (m),
1650 (1,1610 (m), 1370 (m), 15
50 (m), 1030 (1111). Example 6 C-20(13)-formyl was converted to C-20(8)-(hydro
(Dimethyl in B) Generality of reduction to the visiting conductor Hensen
(60-90 mg)
5-6,5r) for 15-20 minutes.
20-! 10 at) NaBH of the instep, (0,8~1
, Of). After addition, excess reducing agent is diluted with klC.
9 water #! It was bravely and carefully cooled down. The mixture was diluted with CH,Ct. diluted with Aqueous post-treatment to release desired alcohol
was achieved with constant electrostatic yield. The following monsters were manufactured by this person.
It was. 1) 6(R), 19-[N,N'-phthalhydrazide]
-9,10-seco-3β-acetoki/-20(S)-(
hydroxymethyl]-pregna-5(10), 7(E)
-Diene CH2Cl, obtained in crystalline material from /ether. m, p, 238 240°C; [α]D=+363°(c
= +1.875'); 1Hnmrδ8.3 (m, W
= 12H2T 2 H + aryl), Z8 (Xin, W-
10H2,2H, aryl), 5.9(d, J=10H
z, C-7) ('), 5.07 (m, C-5H), 4.
78&- and 4.21 (AB system, J=18Hz, C-1
9) (1); 475 (d. J=10Hz, C-6H), 5.47 (m, W=
14H2, C22Hll), 2.05 (S, OAC
), 1.0 (wide single wire, C-21H3), 0.17 (s
, C-C-18H3)iIRv:1c(CHCAs)3
2[]0(br), 2950(vQ), 2900(I
3h), 1750(m). 1650(s), 1610(m), 1380(m), 1
350 (m), (7), pickled violet is cuttle molecular ion m/
e = 552゜2) 6(R), 19-(N, N'-7 talhydrazide]
-9,10-seco-20(8)-[hydroxymethyl]
-3β-tetrahydropyranyloxy-pregna-5 (
10), 7(g)-Diene CN2Cat, obtained as a crystalline material from /ether. m, p, 170-173°C: [α”11) = +341°
(c=0.58); 1Hnmrδ8.3 (Ill,
W: 12Hz + 2Hl aryl), 7.8 (m,
W = = 10h + 2 H + aryl), 5.9 (d
, J=10Hz, C7H), 478 and 4.22 (A
B series, J=18 Hz v C19N9), 4.75
(d + J-10Hz * C-6H), 4.67
(m, THP, C-2'H'), 4.0 (m,
C-3H), 55(m I W-181'lz r C
-22N2, THP + C6'HQ), 10(
Wide nest8. C-21H3), 0.19(s, C-18H
3); IR max5600 (br), 2950 (
s), 2900 (sh). 1650 (8), 1610 (m), 1570 (m), 1
550 (m), 1025 (o+), Sen-1; mass scale
Spectrum molecular ion m/e=574i (in elemental analysis
Actual measurement of i: iA: Sorry C+ 72.96 i) (,7,
96; N14.73iC35H46 (15N2 theoretical value:
C, 73,14; H, 8,07iN, 4.87)
. 3) 6(R)119-[N,N'-7talhydrazide]
-9,10-seco-3β-[tert-butyldimethylsilicate
1-20(S)-Chydroxymethyl]-pre
Guna-5(10),7(E)-Diene CHICl/hexane was obtained as a crystalline product 'N. m, p, 145-148°C; [αID=+312°(c
= 1.22) i'HnmrδB, 5 (m, W= 1
2Hz + 2H, aryl), 7B (mlW=10
FIZ12H, aryl), 5.9 (d, J=1011
z, C-7H), 478 and 4.22 (AB series, J=
18Hz, C-1,9H,), 4.75(d, J=1
oH7, 1c-6H), 4.03(m, C-3H), 5
4 (m, W=14Hz, C-22H,). 1.0 (wide single'/1Mm C21Ha), (188
(s, 5th-butyl), [1,19(s, C-18H3
), 0.07 (s, C1-CH5), ); IRνm
axs500(br), 2950(s), 2900(
sh'), 1640 (s), 1610 (m), 1sao
(a), 1250(s), 1090(s), (7)-1
;Mass spectrum molecular ion m/e=604i (original
Actual value in elementary analysis: H18,70i
Nl 4.47 i CzaH5204, N2Si
Roni 1 Tei (: 4 C, 71, 48i) r, 8
．． 67 iN, 4.63). Implementation full 4 6(R), 19-[N,N'-phthalhydrazide]-9
゜10-Seco-5β-acetoxy-20(S)-ethini
Lu-pregna-5(10),7(E)-dienemethylt
Riphenylphosphonium bromide (60~, 1.2 equivalents)
t) was suspended in THE (6at/). To this, n-button
Chillithium (1.5M solution, 0.15d) was added. The resulting orange solution was dissolved in benzene (6111t).
Example 2 (f) (5β-acetoxyal from 11)
Dehyde (1oowi) was added quickly. After another 10 minutes
, water was added and the mixture was extracted with CH2C12. order
75HI (75
4”) title product was obtained.CH,Ct,/ether
A crystalline material was obtained.田、p、17.5-175℃↓〔
C1[,:+! 186° (c = 0.86);
1Hnmrδ8.3 (ffl, W=12Hz
, 2 H, aryl), 7.8 (m, W=10Hz
, 2H, aryl), 5.9 (d, J = 10
H7, C-7H), 5.6-4.8 (m, c-3H
. 22H, 25H2), 478 and 4.21 (AB series,
J = 18 Hz + C19N2'), 4.75 (d
, J=1CJHy, C-6H), 2.05 (s, O
Ac), α95 (cl, J=7R7, c-21H3)
, 0.17 (s, C-18H3) IIRνmax29
50(m), 1740(S), 1650(s), 161
0 (m), 1570 (s). 1550(B), 1260(8), 1250(s), I
:1n-1; The material is a cuttle molecular ion m/e=528
; (Actual value in elemental analysis: C, 75, 03; H
,7,72;N,5.21+C33H,. 04N2 theory
Value: Coefficient c, 74.97+H, 7,65>. 5.30). Misu Sen-Bee 1 5 1al Production method of inbutylene epoxide Cooled in a water bath
17 methylallyl chloride (2Q Od, 186t
) to 80 chi H2So, (95 chi H2St')41 n
9 ml, H2O 40 ml, 1 eq.) over 30 minutes.
added. The temperature of the mixture was maintained at 5-10°C L, #C,
. After another 3 hours, the mixture was added to ice and approx.
Diluted to a total volume of ml. Separate each layer 2 and distill the fresh residue to remove the by-products.
β, l/-dimethylvinyl chloride and unreacted output
Issue # was removed. These substances are removed at temperatures below 80°C.
It will be done. The dark distillation residue is 1-chloro-2-methylpropylene.
Ropan-2-ol (128f). δ5.47(
s, 2H), 2.97 (a, intersected with I H, D20)
, 1.32 (s, 6H). This material cannot be further purified.
used without. equipped with a mechanical stirrer and condenser and at 80 °C.
Contains KOH (2QQp) in water (125mA')
5. Fed crude chlorohydrin into a 00w11 round bottom flask.
did. The crude epoxide was distilled directly from the reaction mixture. Inbutylene epoxide (489,551
) was obtained. b, p, 51°C (/, ti”8C52°C),
'Hnmrδ2.6(s, 2H), 1.33(s, 6H
). (b) 4-bromo-2-methyl-2-hydroxy-buta
Ethylene in ether (150 m/') at 0°C
3-promopropio*-to (21F) with methylmagnetic
Nesium bromide (3M solution in ether, 1
Drop 25d (excess)! I got 10. After the addition is complete, the mixture
The mixture was stirred for an additional 2 hours at room temperature. Cooler, mix at 0°C.
The compound was dissolved in NH,CL (30t) in water (200d).
Shinki and the dog were cold. Separate each no and ether layer
Wash with water until neutral, then with salt water (~and dry)
Dry. Evaporation yields the crude promoalcohol (727a
) was obtained. Hnmrδ3.53 (t, J==9
Hz. 2H), 2.93 (s, I H, D, exchange with lO)
, 2.07 (t. J=911z, 2H'), 1.77 (s, 6H');
r/it 554(t, J=8.5F17+2T
(), 2.65 (s, wide, 1H), 2.10 (t,
, J=8.5Hz, 2H), 1.26 (s, 6
H) 1°(c) 4-bromo-2-methyl-2-(tri
ethylsilyloxy)-butanepyridine (51111), imidazole (10f) and
and triethylsilyl chloride (10ml).
From previous 5r2(b) in the ether (50d)
Half of the crude bromide was stirred at room temperature for 2 days. to this
Added water. This is treated with acid and then chromatographed.
According to tic, it is uniform over 11t (propione
The desired compound No. 62) was obtained from the sample. 1Hnmrδ3
．． 52 (m, 2H), 2.05 (m, 2H), 1.25
(s, 6H), 1.2-[1,2(m. 15H); IRνmaX (thin film) 300
0 (S'), 2950 (sh), 1460 (m), 14
20 (m), 1! +80(m>, 1565(m), 12
30(s), 1195(8), 1170(m), 110
0(s), 1040(s), 1010(s), 96
5(m), 840(w), 740(s), 72Q(s)
, crn 0 (d) 3-methyl-2-buten-1-yl-tripheny
phosphonium bromide in benzene (4-)
Lomide (1f) and triphenylphosphine (0,
9f) was completely degassed and heated to reflux. 3rd eye
After removal of insoluble substances, 1.2f (85%) of phosphor was removed.
Obtained nium salt (228). Recrystallized from CHgCl, /E tOAc. m,
p, 234-238°C (/!, it 2 3
6-259℃) Night 1Hnmr δ 817]
19b -7,67 (m, i5H, aryl), 5.18 (m
, W=18Hz), 4.75 4-2 (In, 2
H), 1.67 (d, J = 5Hz +5) 1),
1.51 (d, J=5Hz, 5H)i IRνmax
2900(w), 1590(w), 1490(m), 1
455(B), 1110(s), crn-1°let methyldiphenylphosphine oxide methyl
Triphenylphosphonium bromide (6?) is mixed with water (7?
Reflux overnight with KOH (59) in 0d)
Ta. The mixture was allowed to cool to room temperature and then CH2C
Extracted (5X) with 4g. The organic layer was washed with brine, dried and the solvent removed.
Crude solid product (55y) was obtained in essentially quantitative yield. Recrystallized from acetone. n+, p, 115 114℃ (tti132109-
111℃) + ”Hnmrδ8.0-7.3 (m,
10H, 7 reels), 2.0! t(d,,T=13
Hz + 5 H); IRνmax1440(s)
, 1175(13), zH+ [pupil spectrum molecular ion
m/e = 216° (f) 5-hydroquine-3-methy
Methyldiphenylphonuphine oxide (1
, 5f) was suspended in ether (20 m#). to this
Gradually adding BuLl (1,2 parts) turns into an orange solution.
occurred. Add to this inbutylene epoxide (0.8xl
, 1.5 equivalent t) were added. After about 15 minutes, drain the mixture with water.
It was severely cooled down. This mixture was combined with CHmCLtt (2x
) to extract 1- and extract machine 1 (1 g to 44 HC1 aqueous solution)
Washed with liquid/brine and amperated. Dissolve the resulting yellow oil in a water/ether mixture.
The layers were separated. Wash the ether layer once with water
and then combine the aqueous fractions and combine this with CH,C
Extracted with L, (5x). The organic layer was washed with brine and dried. Remove the solvent.
The colorless oil produced is placed in benzene.
Reflux through a Soxhlet containing CaH for 2 h at
I let it happen. Removal of the solvent yielded the crude title compound (1,4f,
70 g) was obtained as an oil. "Hnmrδ8.0-
7.5 (rn, 10H, aryl), 2.5 (m,
w=34Hz, 2H), 1.83(m, W=32Hz,
3H), 1.23 (s, 6H); IRvmax
(CC1,)5500(rn'>,2950(m)
, 144 (1(s), cIrI-16(g) 5-tetra
Hydropyranyloxy-5-methylbut-1-yl-di
Phosphine oxyto (1,4f) from psffl before phenylphosphine oxyto
Dihydropyran (20 mg) and benzene (5*l
) dissolved in This is combined with p-)luenesulfone, v(1
0II#li) was added. 20 hoursffl, mixture't
-11 condensed, added to CH, C1Il and 54 NaH
Washed with aqueous CO3/brine and dried. solvent
Evaporate the crude product -*(1,8r) as a solid essentially
was obtained in a constant yield. recrystallized from acetone
. m, p, 146' 148°C: 1Hnmrδ8.
0-7.5 (rn. 10H, aryl), 4.67 (m, W-611/,
THP, C-2′H), 17(m, W=56FIZ, T
) (P, C-6') (, ), 1.25 (8,6H) compilation
IRνmax2950(m), 1440(no), 11
80 (S), crn-1; (Actual value in elemental analysis: Chi ρ
, 70.80iH, 7,75 Kame P, 8.5 4
i CatH2s'2+3P 硪(N Kami Naosen:
Person C, 7n, 961L 7.85; P, 8.32
). (h) Process for producing lithium nasal adduct of betaine at 0°C.
Methyl trichloride suspended in cooled ether (50 tl)
Phenylphosphonium bromide (2,898f)
Chillithium (2.05M solution, 4*l) was added. child
Inbutylene epoxide (1, Ortr, l, 1,
When 25% f) was added, some insoluble material was immediately removed.
It occurred in After stirring for 15 minutes, the reaction mixture was allowed to stand.
It was allowed to settle, and then the supernatant liquid was removed. solid to generate
The bodies were suspended in ether and transferred to two centrifuge tubes.
I rotated it. Ether has been removed. This operation was repeated until the ether wash became colorless (
Usually 4×). Dry the colorless solid substance to obtain betaine L.
An i-Br adduct (1,5r, 42) was obtained. Bairusi
Stein and lithium ion +, frame test #, TB
vrnax (Nujol) 3500 (Br), 500
0(s), 1440(s), an-”. 1i1r3-(triethylsilylox7)-5-methyl
but-1-yl]-triphenylphosphonium tetraph
Methyltriphenyl borate suspended in THF (40rxl)
Phenyllithium on phosphonium bromide (5f')
(1 eq., 1.5 M solution of 6-) was added. , 15 minutes
Later, inbutylene epoxide (1wtl, 1.25%
) was added, followed by a further 5 minutes later with phenyllithium (1
I prayed for the addition of a second round of this t). Add Ben to this mixture.
Zophenone (1f. approx. 05 equivalents) was added. After stirring for 20 minutes 1-7, acidic
(Lidmus paper) The reaction was continued until 48% HBr in water
It was quenched with liquid. Remove organic solvent on rotary evaporator E-1 water
and wash the aqueous solution N4 with ether.1. unintentionally
Each layer was separated. Remove the water (on a rotary evaporator) and
The raw tlW oil was placed in Cl(,C7,). This was aqueous worked up to give the phosphonium salt (226')(
5,1f) (58%) was obtained as an oil. Hnmrδ
8.17-7.67 (m, 15H. aryl), 5.37 (wide s, -oH), 3.8 (m
, W=32 fiz * CI Ha'), 1.8
(m, W=22Hz, C-2H1), 1.28(s,
(-CH5)B )i IRvmax(CHCL3)
5450 (s'), 3000 (s), 1590 (sh)
, 1440(a). ff1-1゜(jl From the above (1) in silylated CHsCt2 (70d)
Imidazole (54f) in phosphonium salt (5,7f)
Then add triethylsilyl chloride (5wLl)
Ta. After stirring at room temperature for 40 minutes, water was added and the mixture
was diluted with CI (2cz).
Evaporate the 2C22#1 liquid and remove the oily residue with water.
It was distributed between Sun/Ether. Let's play with the water (7 and the residue fcH, 1 person in the clp)
Wash 7"l of this with salt water, dry it and let it evaporate.
ζ 1g (226b) (5,6f, 77mm) of oily substance
That's 4. Is the above fjl in (hl [ion exchange 95% tanol r50m/)?
lanophosphonium salt (3,69) in water (in 20 ali
Sodium tetraphenylborate (2,5f,
1.1 t) of 40 t) was added while stirring. oily residue
A distillate formed which solidified with continued stirring. child
The mixture was filtered for 1 hour to obtain phosphonium tetraphenylboret salt (
4,7El, 92%) as a white, amorphous, non-hygroscopic solid.
and reconstituted from acetone/hexane/ethanol.
It crystallized. m, p, 150 151℃i 1H*mrδ
(acetone-ds) 8.2 6.8 (m, 35 H
, aryl), ro53 (m +W"34H7, CI
Ha'), 1.8 (m+W=24Hz, C-2H*
), 1,! l 5 (s, (-CHi,), 1.25
-0.5 (rn, 15H, -5tEt3)tIRv
rnax 5100 (s'), 2950 (S), 1
580 (m). 1aqo(a), 1440(8), 1110(8), 1
020 (8) J penalty 1; (actual value in elemental analysis: qb
C181,41; H, 7,751P, 3.95F
C,,) T6oBOPSi theoretical value: POSc:. 81.51; H, 7,73; P, 5.96). (Force 6(R), 19-[N, N'-7 talhydrazide
]-9,10-seco-3β-acetoxy-25-hydro
Xycholester-5 (IF), 7 (E). 22(E)-Triene [Method A] Methyl suspended in THF (52d) at 0°C
Triphenylphosphonium proma(t(2,898f)
Add butyllithium (2,0!IM, 4HI) to
Ta. To this, inbutylene epoxide (720 μt, 1 part violet) was added liberally. After another 15 minutes, butylrich
um (4!111) was added. 3 scraps/V of this solution
Actual ellipse example 2(f) ill in Zen (10 Wi)
aldehydes (300~) were added. Red and white disappear to the negative side.
λta. Add water and mix the mixture with CH and CL. Extracted with. Crying place f! ! ! Later, the main product is converted into PTC,
The title compound 1 (105 cm, 51 width) was isolated from
. [Method B] Previous n? Betaine (628~) from fhl is converted into ether
(15 degrees l) and suspended in THF (10rtl)
I let it happen. A stable color is obtained by feeding butyllithium. Next (0.75we, 2 hours vertically regarding steroids,
For P compounds, 1 equivalent) was further added. This mixture
Example 2 tfl in benzene (6 ml)
Added the aldehyde (400 ~) from fl. (about 5 minutes
+1 Jl). After the addition, add water to table 1 and the mixture to
Extracted with CH@C1@. Post-process and table as described above.
A seagull compound (1551711i, 34 excellent) was obtained. [Method C] The phosphonium salt from (h) above (280
Mq, 1.5 per cent dissolved in THF (15we)
[7. To this, phenyllithium (3 parts 11) f was added.
. Aldehyde (206a) in benzene (6HI)
) (1501Rg, 1 hit) was quickly added. 30
Ttc showed no change for minutes so water was added
. As mentioned above, the post + G! (2 then isolated by PTC)
The title product (80Wi, 47%) was obtained. cHs
Crystalline material was obtained from c4/ether. m, p, 175
-177℃; [α]D=+347° (C rumor: = 0.83); HnmrδB, 5 (mlW
=12H2l 2Hl aryl), 7.8(m, W=1
01'lz, 2H, aryl), 5,9(d, J=
10Hz, C-7) (), 5.27 (m, W=
10Hz, C-3H, 22H, 23H), 4.78
and 4.21 (AB system. J = 18Hz, c-19H,), 4.75 (d, J
= 10Hz, C-6H), 2.05 (s, O
Ac), 15(S, C-26H3,27H3'l
, 0.97 (d, J = 7H7, C-21H3),
0.17(s, C18Hs)+THI/max3800
(m), 29sn(s), 2900(sh), 17
50rs), 1650(s), 1610(m), 157
0(s), 1350rs), 1240(s'), 965
(m), m-1;
e-600; (redundancy analysis - measured value of r: 'IC, 7 ro 9
4; H, 8, 17+N, 4.59: C3ヮl-14
6 (j5N □ logic value two C, 73,97i H. 8Q5 i N, 4.66). tml 6(R), 19-CN, N'-7 Talhydra
dido]-9,10-seco-3β-acetoxy-25-hyde
8t1@self(
Phenyl to phosphonium t1g (1,9f) from 1)
Add lithium (1.5M solution, 1.7au11 eq.)
Ta. Aldehyde in benzene (55g/) after a few minutes
(206a) (1 t) was fed in a fed-batch manner for about 1 minute. After a further 5 minutes, water was added and the mixture was dissolved in CHQCl.
, followed by acid post-treatment. The reaction is as described above.
Repeat this step to combine the products and chroma
2.12f (78%) crude yellow raw material
A product was obtained. The mixture (1, ar) was heated at Acm1/H20 for 1.5 hours.
/'rHF (8:1:1) (10 m/). child
This was diluted with CH2CIQ and subjected to aqueous post-treatment.
chromatography, crystallization, 1t (8
5) product was obtained. Furthermore, CH, cza / ete
When recrystallized from
It was pointed out that m, p, 182-184℃; [α
]D=+559°(c=0.84) I JHnmr
δ8.3(m, W=12Hz+2Hz aryl
), z8 (m, W=10H2+2H+aryl), 5.
9 (d, J=10Hz, C-7H), 5.27(
m, W=: 12Hz+C-3H, 22H, 23) 1),
4.78 and 4.21 (AB thread + J-18tlz
, C19H2), 4.75 (d, J-=10Hz, C-
6H'), 2.05 (s, OAC), 1.17 (s
, C-26F(3,27H5'>, 0.9 (d*
J-7Hz, C-21Hs'), 0.17(r-,
, C-18H3); Tf(vmax3650 (m
), 295°(s), 2900(3h'), 175[1
rs), 165o(s), 1610(m), 1570(
s), 1350(s), 124°(s), I-1;
The quality of the material is cuttle molecular ion m/e: 600; (element content
Actual value in analysis: % C, 74,10iH. 8, 1 5 i N + 4.4 7 i
C3TSH4Br15N2 Theory i+i: qA
C, 75,97; H, 8,05; N, 4.66
). ft1l 6(R), 19-[N,N'-phthalhyde
[rad]-9,10-seco-3μ,25-dihydroxy
-cholester-5(11,7(E)-dieneNaHCO3
(10oM9) and 54 Pt/C (15oq) Evening
benzene (5 rxl) and ethanol (5 lt) with
) from the above (1) [class compound (4
50■) was stirred for 24 hours under a hydrogen atmosphere. mixture
It was filtered through Celite and the solvent was removed. ben
This residue in zene (10d) was added with NaO in methanol.
Add H (125 M solution, 2 ml) and add the mixture.
Stir at room temperature for 20 minutes. After acid post-treatment, C
Crystallized from H, Ct2/ether to form 380 layers (91q
The side chain saturated diols shown in Table b) were obtained. m, a, 174
-177℃↓[α1D:+408” (c=0.825
); 1HnmrδB, 3(m, W=12H7,2H
, aryl), 7.8 (m, W=10Hz, 'H. aryl), 5.9 (d, J=10Flz, C-
7H), 478 and 4.22 (AB thread, J=18Hz
, C-19H2), 475 (d lJ =10 Hz
r 0 6 H), 4.11 (m, C-3) (),
1.22 (S, C26H3, 27H3), 087 (wide
Single wire, C-21H,), ols (8,C-
181(,) ; IRνma! 3550(s), 29
50(s), 2900(sh), 1650(s), 16
10 (m), 1sya (a), j 350 (β), m
;(Actual value in -7C* analysis: % C, 74,6
5; H, 8, 66N, 5.06↓C35H4B04Nl
L tl! Value: Excellent c, 74.96+T-1+8631
．． 5.00). 51! ! Ina1A16 Phthalazine-1,4-dione adduct with calciferol
The corresponding 5(E), 7(E), 11M19)-trie
General method for converting the above-mentioned 1ζ [additive (200-600 μg) to ethanol (1
0 m/) and argon in hydrazine (5d)
The water was refluxed overnight at 7 pm. After cooling to room temperature, remove the solvent under reduced pressure.
and the resulting solid was dissolved in water (50 ad) and CH
@c1B (50txe). The two-phase system under argon was dianisyltellurioquinide (1
50~45011di), K2CO, (6tt) and
and 1,2-dibromotetrachloroethane (5?>)
The mixture was then stirred for about 5 hours 1 itl (ttc control
). After acid post-treatment, the mixture was passed through silica gel (12t).
and the product was chromatographed by PTC.
The desired Vitaone D is recovered from trace amounts of tellurium oxides.
The compound was obtained in 85-93% yield. 1) 9.10-seco-3β,25-dihydroxy-
Coresta-5(E), 7(g), 10(19)-Trie
from the adduct (240b) (200IIq) as described above.
It was produced to give 131 mW (92'l). A
Obtained as a solid from tel/hexane. (Q, p, 79-
81℃; [α] r, = +160''' (c = = 0.755
); UV Jtoax275nm (21500)
1Hnmrδ65 and 583 (ABq, J=11)
1z, C-6J 7H), 4.97 (8, C-19
H), 4-67 (a e Cj 9 H), 5-85
(m e W =14 Hz r C-3H), 1.
22 (8, C26H3, 27H!!), 0.95 (wide
A single line. C-21H3), 0.55 (s*C-18Hs
) + IRνmax 3400 (m), 2950 (8)
, 1620 (W) Tomatoe Spectrum Molecular Ion m/e=
=400; (Actual measurement in elemental analysis:%C+77.
50iH, 10,99iC2,, Ha40□ Theoretical value: %
c, 80.94;H,11,07ic2ヮH,,O
,・H20 theoretical value: coefficient (=, 77.46 +) (, 1
1,075'). 2) 3β-(3',5'-dinitrobenzoate)S
Pre-A1 citrate calciferol in terpyridine (5d)
(125η)(z3.5-dinitrobenzoylchloride
(85~, 1.1%). add water to this
, and the mixture was diluted with ether. After beak treatment, S.
was isolated by ptc (129tryi, 70
4'). Crystalline OL91Jw from ether/hexane
Samurai et al.t'L7'c. m, p, 105-107°C: [α
ID=+168°(c=0.97)+lHnmr
δ9.13 (m. 5H, aryl), 6.62 and 5.82 (ABq
, J=11To, 0 6H+ 7H), 5.5 (
m, W==14Hz, C-3H), 5.07 (s,
C-19H), 4.77 (s, C-190), 1.2
5 (s, C-26H3, 27H3), 093 (wide single
, C-21H3), 0.43(s, C-18H3)il
Rνmar3550(m), 2950(s), 2900
(Sh), 1750(8), 1640(w), 1550
rs), 1350(s), 1275(s), cm-';
(Elemental analysis (value: qA c, 6R67; H
,7,85; N, 4.65; C34H46N1
ny Fri! Logical value: C, 6B, A6; H, 7, 8
01N, 4.71). / Example 7 (at 9,10-seco-3β,25-dihydroxy
-Corestar-5(Z), 7(E), 10(19)-) Ri
Entryetheramine (2i^) and a/traceno (
Ben 7/(50m/) to attack 25 strokes)
5.6-L lance compound (12) from Example 6(1)
6Q) Completely degassed/water-cooled jacket
152 from the reaction vessel.
7pu(,%654A56)'etk. 25 for adulterants
irradiate for minutes and transfer the title 5.6-cis compound to the plc.
(961g, 74%) Acetone/Water
obtained as a crystalline substance. m, p, 98-100℃ (tit
, 17'95-100℃); [, cr) o=+77''
(c-(L26); UVλmaz 262nm (
19060); IHnmr (j 6.25 and 41
(ABq,,T=11H2,C-6H#7H),5.
05 (s, a-198), 4.83 (8,0-19H
), 5-9 (m * W”” 18H2I C-6H
), 1.27 (s, 0-26Hs, 27Hg), a
t5 (wide legs, 0-21J), 0.55 (s, C-1
8Hs); IR'maz3500(8), 2950(8
), 2900 (sh), 1640 (W), 1480 (m
), 1580(m), 1055(8), Ca1-1;(
C27H44O2/H20 theory flu in elemental analysis:
%C, 77,46; H, 11,08; Actual 6111 value:
%0.77.29; H, 11,08) O Roussel. Melting point even when mixed with authentic samples supplied by Rough Ruff
did not decrease. (b) 5-(3',5-dinitrobenzoate) ester
The sample was prepared as described in Example 6(2) above. workman
Samurai tl, ta◎”, with a crystalline substance from ether/hexane.
p, 149-150°C (tit, 172147-148
°C);("JD-+9Q°(c-0,6) p (element
Analysis T: (D c5tH46N2o7 buried m 16:
% 0,6a66; H, 7,80; N, 4.71;
Actual m1lfl&: % 0゜6a94;H,'z,a
O;N, 4. sz). Example 8 9.10-Seco-3β-hydroxy-ergostar-5 (
Z), 7(B), 10(19), 22(K)-tet
Raev (D 802 attached ate engineer Lugo Calunferol (
5t) 'lt MT Ru Benzea (100m/) Oh!
Water (50 yd) Add 50 yd of water to the well-stirred mixture.
．． Sulfur dioxide was passed intermittently for 5 hours. After this about 20
The splitting compound VC was passed through with air. ether and salt water
Add ``C'' and separate each 1- and 1+!
The known sulfur dioxide adduct (172a s
173a) was obtained, which was used without further elongation. Example 9 (al 9,10-seco-5p-(triethylsilyl)
oxy)-ergosta-5(i;), 7(K), 1o(
19), for the title compound in 22(E)-tetraene cH2c12c 50m).
imidazole to the corresponding 3-monoalcohol (4,3t)
(42) Then triethylsilyl chloride Cat)
added. Wait a few minutes, add water, and add water/salt water to increase the shoulder + Ik.
It was then anti-cleaned and dried. chromatography
After that, the needed silyl ether is released as an oil.
It was commonly isolated. UVλmBz 274n
m;'Hnmrδ6,45 and 5.87 (ABq
, J"" 11 Hz * O-6H, 7H), 5.2
(m, W-9H2, O-22H, 23H), 4.
92 (s, C-19H), 4.63 (s, 0-19H
), 3.82 (III. W=18Hz, C-5H). (bl 9 , 10-seco-1α-hydroxy-5β
-(triethylsilyloxy)-ergosta-5(K)
. 7(E), 10(19), 22(E)-Tetraev N-
Methylmorpholine N-oxide (NMOX6.32)
50 minutes in CH2C42 (50td) with Takumi Musui
The mixture was stirred. Selenium dioxide (1,5f) was added for 45 minutes.
Kept at t (t) in a knoll (50 m) and warmed to reflux.
Ta. Di! the aH2at2 mixture 'li/J! Fukisu b self (aJ) in chloroethane (50 m7)
et al.) 5.6-) Lance-ergocalciferol induction
The solution was filtered into the bath liquid of the body (5,5f). This mixed Wt force
[The mixture was refluxed and the hot methanol mixture was added.]
The entire reflux was continued for an additional 55 minutes. remove pe-ryo
and diluted the mixture with ca2cz2. All water-based treatment lines
No, then silica gel (40F) chromatography
to yield 2.66y (47%) of the title compound as an oil.
I got it as a thing. UVλmaz z74nm;'1(nm
r d 6.57 and 5.90 (ABq, J=11
Hz, 0-6H, 7H), 5.25(m, W=9Hz
, C! -22,25H), s, os(s, c-19H)
, 4.98 (s, C-19H), 4.65-3.92 (
m, C-IH. 5I(). (cl 9,10-seco-1α,6β-dihydroxy
-Ergostar-5 (E), 7 (K), 1tl (19),
The silyl from (bl) in 22(E)-tetraene T+(F(10d)
Ether 16 oag)? tetrabutylammonium full
The mixture was stirred with olide (460Q) for 60 minutes. blend
After dilution with aa2at2 and aqueous treatment, the title
505 shoulder 9 (84%
) was obtained. Obtained in crystalline material from ether/hexane
. m, p, 1 (15-105°C; @D-+172°(
c=0.58); U■λn, az 272nm (
2261JD)yIHnmr/j 6.38 and 5
．． 82 (ABq, J=11 H2, O-6H, 7H
), 5.18 (110, W=9Hz, 0-22H, 23
H), 4.9 (m, W-9Hz, C-19H2), 4.
55-3.77 (m, C-IH, 3H), 0.57 (θ
+ C-18H5) + IRI'(HaX3500(
s), 2950(8), 2900(ah), 1640(
W), 1460 (m). 1375 (m), 1050 (8), 1υ30 (s),”
−'s 'M ds is the kutle molecule io/m/θ-41
2; (Elemental analysis value, actual condition 100 II: %c, yq, 57
;H, 1oy1; c2BH44o2 theory clay:%c, 81
．． 50;Hz10.79yC28H4402・shi42
H20 theoretical value: %c, 79.76:H. 10.76). (dl 9 , 10-seco-1α-hydroxy-3β
-triethylsilyloxy-ergosta-5(Z), 7
(IIC). ILl(19),22(]1c)-tetrae7phenazi
/(1・20Q) and triethylamine/(number f darkness)
871' in Be7zen (30=d)
a pi (5.6 tres/scarp from bl (6001g)
) was photoisomerized for 50 minutes as described above and 400 Q
(66%) of the title 5.6-cis vitamin was obtained. UV
λmax 265nm; 1flnmrδ6.38 and
and 6, Q13 (ABq, J=11Hz, 0-6H, 7H
), 5.25 (m, W=10Hz, C-19H. 22H, 25H), 5.0 (s, 0-19H), 4.6
~3.92 (m, 0-IH, 3H). (θl 9.10-seco-1α,6β-dihydroxy
-El Costa-5 (Z), 7 (K), 10 (19), 2
Silyl ether derivative 4 from 2(K)-tetrae/niJ i+',' td)
Stir in THy (10 m) at mold temperature with body (200 mg) 'c about 6 + d).
Ta. diluted with ca2ct2, aqueous work-up and then
The dog was SS by pLc and weighed 12911g (82%). Crystallization from ether/hexane gave the title compound. In. p. 141-143 c. (zit.+o613
8 to 140℃): Cs'J D -+54'' (c=
α645); UV λmax264ron (19100
):1Hnmrδ6.55J. - and 6.05 (ABq
, J=1 1H2,C-6H,7H), 5, 16(m
, W=14Hz, 0-i9H, 22H, 2+H), 4.
98 (s, C-19H), 4, 6-3.85 (m, 0-
IH%+H), 0.55(s, 0-18H3)+■R'
ma15 500 (8'), 2950 (8), 29
0 similar sh), 1640 (w), 1460 (rn), 13
70 (m), 1060 (θ), c"l11-';'
Spectrum molecule io/rV/e-4 1 2 ; (element
028H4402”l theoretical value 2%C in elementary analysis, 81.5
0;H. 10.75; 0,7.76; 夷64thl
, :% 0.8L39;n. 10, 60). Example 10 (al9,10-seco-6β-acetoxy-
1α-benzoyloxy-ergosta-5(E),
7(K), 10(19). 22(E)-Tetraene 117 1α-Hydroxy-5β-tri from Example 9(b)
Ethylsilyloxylated 0*(2rlr viridine (25d)) treated with benzoyl chloride (2d)
did. After 50 minutes, boil the water and mix the mixture with all ether.
Diluted. After acid post-treatment, the solvent is removed to form an oily
THF/H20/Ac0H (8'1'5) (3
6, 1. j) The mixture was stirred overnight. diluted with ether
and after aqueous work-up the crude benozoate/alcohol
Place the liquid in benzene (40 ml). To this jL, add triethyl acetate (7 ml) and acetic anhydride (5 ml).
) and 4-dimethylaminopyridine (1511g)
I ran out of money. After 60 minutes, water is added and the mixture is
diluted with tel. r1! and silica (10
1.76 by performing chromatography 1- through f)
% (85%) of the title acetate henzogate in oil form
Obtained as ◎' Hnmra B. 05 (m, W=12
Hz, 2H, aryl), 7.5 (m, W-1 0H
2, 5H. 711-ru)% 6. b8(d, J=11Hz, C!-
6H), 5-B8 (m1W-16Hz
-c-IH, 7H), 5.15 (m, W=113Hz,
0-3) 1, 19H2, 22H, 2! IH), NQ5
(s, CjAc), 0.57 (s.0-0-18H. Rule 6(R), 19-(N, N'-phthalhydra
Dido J-9.10-Secor 1α-benzoyloxy-6
β-acetoxy-ergosta-5(1o), 7(g),
22(i)-Trie/ Vitamin 7 (2r) fc3 from the above (al)
Lid in cH2ct2 (200g) at 0°C
A well-stirred suspension of hydrazide (2?) y (cH
2az2 (20Fnt) and acetic acid (1i).
Pb(OAC)4(4f)(1) solution 'Jt
Added to 7. After consuming the starting material (checked by ttc)
(taste), phthalhydrazide't (removed by filtration)
Ta. Aqueous work-up followed by chromatography
(250) of 1st and 4th floor (52% from 248b)
A 95:5 mixture of 8r and 6(S) isomer was obtained.
. oH2ct27 Hexa/Cleaned out from pure 1&Zhaohua
I got an accessory. m. p. 211-213°C t1. "l o
- +2 9 5° (cxO.a5);' Hnrn
r da5-7.3 (n+, 9H, aryl),
5.95 (m, w-14Hz. C-IH, 7H), 5.28 (m, C-3H), 5.1
7 (m, W = 1 [IHz, C-22H. 25H), 492 and 4.37 (AB series, J-18H
z, 0-19H2), 4.8 (m*C-6H), 2
．． 05 (s, OAc), 0-17 (s r O
-18ki 3)' I Rνmax2950(θ
), 2900 (sh), 1750 (8), 1720 (θ
), 1640 (Sun), 1610 (m), 1265 (S)
, 1245(s), crn-1;
Molecular ion m/e=718t (elemental analysis value, real & I+
III%c, 75.26; H, 7,54; N, 3.
82. '0asHs406N2; J! Li theoretical value: %
C,75,18;)(,7,57;N,3.90). Example 11 (al 9 , 10-seco-6β-(6th-butyldi
methylsilyloxy)-ergosta-5(K), 7
(K). SO2 addition of 10(19), 22(K)-tetraene
aH2oz2 (4
0-) Sulfur dioxide in ergocalciferol
Senryu (5v ergocalcifero as mentioned above)
The crude mixture of tertiary-butyl dimethyl silica
Stirred with luchloride (i!M). 1.5 o'clock 1...
The post-reaction was worked up as described above and subjected to chromatography.
After applying 4,8 r (from ergocalciferol)
66%) of the title compound*' oily epimer at kO-6
obtained as. I Hntnrδ5.22 (m, W=9H
z, C-22H, 2”+) (), 4.64 (m, W-
10H2,0-61(,7H),4. [12(m, W=
16Hz, C-3H), 367 (wide s, 0-i9
H2), 0.91 (a, t-Bu), 3+-0 to 0.6
,59(2XB.0-18H3),0.07B,((Si-OH3)z
). (bj 9.10-seco-6β-triethyl
Oxyergos p-5(E), 7(E), 10(1
9), OfJ2C67 (40
d) Ergocalciferol with wax dioxide yellowing in
710 (5v ergocalcifero as described above)
The crude mixture of triethylsilyl chloride (manufactured from
About 50 minutes later,
The reaction was worked up and chromatographed as described by Aij.
5.5f (7 from ergocalciferol)
4%) of (210b) was used as oil-j 0"14B
mrδ5.22 (m, W=91-1z, G-22
H, 23H), 4.64 (m, Vi=10Hz,
O-6H, 7H)% 4.02(m, W=16H2,
C-5H), 3.67 (broad 8.c-19H2). +cl 9 , 10-Hiko 5β-(5th-butyldi
methylsilyloxy)-20(S)-formyl-pre
guna-5(E), 7(K), 10(19)-triene
802 adduct Vitamin D2 adduct (4,7r) from the above tbl
Treat with oscilloscope and chromatograph as described above in a conventional manner.
F4-fc Temporarily 3.25f (78%) of aldehyde
Do(211a)e[tao'Hnmr a 9.39:
' (m, 0-22H), q, 66 (m +''= 1
6Hz, 0-6H*7H), 4.0(m,'W-
16Hz, U-5H), 566 (wide B, fj-19
H2), 1.15 (d, J=6Hz, 0-21J), O
,a9(s,t-Bu),0.71〇,02
(2xe, 0-1δH3), 0.05B, ((8i-C
I45) 2 and IRyBaz (4 films) 2950 (
s), 29DO(sh), 1720(S), 1660(
W), 1460 (m), 1305 (s)% 1250 (8
), 1150 (m), cm-'. (dl Similarly, siJ (82% yield from C1)
9.10-Seco-5β-(triethylsilyloxy)-
20(S)-formyl-pregna-5(E), 71),
10(19)-TRF(2) 802 adduct is produced
Built rL, 7'ic. ”Lio+nr d9.57 (m
, 0-22H), 4.67 (m, W=12H2, O
-6H, 7H), 3.97 (m. W=16Hz, C-58), 6.65 (wide 8.0-
191(2), 1.15(d, J=6H2,0-21
H5);I) ('maXc'4 film) 29S
LI (8'l, 2900 (sh), 1755 (s), 1
660(w), 146C1(m), 1580(m), 1
310 (θ), 1150 (m), cm-'. Example 12 (at 9,1υ-seco-6β-(#5u butyl dimethyl
tylsilyloxy) -20(S)-(hydroxymethy
l)-pregna-5(E), 7(lil:), 10(1
9) - The aldehyde (3,1f) corresponding to the 802 adduct of triene is generally
The title compound is not written in the same way as described in the book.
A qualitatively quantitative yield was obtained. 'Hnmrδ4.65(m
, //=12Hz, 0-6H,7H)% 4.02
(m, W-16Hz, 0-5H), 3.80-3.
28 (rn, 0-19H2, 22H2), 1.05 (d
, J-6Hz, 0-21J), 0.87(s, t-Bu
), 0.68+0.58 (2xs, C knee 18H3),
0.05(s, (Si-CH3)2 to Rmax(thin
Film) 5550 (br), 2950 (s), 29
00(sh)%1660(w), 1475(m), 13
50 (8), 1275 (θ), 1155 (m), 1-1
0(1) Similarly, 9,10- with a yield of over 90%
Seco-5β-(triethylsilyloxy)-20(S
) -(hydroxymethyl)-pregna-5(K),
7(K). The 802 adduct of 10(19)-triene was prepared. "llr1mrδ4.63 (m, W=12Hz, C-6
H, 7H), 3.95 (m, W-16Hz. 0-5H), 3.77-517 (m, C!-19H2,
22H2); IRνmaX (thin film) 3550
(br), 2950 (s)% 2900 (sh), 166
0 (w), 1460 (m), 1380 (m), 15L]
5(8), 1240(m), 1155(m), α 0 (219,10-seco-6β-(5th-butyldimethyl
silyloxy)-20(S)-(hydroxymethyl)
-Pregna-5(E), 7(K), 10(19)-tri
En adduct of (1) above (3t) k2.5 hours NaHOO5
(52) was stirred in refluxing methanol (50 m) containing
. This was all post-processed as described above to yield 2.36f (90
%) of calciferol. UVλmB,z 27
4nm;'Hnmrδ6.47 and 5.87 (ABq
, J-11Hz, 0-6H, 7H), 4.92(s,
○-19H), 4.65 (s, 0-19H), 4.1
~3.15 (m, 0-5H, 22H2), 1.06 (d
, J-5Hz, C-21H5), 0.9 (s. t-Bu), 0.58 (Japanese, C-18H3), 0.07
8. ((81-OH5)2J. (31Similarly, chromatography was performed from the adduct of (1) above.
9.10-Seco-3β- in 47% yield after application of
(triethylsilyloxy) -20(S)-(hydro
(xymethyl)-pregna-5(K), 7(J), tO(
19). -triene (267d) was produced t″.UVλma
x275Hm; 'Hnmrδ6.43 and 5.
7 (ABq, J = 11 Hz, 0-6H. 7H), 4,9 (s, C-19H), 4.6 (s, C
-19H), 4.03-3.13 (m, C-5H. 22H2). 16 9.10-Seco-6β-hydroxy-20(8)-hydro
Roxymethyl-pregna-5(K), 7()l;), 1
0(19)-) Rie/ [Method A] Phthalazine-attached knife from Example 6 (1) (200 tr
y) (il-hydrazi/, followed by general methods)
Oxidation as described gave the title product (10511, 85%
) was obtained. [Method B] Phthalazino adduct (250Q) from Example 6(5)
All similar conversions yielded the title product, 5th-butyldimenarcisi.
Lylether (166Q, 90%) was obtained. n-stream THF
(10sd) of this material for 1 hour, n-Bu4NF
(1M bath in THF, 2-). Kotaku
was diluted with aH2ct2, subjected to aqueous post-treatment, and
Purified by pta (2670) (107 inches, 87%
) was obtained. [Method C] The product of method B obtained via the corresponding so2 adduct (
160Q) was similarly converted into a labeled adjunct.〇[Method D] The corresponding SO2 adduct in THF (10rIlt) is
The triethylsilyl ether of the title compound obtained via
160Q) to n-Bu4NF (1M solution in THF,
2tMt) at room temperature. After about 30 minutes, start the reaction.
Post-processing (267c) (IO
IQ, 85%) fc obtained. cn2cz2/hex/from
A crystalline substance was obtained by crystallization. m, p, 104-106
U: @)n-+ 190@(c-(L37);UV
'maX 273nm (22640): IHnmrδ
6.5 and 5.83 (ABq, J-11Hz, 0-6
H, 7H), 4.95 (s, 0-19H), 4.62 (
a, C-19H), 4. [18-3.12 (m, C
-5H. 22H2), 1.05(d, J-5Hz, C1-21J
), [1,58(s, O-0-18)(;lHshi, na
, 5450(s), 2980(8), 2950(θh)
, 1635(W), 1450([[1), 1050(8
), 103 similar θ), Sen-1; mass spectrum molecular ion
m/θ-550; (elemental analysis value, actual 611 + value %C17
9,46;H,9,94;c22H54o2 theory i*%
0,79.95;H,10,! 17゜Yi MM Example 14 6(R), 19-[+i, N'-phthalhydrazidono
9.10-Seco-6β-acetoxy-20(S) -(
p-)luenesulfonyloquinemethyl]-Flegner
5(11]). 7(E)-Alcohol from Example 5(1) in dienepyridine (
2,275r) at room temperature as p-)luenesulfonylchlora.
Stir overnight with id (6,25F). Add water to this mixture and mix for about 20 minutes.
Extracted the object with OH2at2 ◎After processing the enemy
Crystallized from cH2ct27' ether to give 2.5F (8
5%) of the required tosylate (216) was obtained. m
, p, 91-92°C p@In = +508° (c =
i/6) ; 'Hnmrδa3(m, W=12Hz
, 2H, aryl), 7.8 (III, W=10H2,
2H, aryl and d, J-7H2,2H,)sil)
, 7.53 (d, , T-7H42H, Tosyl),
5.85 (d, J-10Hz, C-7H), 5.06 (
m, C-3H), 4.78 and 4.2CAB series J-1
8Hz, C-19H2), 4.75(d,, T-10H
z, c-6H), 3.8(m, W-12Hz, 0-2
2H2), 2.43(s, ) sill), 2.
03 (s, OAc), 0.88 (d, J-5Hz
, 0-21 H5), 0.13 (s. 0-18H5); Engineering Rνmax 2950 (θ),
2900(sh), 1750(a), 1650(e)
, 1610(s), 1475(s), 1240(s)
), 1175(s), c+i-1; quality 1 spectrum molecule
Ion m7e-686; (elemental analysis value, real (llHlf
:% C,6B,09;H,6,84;N,400
;S, 4.90;039H4607N2B Theory I1
lil: % 0.61i19; H, 6,75
;N, 4. L12; S, 4.67). Example 15 3-methyl-1-buty/-3-yltetrahydropirani
ether 3-methyl-1-butyn-3-ol (25a+/b
21.72), dihydrobilane (50ad) and p
-Toluefsulfonic acid (5ml/g) t-1 hour at 0°C-
The mixture was mixed together and kept at room temperature for an additional 40 hours. mixture
The product was shrinked and the residue was dissolved in a 5% Nm) 1005 aqueous solution.
This was followed by extraction with benzene. The organic solution was dried and reduced to 57.5 f (86%
) obtained the title ether. b, p, 47℃110.8m
mHg (tit30~33 tjQ, 5mm"; 57
Ci Buddha 5mm170);'Hnmrδ5.6 (m #
THP C-2'H), 2.45(s, 0-11(),
1.51 (s, OHg), 1.48 (s. OH3); Engineering R (thin film) 3550 (a),
2950 (@ ), 2900 (sh), 1125 (g)
, 1070(s), 1030(III), (X-1°
Example 16 1-Mercapto-2-methyl-2-hydroxy-propyl
Ethyl-2-mercaptoacetate) (10m) was added to the drying solution.
(150 mA). Stir this bath solution thoroughly.
cooled to 0°C and diluted with methylmagnesium bromide.
An ether solution (3M bath solution, 1oo*, 55 parts 1i) of
), both parts took 5 hours. Remove the mixture from the water bath
Further, the mixture was stirred for 30 minutes. Ammonium chloride in water
Carefully add um (18f) and neutralize the mixture with hydrochloric acid.
to produce two transparent layers. Separate each layer and
The tell layer was washed with water/brine and dried. Reduce solvent
removed under pressure and distilled the product to give 4.42 thio
a b, p-46℃/16mmHg (tit,
64°/26mm158! L 161" 72201
m ” ” b) ; ' Hnmrδ2.6 (J, J
-9Hz, 0-lH2), 2.5(s, exchange at D20
, -0H), 1.38 (t, Jm9Hz, -8R)
, 1.28 (8,6H, (OH3)2);
Le! Q/e59 (100), 75 (24), 91 (14
). Run 9i117 6CR), 19-(N,N'-7 talhydraji)
-26-thia-9,10-seco-5β-acetoxy-2
5-hydroxycholester-5 (1()), 7DIC)
-diene THF (125d) and HMPTA (
Tosylate from Example 14 (2rd) in
,51r) K 1-mercapto-2-mer from Example 16
Terpurono-2-ol (5d) was added. mixture#
'e Degassed, NaH (50% dispersion in oil, 1.3t)
added. After 2 hours, water was added and the mixture was vented.
Diluted with Zen7'cH2cz2. acid post-treatment followed by
Chromatography and CH2Ct2/H2C
The title sulfuric acid of 1.71f (77%) was crystallized from
I got a de. m-p, 187-188°C; ("lp=+3
48'(c-0,62),"Hnmr a a3(m,
W-12Hz, 2H. aryl), 7.8 (m, W-10H2, 2Hr ant
), 5.9 (d. J-IDHz I 0-7H)% 5.07 (m*C-
3H), 4.78 and 4.18 CAB series, J-18
H2, c-19H2), 4.75 (d, J-10Hz,
C! -6H), 2.58 (s. C-24H2), 2.03 (s, OAc), 1.2
3 (s, C-26H5, 27Ex), 0.98 (J, J
-5Hz, 0-21H5), 0.15(β, 0-18H
5); Engineering R'maz360Q(m), 2950(a),
2900(sh)%t740(s)%1640(s),
1610 (m), 1370 (El), 1350 (e),
1240(a), cm-'; it spectrum molecule io7
m/e-620: (Elemental analysis value, real 6111i:%0
．． 69.47; H, 7, 65; N, 4.43; B, 5.
21;056H4805N2B Theoretical value:%0.69.6
4; H, 7, 79; N, 4.51; 8.5.17). Example 18 23-thia-9,10-seco-3β,25-dihydra
Sea Core Star 5(K), 7(K), 10(19)-)
The adduct of Example 17 as described in Rie/General Methods
It is manufactured as an oil. UVλrnax275nm
'Hnmrδ6.52 and 5J35 (ABq, J-
11Hz, 0-6H. 7H), 4.95(8,0-191(), 4.67(s
, 0-19H), i85(m, W-14H2, C-3H
), 2.63 (s, 0-24H2), 1.3 (El
,0-26H3,27H! S), 1.1 (d, J
=6H2,0-21J),0.58(8,0-18H
3). Example 19 Sachi 5-(3',5'-dinitrobenzoate)-esthetic
Example 6(2) in 67% yield from the adduct of Example 17
扛田ether produced as described for the compound of
A crystalline product was obtained by crystallization from alcohol/hexane. m,
p, 108-110℃; (alp +188@(C-α
742); UVλmaz 272nm (25400)
and 262nm (25400); IHnmra 9.
12 (m, 5H + completion), 6.62 and 5.82
(ABq, J”11Hz, 0-6H, 7H), 533(
m, W-12H2, 0-3H), 5.08(s, 0-1
9H), 4.78 (e, 0-19H), 2.6!1 (s
, 0-24H2), 1.27(s, 0-26H3,
27H3), 1.08(d, J-6Hz, 0-21H4
), 0.45 (s, o-18H3); Engineering R'max 3
600 (m), 2950 (I), 2900 (sh),
1740(s), 1640(m), 1550(8), 1
550(s), 1280(s), 1170(s), (X
-1; mass spectrum molecular ion m/e-612; (original
System analysis, Meika H1! :%0.64.39;H,7,2
6;N, 4.43;S, 5.11;053H4407N
28 fi logical value:%0.64.68;H,7,24;N
, 4.57; 13, 5.23) 6 Example 20 23-thia-9,10-seco-1α-hydroxy-3β
, 25-bis(triethylsilyloxy)-cholester-
5(u), 7(g), 10(19)-triene ca2o
Diol of Example 18 (40 m) in z2 (15 m)
0 to 9) Triethylsilylchloride with one Ibadashiru
Ride (450 μt) was added. After 7 hours water was added and the mixture was diluted with CH2Cl1
did. This was post-treated with acid to obtain a crude bis-Tl2B derivative,
This was used without further purification. Selenium dioxide (1061Ig) was dissolved in methanol (
5 m). N-methylmorpholine-N-oxy
Sid (NMO) (52819) in anhydrous MgS for 30 min
Stirred in cH20t2(5yd) in the presence of O4.
Stirred. This NMO bath solution was mixed with 1,2-dichloroethane (5
11Lt) in a solution of crude bis TES m conductor in
P was added and the mixture was warmed to reflux. This reflux mixture
Compound K 8e02/methanol was added. 55 at reflux
After 20 minutes, remove the heating mantle and heat the mixture to 0H20t2.
and immediately washed with 5% aqueous solution.
Dry. Purified by PTC to 233 mW (actual
65% from the adduct of Example 17]
The compound was obtained as an oil. UVλmaz 274nm
; IHnmra6.58 and 5.92 (ABq, J
-12Hz, 0-6H, 7H), 5.08(s, C-1
9H), 4.97 (s, 0-19H), 4.67-4
．． 03 (+n, 0-IH, 5H), 2.58 (El, 0
-24H2), 1.52(s, 0-26H5,27
Hg)・Example 21 23-thea-9,10-seco-1α, 6β, 25-)
Lihydroxycholester 5 (ffi), 7 (E), 1
Example in 0(19)-triefTHF(5-)
BisTES derivative from 20 (112 mg) with benzene
Anhydrous tetrabutylammonium fluoride in AC3yd)
22 (1 g) was added. 2.25 hours at reflux.
After that the mixture was diluted with ethyl acetate and diluted with water (3X)/brine.
It was washed and then dried. Title triol (50q
, 68%) were isolated from ptc K. Crystalline substance crystallized from CH2Ct2/hexane
4th order, m, p, 129-131℃tC! 'JD-+1
84” (c=0.2175)*UVλmax 2-5
nm(21860);'Hnmrδ6.58 and 59
2 (ABq, J-11Hz, 0-6H, 7H), 5.1
2 (s, 0-19H), 5. [1(s, 0-19H),
4.65-4.0 (m, 0-IH, 5H), 2.67 (
s, C-24H2), 1.28(s, O-26H5
, 27H5), 112(d, J-7Hz, 0-21H5
), 0.57 (a. 0-18H5); Engineering Rνmax 3550 (s), 29
50 (θ), 2900 (ah), 16411 (w), t
o5o(m), 101030(,1-1; mass spectrum
Le molecular ion rrVe-434; (7C nest analysis value, actual measurement
Value 2% 0.71.57; H, 9,57; B, 7.25;
C26H4203B theoretical value 2% C171,84; H,9
, 74; S, 7.38). Example 22 23-thia-9,10-seco-3β,25-dihydrox
Sea Core Star 5(Z), 7(E), 10(19)-)
! J-r-7 Trietherine (1#jJ) and
A/Trace Benzene containing bee (15%)
5.6- ) la from Example 20 in (30 m)
Completely deaerate the bath liquid of Subvita i 7 (648g).
and photoisomerization was carried out as described in Example 6(1). The mixture was irradiated with 1iJJ for 20 minutes and the required title
Vitamins (49i+y, 77%) in oil form by PTC
It was done as a danchuan. UVλmaz 262nm; 1Hnm
r a l, , 25 and 6.0 (ABq, J-1
1Hz, C-6H, 7H)h 5.03(s,
C-19H), 4.82 (s, 0-19H)% 3.
93(m, W-18Hz, 0-3H)%2.67(s
, C! -24H2), 1. ．． 27 (s, O-26
J, 27H5), 1.08(d, J-6Hz, C
-211-15), Q, 55 (sao18J) a implementation
Example 23 5-(5',5'-di
nitrobe/shade) ester was prepared using the method of Example 6 (2J).
Manufactured using a convenient method. Crystallized from ether/hexane
A crystalline substance was obtained. m, p, 145-148
℃t(s o = + 109"(c-α571);
UVλmax 260nm (24900) and 235
Shoulder in nm (50600); IHnmra 9.0
8(m, 3H, aryl), 6.55 and 6.0
6 (ABqsJ-11Hz, 0-6H, 7H), 5. ．．
53 (m, 0-5H), 5.15 (s, C-19H)
, 4.93 (El, 0-19H), 2.65 (s, 0-
24H2), 1.27 (s, c-26H5°27H3)
, 1.08 ((1, J-6H2, 0-21H5), a5
7 (s, 0-18HS), IRWm, 3750 (m)
, 2950(8), 2900(sh), 1750(a)
, 1640(!l), 1550(s) 11345(s)
, 1280(s), 1170(s), 1-1;
Cuttle molecular ion Vθ-612; (elemental analysis value, measured value
: % 0.64.7; H, 7,24; 0.1a25;
N, 4. M;8.5.15;035H44o7N2B
Logical value:%0,64.68;H,7,24;0.1a28
; N, 4.57; S, 5.23). Example 24 25-thia-9,10-seco-1α-hydroxy-6β
,25-His()IJethylsilyloxy)-Choles
ter-5(Z), 7(K), 10(19)-) 'J Eng.
y Fenazi/(40 9) and triethylane (4
Examples in benzene (35 ml) containing
The corresponding 5 (]!l) compound (40my) of 20
Completely degassed and irradiated as above for 55 minutes. 1
37119 (75%) less polar 5 (captivity)
was isolated as an oil by PTC. UV nationality, z
263 nm;'Hnmrδ6.35 and 6.05
(ABq, J-11Hz, C!-6H, 7H), 5.2
7(s, 0-191(), 4.95(s, C-19H)
, 4.6-5.93 (m, 0-IH, 3H), 257
(s, (!-24H2), 1.2(s, C-26
1 (3,27H3). Example 25 25-thia-9,10-seco-1α,3β,25-tri
Hydroxy-cholester-5 (Z), 7 (Fli), 10
(19) - in THF (8td)
Corresponding screw 'I'E8 from Example 24 @ conductor (1
85 mg) and tetrabutylammonium fluoride (
IM bath ff, 2-) in THF was added. 1. at reflux.
After 25 hours the mixture was diluted with cH2cz2. aqueous solution
After post-processing, pea Kniji was purified to yield 1101g (9
0%) title was obtained. ether/hexa
A crystalline substance was obtained by crystallization from 7. m, p, 124~
126℃傅D-+54@(c-0,37): Uv λm
az 264nm (17400);'Hnmr C
6,35 and 6.05 (ABq, J-11Hz, 0-
6H, 7H), 5.35 (s, 0-19H), 5.0 (
a, 0-19H), 4.65-4.0 (m, c-IH,
5H), 2.65 (s. 0-24Hs), 1.27 (s, 0-26H3, 27H
s), 1.1((1, J-6H2, 0-21H3), 0
．． 55 (8,0-18H5); Engineering R'maX3550 (
a), 2950(8), 2900(ah), 1640(
w), 101050(, 101030(, (Jl""1
;The pawndosu is a cuttle molecule io y m/e-454; (element
Analytical value to actual value: %Oe 71.63* Hs 961
t S , Z34; 026H4203 day theoretical value: %
0,71.84;H,9,74;8;7.38). Example 26 25-thia-9,10-seco-1a,5β-bis (formula 5
'-Dinitrobenzoyloxy)-25-hydroxy-
Kov x I! -5 (Z), 7 (K), 10 (19)
- in trix7pyridi/(3d) and be/zene(5-)
Triol (75m) from Example 25 in +
D-3,5-dinitrobency chloride (85■)
t-added. Add water to this and mix the mixture aiIJ.
diluted with tel. Example 6 (post-processed as in 21)
Purified by PLC with 9711 g (68%) of unstable
Bis(dinitrobenzoate) was obtained. 'Hnmr
a 9.8 (m, 6H*aryl), 6.62Ctl
,, T-11H2-C-6H), 6-12 to 5-42
(m-C-I H, 5H* 7H-19H), 532
(11°0-19H), 2.63 (8,0-24H2)
, 1.27 (θ, 0-26H5, 27H3), 1.0
8 (wide single, 0-21H3), 0.22 (s, C-
t8Hg). Example 27 23-thia-9,10-seco-1α, 3β, 2-trich
Droxy: l L/star 5 (z), 7 (K), 10
(19)-) Diene-23,S-oxides methanol (10id)% ether and water (21d)
Sulfide from Example 25 (100 mg) in
't with sodium metaperiod 1 (50Q)
The mixture was stirred at violet temperature. After 6 hours, add an oxidizing agent (2 o my
) 'r added. After a total of 5 hours, turn the mixture on.
Diluted with 2at2. After aqueous solution treatment, plo K
921 g (89%) of the title sulfoxide mixture
Obtained. From acet/, methanol/hexane, ether
It was crystallized and obtained as a solid. m, p, 148-155°C:
(”] o ” + 77° (c-0,691) :U
vλmaz 263nm (18150),'Hnmr
a6. ．． 55 and &05 (ABq, J-11Hg
, 0-6H, 7H), 5.33(s, 0-19H),
5.0 (s, 0-19H), 4.62-i72 (m
, ○-IH, 3H, -0) (, exchange at D20), 2.
83 and 2.75 (wide single wire, 0-24H2), 1
．． 52 and 1.38 (0-26J, 27Hg), 1.
25 (wide single line, 0-21a3), 0.6 (8+0-
18J) 1 work R max 3500 (8), 3300 (g
), 2950 (θ), 2900 (ah), 1620 (W
), 1380(8), 122-like θ), 1070(8),
1[]50(8), 1030(a), 101000(,
a-1; Mass spectrum molecule io 7Vθ-450; (
Elemental analysis value, actual value: %0.69.05 pH, 9,
44p S, l 15 * C26H42048 theoretical value
:%0.6929;H-959p8+7.12
) a Example 28 23-oxa-9,10-seco-3β,25-dihydro
Xinia x fi-5(J), 7(K), 10
(19)-)Silyl ether from C7 Example 152
(160Q) in refluxed THIF (5d) for 40 min.
with n-Bu4NF (1M solution in THF, 1d) at
I pushed forward. This was diluted with cH2ct2 and then subjected to aqueous post-treatment.
and purified by PTC to give the title compound (1021
19.82%). UV AIflaz 274n
m; 1) (nmr 46.47 and 5.85 (ABq
,,J-11Hz,C-6H,7H),4.9(s,C
! -19H), 4.63 (s, 0-19H), 3.8
5 (+n, W-113Hz, 0-5H), i58-3.
07 (m, 0-22H2), 3.18 (s, 0-24
H2), 1.2(s, 0-26H5, 27115)
+ 1.03 (d, J-6Hz, c-21Hg), 0.
58(s,C-18H5) aExample 29 3-(3',5'-dinitrobe) of the product of Example 28
ester) described at i°C for Example 6 (2J).
It was manufactured in the same way as my friend's. Ether/hexane?
A crystalline substance was obtained by crystallization. m-p, 75-77℃; @Io=+176″(c-α
58) ;' Hnmrδ915(m h 5H*
aryl)% 6.58 and 5.78 (A Bq ,
J~11 Hz +O-6I(,7H), 5.3(m
, W-12Hz, 0-3H), 5.05(s, 0-19
H), 4.73 (s, 0-19H),! c57~5.0
7 (m, 0-22H2), 3.2 (a, C-24H2)
, 1.22 (s, C-26H5, 27H3), 1.02
(d,, T-6Hz, 0-21H5), α47(s, 0
-18H3); Engineering Rvmax 5500 (m), 295
0 (s), 2900 (sh). 1730 (8χ1640(m), 1550(s')%1
460(m), 1540(s), 1270(8). 1165 (m), cm-1; mass spectrum molecule io7
rnleem596; (Elemental analysis value, actual value: %C,
6651;H,zss;N,4.56;053H440
8N2 theoretical value: %C, 66,42; H, 7,43; 11
゜4.70). Example 30 23-oxa-9,10-seco-5β-(ed. tertiary butyl
dimethylsilyloxy')-25-hydroxy-cholace
Tar-5(Z), 7(E), 10(19)-)') x
Ninozen containing Nfenazino (55■)
. (30ad) and triethyl aban (3er).
Corresponding 5 from Example 52 (physical compound (160Q))
It was completely cleaned and irradiated as described above for 30 minutes.
. This was purified by jL f p/-c (273a) (
138 g, 86%) obtained a UV rmx=263
nm; IHnmr a 6.25 and 6.0 (ABq
, J-11Hz, 0-6H, 7H), 5.05(s, C
! -19H), 4.82 (s, 0-19H), 5.92
(m, W-18Hz, 0-3H), 3.62-3.10
(m, C-22H2), 3.20(s, C!-24H
2), 1.23 (s, 0-26H5, 27H3), 1
．． 05(d, J-6Hz, O-0-21H, 0,91(
e, t-Bu), α58(8,C'-18H5), 0.
05(8,(Si-CF2)2J. Example 31 25-OkiT-9,10-1!-1:'-3β,25-
Dihydroxy-:l L/ Star 5 (Z), 7 (Lf
fl), tO(19)-triene Correspondence from Example SO
6-tertiary butyldimethylsilyl ether (138
n-Bu41JF (T) in refluxing THp (5 m)
Stirred with 1M solution in HF, 2d). 45 minutes later
The mixture (diluted with J2C62) was subjected to aqueous work-up.
Then, it was purified by pic to give diol (275b) (9
1 portion, 85%) was obtained as an oil. UVλmax26
3nm; IHnmra a 6.24 and 6.04 (A
Bq, J-11H2, 0-6H, 7H), 5.03(
a, 0-19H), 4.83 (s, C-19H), 3.
92(m, W-18Hz, C-5H)%157-5.1
2cm, C-22H2'), 525 (8,0-24H2
), 1.22 (Ii, 0-26H5+ 27H5), 1
．． 03 ((1, J-6Hz, C-21H3), 0,57
(8,0-18H5). Example 52 5-(5',5'-dinitrobe) of the product of Example 51
ester) was prepared as in Example 6(2).
It was built. Crystallized from ether/hexa/
a ml obtained at 136-138°C: ("l D-"1
01°(c-α615);'Hnmr a 9.12(
m, 5H, aryl). &22 and 6.01 (ABq, J=11Hz, C-6
H, 7H), 5.23 (m, W-18Hz, 0-3H)
,5. i(8,0-19H), 4.92(s, 0-1
9H), 557-3.1 (m + O-22H2),
3.2 (s, 0-24H2), 1.22 (a, O-
26H5e27H3), 105(d, J=6Hss, 0
-21H3), 0.55 (s, 0-18J). Engineering Rνmax 3550 (m), 2950 (s), 29
00(sh), 1750(a), 1650(m), 1
555(s), 1470(m), 1350(8), 1
280(S), ca-1; quality-spectrum molecular ion
m/e-596;
Ifi: % 0, 66.34; H, 7, 37; N
, 4.61 ;05sEss08M2 theory condition:%0
, 66.42; J7.43; N, 4.70). Actual example 63 26-mankif -9,10-seco-5β- (tertiary
(dimethylsilyloxy)-25-()ethylsilyl
Oxy)-cholester-5(Fl, 7(h), 1o(1
9) - in Torie/cH2cz2 (10sd)! From Example 52
25-hydroxy compound (30089) was incubated for 16 hours.
Midazole (200Q) (Trie in the presence of D)
This was treated with silyl chloride (130 μt).
Acid work-up of n yields the title bis-silylated calciferol.
(274) is obtained, and this can be used in the next step without further aS.
was used. Example 34 23-oxa-9,10-seco-1α-hydroxy-3
β-(5th-butyldimethylsilyloxy)-25-(
Triethylsilyloxy)-Cholesta-5(K), 7(
E), 10(19)-) Liene selenium dioxide (60 g
) was stirred in methanol (4wt) for 45 minutes. N
MO(500A9) in the presence of anhydrous MgSO4 for 30 min
The mixture was stirred in aH2cz2 (4d) at a lower temperature. this
Example of NMO solution in 1.2-V chloroethano
P in solution of bissilyl ether from 36 and
The mixture was warmed to reflux. In this reflux mixture, Sω2
7 methanol mixture was added. Heat mantle after 23 minutes
and the product was worked up as previously described and isolated.
t90m9 (51 based on the product of Example 52)
%] of the title 1α-hydroxylated product was obtained. UVλmax 274nm;
'Hnmrδ6.55 and! ! 18B (MuBq,,T
-i2Hz, 0-6H, 7H), 5.1 (s ho-
19H), 5.0 (3,0-19H), 4.75-4.
02 (m, 0-IH, 3H), 565-i12 (m,
C-22H2), 525(e, (!-24H2). Example 35 23-oxa-9,10-seco-1α,5β,25-t
Lichtology Colester 5 (B), 7 (K), 1o (
19) - Bis from Example 54 in Trier/THF (6 ml)
Silyl ether (1 tatg) for 1 hour nBu4N)F
The mixture was diluted with CH20t2. This was subjected to aqueous work-up.
After subsequent purification by pla, the title triol (
105Q, 84%) tl-obtained. Chloroform/hexa
A crystalline substance was obtained by crystallization from the sample. m, p. 141~b (20554);'Hnmr (400MHz) 66.5
8(d,,T-12Hz), 5.89(4,J=i2H
z), 5. L5 (s, 0-19H), 4.98 (s, 0
-19H), 4.50('m, W=12H2,0-IH
), 4.26 (m, W-20Hz, Q-5H), A4
3 (m. 1H), K30-3.15 (m, 0-22H2, 24H
2), 1.20 (a, 0-26H5, 27H51
゜1.02 (d, J-6Hz, 0-21J) h A58
(s, C-18H3); Engineering Rνmaz3500 (s),
2950(a), 2900(ah), 1640(w),
1450 (m), 1580 (m), 1360 (m), 1
045(8), α-1; Mass spectrum molecular ion Ve
-418; (Elemental analysis value, actual value: %0.74.76
;H11α53;C25H4204 theoretical value: ~0.74
ゐ0; H9IQ, 11). Example 56 23-oxa-9,10-seco-1α-hydroxy-3
β-(tert-butyldimethylsilyloxy)-25-(
) riethersilyloxy)-cholester-5(Z), 7(
g), 1o(t9)-) lienfenazine (40 mg
) and penze containing triethylazun (4 drops)/
The corresponding 5(
Sanitized Somono (200119) for 35 minutes as described above.
After irradiation with Noviara 7p and purification by PTC
155 ■ (78%) of the title compound in a less polar oil.
s UVλmaz 263 nm;'
Hnmr a 6.30 and &01 (ABq, J=
12Hz, 0-6H, 7H), 5.25(s, 0-1
9H), 4.97(s, 0-191(), 4.67~
3.9 (m, O-I H. 31(), 5.53~!A, 07(m, 0-22H+)
, 3.17(a, 0-24H2). Example 37 23-oxa-9,10-seco-1α,5β,25-
) Rihydroxycovy,,ter5(Z),7(E),
10(19)-) Lien Bissilyl ether (155-) from Example 56 and
n-Bu4NF (1 Mfct solution in THF, 2-)
ft1 hour reflux TH? (5g) and stirred together. This tl was diluted with 0H20t2 and subjected to aqueous work-up.
The title triol (252a) was made from wood by PLC.
(77Q, 77%) was obtained. Crystal from ether/hexane
It was obtained in crystalline form. IILpe 121-125℃
:C”Jn-+47°(c-(L6)s Uvλm
Bz 264nm (17200);'Hnmra 63
7 and 6.05 (ABq h J-11Hz, O-
6H, 7H),! 133 (e. 0-1911, 5.0 (11,0-19H), 4.5
7~i87 (m, 0-IHjH), 56~! 1.1 (
m s O-22H2), 523 (s, 0-24H2)
, 1.23 (s, 0-26H4, 27H3), 1.05
(d, J-6Hz, C-211(5), 0.58(s,
0-18H3); IRνmax 3500(s), 29
50(8), 2900(sh), 1640(w), 14
50 (m), 1380 (m), 1360 (m), 104
5(8), cm-1; mass is the cuttle molecular ion m/e
-418; (Elemental analysis E, actual value: %0.74.47
;H,9,97;026H4204 Theoretical value:%0,74
．． 60*H, t0.1t). Example 58 9.10-Seco-3β-(triethylsilyloxy)-
20(S)-(p-)luenesulfonyloxymethe
)-Pregna-5(z), 7(g), to(19)-
Triene [Method A] Example 13 (DI or
! Tosilic to the hydroxy compound of et al. (400mp)
Add loride (350 tbsp) to the mixture at room temperature
Stir overnight. Add water to this and dilute the mixture with ether.
I interpreted it. 5 after acid post-treatment and purified by PTC.
10 ml (58%) of the title tosylate was obtained. IHnm
r δ 7.75 (d,, T-811 (Z, 2H, A1
Nor), 7.28(d,, 1r-e8Hz, 2T(,
IJ-R), 6.43 and 5-81 (ABq, J
= 11 Hz, O-6H67H), 4.92 (s, 0
-19H), 4.65 (s, 0-19H), 4.2
~3.57 (m, O-!H, 22H2), 2.48 (s
, A1) - Ru CH3) p engineering R'l1naX (thin film
film) 2960(a), 2900(ah), 160
0 (W), 1460 (m), 1360 (s), 1190
(8), 1175 (8), 1090 (s), α-1° [
Method B] Crude 9.10-cell from Example 12 (11) at 5°C
co-3β-triethylsilyloxy-20(8) -(
hydroxymethyl)-pregna-5(g), 7(E). 10(19)-) Rien's 802 side dishes (52t>'
Together with 1rp-toluenesulfonylchloride l' (4f)
The mixture was stirred overnight in pyridine (40d) at 7'C, and the reaction was brought to 0.
℃, water was added and after a few minutes the mixture f:, mt
After work-up with 11rIk diluted with 2o, the crude oil product (
281) in ethanol (100m+/) for 1 hour.
The mixture was refluxed in the presence of NaHOO5 (4t). Stir the mixture and add between aa2az27' water/salt water.
It was distributed. Dry the organic solution and chromatograph
The same nmr and product obtained by the method
Required bits of 2,64F (70%)
Bun (278c) was obtained. Example 59 9.10-Seco-3β-hydroxy-2,0(1-(F)
[fluoromethyl]-pregna-5(E), 7(K), 10
(19) - Tosilane from Example 58 in triene THir (5 m)
(200 g) in n-Bu4NIP CTHF
M solution, 1-) was refluxed for 45 minutes. This mixture
The material was diluted with 0H20t2. He buried this in water.
The title block of 70111C (65%) was purified by ptC.
fluoride (279) was obtained・'Hnmrδ6.5 and
and 5.83 (ABq, J-11Hz, C-6H, 7H
), 4.97 (s , o-19H), 4.7 (br, s
, 0-j9H, 22H), 4.2-3.6(m, (!-
3H, 22H), 1-1 (cl, Jken 6Hz +
021 H3), a6 (a, 0-18H5). Example 140 9.10-Seco-1α-hydroxy-5β-(triethyl
Lucilyloxy) -20(S) -(p-toluene
sulfonyloxymethyl)-pregna-5(E), 7(
lu). 10(19)-triene selenium dioxide (56m11?)'r 7-k for 45 minutes
The mixture was stirred in a 15 m2 tank. NMO(28
0Q) in the presence of Yansui MgBO4 for 60 minutes at 0H20t
2 (3,5d). This NMO solution'
It, carried out in 2-dichloroethane (A5aJ)
In solution of the 1-desoxylated adduct (308 staves) from Example 6B
and the mixture was warmed to reflux. Konni S
Add θ0210H5ON mixture and reflux for an additional 5.5 minutes.
continued the flow. The reaction mixture was cooled in a water bath and cu2
Dilute with 2 oz and post-process as above to 180q
C57%) title 1-HiF' o 'P si compound't
I got lJ. 1Hnmrδ7.75 (a a 5 mouths
8H2. 2H, aryl), 7.28(d, J-8Hz, 2H
, aryl), 6.43 and 5.81 (ABq,
J-11Hz, 0-6H, 7H), 5. []5(a,
0-19H)%4.95(a,C!-19H), 4.
65~lb (m r C-I H, 5H, 22H2)
, 2.48 (s. ary-A-OH3). Example 41 9.10-Seco-1α,3β-dihydroxy-20 (S
) -(p-)rue/sulfonyloxymethyl)--/
Wagner-5(m), 7(E), 10(19)-) Lien
n-Bu4NIP (1M solution in THF, 0.4a
Example 4 in THF (5Id) containing i/)
0 to 3-) 84 ethylsilyl ethers (1
sOsp) t - Stirred for 15 minutes - Mixture in cH2cz
Diluted with 2. After the aqueous post-treatment, PTC IC
Yosu purification yielded the title diol of 118Q (81%).
. Obtained as a solid by crystallization from 0H2CL2/hexane. m, 1) -97 to 99°C convulsions - + 132' (c-
[157), 'UVλ, a, 272 nm (23560
) and 218 nm (15920);') Inmra
7.75'(d*J=8 H2a 2 Hsa
Reel) % 7.28 ((1,, Tm8Hz, 2H,
A I] - Ale), 6.45 and 5.81 (MuBq, J-
11H2, ○-6H, 7H), 5.03(s, 0-1
9H), 4.93 (s, c-19H)% 4.63~
3.53 (m, C!-1H.5H,22H2), 2.5<8.71nor-0H3)
, 1.02 (d, J-6Hz, 0-21Hs), Q,
57(8,0-18H5)', IRymaXxsao(
s), 295G(s), 2900(sh), 1600(
w), 1450 (m), 1555 (11), 1190 (
a), 1175(s), 1-1゜Example 42 9.10-Seco-1α-hydroxy-5β-(l ether
silyloxy) -20(8) -(p-)rue/s
sulfonyloxymethyl)-phlebnar-5(Z), 7(1
). Benzene (351
Real m in sl)? 1J40; corresponding to t5- et al.
5(E) adduct (2251N) as a linear sensitizer for 30 minutes
As mentioned above using Andrase:/C45Mf)k
The surface of 185■ (82%) was irradiated with PTA.
The title compound was obtained. UVλmax 265nm and 21
6nm; 1Hnmra 7.75 (tl, :J-8H
z, 2H, aIJ/l') % 7.5 (a,
Js”8H2I 2Hl aryl) , 6.28 and
5.98 (ABq, J-11Hz, 0-61L7H)
, 5.28 (s, C-19H), 4.92 (6, c-1
9H), 4.55-i58(m*o-1)1.3H-2
2H2), 2A5Ca, aryl-cub). Example 45 9.10-Seco-1α16β-dihydroxy-20(8
) -(p-toluenesulfonyloxymethyl)-furae
Buna-5(Z), 7(ko), 10(19)-) 1) E
n-Bu4'NF (IMiFF solution in THtF,
0.32wt)t” containing THIF (5rst)
Implementation in 91) 4 Silyl ether of S i> et al.
(1851,9) was stirred at room temperature for 15 minutes. This n.
diluted with on2ot2, aqueous workup followed by pta.
Purification to give the title diol (110 mg, 75%).
Ta. UVλmax 265nm (17427) and 2
16nm (18672);'Hnmrδ7.6B(d,
J-8Hz, 2H. Aryl), 7.25CeL, :J-8Hz, 2H
, aryl) s 6.28 and 5.97 (ABq,
J-11Hz, 0-6H, 7H), 5.27(s, 0-
19H), 4.93 (s, 0-19H), 4.57-i
6 (m, C-1H, 3H, 22H2), 2.45 (s. Aryl-0H5)% 1.05 (a, J-6Hz
, 0-21 H3), 0.52 (θ, o-18H5)
. Implementation fl144 1-Aguno-2-methyl-2-hydroxy-propa 1 Hydrogenation in ether (200d) at 0°C
In a well-stirred mixture of aluminum lithium (12F)
Acetone in ether (50-) over 1 hour
A solution of anohydrin (11, 2f, 12m) was added
. The mixture was stirred overnight at room temperature. He, water cooled to 0℃
(24TRt) was carefully fed. Anhydrous after quenching
Add Na2day 04 (659) and continue stirring at room temperature.
It continued for 2.5 hours. The solids are removed and the ether is vaporized.
The title compound was evaporated and distilled to give 4.8f (41%) of the title compound.
Obtained as a viscous colorless liquid. 'b, p, 74-76 V
14mmHg (tit16' 62~b1,4465(
tit'll'nD-1,4467);'Hnmr
a 2.6 (8, 2H), 1.87 (s, 3H, D20
), 1.2 (θ, 6H); ■RvDlla
X (thin film) 3400 (s), 3000 (m)
, 1600 (m), 1475 (m), 1380 (m),
1360 (m), 1220 (m), 1170 (m), 1
110 (m), 960 (m), scratch-1° Example 45 26-aza-9,10-seco-1α, 3β, 25-tri
Human naloxy-”' Sl-5(z) e
7(Et) + 10(19EF !J En1-
Azeno-2-methyl-2-hydroxy-propane (α5
+d) tosylate from Example 44 (100
1 g) of the solution was degassed and heated at 50-55°C for 6 hours.
[Stirred under argon at room temperature for 12 hours]
. The solution was diluted with cH2cz2 and washed with water/13i water.
It was then dried and purified by pLC to yield 44
3%) of the title triol was obtained. (b) D −+ 24
” ;UV Fuku, Engineering 264nm (15400) ;'H
nmrδ6.58 and 6.07 (ABq, J=1
1Hz, C-6H, 7H), 535(s, 0-19H)
, 5.02 (8,0-19H), 4.67-5.9'5
(m, 0-IH, 3H), 2.5(s, 0-24H2
), 1.2 (s, o-26J, 27H5), 1.0
2 (d, J-6Hz, C-21Hs), 0.5
7 (s, C-18H5): Engineering H'max 3500 (s
), 2950(8), 2900(sh), 1640(W
), 1460(m), 1380(m), 101055(
, 1-1; Mass measurement, actual value: 417.3242; 0
26H4SO5N theoretical value: 417.5245° Example
46 26-aza-9,10-seco-1α, 6β, 25-)
Rehydro * C = I V X fi -5 (Z)
, 7(E), 10(19)-) Geno-25-acetyl in methanol (5
−) Examples derived from the aforementioned tosylates in
The crude amine from 45 was treated with acetic anhydride (Q, 2d)
Ta. The mixture was diluted with cH2cz2 and washed with brine.
It was then dried and subjected to I)tC to give 501g
55%] of the table amide was obtained. cu2cz2
It was obtained as a solid by crystallization from /hexane. ! E1.1),
107~109℃: (!r)o -14゜(c-I1
49)”, UV 2Inaz 265nm (16275
);'Hnmrδ6.37 and 6.05 (ABq, J
=11Hg, 0-6H, 71(), 5.35(s, C
-19H), 5.0 (s*C-19H), 4.6
5-4.02 (m, c-IH, 3a), 14 (s, 0-
24H2), 2.17 (θ, acetyl), 1.22 (e
, Cj-26H5, 27H3), 0.95 (d, J-7
Hz, ○-21H3), α6(s, Cj-18Hs);
Engineering RνmaX5550(8), 2950(s), 290
0 (sh), 1641) (s), 1460 (m), 16
80 (m), 101055 (, cm-1; (elemental analysis value
, Actual value: %C970,80;H,10,12;N,2
．． 77;028H4SO4N Theoretical value: C17516;H
,9,87;N,i05;C25H4sO4N-HzO
Filled @flu'% 0,7α40;H,9,92;
N, 2.93). Example 47 9.10-seco-6β,25-dihydroxy-cholesta
-5(K), 7(E), 10(19) -Trie
/Magne/HCl diluted with rum flakes /Water/Acetone
/ Washed with ether and dried with JX nitrogen for 24 hours.
Magnesium gold) 84 (82mg)
Distilled (from LiAtH4) THF (10-
) in 1-promo 4-methyl-4-triethylsilyl
Butane (1f) was refluxed for 2 hours. Put iodide 1i14 (100IIg) into a flask and add 0
Purged with argon while cooling to .degree. The above mentioned
Add Grignard solution (5d) and keep at 0°C for another 50 minutes.
This purple mixture was then stirred. in ether (2-)
Tosylate (278c) (200 Otori 9) bath solution
Then, the mixture was stirred at room temperature for 40 minutes. add water
and the reaction mixture was extracted with ether. After acid post-treatment
contaminated with large amounts of low molecular weight per-alkyl residues due to PTC.
A non-8.1 product was isolated. Add this mixture to 2
n-Bu4NF (THF
of 1M solution, 2 il/). This is CH
Diluted with 2Cl2 followed by aqueous work-up and ptC.
Further purification yielded 11011g [tosylate (278c)]
82%] of the title diol was obtained. All aspects of the physical and spectroscopic properties of this material are
was consistent with the product obtained from the phthalazine adduct. Example 48 9.10--k =y-3β*25-dihydroxy-
Corestar-5(Z), 7(K), 10(19)-)
IJ x T containing anthracene (25q)
Lupe/sen (30m) and triethyl ain <51f
4) Product from Example 47 (10 (1 g)
Thoroughly degassed and irradiated for 1 hour as described above to reduce %p.
5(z) chemical compound (90119) manufactured by TC and titled
, 82%). Physical properties and spectroscopy of this material
Target 81. 'R is obtained via the 7-talazine adduct in all aspects.
The product was consistent with the one obtained. This substance and Lucel Ruff
Mixed with authentic samples kindly provided by Rough Co., Ltd.
Melting point measurements did not decrease. Example 49 9.10-Seco-1α,3β-his(triethylsilyl
oxy)-20(S)-(p-)luenesulfony
oxymethyl)-pregna-5(Z), 7(K), 1
0(19)-triene imidazole (75q) and triethylsilylchlora
(45μt) in OH2at2C5ml>
Tosylate (276b) (100my) in about
Stirred for 15 minutes at room temperature. Add water to this and the mixture
was diluted with oa2cz2. This is post-treated with acid to make it non-polar.
The title bissilyl ether was obtained, which required further purification.
It was never used. Example 50 9.10-Seco-1α,3β,25-)rihydroxy
Collection x j'-5(Z), 7(E), 10(19)-t
The alkyl prepared as described above at 0°C
The above copper test sample in THF (swt)
(276c) and the mixture was heated to 25
Stir for minutes at room temperature. After this as in Example 6 (1)
Processed and purified with polyelectrolytic low molecular weight alkyl residues
A contaminated tristriethylsilyl derivative 1 was obtained. child
The mixture was placed in TTHF (5,1) for 20 min at room temperature.
treated with n-Bu41JF (1M solution in THF, 4d).
Treat, then reflux for 1.5 hours and work up as usual.
mI7 by science and pta! and then print the iso
Steroids contaminated with 100ml (10my)
Triol [68q% (2761)] to 66%
A mixture of was obtained. This material was dissolved in aHct5 and
The essential product was purified by its crystalline cHat3 bath solvate (25 m
9') served as a samurai. m, p, 99-105°C (tit
106~112℃142゜103~106℃158)
;(b)D (Et20)-+55°(0-0,86)
;UVλmax 264nm (16820);'Hn
mrδ (7 sen) n-d6) 8.07 (s, 0HCt3
), 6.65 and 6.18 (ABq, J-12Hz
, 0-6H, 7H), 5.38 (θ, C-19H), 4
．． 93 (s, 0-19H), 4.7-407 (m, 0
-1H, 3H), 1.2 (s, 0-26J, 27J),
1.0 (wide single wire C-21H3), 0.6 (s, C!-
18H5); Engineering Rνmax 3500 (s), 2950
(a) m2900(ah), 1640(w), 148
0(m), 1440(m), 1680(m), 136
0(m)m1140(m), 1[]50(8). Example 52 25-oxa-9,10-seco-6β-(5-butyl
dimethylsilyloxy)-25-hydroxy-cholesta
-5(E), 7(ffi), 10(19)-triene (
22-hydroxy compound (1
671:+) for 55 minutes dibenzo-18-crown-6
(100Q) and potassium tert-butoxide (500Q)
19) in the presence of inbutylene epoxide (1t
refluxed with at). Add water to this and make the mixture
Diluted with OH2ct2. organic)- to aqueous 5PO4/
Wash with 15% NaHOO5 aqueous solution/salt water and dry.
I let it happen. This was purified by PTA to 560% (67%
) a slightly less polar oily product was obtained. 'Hn
mr66.45 and 5.85 (ABq, J=12H
z, ○-6H, 7H), 4.9 (IllO-19H),
4.63 (s, 0-19H), A92 (m, W=18H
z, C-5H), i65-3.12 (m, 0-22H2
), 3.22 (s, 0-24H2), 1.23 (e, C
-26H5°27H5), 1.05(d, J-6Hz,
0-21Hs), Q, 92(e, t-Bu),
Q, 6° (8,0-18H3), 0.05 #e((S
i-OH, 5)2).

Claims (1)

[Scope of Claims] 1) General formula [wherein R represents a hydrogen atom or a hydroxyl-protecting group, Y represents a hydrogen atom or an optionally protected hydroxyl group, X represents a residue of genophile, and RIH halogen atom, hydrocarbylsulfonyloxy group or formula -z-R5- (where 2 is -0-1-
S-1-8O-1-NI (4- or -CR4R5- and R5, R4 and R5 are the same or different hydrogen atoms or a straight chain or branched chain having 1 to 12 carbon atoms) represents a chain aliphatic group (which may optionally have one or more substituents),
and R2 represents a hydrogen atom, or R1 and R
2 together represent an oxo group or an optionally substituted alkylidene group provided that R1 and R2 together with the group to which they are attached -CM(CH3)CH-, represent a branched 17β of vitamin D2 or vitamin D5. - not representing a group having a hydrocarbyl side chain skeleton]. 2) The compound according to claim 1, wherein Genophile is 602 or a diacylazo compound. 5) General formula ■ or F/a F/a (cis) ■ (trans) (in the formula, R, Y, R1 and R2 are as defined in claim 1 above)
Compounds as described in Section 1). 4) In the formula, R1 is a halogen atom, and hydroxyl is a tosyloxy group or a tosyloxy group (in the formula, 2' is 10-1-s-1-NH- or 18O-
and R6 represents a hydrogen atom or a hydroxyl-protecting group) and R2 represents a hydrogen atom or R1 and R2 taken together form a hydrogen atom and an optionally protected hydroxyl group. Claims 1 to 3 represent an alkylidene group having 1 to 8 carbon atoms optionally substituted with one or more selected substituents.
General formula 1 as described in any one of 3. IV Next is F/
Compound a. 5) 2) consisting of subjecting to oxidative cleavage the compound of [formula R%Y and A process for producing a compound of the general formula I according to claim 1, wherein the oxo group represents an oxo group. 6) A process according to claim 5, wherein the aldehyde of formula (1) formed is then reduced to give a compound of formula I, in which R1 is a hydroxyl group. 7) The aldehyde of formula I formed is then reacted with a Witteitsch reagent to give a compound of formula I in which R1 and R2 together represent an optionally substituted alkylidene group, and then optionally 6. A method according to claim 5, wherein the double bond is reduced. 8) after deprotection of the corresponding compound of formula I according to claim 1 by removal of the genophilic residue
General formula I according to claim 5, which consists of isomerizing the obtained compound of formula V to a compound of 2Na.
A method for producing a compound of V or tfF/a. 9) according to any of the preceding claims 6 or 8, wherein the product obtained has a hydroxyl group as R1 and this hydroxyl group is converted into a halogen atom or a hydrocarbylsulfonyloxy group. the method of. 10) The product obtained has a halogen atom or a hydroxyl or hydrocarbylsulfonyloxy group as R1 in the formula, and the product has the following formula: −Z
A process according to any one of the preceding claims 6, 8 and 9, which is converted into a product representing the group R5.