JPH0378398B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to oxabicycloheptane derivatives and related compounds, and more particularly to novel 7-oxabicycloheptane and 7-oxabicyclohepten prostaglandin analogs useful as cardiovascular agents and uses thereof. The compounds of the present invention are effective, for example, in the treatment of thrombosis, and include compounds represented by the following formula and all stereoisomers thereof. [In the formula, A and B may be the same or different, A is CH=CH or (CH ₂ ) ₂ , B is CH=
CH, C≡C or ( _CH2 ) ₂ , m is 1-8, X is OH;

[Formula] CO ₂ R ¹ (where R ¹ is H or lower alkyl); or

[Formula] (where Z is H, lower alkyl, aryl, SO ₂ -Q
(Q is lower alkyl or aryl),

[Formula] or OR ² (R ² is H)), Y is aryl (lower) alkyl; alkenyl;
Alkynyl; aryl; pyridyl; substituted pyridyl; pyridyl (lower) alkyl; thienyl; substituted thienyl; thienyl (lower) alkyl; cycloalkyl; substituted cycloalkyl; cycloalkylalkyl; If C, then Y
may be alkyl) The symbol 〓 represents a single or double bond. ]. If the mark is a double bond, A must be CH═CH, B may be CH═CH or (CH ₂ ) ₂ and Y is a group other than alkenyl and alkynyl. As is clear from the above, the compounds of the present invention [] include compounds represented by the following formulas [] and []. Throughout the specification, lower alkyl or alkyl refers to straight-chain or branched groups not exceeding 12 carbon atoms (preferably 8 carbon atoms), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl), various branched groups equivalent thereto, etc. and which further carries substituents such as halogen (eg F, Br, Cl or), CF ₃ , alkoxy, aryl, alkylaryl, haloaryl, cycloalkyl or alkylcycloalkyl. Substituted pyridyl includes pyridyl substituted with 1 or 2 substituents selected from halogen or lower alkyl. Substituted thienyl includes thienyl substituted with 1 or 2 substituents selected from halogen or lower alkyl. Cycloalkyl has 3 to 12 carbon atoms (preferably 3
~8) Saturated carbocyclic groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,
(including cyclododecyl), and any of these groups may be substituted with 1 to 2 halogens, 1 to 2 lower alkyl and/or lower alkoxy. Aryl or Ar has 6 carbon atoms in its cyclic part
~10 monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl (substituents on phenyl or naphthyl are lower alkyl, halogen (including chlorine, bromine, fluorine) or lower may be alkoxy)
includes. Aralkyl, arylalkyl or aryl(lower)alkyl includes lower alkyl as defined above having an aryl group (eg benzyl). Lower alkoxy or alkoxy includes any of the lower alkyls or alkyls described above attached to an oxygen atom. Lower alkenyl or alkenyl has 3 carbon atoms
Includes unsaturated hydrocarbon groups having ~6 and one carbon-carbon double bond. Representative alkenyl groups are
For example, 2-propenyl, 1-propenyl, 1-
Includes butenyl, 2-butenyl, 3-butenyl, and the like. Lower alkynyl or alkynyl has 3 carbon atoms
to 6 unsaturated hydrocarbon groups having one carbon-carbon triple bond. Representative alkynyls include, for example, 1-propynyl, 1-butynyl, 2-propynyl, 2-butynyl, 3-butynyl, and the like. Halogen or halo includes chlorine, bromine, fluorine or iodine, of which fluorine is preferred. The group (CH ₂ ) _n includes straight chain or branched groups in which the straight chain portion has 1 to 8 carbon atoms, and such groups can contain one or more lower alkyl substituents. Groups included in (CH ₂ ) _n include CH ₂ , CH ₂ CH ₂ , (CH ₂ ) ₃ , (CH ₂ ) ₄ ,
(CH ₂ ) ₅ , (CH ₂ ) ₆ , (CH ₂ ) ₇ ,

【formula】

【formula】

【formula】

Examples include [Formula]. Among the compounds [], compounds [] having the following groups are preferred: A is (CH ₂ ) ₂ or CH=CH, m is 2-4, X
is CO ₂ H, CO ₂ − (lower alkyl) or

[Formula] B is (CH ₂ ) ₂ or CH= CH, Y is CH ₂ C ₆ H ₅ ,

[Formula] cycloalkyl (especially cyclohexyl), 1-methylcyclohexyl, cycloalkylalkyl,

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

[expression] or

[Formula] The compound of the present invention [] can be produced as explained below. X is _CO2R1 , A is ( _CH2 ) ₂ or -CH ⁼ CH
A compound [] in which -, B is (CH ₂ ) ₂ or -CH=CH- can be produced according to the following reaction scheme. In the above reaction scheme, a lower alkyl ester starting material containing a hydroxymethyl group, i.e., compound compound []) or A is -
(CH ₂ ) ₂ - aldehyde (compound [A])
get. In this manner, the compound [] is subjected to a Collins oxidation reaction by reacting it with chromium oxide in pyridine, for example, to obtain an aldehyde [] in which A is -CH=CH-. Further, the compound [] is reduced by reacting with hydrogen over a palladium/carbon catalyst to produce a hydroxymethyl compound [A] in which A is (CH ₂ ) ₂ , and the obtained compound [A] is subjected to Collins oxidation. (Collins
oxidation) reaction to obtain an aldehyde [A] in which A is (CH ₂ ) ₂ . Then the formula: [In the formula, R ¹ may be lower alkyl. m
has the same meaning as above. ] A compound represented by (compound [] where A is -CH=CH- or compound [A] where A is (CH ₂ ) ₂ ) and the formula: [In the formula, Y has the same meaning as above. ] A dialkoxyphosphonate such as the compound represented by is added to a dimethoxyethane (DME), ether, tetrahydrofuran, toluene, etc. in a molar ratio of compound [ ] or [A]: compound [A] of about 1 to 0.5:1. The reaction in the presence of sodium hydride or lithium diisopropylamide in an inert organic solvent gives the formula: [In the formula, Y and m have the same meanings as above. ] A compound represented by (where A is (CH ₂ ) ₂ or -
CH=CH-) is obtained. This compound [ ] is reduced by any of the three methods described above to give the formula: [In the formula, Y and m have the same meanings as above. ] Compound (A is (CH ₂ ) ₂ and B is (CH ₂ ) ₂
Compound [A] where A is -CH=CH-, B is (CH ₂ ) ₂ or A is (CH ₂ ) ₂ or -CH=CH-, B is -CH=CH-
Compound [C]) is obtained. This ester body [A], [B] or [
C] with a base such as lithium hydroxide and then neutralized with an acid such as dilute hydrochloric acid or oxalic acid to form the ester with the formula: [In the formula, Y and m have the same meanings as above. ] Compound (A is (CH ₂ ) ₂ and B is (CH ₂ ) ₂
Compound [A] where A is -CH=CH-, B is (CH ₂ ) ₂ or A is (CH ₂ ) ₂ or -CH=CH-, B is -CH=CH-
Convert to compound [C]). The obtained compound [A], [B] or [
C] and [A], [B] or [C]
respectively, A is (CH ₂ ) ₂ or −CH=CH−,
B is (CH ₂ ) ₂ or -CH=CH- ester [] (the compound of the present invention where X is CO ₂ R ¹ and R ¹ is lower alkyl []) and acid [] (X is CO ₂ R ¹ ,
This is a compound of the present invention []) in which R ¹ is H. X is

[Formula] Z is

The compound of the present invention [] which is [Formula] is an acid [A], [B] or [
C] and P-nitrophenol, N,
The active P-nitrophenyl ester is prepared by reaction in the presence of a coupling agent such as N'-dicyclohexylcarbodiimide, which is then combined with the formula: [In the formula, M represents a metal (especially an alkali metal). Q has the same meaning as above. ] by reacting an alkali metal amide (for example, sodium acetamide (produced by reacting sodium hydride and acetamide) represented by the formula []:[] at a molar ratio of about 1 to 0.2:1) This product has the following formula: [In the formula, A, B, m, Q and Y have the same meanings as above. ]. X is

[Formula] The compound of the present invention [] in which Z is SO ₂ -Q can be produced by the method described below. The ester body [] and the silyl protected compound, preferably the formula: [In the formula, R ³ is lower alkyl or aryl,
Y' can be lower alkyl or aryl (preferably t-butyl) and Hal can be halogen (preferably chlorine or bromine). ] The compound represented by (for example, t-butyldimethylsilyl chloride) is mixed in a molar ratio of compound []:[B] of about 0.9 to 0.3:1, dimethylformamide,
Reaction in the presence of an inert solvent such as acetonitrile or dimethylacetamide and a weak organic base such as imidazole, triethylamine or 4-(N,N-dimethylamino)pyridine gives the formula: [In the formula, A, B, m, Y, R ³ and Y' have the same meanings as above. ] A protected silyl ester represented by the formula is obtained. By treating this ester [XII] with a base such as lithium hydroxide, and then neutralizing it with an acid such as oxalic acid or dilute hydrochloric acid, the ester [XII] is converted to the formula: [In the formula, A, B, m, Y, R ³ and Y' have the same meanings as above. ] Convert to the corresponding acid shown below. The protected acid [] and the sulfonyl isocyanate represented by the formula: O=C=N-SO ₂ Q [] (wherein, Q has the same meaning as above) are combined in a molar ratio of the compound []:[] about 1 to 0.2:1 in the presence of an inert organic solvent such as tetrahydrofuran and an organic base such as triethylamine to form the formula: [In the formula, A, B, m, Q, Y, Y' and R ³ have the same meanings as described above. ] A compound represented by is obtained. By treating the above compound [] with, for example, tetrabutylammonium fluoride,
By removing the silyl protecting group of the compound [], the formula: [In the formula, A, B, m, Q and Y have the same meanings as above. ] Compound (where X is

[Formula] The compound of the present invention []) in which Z is SO ₂ -Q can be obtained. X is

[Formula] The compound of the present invention [] in which Z is H can be produced by the following method.
The compound [A], [B] or [C],
i.e. the formula: [In the formula, A, B, m and Y have the same meanings as above. ] Acid and p-nitrophenol (PNP)
with a catalytic amount of base (e.g., 4-dimethylaminopyridine), in a molar ratio of acid:PNP of about 1 to 0.2:1;
The above acid [A], [B] or [C] is converted to the formula: [In the formula, A, B, m and Y have the same meanings as above. ] It is converted into the corresponding p-nitrophenol ester shown by Next, by reacting this p-nitrophenol ester () with ammonia, the formula: [In the formula, A, B, m and Y have the same meanings as above. ] Amide compound (X is

[Formula] Z is H The compound of the present invention []) can be obtained. X is

[Formula] The compound of the present invention [] in which Z is lower alkyl is obtained by reacting p-nitrophenyl ester [] with an alkylamine or an arylamine at a molar ratio of ester []:amine of about 1 to 0.1:1. Formula: [In the formula, Z' represents alkyl or aryl. A, B, m and Y have the same meanings as above. ] It can be obtained by manufacturing the compound shown in the following. In addition, the dialkoxyphosphonate [A]
is the formula: [In the formula, Y has the same meaning as above. ] Acetate ester and formula: The phosphonate represented by is mixed in the presence of n-butyllithium at a molar ratio of compound [C]:[D] of about 1 to
It can be obtained by reacting at a ratio of 0.2:1. X is

[Formula] The compound of the present invention [] in which Z is OH is prepared by combining the above ester [A], [B] or [C] with hydroxylamine in a solvent such as methanol in the presence of a strong base such as potassium hydroxide. Reacted in an inert solvent, for example neutralized with glacial acetic acid, the formula: [In the formula, A, B, m and Y have the same meanings as above. ] It can be obtained by manufacturing the compound shown below. The compound of the present invention [] in which X is OH is the ester body [A], [B] or [C],
For example, it is subjected to a reduction reaction with lithium aluminum hydride in the presence of an inert solvent such as tetrahydrofuran, and the formula: [In the formula, m and Y have the same meanings as above. ] It can be obtained by producing the corresponding compound shown below. X is tetrazolyl

The compound of the present invention [], which is [Formula], can be produced by the method shown below.
can be done. formula: (Disclosed in U.S. Pat. No. 4,143,054)
Manufactured using the same method. ) and the formula: (C ₆ H _Five ) ₃ P(CH ₂ ) _n ′CN _Four ・HBr [F] [In the formula, m' represents 1 to 8. ] Wittzig reagent shown in
oxide or sodium hydride-dimethylsulfonate
In the presence of oxide, the molar ratio of compound [E]:[F] is approx.
React at a ratio of 1 to 0.2:1, formula: [In the formula, m' has the same meaning as above. ] A compound represented by
The formula for the oxidation reaction is: [In the formula, m' has the same meaning as above. ] A compound represented by is obtained. The above aldehyde [] is converted into the above compound
Regarding the manufacturing method of [] or [A],
Similarly, dialkoxyphosphonate [A]
React with the formula: [In the formula, m' and Y have the same meanings as above. ] A compound in which X is tetrazolyl []
and further reduce it as above to obtain the formula: [In the formula, m and Y have the same meanings as above. ] A compound in which X is tetrazolyl []
can be obtained. In addition, the above-mentioned Witschig reagent [F] is a journal.
of Medicinal Chemistry (J.Med.
Chem.) Volume 22, 1341 (1979), page 1343
It can be prepared according to the method and following reaction scheme.
can. B is -C≡C-, A is (CH ₂ ) ₂ or −CH=
The compound of the present invention [] which is CH- is as shown below.
It can be manufactured by the method. formula: [In the formula, A is (CH ₂ ) ₂ or -CH=CH-
Was. m and R ¹ has the same meaning as above. ] Aldehyde and formula: [In the formula, X' is halogen (preferably chlorine or
represents bromine. Y has the same meaning as above. ] (U.S. Pat. No. 4,169,145)
manufactured as disclosed in . ), the compound
With a molar ratio of [A]:[G] of about 1 to 0.2:1, tetra
Potassium t-butoxide or
of sodium hydride in dimethyl sulfoxide
The resulting phosphonate product
α-haloenone (this is a mixture of E and Z isomers)
It is a compound. ) in tetrahydrofuran, potassium
Treatment with a base such as t-butoxide
From the formula: [In the formula, A is -(CH ₂ ) ₂ - or -CH=CH-
represents. m, R ¹ and Y has the same meaning as above. ] The compound represented by (the present invention in which B is -C≡C-)
Compound []) can be obtained. The above ynone compound [] is further added with borohydride
Thorium - by reduction with cerous chloride
Compound [A] can be obtained. similar operation
Created by Example 23 and U.S. Pat. No. 4,169,145
and Il.Farmaco-Ed.Sc.O Vol.31-fasc.10pp.763
~766 (1975) with C. Gandolfi
α−Halo−α,β− by the co-researcher
unsaturated Ketones: a synthetic
approach to 13−dehydroprostaglan−dins
It is described in a paper titled Other compounds where B is -C≡C- are compounds
[XI], [], [], [], [], [

], [XI], [] and [] production
can be manufactured according to the above operations for
Ru. Compounds included in the compounds of the present invention [], such as
Wachi style: [In the formula, A is CH=CH, X is CO ₂ R ¹ And it is
good. B and Y have the same meanings as above. ] The compound represented by should be manufactured by the following method.
I can do it. formula: The unsaturated di-acid compound represented by (U.S. Patent No.
No. 4143054. ) out
used as an emitter and disclosed in U.S. Pat. No. 4,143,054.
Process the expression as shown: [In the formula, m and R ¹ has the same meaning as above. ] A compound represented by is obtained. Then this compound [
] using the compound [B] and [
Process according to the method explained in the production of [C]
The compound of the present invention [] can be obtained by
Ru. X is CO ₂ R ¹ Other unsaturated compounds that are groups other than
[] is the above compound where A is -CH=CH-,
[XI], [], [], [], [], [

], [XI], [] and []
Manufactured according to the method described in the case of manufacture
be able to. The compounds of the present invention have the formulas [], [], and []
There are 5 irregular centers as indicated by the star (*) inside.
has. There is no asterisk in each of the above formulas.
but all stereoisomers of these compounds exist
It is clear that the various stereoisomers
All are within the scope of this invention. The various stereoisomers of the compounds of the invention, i.e.
Exo, cis-end and all trans types
and stereoisomer pairs were prepared as shown in the Examples below.
developed and disclosed in U.S. Pat. No. 4,143,054.
It can be manufactured using emitting substances and following its operations.
can. Examples of such stereoisomers are shown below. The wavy line (〓) in the above formula represents formula [a],
[b], [c] and [d] hydroxy group
is either R(β) or S(α)
show. For convenience, the core of each compound herein is This nucleus is shown as What should be understood can be expressed as
It is. The compound of the present invention can be used as a platelet aggregation inhibitor.
Blood clots such as coronary thrombosis and cerebral thrombus formation
is a useful cardiovascular agent for treating diseases. Ma
The compounds of the present invention may be used to treat myocardial diseases such as angina pectoris.
Selection with vasodilatory effect for the treatment of ischemia
thromboxane A ₂ It is a synthetase inhibitor.
The active compound of the invention may be about 1 to 100 mg/Kg,
Preferably about 1 to 50 mg/Kg, especially about 2 to 25 mg/Kg
Take an effective dose of once a day or divided into 2 to 4 times a day.
Various people known to be more susceptible to the above-mentioned diseases
Can be administered orally or parenterally to mammals.
I can do it. The active compounds of the invention include this compound [] or
is a mixture of two or more of them in a unit dosage form.
Tablets and capsules containing approximately 5 to 500 mg per mold
used in compositions such as agents, solutions or suspensions;
can be used. The active compound makes this physiological
Pharmaceutically acceptable medium or carrier, excipient, binder
Mixtures, preservatives, stabilizers, flavoring agents, etc.
combination in a conventional manner consistent with pharmaceutical practice.
They can be formulated together. Such pharmacology
In addition to the commercial uses, the compounds of the present invention []
Certain types of compounds can be combined with other types of compounds as mentioned above.
It is useful as an intermediate for the production of products. Next, examples will be given of preferred compounds of the present invention.
The manufacturing method will be specifically explained. Example 1 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo[2.2.1]
Production of hept-2-yl]-5-heptenoic acid: A [1β,2β(5Z),3α,4β]-7-[3-formi
Ru-7-oxabicyclo[2.2.1]hept-2
-yl]-5-heptenoic acid methyl ester production
Preparation: - Add a solution of 8.7 ml of pyridine in 200 ml of dichloromethane.
Add 5.38g of chromium trioxide to this while stirring vigorously.
Add in small amounts at a time. After the addition is complete, pour the mixture into
Stir at room temperature for 20 minutes, add 8g of Celite, then dilute
In 10ml of chloromethane [1β, 2β (5Z), 3β, 4β] -
7-[3-(hydroxymethyl)-7-oxabi
cyclo[2.2.1]hept-2-yl]-5-hept
Thenic acid methyl ester (U.S. Pat. No. 4,143,054)
manufactured as disclosed in . ) 2.58g (9.6mm)
(remol). Stir the mixture for 20 minutes at room temperature.
Stir and pass through Celite. 5% liquid
With sodium bicarbonate (100ml x 2), 10% salt
With acid (100ml x 2) and 5% sodium bicarbonate.
Wash with water (100ml x 2). This zicro
Dry the lomethane solution with magnesium sulfate and reduce
Concentrate under pressure. The residue is silica-CC-7
(200 ml) was subjected to upper chromatography, (1)
Lolomethane, (2) eluting with diethyl ether
Obtain 2g of Rudehyde. NMR (C-13 and protein)
roton), the product is an isomer (90% cis-
and 10% trans-aldehyde).
It was shown that it was a compound (long time under reduced pressure at room temperature).
Decomposes when dried for a long time. ). on silica gel,
TLC with benzene/ethyl acetate (4:1)
The Rf value of is 0.5 (visualized by vanillin and heating). B 1β, 2β (5Z), 3α, (1E), 4β]-7-[3-
3
-oxo-3-cyclohexyl-1-propenylate
)-7-oxabicyclo[2.2.1]hept-2
-yl]-5-heptenoic acid methyl ester production
Preparation: - 50% sodium hydride under argon atmosphere
0.180g (3.75mmol, 1.44eq) and anhydrous dimeth
In a slurry of 60 ml of xyethane (DME),
Oxo-2-cyclohexylethyldimethylphos
0.870 g (3.75 mmol, 1.44 equivalents) of sulfonate
Add a mixture of 10 ml of dimethoxyethane at 0°C.
Ru. The mixture was stirred at 25 °C for 1.5 h, and this solution
(25℃) [1β, 2β (5Z), 3α, 4β)] -7 - [3
-Formyl-7-oxabicyclo [2.2.1]
Methylbut-2-yl]-5-heptenoate
0.700g (2.6
mmol) and 10 ml of dimethoxyethane.
Add. After 1 hour, add 0.5ml of glacial acetic acid and react.
Stop, concentrate and dissolve in 200 ml of ether.
Wash with 150 ml of 5% potassium hydrogen carbonate, and rinse with anhydrous sulfur.
Dry with magnesium acid and concentrate. LP the residue
-1 Flat chromatography on silica gel
with ether/hexane (3:7)
Elution and purification yielded 0.515 g of compound B (yield
52%). C1 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cyclohexyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester, and C2 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(3-cyclohexyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1] Hept-2-yl]-5-heptenoic acid
Production of methyl ester: - Under argon atmosphere, 0.515 g of the compound of item B above.
(1.38 mmol) in a 15 ml solution of dry methanol,
Cerium chloride heptahydrate 0.513g (1.38 mmol,
1 equivalent) at 25°C. Stir the mixture for 10 minutes.
Stir, cool to 0°C and add sodium borohydride.
Add 0.0532 g (1.38 mmol, 4 equivalents). 0
After stirring at ℃ for 20 minutes, add 1 ml of acetone and react.
was stopped, concentrated under high vacuum, and extracted with ethyl acetate.
Dilute with 100ml and wash with 100ml of saline. Vinegar the water layer
Re-extract with 100 ml of ethyl acid. Combine the organic layers
Dry with anhydrous magnesium sulfate and concentrate. residue
onto an LP-1 silica gel column, and then
romatographed, ethyl acetate-hexane
The standard
0.210g of the compound in section C1 and the compound in section C2
Obtain 0.191g. D [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β−7−[
3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo[2.2.1]
Preparation of heptenoic acid: - 30 ml of 80% tetrahydrofuran-water solution (0
(cooled to ℃) the alcohol ester of section C1 above.
Dissolve 0.200g (0.53mmol) of 1N hydroxide
Add 5.3 ml of lithium solution dropwise. Mixture at 0℃
Stir with water, slowly warm to 25℃, and stir for 18 hours.
Stir. Evaporate THF under high vacuum and remove residual
Dilute the substance with 10ml of water and adjust the pH with 10% oxalic acid aqueous solution.
3, add ether (60 ml x 3 times) and food.
Extract with brine (50 ml). The product is treated with anhydrous sulfuric acid.
Dry with magnesium and concentrate to obtain an oil. This oil was distilled on CC-7 silica gel.
Purified by gradient elution with pentane/ether,
Pass through a polycarbonate membrane. altitude loss
Evaporate the solvent under pressure for 10 days to obtain 0.165 g of the title compound.
(86%). On silica gel, ethyl acetate/
Rf value of TLC with hexane (4:1) is 0.58
Quite a bit. Elemental analysis, calculated values: C, 72.89%; H, 9.45%, actual values: C, 72.68%; H, 9.15%. Example 2 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
Production of hept-2-yl]-5-heptenoic acid:
- 80% tetrahydrofuran (THF)-water solution
In 30 ml (0°C), C2 (alcohol of Example 1)
1M lithium hydroxide solution was added to 0.166g of the ester compound.
Slowly add 4.4ml of liquid. Stir the mixture at 0°C.
Stir and warm to 25°C while stirring for a further 18 hours.
Ru. Evaporate the THF and dilute the residue with 10 ml of water.
Adjust the pH to 3 with 10% oxalic acid aqueous solution and add
Extract with gel (60 ml x 3 times) and saline (50 ml).
put out Dry the product with anhydrous magnesium sulfate.
Dry and concentrate to obtain an oil. CC-7 for oily substances
On silica gel column, pentane-ether gradient
Chromatography with eluent
Passed through a carbonate membrane and then under reduced pressure
Remove the solvent and obtain 0.043g of the title compound as an oil.
(27%). On silica gel, ethyl acetate/
Rf value of TLC with hexane (4:1) 0.38. Elemental analysis, calculated values: C, 72.89%; H, 9.45%, actual values: C, 72.33%; H, 9.36%. Mole equivalent of the title compound (slowly migrating isomer)
Calculated values corrected for 0.16 moles of water; C, 72.33%; H, 9.47%. Example 3 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(4-cyclopencyl-3-hydroxy-1
-butenyl)-7-oxabicyclo[2.2.1]
Production of pt-2-yl]-5-heptenoic acid: - A [1β, 2β (5Z), 3α (1E), 4β]-7-[3-
(3-oxo-4-cyclopentyl-1-bute
Nyl)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid methyl ester
Production: - 50% sodium hydride in mineral oil under argon atmosphere
0.240 g (4.76 mmol, 1.1 equivalents) and dimeth
In a slurry of 60 ml of xyethane (DME),
Oxo-3-cyclopentylpropyldimethyl
1.26 g (5.41 mmol, 1.2 eq.) of phosphonate
A mixture of 10 ml of DME is added at 0°C. blend
Stir for 1 hour at 25°C under argon atmosphere.
[1β, 2β (5Z), 3α, 4β] −
7-[3-formyl-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester (as described in Example 1, Section A)
Manufactured by ) 1.2g (4.53 mmol) and
Add a mixture of 10 ml of DME. After 1 hour, ice vinegar
Stop the reaction by adding 1 ml of acid, concentrate, and
Dissolve in 300ml of gel. 5% ether solution on charcoal
Potassium oxyhydrogen (100ml x 3 times) and saline solution
(100ml). The organic layer is treated with anhydrous magnesium sulfate.
1.76 g of the crude product labeled A was obtained by drying with a
obtain. This crude oil can be used in the next reaction without refining.
used directly in the reaction process. B [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(4-cyclopentyl-3-hydroxy-
1-Butenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Stell, and C [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(4-cyclopentyl-3-hydroxy-
1-Butenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Preparation of stell:- Crude product of item A above under argon atmosphere.
A solution of 1.76 g of dry methanol in 30 ml contains 35% water.
Cerium chloride 1.73g (4.53 mmol, 1 equivalent)
Add at 25°C. Stir the mixture for 10 minutes at 25°C
Then, cool to 0℃ and add sodium borohydride.
Slowly add 0.175g (4.53 mmol, 4 equivalents)
I can do it. After stirring for 10 min at 0 °C, the reaction mixture was saturated.
Pour into 200 ml of ammonium chloride. Mixture
Extract with ether (100ml x 3 times) and ether extraction
Wash items with water (100ml x 3 times) and saline solution (100ml).
cormorant. The organic layer was dried with anhydrous magnesium sulfate and concentrated.
Shrink. The residue was purified by ethyl acetate/hexyl acetate on Waters HPLC.
Purified and separated by elution with San (1:3) and labeled
0.276g of the compound of section B and 0.225g of the compound of section C
get. On silica gel, hexane/ethyl acetate (1:
Rf value of TLC according to 1): Compound B = 0.50 equivalent,
Compound C=0.45 equivalent. D 1β, 2β (5Z), 3α, (1E, 3S ^* ), 4β〕−7−
[3-(4-cyclopentyl-3-hydroxy 1
-butenyl)-7-oxabicyclo[2.2.1]
Production of pt-2-yl]-5-heptenoic acid: - 0.161 g of alcohol ester of item B above
(0.42 mmol) in 80% tetrahydrofuran
Dissolve in 20ml of water solution, cool to 0℃ and add 1N water.
Add 4.2 ml of lithium oxide solution dropwise. mixture
Stir at 0°C and then continue stirring for 18 hours.
Gently heat to 25℃. under high altitude decompression
Evaporate the THF and dilute the residue with 10 ml of water.
Adjust the pH to 3 with 10% oxalic acid aqueous solution and dilute with ether.
(50ml x 3 times). The organic layer was dissolved in water (50 ml).
x 3 times) and saline (50 ml). product
was dried with anhydrous magnesium sulfate and concentrated to an oily state.
get something This oil was applied to a CC-7 silica gel column.
Gradient elution with distilled pentane/ether
Pass through a recarbonate membrane. altitude decompression
Evaporate the solvent for 10 days under [1β, 2β (5Z), 3α
(1E, 3S ^* ),4β]-7-[3-(3-cyclopene
thyl-3-hydroxy-1-butenyl-7-o
xabicyclo[2.2.1]hept-2-yl]-5
-0.151 g (99.3%) of heptenoic acid was obtained. silica
on the gel with ethyl acetate/hexane (4:1).
Equivalent to TLC Rf value 0.48. Elemental analysis Calculated values: C, 72.89%; H, 9.45%; Actual values: C, 72.59%; H, 9.26%. Example 4 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β]−7−[
3
-(4-cyclopentyl-3-hydroxy-1-
butenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid production: - Alcohol ester of item C (in Example 3)
Made as described. ) 0.100g (0.27mm)
) in 10 ml of 80% tetrahydrofuran-water solution.
Dissolve and cool to 0°C in 1N lithium hydroxide solution.
Add 2.7ml dropwise. The mixture was stirred at 0 °C and then
Slowly heat to 25°C while stirring for 18 hours.
Warm up. Evaporate THF under high vacuum and remove residual
Dilute the substance with 10ml of water and adjust the pH to 3 with 10% oxalic acid aqueous solution.
and extract with ether (50 ml x 3 times).
The organic layer was mixed with water (50 ml x 3 times) and saline solution (50 ml).
wash with Dry and concentrate with anhydrous magnesium sulfate,
Obtain an oily substance. This oil was evaporated onto a CC-7 silica gel column.
Gradient elution with diluted pentane/ether
purified by passing through a carbonate membrane.
Ru. Evaporate the solvent under high vacuum for 10 days and mark
0.090g (92.0%) of the compound was obtained. On silica gel, ethyl acetate/hexane (4:
1) corresponds to the TLC Rf value of 0.38. Elemental analysis Calculated values: C, 72.89%; H, 9.45%; Actual values: C, 72.73%; H, 9.70%. Example 5 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(4-cyclopentyl-3-hydroxy-1
-butenyl)-7-oxabicyclo[2.2.1]
Methylbut-2-yl]-5-heptenoate
Preparation of the compound:- The title compound was prepared as described in Section B of Example 3 above.
Synthesize. This product was evaporated onto a CC-7 silica gel column.
Gradient elution with diluted pentane/ether
Purify through carbonate membrane. 12 under altitude decompression
The product was obtained by evaporating the solvent for several days. On silica gel, ethyl acetate/hexane (1:
Equivalent to TLC Rf value 0.50 according to 1). Elemental analysis (containing 0.16 mol of water) Calculated values: C, 72.79%; H, 9.64%; Actual values: C, 72.79%; H, 9.58%. Example 6 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(4-cyclopentyl-3-hydroxy-1
-butenyl)-7-oxabicyclo[2.2.1]
Methylbut-2-yl]-5-heptenoate
Preparation of the compound:- The title compound was prepared as described in Section C of Example 3 above.
Synthesize. The product was distilled on a CC-7 silica gel column.
Gradient elution with pentane/ether
Purify by passing through a nate membrane. 12 days under high altitude decompression
Evaporation of the solvent gave the product. On silica gel, ethyl acetate/hexane (1:
Equivalent to TLC Rf value 0.45 according to 1). Elemental analysis (contains 0.21 mol of water) Calculated values: C, 72.61%; H, 9.64%; Actual values: C, 72.61%; H, 9.62%. Example 7 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-hydroxy-4-phenyl-1-butene
Nyl)-7-oxabicyclo[2.2.1]hept-
Production of 2-yl]-5-heptenoic acid: - A [1β, 2β (5Z), 3α (1E), 4β]-7-[3-
(3-oxo-4-phenyl-1-butenyl)-
7-Oxabicyclo[2.2.1]hept-2-i
Production of [ru]-5-heptenoic acid methyl ester:
- freshly distilled diisopropylamine
Mixture of 0.4116g and 80ml dry toluene (-78℃)
, a hexane solution of n-butyllithium
Add 2.3 ml (3.71 mmol) of (1.6M). mixture
Stir the mixture for 5 minutes and add 2
-oxo-3-phenylpropyldimethylphos
Added 0.9525 g (3.91 mmol, 1.1 eq.) of honate.
I can do it. Heat the mixture to 25°C while stirring.
Ru. In this mixture [1β, 2β (5Z), 3α, 4β]-7
-[3-formyl-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester (prepared according to Section A of Example 1)
It will be done. ) Add 0.938g (3.55 mmol). 2.5
After an hour, the reaction was stopped with 0.5 ml of glacial acetic acid and
Dilute with 300ml of tel. 5% ether solution on charcoal
Sodium oxyhydrogen solution (100ml x 3 times) and
Wash with saline (100ml). The organic layer was washed with anhydrous sulfuric acid.
Dry with magnesium and concentrate to obtain 1.22g of crude oil.
obtain. This oil can be processed for the next reaction without purification.
Use in moderation. B [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-1-phenyl-1-but
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester,
and C [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenyl-1-but
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester
Preparation of:- In an argon atmosphere, the crude product of item A above.
A solution of 1.22 g of dry methanol in 30 ml contains 35% water.
Cerium chloride 1.18g (2.64 mmol, 1 equivalent)
Add at 25℃. Stir the mixture for 10 minutes at 25°C
Then, cool to 0℃ and add sodium borohydride.
Slowly add 0.119g (2.64 mmol, 4 equivalents)
I can do it. After stirring for 10 min at 0 °C, the reaction mixture was saturated.
Pour into 200 ml of ammonium chloride. Mixture
Extract with gel (100ml x 3 times). Ether drawing
Pour the extract into water (100ml x 3 times) and saline solution (100ml
ml). The organic layer was treated with anhydrous magnesium sulfate.
Dry and concentrate. 30% ethyl acetate in hexane on Waters HPLC
Separate and purify by elution with B
0.299g of the compound in section C and 0.272g of the compound in section C
obtain. On silica gel, ethyl acetate/hexane (1:
Rf value of TLC according to 1), compound of B term: 0.44
Equivalent, Compound of Section C: Equivalent to 0.35. D [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenyl-1-but
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid production: - 0.299 g of alcohol ester of item B above
(0.78 mmol) in 80% tetrahydrofuran
Dissolve in 50 ml of water solution, cool at 0℃ and add 1N water.
Add 7.8 ml of lithium oxide solution dropwise. mixture
Stir at 0°C, then heat to 25°C for 15 hours.
Warm up slowly. Evaporate THF under high vacuum
dilute the residue with 10 ml of water and add 10% oxalic acid.
Adjust the pH to 3 with an aqueous solution and add ether (100ml x
3 times) Extract. Water the organic layer (100ml x 3 times)
and wash with saline (100 ml). Anhydrous product
Dry with magnesium sulfate and concentrate to obtain an oil.
Ru. This oil was distilled onto a CC-7 column.
Gradient elution with polycarbonate/ether
Purify by passing through a membrane.
[1β,
2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3-(3-
Hydroxy-4-phenyl-1-butenyl)-
7-Oxabicyclo[2.2.1]hept-2-i
0.131 g of L]-5-heptenoic acid was obtained. Elemental analysis Calculated values: C, 74.55%; H, 8.16%; Actual values: C, 74.42%; H, 8.21%. Example 8 Alcohol ester of item C (Example 7)
Product) 0.272g in 80% tetrahydrofuran-water
Dissolve in 40ml of solution, cool to 0℃ and add 1N sodium hydroxide.
Add 7.1 ml of thorium solution dropwise. Mixture at 0℃
Stir and then slowly warm to 25°C over 15 hours.
Warm up. Evaporate THF under high vacuum and remove residual
Dilute the substance in 10ml of water and adjust the pH to 3 with 10% oxalic acid aqueous solution.
and extract with ether (100 ml x 3 times).
The organic layer was dissolved in water (100 ml x 3 times) and saline solution (100 ml).
ml). Dry the product with anhydrous magnesium sulfate.
Dry and concentrate to obtain an oil. This oil was evaporated onto a CC-7 silica gel column.
Gradient elution with diluted pentane/ether
purified by passing through a carbonate membrane.
Ru. [1β,
2β (5Z), 3α (1E, 3R ^* ), 4β-7-[3-(3-hi)
Droxy-4-phenyl-1-butenyl)-7-
Oxabicyclo[2.2.1]hept-2-yl]-5
- Obtained 0.176 g of heptenoic acid. Elemental analysis (containing 0.17 mol of water) Calculated values: C, 73.93%; H, 8.19%; Actual values: C, 73.93%; H, 7.94%. Example 9 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cyclopentyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
Production of hept-2-yl]-5-heptenoic acid:
- A 1β, 2β (5Z), 3α (1E), 4β]-7-[3-(
3
-oxo-cyclopentyl-1-propenyl)
-7-Oxabicyclo[2.2.1]hept-2-
Preparation of [yl]-5-heptenoic acid:- Freshly distilled diisopropylamine
0.3756g (3.71mmol, 1.1eq) and dry toluene
n- in hexane to a mixture of 80 ml (-78°C) of n-
Butyllithium (1.6M) solution 2.3ml (3.71ml)
moles, 1.1 equivalents). Stir the mixture for 5 minutes.
Stir and add 2-oxo-2-siloxane to the mixture (-78°C).
Clopentylethyldimethylphosphonate
Add 0.8917g (4.05 mmol, 1.2 equivalents).
Warm the mixture to 25°C with stirring and
[1β, 2β (5Z), 3β, 4α]-7 to the compound (25℃)
-[3-formyl-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester (product of Example 1) 0.900g
(3.41 mmol) is added. After 2.5 hours, glacial acetic acid
Stop the reaction by adding 0.5 ml and 300 ml of ether.
Dilute with Add this ether solution to 5% hydrogen carbonate.
Sodium solution (100ml x 3) and saline solution
(100ml). The organic layer is treated with anhydrous magnesium sulfate.
Dry and concentrate to obtain 1.26 g of crude oil. child
Use the oil in the next reaction step without purification.
do. B [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-3-cyclopentyl-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester, and C [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(3-hydroxyl-3-cyclopentyl
-1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of methyl ester: - Under argon atmosphere, crude product of item A above.
A solution of 1.25 g of dry methanol in 30 ml contains 35% water.
Cerium chloride 1.29g (3.41 mmol, 1 equivalent)
Add at 25°C. Stir the mixture for 10 minutes at 25°C
Then, cool to 0℃ and add sodium borohydride.
Slowly add 0.130g (3.41 mmol, 4 equivalents)
I can do it. After stirring for 10 min at 0 °C, the reaction mixture was saturated.
Pour into 200 ml of ammonium chloride. Mixture
Extract with gel (100ml x 3 times). Ether drawing
Pour the extract into water (100ml x 3 times) and saline solution (100ml
ml) and the organic layer was washed with anhydrous magnesium sulfate.
Dry and concentrate. 30% ethyl acetate in hexane on Waters HPLC
Separate and purify the compound of title B by elution with
0.426 g and 0.297 g of the title C compound were obtained. On silica gel, ethyl acetate/hexane (1:
Rf value of TLC according to 1): Compound 0.55 phase of B term
This corresponds to 0.42 of the compound in Section C. D [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cyclopentyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production: - 0.426 g of alcohol ester of item B above
(1.18 mmol) in 80% tetrahydrofuran
Dissolve in 50ml of water solution, cool to 0℃ and add 1N water.
11.8 ml of lithium oxide solution are added dropwise. mixture
Stir at 0°C and then leave to cool for 15 hours.
Warm to 25℃. Evaporate THF under high vacuum
dilute the residue with 10 ml of water and add 10% oxalic acid.
Adjust the pH to 3 with an aqueous solution and add ether (100ml x
3 times) Extract. Water the organic layer (100ml x 3 times)
and wash with saline (100 ml). Anhydrous product
Dry with magnesium sulfate and concentrate to obtain an oil.
Ru. This oil was distilled onto a CC-7 column.
Gradient elution with polycarbonate/ether
Purify by passing through a membrane.
The solvent was evaporated for 11 days under high vacuum, and [1β, 2β
(5Z), 3α (1E, 3S ^* ), 4β]-7-[3-(3-shi
Clopentyl-3-hydroxy-1-propenylate
[ru]-7-oxabicyclo[2.2.1]hept-2
0.252 g of -yl]-5-heptenoic acid was obtained. Elemental analysis Calculated values: C, 72.39%; H, 9.25%; Actual values: C, 72.49%; H, 9.29%. Example 10 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(3-cyclopentyl-3-hydroxy-1
-propenyl]-7-oxabicyclo[2.2.1]
Production of hept-2-yl]-5-heptenoic acid:
- The alcoholic acid produced in Example 9, Section C above.
0.297g (0.82 mmol) of stellate form in 80% tetrahydrogen
Dorofuran-Dissolve in 40 ml of water solution and cool to 0℃.
Then add 8.2 ml of 1N lithium hydroxide solution dropwise. Mixed
The mixture was stirred at 0°C and then incubated for 15 hours.
Warm the chestnuts to 25℃. Evaporate THF under high vacuum
dilute the residue with 10 ml of water and add 10% oxalic acid solution.
Adjust the pH to 3 with a solution and add ether (100ml x 3 times)
Extract. The organic layer was washed with water (100ml x 3 times) and food.
Wash with salt water (100ml). The product is treated with anhydrous sulfuric acid magne
Dry with Si and concentrate to obtain an oil. This oil was distilled onto a CC-7 column.
Gradient elution with polycarbonate/ether
Purify by passing through a membrane. altitude loss
Evaporation of the solvent under pressure for 11 days yielded 0.304 g of the title compound.
I got it. Elemental analysis Calculated values: C, 72.39%; H, 9.25%; Actual values: C, 72.31%; H, 9.45%. Example 11 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-N-ace
Chil-7-[3-(3-cyclohexyl-3-hypolymer)
Droxy-1-propenyl)-7-oxabisi
Chlo[2.2.1]hept-2-yl]-5-hepte
Production of amide: − [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]−7−[
3
-(3-cyclohexyl-3-hydroxy-1-
propenyl)-7-oxabicyclo[2.2.1]hep
t-2-yl]-5-heptenoic acid (raw from Example 1)
product) 0.1826g (0.50mmol) and 3ml of anhydrous THF
Add p-nitrophenol (PNP) to the mixture
0.0765g (0.55mmol, 1.1eq), 4-dimethyl
Approximately 0.005 g of aminopyridine and N,N'-dicyclo
Hexylcarbodiimide (DCC) 0.1133g (0.55mm)
1.1 eq.). Under an argon atmosphere,
The mixture was stirred at 25°C for 2 hours, and an additional 0.0350 g of PNP was added.
(0.25 mmol, 0.5 equiv.) and DCC 0.0520 g (0.25 mmol, 0.5 equiv.)
limole, 0.5 eq.) and stirred the mixture for 1 hour.
A p-nitrophenol ester solution is obtained.
0.060 g (1.25 mmol) of 50% sodium hydride in mineral oil
(washed three times with dry pentane) and acetate
Mido 0.0923g (1.25mmol, 2.5eq) anhydrous
Place 3ml of THF solution under argon atmosphere in advance.
After stirring at 25°C for 3 hours, the above p-nitrogen solution was added to the solution.
Add the trophenol ester solution with a syringe.
Ru. The clear colored mixture was stirred for 1 hour until it was saturated.
In a solution of 50 ml of ammonium chloride and 5 ml of 2N hydrochloric acid.
Add slowly and extract with ethyl acetate (50ml x 2)
Then, wash with 20 ml of water and 20 ml of saline solution, and rinse with anhydrous sulfuric acid.
Dry with magnesium. This ethyl acetate solution
After cooling to 0℃ for 18 hours, PNP crystallized from the solution.
Separately, the solution was evaporated to obtain approximately 0.200 g of crude oil.
Ru. On LP-1 silica gel, hexane/ethyl acetate
Flash chromatography using 1:1 ratio
and then Whatman1mmPKGF silica gel
On a plate (20 x 20 cm), hexane:ethyl acetate
Preparative thin layer chromatography with eluent
When subjected to
(5Z), 3α (1E, 3S ^* ), 4β]-N-acetyl-7-
[3-(3-cyclohexyl-3-hydroxyl-
1-propenyl)-7-oxabicyclo [2.2.1]
Hept-2-yl]-5-heptenamide 0.039g
(19%). Elemental analysis, C _{twenty four} H ₃₇ NO. _Four Calculated values: C, 71.43%; H, 9.24%; N, 3.47%; Actual values: C, 71.30%; H, 9.31%; N, 3.63%. Example 12 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-N-(phenylsulfony
) Production of -5-heptenamide: - A [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-Cyclohexyl-3-t-butyldimethy
Lucilyloxy-1-propenyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5-
Production of heptenoic acid methyl ester: - [1β, 2β (5Z),
3α (1E, 3S ^* ), 4β]-7-[3-cyclohexyl
-3-hydroxy-1-propenyl)-7-o
xabicyclo[2.2.1]hept-2-yl]-5
-heptenoic acid methyl ester (as described in Example 1)
It is made like this. ) 0.5408g (1.44 mmol)
and 5 ml of anhydrous DMF, add dimethyl-tert-
Butylsilyl chloride 0.4335g (2.9 mmol,
2 equivalents) and imidazole 0.3923g (5.76 mmol)
4 eq.) and stir for 2 hours. solvent
Evaporate and dilute the remaining oil with 150 ml of ether.
and 25 ml of saturated ammonium chloride and saturated hydrogen carbonate.
Wash with 25 ml of sodium and anhydrous magnesium sulfate.
Dry and evaporate to obtain 0.760 g of the compound of section A.
obtain. B [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-Cyclohexyl-3-t-butyldimethy
Lucilyloxy-1-propenyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5-
Production of heptenoic acid: - 0.760 g (1.4 mmol) of the ester form of the above A item
and 1N lithium hydroxide in water to 80 ml of 80% THF aqueous solution.
Add 20 ml of aluminum and incubate at 25 °C under argon atmosphere for 30 min.
Stir for an hour. Adjust the mixture to PH3 equivalent with oxalic acid.
Adjust, dilute with 500 ml of water and dilute with ether (250 ml
×3 times) Extract. Add 100ml of water to the ether layer.
Wash with 100ml of saline solution, and add anhydrous magnesium sulfate.
Dry and evaporate to obtain an oil. C [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-Cyclohexyl-3-t-butyldimethy
Lucilyloxy-1-propenyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-N-
(Phenylsulfonyl)-5-heptenamide
Manufacture: - 0.161 g of the above B acid under argon atmosphere
(0.34 mmol) and 3 ml of anhydrous THF (25
0.0687 g (0.68 mmol) of triethylamine
(2.0 eq.) and benzene sulfonate isocyanate.
Add 0.1245 g (0.68 mmol, 2.0 eq.
The mixture was stirred for 1 hour and diluted with 50 ml of ethyl acetate.
10 ml of saturated ammonium chloride, 10 ml of water and
Wash sequentially with 10 ml of saline solution and anhydrous magnesium sulfate.
Dry in a vacuum to obtain 0.260 g of oil. this product
on LP-1 silica gel, 1% in methylene chloride
Flash chromatography with methanol eluent
Purified with Roughy and labeled as a grayish white solid under Item C.
Obtain 0.2128 g (99%) of the compound. D [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cyclohexyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-N-(phenylus
Preparation of sulfonyl)-5-heptenamide:- 0.2128 g (0.35 mmol) of the above compound C
Tetrabutylammonium in a mixture of 3ml THF
Add 1.1 g (3.5 mmol, 10 equivalents) of fluoride.
Then, incubate this solution at 45°C for 66 hours under an argon atmosphere.
Reflux for a while. Cool the reaction mixture and dilute with ether 50
dilute with ml and wash with 10 ml of saturated ammonium chloride.
Then, extract the aqueous layer with 20 ml of ether. ether
Combine the solutions and wash with 10 ml of water and 10 ml of saline.
Dry with anhydrous magnesium sulfate. This crude production
onto LP-1 silica gel, hexane:acetic acid ethyl
Chromatography with chill (1:1) eluent
[1β, 2β
(5Z), 3α (1E, 3S ^* ), 4β]-7-[3-(3-shi
Chlorhexyl-3-hydroxy-1-propenylate
)-7-oxabicyclo[2.2.1]hept-2
-yl]-N-(phenylsulfonyl)-5-h
0.095 g (yield 54%) of putenamide was obtained. Elemental analysis Calculated values: C, 67.11%; H, 8.10%; N, 2.65%; Actual values: C, 67.03%; H, 7.83%; N, 2.79%. Example 13 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-N-(methylsulfonyl)
- Production of 5-heptenamide: - A [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cyclohexyl-3-t-butyldi
Methylsilyloxy-1-propenyl)-7-
Oxabicyclo[2.2.1]hept-2-yl]-
N-(methylsulfonyl)-5-heptenamide
Production of: − [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
(3-cyclohexyl-3-t-butyldimethy
Lucilyloxy-1-propenyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5-
Heptenoic acid (product of Example 18, Section B) 0.176g
(0.38 mmol) and 3 ml of anhydrous THF,
Triethylamine 0.187g (1.85 mmol, 5 equivalents)
amount) and methylsulfonyl isocyanate 0.224g
(1.85 mmol, 5 eq.) is added. mixture
Stir at 25°C for 1 hour under an argon atmosphere, then add acetic acid.
Saturated ammonium chloride 10 diluted with 50 ml of ethyl
ml, washed sequentially with 10 ml of water and 10 ml of saline, and
Dry with magnesium hydrosulfate. crude product
On LP-1 silica gel, ethyl acetate:hexane
(1/2) Flats due to solution (as eluent)
Purified by cyclochromatography to form a clear oil.
0.125g of the compound of title A (yield 61%)
get. B [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cyclohexyl-3-hydroxy-
1-propynyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-N-(methylsulf
Production of (honyl)-5-heptenamide: - 0.125 g of the compound of item A above under argon atmosphere
(0.23 mmol) in a mixture (25 °C) of tetra
Butylammonium fluoride 0.7256g (2.3ml)
10 equivalents). Mixture at 45°C for 15
Reflux for an hour, cool and dilute with 50 ml of ether.
Wash with 10 ml of saturated ammonium chloride. aqueous layer
Extract with 20 ml of ether, combine the ether solution and add 10 ml of water.
ml and washed with 10 ml of saline, anhydrous sulfuric acid magnesi
Dry with um. Transfer the crude product to LP-1 silicage
Hexane:ethyl acetate (2:3) solution
Flash chromatography (as eluent)
Refined with roughy as clear colorless oil
[1β, 2α (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
−
(3-cyclohexyl-3-hydroxy-1-
propenyl)-7-oxabicyclo[2.2.1]
[but-2-yl]-N-(methylsulfonyl)-
Obtained 0.0321 g of 5-heptenamide (yield 32%)
Ta. Elemental analysis Calculated values: C, 62.84%; H, 8.48%; N, 3.19%; Actual values: C, 62.72%; H, 8.47%; N, 3.22%. Example 14 [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
Production of hept-2-yl]-5-heptenoic acid:
- A [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cyclohexyl-3-hydroxy-
1-propynyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of: − Sodium hydride (0.280 g, 5.9 mmol
(50% in oil)) and 100 ml of anhydrous dimethoxyethane
Add slurry to dimethyl-2-oxo-2-cyclo
Hexylethylphosphonate 1.37g (5.9 mmol)
Treat with 10 ml of DME solution (0°C). Mixed
The mixture was stirred at room temperature for 2 hours, then 1β, 2α
(5Z), 3α, 4β]-7-[3-formyl-7-o
xabicyclo[2.2.1]hept-2-yl]-5
- 1.1 g (4.1 mol) of heptenoic acid methyl ester
Treat with 10ml DME solution. Mixture at room temperature 1.5
Stir for an hour and add 0.354 g (5.9 mmol) of glacial acetic acid.
to stop the reaction and concentrate under reduced pressure. residual
Dissolve the substance in ether and add 5% potassium bicarbonate
(100ml x 1 time). The ether layer is
Dry over magnesium and concentrate under reduced pressure. residue
on LP-1 silica gel, hexane/ether
(7:3) for chromatography.
Purification yields 1.1 g of oil. 1.1g of this crude oil and cerium chloride heptahydrate
A solution of 1.1 g (2.9 mmol) in 30 ml of methanol on ice
Cool in a bath and add 0.112g of sodium borohydride.
(2.9 mmol) was added in small amounts over 30 seconds.
Understand. Stir the mixture at room temperature for 10 minutes and add saturated salt.
Pour into 200ml of ammonium chloride solution and add ethyl acetate.
(100ml x 5 times). Combine the extracts
Dry with magnesium sulfate and concentrate. residue
Hexane/ethyl acetate on LP-1 silica gel
Column chromatography eluting with (4:1)
- to obtain 0.33g of the compound of title A.
Ru. On silica gel, hexane/ethyl acetate
Rf value of TLC of compound of term A according to (1:1)
0.5. B [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cyclohexyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production: - Alcohol ester obtained in the above section A
0.33g (0.9 mmol) of tetrahydrofuran/
Dissolve in 65ml/15ml of water, cool to 0°C, and
Add dropwise a solution of lithium chloride (9 mmol) in 9 ml of water.
Process. The mixture was heated to 0°C for 1 hour and then to room temperature.
Stir for 7 hours and leave in the refrigerator until the weekend. Mixed
Adjust the mixture to PH3 with 10% oxalic acid and add 500ml of water.
and extract with ether (200ml x 3 times).
Combine the ether extracts, wash with saline, and add sulfuric acid.
Dry over magnesium and concentrate under reduced pressure. residue
on LP-1 silica gel, 2% methanol/di
Flash chromatography eluting with chloromethane
Purified by roughy to obtain 0.200g of the title compound.
Ta. This was further distilled on CC-7 silica gel.
300ml pentane, pentane/ether (distilled)
(1:1) equivalent to 200ml and ether (distilled)
Purified by elution with 300ml Millipore
Pass through a filter. TLC Rf with ethyl acetate on silica gel
Equivalent to value 0.33 (PMA spray and heating). Example 15 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
Production of hept-2-yl]-5-heptenol
Structure: - 1β, 2β (5Z), 3α, 4β] -7-[3-(3-sik
B
hexyl-3-hydroxyl-1-propenyl)
-7-oxabicyclo[2.2.1]hept-2-i
]-5-heptenoic acid methyl ester (Example 1
It is made as described in . ) 0.400g (1.1 mm)
) and 10 ml of anhydrous tetrahydrofuran (THF)
Aluminum hydride in THF to the mixture (0°C)
Slowly add 0.6 ml of lithium 1M solution. blend
was stirred at 0°C for 30 minutes and then dissolved in a 3% water-THF solution.
Stop the slow reaction. Dried celite 0.500g
was added, the mixture was stirred for 1 hour, and 100 ml of ether was added.
The mixture was diluted with water and filtered to obtain 0.325 g of the title compound. Example 16 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-hydroxy-3-cyclohexyl-1
-propenyl)-7-oxabicyclo [2.2.1]
Production of hept-2-yl]-5-heptenamide
Preparation: - 0.4565 g of the acid product prepared in Example 1 above.
(1.3 mmol) and 10 ml of anhydrous THF.
-Nitrophenol 0.1913g (1.4 mmol), 4,
Approximately 0.010 g of 4-dimethylaminopyridine and N,
N′-dicyclohexylcarbodiimide 0.2833g
(1.4 mmol). Place the mixture under argon atmosphere
Stir for 2 hours at 25°C under air, and add anhydrous anhydride to the solution.
Let the Monia slowly foam for 1 hour. solvent
was evaporated and the crude oil was purified on silica gel with dichloromethane.
Column chromatography with 5% methanol in methane eluent
Matographic purification yielded 0.3332 g of the title compound. Example 17 [1β, 2β (5Z), 3α (1E, 2S ^* ), 4β]-N-pro
Pyr-7-[3-(3-hydroxy-3-cyclo
hexyl-1-propenyl)-7-oxabisi
Chlo[2.2.1]hept-2-yl]-5-hepte
- Preparation of p-nitrophenol amide as described in Example 16 above.
Propylamine 0.590g
(10 mmol) is added and the mixture is stirred for 3 hours.
The solvent was removed under reduced pressure, and the resulting crude oil was poured onto silica.
On gel, hexane/ethyl acetate (1:2) solution
Purified by column chromatography using (eluent)
0.2195 g of the title compound was obtained. Example 18 [1β, 2β (5Z), 3α (1E, 2S ^* ), 4β]-N-hue
Nyl-7-[3-(3-hydroxy-3-cyclo
hexyl-1-propenyl)-7-oxabisi
Chlo[2.2.1]hept-2-yl]-5-hepte
Production of amine amide:- Using aniline instead of propylamine,
Work-up as described in Example 17 gave the title compound. Example 19 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cycloheptyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
Production of hept-2-yl]-5-heptenoic acid:
- A [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-oxo-3-cycloheptyl-3-
Hydroxy-1-propenyl)-7-oxabi
cyclo[2.2.1]hept-2-yl]-5-hep
Preparation of thenic acid: - 50% sodium hydride in mineral oil under argon atmosphere.
0.1994 g (4.15 mmol, 1.1 eq.) of
In a slurry of 100ml of methoxyethane (DME),
2-oxo-2-cycloheptylpropyldime
Chillphosphonate 1.108g (1.49 mmol, 1.2 equivalents)
A mixture of 20 ml of DME and 20 ml of DME is added at 0°C.
The mixture was stirred at 25°C for 1 hour under argon atmosphere.
do. This solution (25°C) was added as described in Example 1.
Made from sea urchin [1β, 2β (5Z), 3α, 4β]-7-
[3-formyl-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
1.013 g (3.77 mmol) of Stell and 20 ml of DME.
Add mixture. After 30 minutes, add 1 ml of glacial acetic acid.
Stop the reaction, concentrate and dissolve in 500ml of ether.
Understand. Ether solution with 5% potassium bicarbonate
(100ml x 3 times) and saline (100ml),
Dry with anhydrous magnesium sulfate and concentrate. residue
on an LP-1 silica gel column with ether/helical
Flash chroma eluting with xane (3:7)
The compound of the title A is purified by tography.
Obtain 0.898 g (61.7% yield). B [1β, 2β (5Z), 3α (1E, 2S ^* ), 4β〕−7−
[3-(3-cycloheptyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester, and C [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(3-cycloheptyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of methyl ester: - Under argon atmosphere, compound 0.898 of section A below.
g (2.32 mmol) in 20 ml of dry methanol
Cerium chloride (containing 35% water) 0.889 at 25℃
g (2.32 mmol, 1 eq.). blend
Stir at 25℃ for 10 minutes, cool to 0℃ and hydrogenate.
Sodium boron 0.0897g (2.32 mmol, 4
(equivalent amount) slowly. Stir for 10 minutes at 0℃
Afterwards, the reaction mixture is saturated with ammonium chloride (150 ml).
Pour into. Mixture with ether (100ml x 3 times)
Extract. Add ether extract to water (100ml x 3 times)
and wash with saline (100 ml). Anhydrous organic layer
Dry with magnesium sulfate and concentrate. The residue was purified on Waters HPLC with ethyl acetate/hexane.
Purification by elution with San (1:3)
0.270g of the compound and 0.243g of the compound of title C (yield)
rate of 56.9%). On silica gel, ethyl acetate/hexane (1:
Rf value of TLC according to 1): Compound 0.61 phase of B term
This corresponds to 0.51 of the compound in Section C. D [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-cycloheptyl-3-hydroxy-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production: - 0.163 g of alcohol ester of item B above
(0.42 mmol) in 80% tetrahydrofuran
Dissolve in 15ml of water solution, cool to 0℃ and add 1N water.
Add 4.3 ml of lithium oxide. Mixture at 0℃
Stir and heat to 25°C with stirring for 15 hours.
Boil and warm. Evaporating THF under high vacuum
evaporate, dilute the residue with 10 ml of water and add 10% oxalic acid.
Adjust the pH to 3 with an aqueous solution, and use ether (30 ml x 3
times) extract. Add this organic layer to water (30ml x 3 times)
and brine (30 ml), and the product was washed with anhydrous sulfuric acid.
Dry with magnesium acid and concentrate to obtain an oil.
Ru. Pen distilled oil on CC-silica gel
Gradient elution with polycarbonate/ether
Purify by passing through a membrane. Melted under high vacuum for 4 days
Evaporate the solvent to obtain 0.153g (97.3%) of the title compound.
I got it. On silica gel, ethyl acetate/hexane
(3:1) equivalent to TLC Rf value of 0.44. Elemental analysis (contains 0.18 mol of water) Calculated values: C, 72.74%; H, 9.64%; Actual values: C, 72.74%; H, 9.62%. Example 20 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(3-cycloheptyl)3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
Preparation of hept-2-yl]-5-heptenoic acid:
0.153g (0.39 mmol) of alcohol ester
Dissolved in 15 ml of 80% tetrahydrofuran-water solution
Cool to 0°C and add 3.9ml of 1N lithium hydroxide.
Add. The mixture was stirred at 0 °C and then for 18 h.
Slowly heat to 25℃ while stirring.
Evaporate the THF under high vacuum and dissolve the residue in 10 ml of water.
diluted with water, adjusted to pH 3 with 10% oxalic acid aqueous solution,
Extract with ether (100 ml x 3). organic layer
Wash with water (30ml x 3 times) and saline solution (30ml),
The product was dried over anhydrous magnesium sulfate and concentrated.
Obtain an oily substance. This oil was distilled over CC-7 silica gel.
Gradient elution with pentane/ether, polycarbonate
Purify by passing through a membrane. high
The title compound was obtained by evaporating the solvent under reduced pressure for 4 days.
0.145g (98.3%) was obtained. on silica gel with ethyl acetate (3:1)
Equivalent to TLC Rf value 0.34. Elemental analysis (containing 0.17 mol of water) Calculated values: C, 72.78%; H, 9.64%; Actual values: C, 72.78%; H, 9.76%. Example 21 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(4-cyclohexyl-3-hydroxy-1
-butenyl)-7-oxabicyclo[2.2.1]
Production of pt-2-yl]-5-heptenoic acid: - A [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-oxo-4-cyclohexyl-1-
butenyl)-7-oxabicyclo[2.2.1]hep
Preparation of t-2-yl]-5-heptenoic acid:- Freshly distilled diisopropylamine 0.4027
g (3.98 mmol, 1.05 eq.) and dry toluene
30 ml of the mixture (-78°C) was added with n-butane in hexane.
2.49 ml (3.98 mmol) of chilllithium (1.6M) solution
1.05 equivalents). Stir the mixture for 5 minutes
and added 2-oxo-2-cyclo to the mixture (-78°C).
lohexylpropyldimethylphosphonate
Add 1.034 g (4.17 mmol, 1.1 equivalents).
Warm the mixture to 25°C with stirring and
[1β, 2β (5Z), 3α, 4β]-7 to the compound (25℃)
-[3-formyl-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester (as described in Example 1)
Manufactured. ) Add 1.0g (3.79 mmol)
Ru. After 4.5 hours, add 0.5 ml of glacial acetic acid to stop the reaction.
Stop and dilute with 300 ml of ether. This a
The solution was diluted with 5% sodium bicarbonate solution (100
ml x 3 times) and saline (100 ml). Yes
The organic layer was dried with anhydrous magnesium sulfate and concentrated.
1.38 g of crude oil is obtained. refine this oil
Use it in the next reaction step without removing it. B [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(4-cyclohexyl-3-hydroxy-
1-Butenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Stell, and C [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(4-cyclohexyl-3-hydroxy-
1-Butenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Preparation of stell:- Under argon atmosphere, 1.05 of the crude product of the above part A
g of salt containing 35% water in 25 ml of dry methanol.
1.04 g (2.71 mmol, 1 equivalent) of cerium chloride
Add at 25°C. Stir the mixture for 10 minutes at 25°C
Then, cool to 0℃ and add sodium borohydride.
Slowly prepare 0.105g (2.71 mmol, 4 equivalents)
Add. After stirring for 10 min at 0°C, the reaction mixture was saturated.
Pour into 150ml of Japanese ammonium chloride. Mixture
Extract with ether (100ml x 3 times). ether
The extract was mixed with water (100ml x 3 times) and saline solution (100ml
ml) and the organic layer was washed with anhydrous magnesium sulfate.
Dry and concentrate. 30% acetic acid in hexane on LP-1 silica gel
Separation and purification by elution with ethyl yielded the title B.
Obtained 0.233g of the compound and 0.111g of the compound with title C.
Ru. On silica gel, ethyl acetate/hexane (1:
Rf value of TLC according to 1): Compound 0.51 phase of B term
This is equivalent to 0.36 of the compound in Section C. D [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(4-cyclohexyl-3-hydroxy-
1-Butenyl)-7-oxabicyclo [2.2.1]
Production of hept-2-yl]-5-heptenoic acid
−: 0.233 g (0.6 mmol) of the product of item B above.
Dissolved in 25 ml of 80% tetrahydrofuran-water solution
Then cool to 0℃ and add 1N lithium hydroxide solution 6.0℃.
Add ml dropwise. The mixture was stirred at 0 °C and then
Slowly heat to 25℃ over 15 hours. high
Evaporate the THF under reduced pressure and remove the residue with 10 ml of water.
Dilute with water and adjust the pH to 3 with 10% oxalic acid aqueous solution.
Then extract with ether (50 ml x 3). organic
The layer was washed with water (50 ml x 3) and saline (50 ml).
wash. Dry the product with anhydrous magnesium sulfate,
Concentrate to obtain an oil. This oil was distilled onto a CC-7 column.
Gradient elution with polycarbonate/ether
Purify by passing through a membrane.
The solvent was evaporated for 7 days under high vacuum, and [1β, 2β
(5Z), 3α (1E, 3S ^* ), 4β]-7-[3-(4-shi
Chlorhexyl-3-hydroxy-1-buteny
)-7-oxabicyclo[2.2.1]hept-2
-yl]-5-heptenoic acid 0.2067g (91.5%)
I got it. Elemental analysis (contains 0.2 mol of water) Calculated values: C, 72.68%; H, 9.65%; Actual values: C, 72.68%; H, 9.72%. TLC Rf with ethyl acetate on silica gel
Equivalent to value 0.41. Example 22 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(4-cyclohexyl-3-hydroxy-1
-butenyl)-7-oxabicyclo[2.2.1]
Preparation of [but-2-yl]-5-heptenoic acid: - Alcohol ester produced in Section C of Example 21 above.
0.111g (0.28 mmol) of stellate body in 80% tetra
Dissolve in 15 ml of hydrofuran-water solution and cool to 0°C.
Add 2.8 ml of 1N lithium hydroxide dropwise. mixture
Stir the mixture at 0°C and then let it simmer for 15 hours.
Warm to 25℃. Evaporate THF under high vacuum
dilute the residue with 10 ml of water and dissolve in 10% oxalic acid.
Adjust the pH to 3 with liquid and extract with ether (30ml x 3 times).
put out The organic layer was mixed with water (30ml x 3 times) and saline solution.
(30ml). The product is anhydrous magnesium sulfate
Dry and concentrate to obtain an oil. This oil was evaporated onto a CC-7 silica gel column.
Gradient elution with distilled pentene/ether and polycarbonate
Purify through carbonate membrane. 7 under high altitude decompression
Evaporate the solvent for days [1β, 2β (5Z), 3α (1E,
3R ^* ), 4β]-7-[3-(4-cyclohexyl-3
-hydroxy-1-butenyl)-7-oxabisi
Chlo[2.2.1]hept-2-yl]-5-heptene
0.1028 g of acid was obtained. Elemental analysis Calculated values: C, 73.36%; H, 9.64%; Actual values: C, 73.03%; H, 9.61%. Rf value of TLC with ethyl acetate on silica gel
Equivalent to 0.32. Example 23 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-hydroxy-4-(3-thienyl)-1
-butenyl)-7-oxabicyclo[2.2.1]
Production of pt-2-yl]-5-heptenoic acid: - A [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-oxo-4-(3-thienyl)-1-
butenyl]-7-oxabicyclo[2.2.1]hep
Preparation of t-2-yl]-5-heptenoic acid:- Freshly distilled diisopropylamine 0.4027
g (3.98 mmol, 1.05 eq.) and dry toluene
30 ml of the mixture (-78°C) was added with n-butane in hexane.
2.47 ml (3.98 mmol) of chilllithium (1.6M) solution
1.05 equivalents). Stir the mixture for 5 minutes
and added 2-oxo-3-(3
-thienyl)propyldimethylphosphonate
Add 1.034 g (4.17 mmol, 1.1 equivalents).
Warm the mixture to 25°C with stirring and
[1β, 2β (5Z), 3β, 4β]-7 to the compound (25℃)
-[3-formyl-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester (as described in Example 1)
Manufactured. ) Add 1.0g (3.79 mmol)
Ru. After 3 hours, add 0.5 ml of glacial acetic acid to stop the reaction.
Stop and dilute with 300 ml of ether. This a
The solution was diluted with 5% sodium bicarbonate solution (100
ml x 3 times) and saline (100 ml). Yes
The organic layer was dried with anhydrous magnesium sulfate and concentrated.
1.05 g of crude oil is obtained. refine this oil
Use it in the next reaction step without removing it. B [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-4-(3-thienyl)-
1-Butenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Stell, and C [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-[3-hydroxy-4-(3-thienyl)-
1-Butenyl]-7-oxabicyclo[2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Preparation of stell:- Crude product of item A above under argon atmosphere.
A solution of 1.427 g of dry methanol in 30 ml of 35% water
Contains cerium chloride 1.416g (3.69 mmol, 1
equivalent amount) at 25°C. Mixture at 25℃ for 10 minutes
Stir for a while, cool to 0°C, and add sodium borohydride.
0.1427 g (3.69 mmol, 4 equivalents) of
Add. After stirring for 10 min at 0°C, the reaction mixture
Pour into 200 ml of saturated ammonium chloride. blend
Extract with ether (100ml x 3). A
Teru extract in water (100ml x 3 times) and saline solution
(100ml) and remove the organic layer with anhydrous magnesium sulfate.
Dry and concentrate in a vacuum. 35% ethyl acetate in hexane on Water HPLC
Separate and purify the compound of title B by elution with
0.201 g of the compound of title C was obtained. On silica gel, ethyl acetate/hexane (1:
Rf value of TLC according to 1): Compound 0.39 phase of B term
This corresponds to 0.29 of the compound in Section C. D [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-[3-hydroxy-4-(3-thienyl)-
1-Butenyl]-7-oxabicyclo[2.2.1]
Production of hept-2-yl]-5-heptenoic acid:
- 0.201g of alcohol ester of item B above
(0.52 mmol) in 80% tetrahydrofuran
Dissolve in 20ml of water solution, cool to 0℃ and add 1N water.
Add 5.2 ml of lithium oxide solution dropwise. mixture
Stir at 0°C and then leave to cool for 15 hours.
Warm to 25℃. Evaporate THF under high vacuum
dilute the residue with 10 ml of water and add 10% oxalic acid.
Adjust the pH to 3 with an aqueous solution and add ether (100ml x
3 times) Extract. Water the organic layer (100ml x 3 times)
and wash with saline (100 ml). Anhydrous product
Dry with magnesium sulfate and concentrate to obtain an oil.
Ru. This oil was distilled onto a CC-7 column.
Gradient elution with polycarbonate/ether
Purify by passing through a membrane.
The solvent was evaporated for 7 days under high vacuum, and [1β, 2β
(5Z), 3α (1E, 3S ^* ), 4β]-7-[3-[3-hi
Droxy-4-(3-thienyl)-1-buteny
[ru]-7-oxabicyclo[2.2.1]hept-2
-yl]-5-heptenoic acid 0.150g (76.6%)
Obtained. Elemental analysis Calculated values: C, 66.99%; H, 7.49%; Actual values: C, 66.76%; H, 7.67%. TLC Rf with ethyl acetate on silica gel
Equivalent to value 0.53. Example 24 [1β, 2β (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-[3-hydroxy-4-(3-thienyl)-1
-butenyl]-7-oxabicyclo[2.2.1]
Preparation of [but-2-yl]-5-heptenoic acid: - Alcohol ester produced in Section C of Example 23 above.
0.170g (0.44 mmol) of stellate body in 80% tetra
Dissolve in 20 ml of hydrofuran-water solution and cool to 0°C.
Add dropwise to 4.4 ml of 1N lithium hydroxide solution.
The mixture was stirred at 0°C and then boiled for 15 hours.
Warm up to 25℃. THF under high vacuum
Evaporate and dilute the residue with 10 ml of water to give 10%
Adjust the pH to 3 with an acid aqueous solution, and add ether (50ml x 3).
times) extract. The organic layer was mixed with water (30ml x 3 times) and
Wash with saline (30 ml). The product is treated with anhydrous sulfuric acid magne
Dry with Si and concentrate to obtain an oil. This oil was evaporated onto a CC-7 silica gel column.
Gradient elution with diluted pentane/ether
purified by passing through a carbonate membrane.
Ru. The solvent was evaporated under high vacuum for 7 days to obtain [1β,
2β (5Z), 3α (1E, 3R ^* ), 4β]-7-[3-[3-
Hi
Droxy-4-(3-thienyl)-1-butenyl]
-7-oxabicyclo[2.2.1]hept-2-i
0.106 g (63.9%) of L]-5-heptenoic acid was obtained. Elemental analysis Calculated values: C, 66.99%; H, 7.49%; Actual values: C, 66.80%; H, 7.65%. Rf value of TLC with ethyl acetate on silica gel
Equivalent to 0.45. Example 25 [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-[3-hydroxy-4-(3-thienyl)-1
-butenyl)-7-oxabicyclo[2.2.1]
Methylbut-2-yl]-5-heptenoate
Production of tel:-A [1β, 2α(5Z), 3α, 4β]-7-[3-formi
Ru-7-oxabicyclo[2.2.1]hept-2
-yl]-5-heptenoic acid methyl ester production
Preparation: - using N-methylnitronitrosoguanidine
An ether solution of diazomethane is prepared by
Prepare (this guanidine compound in 50 ml of ether)
Add 9 ml of 40% potassium hydroxide dropwise to 3 g of the substance at 0°C.
do). This solution (with potassium hydroxide pellets)
dry), [1β, 2α (5Z), 3α, 4β]-7-[3-
(Hydroxymethyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester (as described in U.S. Pat. No. 4,143,054)
It is made like this. ) 2.54 g (10 mmol)
in 150 ml of ether for 10 minutes with stirring.
Cross over and add drops. Continue stirring for 30 minutes at 0°C.
At the end of the process, add 1.5 ml of acetic acid to remove excess diazo.
Decomposes methane. Add this solution to sodium bicarbonate.
sodium sulfate solution and saline solution.
and concentrated under reduced pressure to obtain 2.60 g of ester.
get. Chromium trioxide pyridine in anhydrous methylene chloride
Prepare a solution of chromium salt (5.9g of chromium trioxide)
(59 mmol), pyridine 9.5 ml (118 mmol)
and 200 ml of methylene chloride) at room temperature.
Stir for 25 minutes. Add this to dry celite (100℃
(dried overnight) 8 g, then 2.61 g of the above ester
g (9.8 mmol) in 5 ml of methylene chloride solution.
Add. Stir this mixture for 15 minutes under nitrogen atmosphere.
Stir for further processing. Celite - Trioxide
Remove the ROM mixture and dilute the liquid with saturated sodium bicarbonate.
solution (100ml x 2), water (200ml) and
and saline solution (100 ml). Sodium sulfate
After drying over nitrogen, the mixture was concentrated under reduced pressure to obtain the standard
2.34 g of the above aldehyde compound was obtained. B [1β, 2α (5Z), 3α (1E), 4β]-7-[3-
(3-oxo-4-(3-thienyl)-1-butene
Nyl)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid methyl ester
Production: - Sodium hydride 0.185 under argon atmosphere
g (3.85 mmol, 50% mineral oil dispersion) dried
Suspend in 70ml of DME. Do not stir vigorously at room temperature.
To this, 2-oxo-3- in 10 ml of dry DME
(3-thienyl)propyldimethylphosphonate
Add dropwise 1.303 g (5.25 mmol) of
A suspension is obtained. ). Dry after stirring for 90 minutes
0.932g of aldehyde of the above A in 5ml of DME
(3.5 mmol) and continued stirring for 3 hours.
Add acetic acid to stop the reaction and add 250ml of ether.
Pour a considerable amount and add saturated sodium bicarbonate and
Wash with water and salt and dry with magnesium sulfate.
Ru. Evaporate the solvent by filtration under reduced pressure to produce
Transfer 1.85 g of yellow-green oil to chroma gel onto silica gel.
Petroleum ether/ether
Elute with (4:1), (3:1) and (2:1)
Purify by chromatography. desired
As the transenone form of [1β, 2α (5Z), 3α
(1E),4β]-7-[3-(3-oxo-4-(3
-thienyl)-1-butenyl]-7-oxabisi
Chlo[2.2.1]hept-2-yl]-5-hepte
0.469 g (36%) of acid methyl ester is obtained. C [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-[3-hydroxy-4-(3-thienyl)-
1-Butenyl]-7-oxabicyclo[2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Stell, and D [1β, 2α (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(3-hydroxy-4-(3-thienyl)-
1-Butenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Manufacture of stell:- 0.475g (1.22ml) of the enone compound of item B above.
mol) in 12 ml of methanol and 1.2 ml of THF.
Then, cool to 0℃ and add cerous chloride/7.6 water.
Add 0.469 g (1.22 mmol) of
Sodium borohydride 0.0453g (1.22 mmol)
) is added little by little. 8 minutes, excluding ice bath
Continue stirring. Saturate the reaction mixture with ammonium chloride
The product was diluted with ethyl acetate (50 ml).
Extract (5 times) and dry with sodium sulfate.
After this, the solvent is evaporated and the resulting viscous
Transfer 0.550 g of the oily substance onto a silica gel column.
Applied to matoography, petroleum ether/ether
Purification by elution with 7:3 to 1:1
0.317g (66%) of isomer of term C and term D
0.115 g (24%) of the isomer was obtained. On silica gel, ether/petroleum ether
(3:2), Rf value of TLC with vanillin 0.22. Elemental analysis (compound of title C: C _{twenty two} H ₃₀ O _Four S and
Calculated values: C, 67.66%; H, 7.74%; S, 8.21%; Actual values: C, 67.28%; H, 7.76%; S, 8.01%. Example 26 [1β, 2α (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(3-hydroxy-4-(3-thienyl)-1
-butenyl]-7-oxabicyclo[2.2.1]
Production of pt-2-yl]-5-heptenoic acid: - Under argon atmosphere, [1β, 2α (5Z), 3α (1E,
3R ^* ), 4β]-7-[3-(3-hydroxy-4-
(3-thienyl)-1-butenyl]-7-oxabi
cyclo[2.2.1]hept-2-yl]-5-hepte
acid methyl ester (ester of Example 25, Section D)
body) 0.0937g (0.24 mmol), THF13ml and water
Dissolve in 2.4ml. The mixture was cooled to 0°C and this
At this point, add 2.4 ml of 1N lithium hydroxide. blend
Warm to room temperature and continue stirring for an additional 6.5 hours. mixture
Adjust the pH to 3 with saturated oxalic acid and pour into 80ml of water.
ingredient. Extract the product with ether (40-60ml x 3 times)
do. Combine the ether layers and add water (40ml x 3 times) and
Wash with salt water (25 ml) and dry with magnesium sulfate.
dry Evaporate the solvent under reduced pressure through filtration to give a colorless
0.0885 g (98%) of oily product was obtained. silica gel
Above, Rf values of TLC with ether and vanillin
0.25. Elemental analysis, C _{twenty one} H ₂₈ O _Four As S, calculated value: C, 66.99%; H, 7.50%; S, 8.52%; actual value: C, 66.64%; H, 7.31%; S, 8.52%. Example 27 [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-[3-hydroxy-4-(3-thienyl)-1
-butenyl]-7-oxabicyclo[2.2.1]
Production of pt-2-yl]-5-heptenoic acid: - Under argon atmosphere, [1β, 2α (5Z), 3α (1E,
3S ^* ), 4β]-7-[3-[3-hydroxy-4-
(3-thienyl)-1-butenyl]-7-oxabi
cyclo[2.2.1]hept-2-yl]-5-hepte
acid methyl ester (ester of Example 25, Section C)
body) 0.237g (0.608 mmol) in THF32ml and water 6
ml and cooled to 0°C. 1N lithium hydroxide
Add 6 ml and warm the mixture to room temperature. Stir for 6.5 hours
After stirring, the mixture is adjusted to pH 3 with saturated oxalic acid.
Pour this into 200 ml of water and dissolve the product in ether (100 ml).
~150ml x 3) Extract. Combine the ether layers
Wash with water (100ml x 3 times) and saline solution (50ml),
Dry with magnesium sulfate. After this, the
Evaporation of the solvent under pressure yielded 0.2126 g of colorless oil.
(92%). On silica gel, ether, vani
Rf value of TLC due to phosphorus is 0.32. Elemental analysis, C _{twenty one} H ₂₈ O _Four S・0.2H ₂ Calculated values for O: C, 66.36%; H, 7.53%; S, 8.43%; Actual values: C, 66.51%; H, 7.77%; S, 8.07%. Example 28 [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-[3-hydroxy-4-phenoxy-1-but
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid production:-A [1β, 2α(5Z), 3α(1E), 4β]-7-[3-
[3-oxo-4-phenoxy-1-butenyl]
-7-Oxabicyclo[2.2.1]hept-2-
Production of [yl]-5-heptenoic acid: - Under argon atmosphere, sodium hydride 0.264
g (5.5 mmol (50% in mineral oil)) of dry dimeth
Suspend in 50 ml of xyethane. 2-oxo-3-
Phenoxypropyl dimethylphosphonate 1.9
g (7.5 mmol) in 10 ml of DME is added.
The mixture will be almost clear and a precipitate will come out of solution.
It begins to generate. After 45 minutes, dist
Added HMPA (hexamethyl phosphate triamide)
and stir the mixture for an additional 45 minutes at room temperature. this
Aldehyde form: [1β, 2α (5Z), 3α, 4β]-7
-[3-formyl-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester 1.33g (5 mmol) DME4
ml solution and the mixture is stirred at room temperature overnight.
The reaction was stopped by adding 0.6 ml of glacial acetic acid, and the mixture was removed under reduced pressure.
Remove the solvent. Dissolve the residue in ether,
3 times with 1N hydrochloric acid and 2 times with saturated sodium bicarbonate.
Wash twice. Add this ether solution to magnesium sulfate.
and remove the solvent under reduced pressure to obtain 2.25 g of oil.
get. Spread this on 110g of silica gel 60,
Ether-petroleum ether
(2:3) to give the desired compound shown in section A.
0.906 g (46%) of the compound was obtained. B [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenoxy-1-
butenyl)-7-oxabicyclo[2.2.1]hep
t-2-yl]-5-heptenoic acid methyl ester
Le, and C [1β, 2α (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenoxy-1-
butenyl)-7-oxabicyclo[2.2.1]hep
t-2-yl]-5-heptenoic acid methyl ester
- 0.906 g of compound of section A under argon atmosphere
(2.27 mmol) and cerium chloride hydrate 0.872
g (2.27 mmol, 35.7%), methanol 22
ml and dissolve in 2 ml of THF. Place this solution on an ice bath.
Cool, sodium borohydride 0.086g
(2.27 mmol) in small portions over 30 seconds.
The ice bath was removed and the mixture was stirred for 8 minutes, then brought to saturation.
Pour into 200 ml of ammonium chloride solution. product
was extracted with ethyl acetate (50ml x 5 times) and dried.
A viscous oil that remains after removing the solvent under reduced pressure.
Obtain 0.9g. Place this on 50g of silica gel 60 and
romatographed, ether-petroleum ether
The isomer of term B was eluted with tel (3:2).
0.445g (49%) and 0.268g of the isomer of heading C
(29%). On silica gel, ether-stone
TLC with oil ether (2:1), vanillin
Rf values of 0.32 and 0.21. D [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenoxy-1-
butenyl)-7-oxabicyclo[2.2.1]hep
Production of t-2-yl]-5-heptenoic acid: - In a nitrogen atmosphere, the methyl ester of the above item B
0.438g (1.1 mmol) in THF55ml and water 10.5ml
dissolve in Cool this solution on an ice bath and add 1N
Add 11.0ml of lithium hydroxide. Except for the ice bath,
The mixture is stirred at room temperature for 6 hours. saturated oxalic acid
Add the solution, adjust the pH to 3, and pour the mixture into 400ml of water.
Pour into. Product with ether (200ml x 3 times)
The ether extracts were combined and saturated with water three times.
Wash once with sodium chloride solution and dry.
Remove the solvent under pressure and leave it as a viscous oil.
0.407 g (95%) of the compound of title D was obtained. S
TLC on licagel with ether and vanillin
Rf value of 0.29. Elemental analysis, C _{twenty three} H ₃₀ O _Five ・0.2H ₂ As O, calculated value: C, 70.81%; H, 7.86%, actual value: C, 70.86%; H, 7.85%. Example 29 [1β, 2α (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(3-hydroxy-4-phenoxy-1-butyl
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid production: - Under argon atmosphere, [1β, 2α (5Z), 3α (1E,
3R ^* ), 4β]-7-[3-(3-hydroxy-4-ph)
enoxy-1-butenyl)-7-oxabicyclo
[2.2.1] Hept-2-yl]-5-heptenoate
Tyl ester (methyl ester of Example 28, Section C)
body) 0.121g (0.3 mmol), THF15ml and water
Dissolve in 2.9ml. Cool this solution on an ice bath and
Add 3.0 ml of 1N lithium hydroxide. except for the ice bath
The mixture is stirred at room temperature for 6.5 hours. Oxalic acid saturation
Adjust the pH to 3 with a hydrating solution and pour the mixture into 125 ml of water.
The product was extracted with ether (50 ml x 3) and
Combine the extracts with water and dilute with saturated sodium chloride three times.
Wash once with silica solution and dry with magnesium sulfate.
Remove the solvent under reduced pressure and mark as a viscous oil.
0.109 g (93%) of the compound is obtained. On silica gel,
Rf value of TLC with ether and vanillin is 0.15. Elemental analysis, C _{twenty three} H ₃₀ O _Five ・0.2H ₂ As O, calculated value: C, 70.81%; H, 7.86%, actual value: C, 70.66%; H, 7.65%. Example 30 [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-hydroxy-4-phenyl-1-butene
Nyl)-7-oxabicyclo[2.2.1]hept-
Production of 2-yl]-5-heptenoic acid: - A [1β, 2α (5Z), 3α (1E), 4β]-7-[3-
(3-oxo-4-phenyl-1-butenyl)-
7-Oxabicyclo[2.2.1]hept-2-i
-Production of 5-heptenoic acid: - Under argon atmosphere, sodium hydride 0.238
g (4.95 mmol (50% in mineral oil)) of dry lime
Suspend in 90 ml of toxyethane. 2-oxo-3
-Phenylpropyldimethylphosphonate 1.63
g (6.75 mmol) in 10 ml of DME solution,
The mixture is stirred at room temperature for 90 minutes. To this [1β,
2α(5Z), 3α, 4β]-7-[3-formyl-7-
Oxabicyclo[2.2.1]hept-2-yl]-
5-heptenoic acid methyl ester (described in Example 25)
It is made as shown. ) 1.2g (4.5 mmol)
Add 5 ml of DME solution and keep the mixture at room temperature for 4.5 h.
Stir for a while. Stop the reaction by adding 0.5ml of glacial acetic acid.
and remove the solvent under reduced pressure. ether residue
and saturated sodium bicarbonate solution.
Ru. The ether layer is further saturated with sodium bicarbonate.
and dried over magnesium sulfate under reduced pressure.
Dry to obtain 2.25 g of oil. 120g of this
chromatographed on Ricagel 60.
Elute with ether-petroleum ether (2:3) and obtain the standard
Compound of item A (single spot substance) 0.980g
(60%). B [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenyl-1-but
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester,
and C [1β, 2α (5Z), 3α (1E, 3R ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenyl-1-but
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester
Production of: - under argon atmosphere, the compound of the above item A 0.980
g (2.6 mmol) and cerium chloride () hydrated
0.982 g (2.5 mmol) of water (35.7% water) was
Dissolve in 25ml of tanol and 2ml of THF. ice the solution
Cool in a bath and add 0.097g of sodium borohydride.
(2.6 mmol) in small portions over 30 seconds. ice
The bath was removed, the mixture was stirred for 8 minutes, and saturated aqueous chloride was added.
Pour into 200 ml of ammonium solution. The product was dissolved in acetic acid.
Extract with chill (50ml x 5 times), dry and under reduced pressure.
After removing the solvent, 0.930 g of a viscous oil was obtained.
Chromatograph this on 65g of silica gel 60.
- ether - petroleum ether (3:2)
Eluted with 0.446 methyl ester of the heading B
g (45%) and 0.156 g of the isomer of title C
(16%). On silica gel, ether-stone
TLC with oil ether (3:2), vanillin
Rf values 0.44 and 0.30. D [1β, 2α (5Z), 3α (1E, 3S ^* ), 4β〕−7−
[3-(3-hydroxy-4-phenyl-1-but
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid production: - Under argon atmosphere, the methyl ester of item B above
0.440g (1.14 mmol) of 100g of chloride in 58ml of THF and water.
Dissolve in 11ml. Cool the solution in an ice bath and stir.
While stirring, add 11.4 ml of 1N lithium hydroxide. ice
The bath is removed and the mixture is stirred at room temperature for 6 hours. Tired
Add oxalic acid solution to adjust the pH to 3, and add this mixture.
Pour the mixture into 400ml of water. product in ether
(200ml x 3 times) and combine the ether extracts.
and three times with water and once with saturated sodium chloride solution.
Wash with water, dry and remove the solvent under reduced pressure to remove the oil.
0.425 g (98%) of the title compound was obtained. S
TLC on licagel, ether, vanillin
Rf value of 0.18. Elemental analysis, C _{twenty three} H ₃₀ O _Four ・0.3H ₂ As O, calculated value: C, 73.49%; H, 8.21%, actual value: C, 73.66%; H, 8.52%. Example 31 [1β, 2α (5Z), 3α (1E, 3R ^* ), 4β]-7-[3
-(3-hydroxy-4-phenyl-1-butene
Nyl)-7-oxabicyclo[2.2.1]hept-
Production of 2-yl]-5-heptenoic acid: - Under argon atmosphere, [1β, 2α (5Z), 3α (1E,
3R ^* ), 4β]-7-[3-(3-hydroxy-4-ph)
enyl-1-butenyl)-7-oxabicyclo
[2.2.1] Hept-2-yl]-5-heptenoate
Tyl ester (methyl ester of Example 30, Section C)
body) 0.150g (0.39 mmol) in THF20ml and water 3.8
Dissolve in ml. Cool the solution in an ice bath and add 1N hydroxide
Add 3.9ml of lithium. Remove the ice bath and pour the mixture into
Stir at room temperature for 6 hours. PH3 with saturated oxalic acid solution
and pour the mixture into 150ml of water. Extract the product
Extract with ether (50ml x 3 times) and extract the ether extract.
Combine and wash three times with water and once with saturated sodium chloride.
Remove the solvent by drying with magnesium sulfate, and remove the
0.142 g (97%) of the compound described in Section B was obtained. silica
TLC on gel, with ether and vanillin
Rf value 0.12. Elemental analysis, C _{twenty three} H ₃₀ O _Four ・0.2MH ₂ As O, calculated value: C, 73.84%; H, 8.19%, actual value: C, 74.00%; H, 8.39%. Example 32 [1β, 2β (5Z), 3α (3S ^* ), 4β]-7-[3-(
3
-hydroxy-1-octynyl)-7-oxa
Bicyclo[2.2.1]hept-2-yl]-5-h
Production of putenoic acid:-A [1β, 2β(5Z), 3α(1EZ), 4β]-7-[3
−
(2-bromo-3-oxo-1-octenyl)-
7-Oxabicyclo[2.2.1]hept-2-i
] - Production of 5-heptenoic acid: - 0.144 g of 50% sodium hydride in mineral oil (3 ml)
Rimol) and anhydrous dimethoxyethane (DME) 40
ml of slurry, 1-bromo-2-oxohep
Tyldimethylphosphonate 0.9632g (3.2ml)
Add 5 ml of DME solution (mol). Mixture at 25℃
Stir for 90 minutes at [1β, 2β (5Z), 3α, 4β]-7
-[3-formyl-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Methyl ester (prepared as described in Example 1)
It will be done. )0.700g (2.6mmol) of DME in 5ml solution
is added and the mixture is stirred at 25°C for 3 hours. ice vinegar
Add 0.2 ml of acid to stop the reaction, and dissolve under reduced pressure.
Excluding media. The residue was diluted with ether and saturated with charcoal.
Wash with sodium hydroxide solution. Sulfurize the ether layer
Dry over magnesium chloride, filter and dry under reduced pressure.
Dry to obtain 1.2 g of oil. Add this to silica gel
Top, chromatographed with ethyl acetate,
Mixture of E and Z isomers eluted with hexane
0.9940 g of the compound of title A is obtained. B [1β, 2β (5Z), 3α (3S ^* R ^* , 1EZ), 4β]−7
-[3-(2-bromo-3-hydroxy-1-o
ctenyl)-7-oxabicyclo[2.2.1]hep
t-2-yl]-5-heptenoic acid methyl ester
- Production of ketone compound of term A in 20 ml of methanol 0.994
g (2.1 mmol) and cerium chloride heptahydrate
0.9795 g (2.5 mmol) of the mixture (0°C),
Sodium borohydride 0.094g (2.5mmol
). Stir the mixture for 10 minutes and add saturated salt
Pour into 200ml of ammonium chloride solution and add anhydrous sulfuric acid solution.
Dry with magnesium and meet the heading B as an oily substance.
Obtain 1.0 g of compound. C [1β, 2β (5Z), 3α (3S ^* ), 4β]-7-[3
−
(3-hydroxy-1-octynyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5-
Heptenoic acid methyl ester, and D [1β, 2β (5Z), 3α (3R ^* ), 4β]-7-[3
−
(3-hydroxy-1-octynyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5-
Production of heptenoic acid methyl ester: - 1.0 g (2.1 mmol) of the compound of item B above and
Add potassium to a mixture of 10 ml of water and tetrahydrofuran.
Add 0.480 g (4.3 mmol) of Mut-butoxy.
Ru. The mixture was stirred for 15 minutes and acidified with 0.1N hydrochloric acid.
extracted with ethyl acetate and saturated sodium bicarbonate.
Wash with aluminum and dry with anhydrous magnesium sulfate.
0.862 g of oil was obtained. This substance is silica
The top was subjected to chromatography and ether-hemolyzed.
Purification by elution with xane (1:1) yielded section C.
0.310g of the isomer of and 0.253g of the isomer of heading D
obtain. With ether-petroleum ether (1:1)
Rf values of 0.45 and 0.40 respectively. E [1β, 2β (5Z), 3α (3S ^* ), 4β]-7-[3
−
(3-hydroxy-1-octynyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5-
Production of heptenoic acid: - 0.310 g (0.79 mmol) of the ester form of the above C
Dissolve 40 ml of THF and 10 ml of water and cool to 0℃.
Add 6.9 ml of 1N lithium hydroxide solution.
The mixture was stirred at 25°C for 6 h and diluted with 10% oxalic acid.
Adjust the pH to 3, dilute with 300ml of water, and add ether.
Extract (200ml x 3 times). Water the ether layer
Wash with salt water and dry with anhydrous magnesium sulfate.
0.00282 g of the title compound was obtained. Example 33 [1β, 2β (5Z), 3α (3R ^* ), 4β]-7-[3-(
3
-hydroxy-1-octynyl)-7-oxa
Bicyclo[2.2.1]hept-2-yl]-5-h
Production of putenoic acid: - 0.253 g of the ester of Example 32, Section D
(0.64 mmol) was dissolved in 40 ml of THF and 10 ml of water,
Cool to 0°C and add 7 ml of 1N lithium hydroxide.
Stir the mixture for 6 hours and adjust the pH to 3 with oxalic acid.
diluted with 200ml of water and diluted with ether (200ml x 3
times) extract. Wash the ether layer with water and brine.
The title compound was obtained by drying with magnesium sulfate.
0.00226g was obtained. Examples 34 and 35 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-6-[3
-(3-hydroxy-3-cyclohexyl-1
-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-1-(1H-tetrazol-
5-yl)-4-hexene, and [1β,2β(5Z),3α(1E,3R ^* ), 4β〕−6−
[3-(3-hydroxy-3-cyclohexyl-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-1-(1H-tetra
Production of sol-5-yl)-4-hexene:-A [1β,2β(5Z),3β,4β]-6-[3-hydro
oxymethyl-7-oxabicyclo [2.2.1]
[but-2-yl]-1-(1H-tetrazol-5
-yl)-4-hexene production: -triphenyl-4-(1H-tetrazol-5-
yl)-butylphosphonium bromide 5.5g
(11.8 mmol) and tetrahydrofuran
(THF) to 100 ml of the mixture (0°C), add potassium
Add 1.39 g (11.8 mmol) of t-butoxide.
Ru. The mixture was stirred at 25°C for 30 min and added with 30 ml of THF.
Endo-octahydro-5,8-epoxy
-1H-benzopyran-3-ol (U.S. patent
Manufactured as described in No. 4143054. ) added
Ru. The mixture was stirred for 2 hours and diluted aqueous hydrochloric acid was added.
to stop the reaction. Ethyl acetate 250% aqueous layer
Combine the organic solutions and evaporate under reduced pressure.
dilute with 500ml of 5% sodium bicarbonate solution.
Wash with 100ml of ether and adjust the pH to 3 with dilute hydrochloric acid.
Separate and extract with ethyl acetate (500ml x 3 times).
This organic solution was combined with anhydrous magnesium sulfate.
Dry and chromatograph on silica.
Purified by elution with 5% methanol in methylene chloride.
0.756 g of the compound of title A is obtained. B [1β, 2β (5Z), 3β, 4β]-7-[3-formi
Ru-7-oxabicyclo[2.2.1]hept-2
-yl]-1-(1H-tetrazol-5-yl)-
Production of 4-hexene: - Under argon atmosphere, 0.756 of the compound of item A above.
g (2.5 mmol) and 15 ml of anhydrous methylene chloride
Pyridinium chloride chromate in the mixture (25°C)
Add 0.110 g (5.4 mmol) of salt. mixture
Stir for 3 hours, dilute with 100 ml of ether and filter
Pass through Rossil and evaporate to obtain the
0.672 g of compound is obtained. C [1β, 2β (5Z), 3α, 4β]-7-[3-formi
Ru-7-oxabicyclo[2.2.1]hept-2
-yl]-1-(1H-tetrazol-5-yl)-
Production of 4-hexane: - 0.690 g (2.3 mmol) of the alcohol of item B above
0.066 g (1.25 g) of sodium methoxide
mmol). Stir the mixture at 25°C for 2 hours.
Stir and dilute with 50 ml of saturated ammonium chloride.
Extract with ether (100ml x 4 times). ether
Wash the layer with saline and dry with magnesium sulfate.
0.685 g of the title C compound is obtained. D [1β, 2β (5Z), 3α (1E), 4β]-7-[3-
(3-oxo-3-cyclohexyl-1-pro
penyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-1-(1H-tetrazol-5-yl)
- Production of -4-hexene: - 0.190 g (3.9 mmol, ore) of sodium hydride
50% in oil) and anhydrous dimethoxyethane (DME)
Add 2-oxo-2-cyclohexyl to 60 ml of the mixture.
Sil ethyl dimethyl phosphonate 0.880g (3.9
mmol). Mixture at 25°C for 1.5 hours
Stir and add the compound of item C to this solution (25°C).
Add a mixture of 0.68 g of DME and 10 ml of DME. 1 o'clock
After a while, add 0.5 ml of glacial acetic acid to stop the reaction.
Concentrate and dissolve in 500 ml of ether. ether
Wash the solution with 100 ml of water and 100 ml of saline solution, and wash it with a sulfuric acid mug.
Dry over nesium, over silica, in methylene chloride
Chromatography with 5% methanol eluent
- to obtain 0.823 g of the compound of title D. E [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β〕−6−
[3-(3-hydroxy-3-cyclohexyl-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-1-(1H-tetra
Sol-5-yl)-4-hexene, and F [1β,2β(5Z),3α(1E,3R ^* ), 4β〕−6−
[3-(3-hydroxy-3-cyclohexyl-
1-propenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-1-(1H-tetra
Preparation of sol-5-yl)-4-hexene: - under argon atmosphere, 0.823 of the compound of item D above
g (2.15 mmol) in 20 ml of dry methanol
0.890g (2.32ml) of cerium chloride heptahydrate
limol) at 25°C. Cool the mixture to 0℃
Coconut, sodium borohydride 0.0890g (2.32
mmol). Stir this for 10 minutes until it is saturated.
Dilute with 150ml of ammonium chloride and ether.
(100ml x 3 times), washed with water and diluted with anhydrous sulfuric acid.
Dry with magnesium. Waters residue
Dissolved in 2% methanol in methylene chloride on HPLC.
Separated and purified, 0.232 g of the compound of section E was obtained.
0.211 g of the compound described in Section F was obtained. Example 36 [1β, 2β (5Z), 3α (1E, 3S ^* ,4R ^* ,S ^* ), 4β]
-7-[3-(3-hydroxy-4-methyl-o
ct-1-en-6-ynyl)-7-oxabi
cyclo[2.2.1]hept-2-yl]-5-hep
Production of thenic acid: - A [1β, 2β (5Z), 3α (1E, 4R ^* S ^* ), 4β]−7
−
[3-(3-oxo-4-methyl-oct-1-
(en-6-ynyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of methyl ester: - Sodium hydride 0.3016 under argon atmosphere
g (50% in mineral oil) and anhydrous dimethoxyethane
(DME) 150ml slurry, 2-oxo-3
-Methylhept-5-indimethylphosphonate
(manufactured as described in U.S. Pat. No. 4,235,930)
It will be done. ) 1.32 g (5.7 mmol) and 15 ml of DME.
Add the mixture at 0°C. Mixture at 25℃ for 1.5 hours
Stir for a while and add [1β, 2β
(5Z), 3α, 4β]-7-[3-formyl-7-o
xabicyclo[2.2.1]hept-2-yl]-5
-Heptenoic acid methyl ester (formation of Example 1)
mixture of 1.05 g (3.9 mmol) and 15 ml of DME
add things After 1 hour, add 0.7ml of glacial acetic acid.
Stop the reaction, concentrate and dissolve in 500ml of ether.
Dissolve and add 5% sodium hydrogen carbonate (100ml x 3 times)
and wash with saline (100 ml). organic layer with sulfuric acid
Dry with magnesium and concentrate to obtain the crude product labeled Section A.
1.66 g of product is obtained. B [1β, 2β (5Z), 3α (1E, 3S ^* ,4R ^* S ^* ), 4β]
-7-[3-(3-hydroxy-4-methyl-o
ct-1-en-6-ynyl)-7-oxabi
cyclo[2.2.1]hept-2-yl]-5-hep
thenic acid methyl ester, and C [1β, 2β (5Z), 3α (1E, 3R ^* ,4R ^* ,S ^* ),
4β]-7-[3-(3-hydroxy-4-methyl
-oct-1-en-6-ynyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5
Preparation of putenoic acid methyl ester:- Drying of the product of section A above under an argon atmosphere.
Cerium chloride heptahydrate in 30ml methanol solution
1.8 g (4.6 mmol) of the compound are added at 25°C. child
Cool the mixture to 0°C and add sodium borohydride.
Add 0.180 g (4.6 mmol) of um. blend
Stir at 0°C for 10 min and add saturated ammonium chloride.
Dilute with 200ml and extract with ether (100ml x 3 times).
put out Wash the ether layer with water and saline;
Dry with anhydrous magnesium sulfate. The residue was purified on Waters HPLC in ethyl acetate/hexane.
Purified by elution with xane (1:4), labeled section B.
0.232g of the compound and 0.216g of the compound of the title C
obtain. D [1β, 2β (5Z), 3α (1E, 3S ^* ,4R ^* ,S ^* ),
4β]-7-[3-(3-hydroxy-4-methyl
-oct-1-en-6-ynyl)-7-oxy
Sabicyclo[2.2.1]hept-2-yl]-5-
Production of heptenoic acid: - 0.232 g of alcohol ester of item B above
(0.6 mmol) in 80% tetrahydrofuran-water
To this solution (0℃), dissolve in 30ml of a solution of
Add 5.5 ml of 1N lithium hydroxide solution. blend
diluted with 10ml of water and adjusted to pH3 with oxalic acid,
Extract with ether (100ml x 3) and with saline.
Wash. Dry the product with anhydrous magnesium sulfate.
After drying, 0.172 g of the title compound was obtained. Example 37 [1β, 2β (5Z), 3α (1E, 3R ^* ,4R ^* S ^* ), 4β〕−
7-[3-(3-hydroxy-4-methyl-oc
T-1-en-6-ynyl)-7-oxabisi
Chlo[2.2.1]hept-2-yl]-5-hepte
Production of acid: - Example 36, Section C instead of the compound in Section B
Using the compound, process in the same manner as in Section D and mark
I got a compound. Example 38 [1β, 2β (5Z), 3α (1E, 3S ^* ,4R ^* S ^* ,5Z),
4β]-7-[3-(3-hydroxy-4-methyl
-octadiene)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of: - 2-oxo-3- in the treatment of Example 36 above
Methyl-hept-5-indimethylphosphonate
cis-2-oxo-3-methyl-hep instead of
T-5-ene dimethylphosphonate [this compound
is 2-oxo-3-methyl-hept-5-indi
By catalytic reduction of methylphosphonate
obtained (Journal of American Chemical
Society Vol. 78, p. 2518 (1956)). ] using
The title compound was obtained by the same treatment. Example 39 [1β, 2β (5Z), 3α (1E, 3R ^* ,4R ^* S ^* ,5Z),
4β]-7-[3-(3-hydroxy-4-methyl
-1,5-octadiene)-7-oxabisic
B[2.2.1]Hept-2-yl]-5-heptene
Preparation of acid: - 2-oxo-3- in the treatment of Example 37 above
Methyl-hept-5-indimethylphosphonate
cis-2-oxo-3-methyl-hep instead of
Similarly, using t-5-enedimethylphosphonate
The title compound was obtained. Example 40 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-N-hydroxy-5-h
Production of putenamide: - 0.200 g (0.53 ml) of the compound of Example 1, Section C1
Limol) and 20 ml of 95% ethanol.
Roxiamine hydrochloride 0.3657g (5.3 mmol)
and 0.4346 g (5.3 mmol) of sodium acetate.
I can do it. The mixture was refluxed under argon atmosphere for 18 hours.
Cool to 25℃, dilute with 200ml of ether, and add water.
Wash with 20 ml and 20 ml of saline solution, and rinse with anhydrous sulfate magnesia.
This was dried on silica gel and chromatographed.
Roughy and eluted with 5% methanol to obtain the title
0.1056 g of compound was obtained. Example 41 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-[3-(3-pyridyl)-3-hydroxy-1
-propenyl]-7-oxabicyclo[2.2.1]
Production of hept-2-yl]-5-heptenoic acid:
- 2-oxo-2-cyclo in Example 1 above
instead of hexylethyldimethylphosphonate
2-oxo-2-(3-pyridyl)ethyldimethy
phosphonate (prepared as described above).
The title compound was obtained by the same treatment. Example 42 [1β, 2β (5Z), 3α (1E, 3S ^* ), 4β]-7-[3
-[4-3-pyridyl)-3-hydroxy-1-
butenyl]-7-oxabicyclo[2.2.1]hep
Preparation of t-2-yl]-5-heptenoic acid: - 2-oxo-2-cyclo in Example 1 above
2-O instead of hexyldimethylphosphonate
xo-3-(3-pyridyl)propyldimethylpho
The title compound was obtained by the same treatment using sulfonate.
Obtained. Examples 43 and 44 [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β]-7-
[3-(3-hydroxy-4-phenyl-1-pe
(tenyl)-7-oxabicyclo[2.2.1]hep
[t-2-yl]-5-heptenoic acid (quickly moving)
isomer A), and [1β, 2α (5Z), 3α (1E, 3α, 4β), 4β]-7
-[3-(3-hydroxy-4-phenyl-1-
pentenyl)-7-oxabicyclo[2.2.1]
[but-2-yl]-5-heptenoic acid (fast moving
Preparation of isomer B): - A Preparation of methyl 2-phenylpropionate: - 2-phenylpropionate in 180 ml of methanol and 2 ml of concentrated sulfuric acid.
8.4 g (56 mmol) of lupropionic acid for 4 hours
Heat to reflux. Cool the reaction mixture to room temperature and reduce.
Concentrate under pressure to the equivalent of 30 ml, and add this to 100 ml of ice water.
Pour it properly. Pour the product into ether (150ml x 3 times)
extract and dissolve the extract in saturated sodium bicarbonate and
Wash with water and dry with magnesium sulfate.
A yellow oil was obtained by evaporating the solvent through filtration.
Distilled 8.9g and produced 8.34g (51mm) of colorless oil.
). Yield 91%, boiling point 73℃/1.5mmHg. B 2-oxo-3-phenylbutyldimethylphos
Manufacture of sulfonates:- 12.4 g (100 ml) of dimethyl methylphosphonate
Magnetic stirring of 90 ml of THF solution (-78℃) of
While doing this, add 62.5ml of 1.6Mn-butyllithium.
(100 mmol) is added dropwise. Stir at -78℃ for 30 minutes.
Continue stirring, and then add 8.2 g of the ester form of item A above.
(50 mmol) dropwise to obtain a yellow solution. −78
After stirring for 3 hours at °C, the mixture was warmed to room temperature and 1
Stir for an hour. Add acetic acid to adjust the pH to 5-6.
The reaction is stopped by Remove solvent under reduced pressure.
and add 100ml of water. Product methylene chloride
(100ml x 3 times), and the extract was saturated with carbonic acid.
Wash with sodium hydrogen and water, magnesium sulfate
Dry with. Through this, the solvent is evaporated,
A yellow oil is obtained. This is fractionally distilled to obtain the desired
8.1 g (31.6 mmol) of compound are obtained. Yield 63
%, boiling point 142-144℃/0.2mmHg. C [1β, 2α (5Z), 3α (1E), 4β]-7-[3-
(3-oxo-4-phenyl-1-pentenyl)
-7-Oxabicyclo[2.2.1]hept-2-
Preparation of yl]-5-heptenoic acid methyl ester
Preparation: − Under argon atmosphere, sodium hydride 0.201
g (4.18 mmol, 50% in mineral oil) was distilled
Suspend in 70 ml of dimethoxyethane and add the
1.45 g (4.7 mmol) of DME10 sulfonate
ml solution and stir the mixture for 90 min at room temperature.
Ru. Then [1β, 2α (5Z), 3α, 4β]-7-[3
-Formyl-7-oxabicyclo [2.2.1]
Methylbut-2-yl]-5-heptenoate
1.031g (3.8 mmol) of 5ml DME solution
and the mixture is stirred at room temperature overnight. glacial acetic acid
Stop the reaction by adding 0.5ml and remove the solvent under reduced pressure.
except for. ether and saturated sodium bicarbonate
Add and separate each layer. Carbonate saturates the ether layer
Wash once with sodium hydrogen solution and rinse with magnesium sulfate.
Dry in a vacuum, filter, and dry under reduced pressure to obtain a viscous
Obtain an oily substance. Add this to silica gel 60 (110g)
Top, chromatographed, ether-stone
Eluted with oil ether (2:3) as an oil.
0.992 g (66%) of the title C compound is obtained. early
Isolate 0.098g (6.5%) of the substance that moves rapidly.
Reo ¹ Cis double bond isomer by H-NMR
was identified. D [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β] −
7
-[3-(3-hydroxy-4-phenyl-1-
pentenyl)-7-oxabicyclo[2.2.1]
Methylbut-2-yl]-5-heptenoate
Preparation of tel (fast migrating isomer A): - 0.99 g (2.49 mmol) of the compound of section C above and
Cerous chloride 7.6 hydrate 0.954g (2.49ml)
Dissolve rimol) in 25 ml of methanol and 2 ml of THF.
Ru. Cool this solution in an ice bath and remove the borohydride solution.
Thorium 0.0941g (2.5 mmol) in small amounts
Add for 30 seconds. Remove the ice bath and stir the mixture for 10 minutes.
Stir, then 200ml of saturated ammonium chloride solution
Pour into. The product was mixed with ethyl acetate (50ml x 5 times)
Extract. Combine the ethyl acetate extracts in a sulfuric acid mug
Dry over sodium chloride, filter, and remove solvent under reduced pressure.
0.953 g of a viscous oil is obtained. Add this to silica
Chromatography was carried out on 60 g of gel.
Elute with petroleum ether (3:2) and transfer quickly.
0.616 g of almost clear isomer that moves slowly and
moving isomers (i.e. [1β, 2α(5Z), 3α
(1E, 3β), 4β]-7-[3-(3-hydroxy-
4-phenyl-1-pentenyl)-7-oxa
Bicyclo[2.2.1]hept-2-yl]-5-h
(putenoic acid methyl ester) 0.150g (15%)
obtain. On silica gel, ether-petroleum ether
(3:2) and TLC with vanillin has an Rf value of 0.35 and
and 0.25. The fast-moving isomer A is chromatographed again.
roughy, eluted with the same eluent and labeled
0.605 g (61%) of the compound of term D is obtained. E [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β] −
7
-[3-(3-hydroxy-4-phenyl-1-
pentenyl)-7-oxabicyclo[2.2.1]
[but-2-yl]-5-heptenoic acid (fast moving
isomer A), and [1β, 2α (5Z), 3α (1E, 3α, 4β), 4β]-7
-[3-(3-hydroxy-4-phenyl-1-
pentenyl)-7-oxabicyclo[2.2.1]
[but-2-yl]-5-heptenoic acid (fast moving
Production of isomer B): - 0.599 g (1.5 mm) of the methyl ester of the above D
Dissolve rimol) in 75 ml of THF and 13.5 ml of water,
Treat with 15 ml of 1N lithium hydroxide solution. this
The mixture was stirred at room temperature for 5 hours under argon atmosphere.
do. Add saturated oxalic acid solution to adjust pH to 3
and pour the mixture into 450ml of water. Aether the product
Extract with a bottle (200 ml x 3 times). ether extraction
Combine the ingredients and add water (200ml x 3 times) and saturated sodium chloride.
Wash with um solution (200ml x 1 time) and soak in sulfuric acid magne.
Dry with sodium chloride, filter, and dry under reduced pressure to form an oil.
Obtain 0.544g (94%) of product. Add this to silica gel
60, subjected to chromatography, methylene chloride
The two isomers were eluted with 3% methanol in
obtain. The fast moving isomer A is [1β, 2α (5Z),
3α (1E, 3α, 4α), 4β]-7-[3-(3-hydro
Roxy-4-phenyl-1-pentenyl)-7
-Oxabicyclo[2.2.1]hept-2-yl]
-5-heptenoic acid, slow migrating isomer B
(0.205g) is [1β, 2α (5Z), 3α (1E, 3α,
4α), 4β]-7-[3-(3-hydroxy-4-
Phenyl-1-pentenyl)-7-oxabisi
Chlo[2.2.1]hept-2-yl]-5-hepte
acid. The mixture calculated by adding an additional 0.112g
The total yield of compound fractions is 78%. silica gel
Top, 5% in methylene chloride, with vanillin
TLC Rf values 0.40 and 0.32. Elemental analysis, C _{twenty four} H ₃₂ O _Four As, Calculated value: C, 74.97%; H, 8.39%, Actual value: C, 74.84%; H, 8.42%. TLC and spectral data indicate that this material
More than 95% of substances that move quickly (isomer A)
It shows that there is. Example 45 [1β, 2α (5Z), 3α (1E, 3β), 4β]-7-(3
−
(3-hydroxy-4-phenyl-1-pente
Nyl)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid (a slow-migrating compound)
production of the methyl esters described in Examples 43 and 44 above.
isomer (slow moving isomer), i.e. [1β, 2α
(5Z), 3α (1E, 3β), 4β]-7-[3-(3-hi)
de
Roxy-4-phenyl-1-pentenyl)-7-
Oxabicyclo[2.2.1]hept-2-yl]-5
- Heptenoic acid methyl ester 0.144g (0.36ml
mol) in 18 ml of THF and 3.2 mg of water. 1N
Add 3.6ml of lithium hydroxide solution and
Stir at room temperature under gas atmosphere for 5 hours. Oxalic acid
Adjust the pH to 3 by adding a saturated solution of
Pour into 150ml. Product with ether (75ml x 3 times)
Extract, combine the ether extracts, and add water (75 ml x 3
times) and 75 ml of saturated sodium chloride solution.
This solution was dried over magnesium sulfate and reduced by filtration.
Remove the solvent under pressure and obtain 0.136 g (98%) of the title product.
I got it. 5% meth in methylene chloride on silica gel
TLC R with nol, vanillin _f Value 0.22. Elemental analysis, C _{twenty four} H ₃₂ O _Four As, Calculated value: C, 74.94%; H, 8.39%, Actual value: C, 74.58%; H, 8.36%. Example 46 [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-[3
−
[3-hydroxy-4-(2-methylphenyl)
-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
(Fast migrating isomer): - A 2-oxo-3-(2-methylphenyl)
Preparation of lopyldimethylphosphonate:- In 130 ml of distilled THF under argon atmosphere,
9.1 ml of distilled dimethyl methylphosphonate
(10.5 g, 77 mmol) solution cooled to -78°C
70ml of 1.15N n-butyllithium in hexane
(80 mmol) solution is added dropwise over 30 minutes.
After the addition was complete, stir the mixture at -78°C for 30 min.
Ru. o-Tolylacetic acid methyl ester 6.56g (40
7 ml of THF solution was added dropwise over 15 minutes,
After stirring at -78℃ for 3.5 hours, remove the cold bath for 1 hour.
Continue stirring. Adjust the pH to 6 by adding acetic acid.
The reaction is stopped by Remove solvent under reduced pressure.
Add 100ml of water to the residue and pour the product into chloride solution.
Extract with tyrene (100ml x 3 times). extract
Combine once with saturated sodium bicarbonate and once with water.
Wash twice, dry with magnesium sulfate, and store under reduced pressure.
Exclude solvent. Distill the residue to obtain 3.8g of the title compound.
(37%). Boiling point 133-135℃/0.1mmHg. B [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-oxo-4-(2-methylphenyl)-
1-Butenyl]-7-oxabicyclo[2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Preparation of stell: − Sodium hydride 0.201 under argon atmosphere
g (4.18 mmol, 50% in mineral oil)
Suspend in 70 ml of methoxyethane. Section A above
1.46 g (5.7 mmol) of sulfonate in 7 ml of DME
Add the solution and stir the mixture for 90 minutes at room temperature.
To this, [1β, 2α (5Z), 3α, 4β]-7-[3-ho
lumil-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester
Add 1.031 g (3.8 mmol) of DME in 5 ml,
The mixture is stirred at room temperature overnight. Add 0.5ml of acetic acid
to stop the reaction, remove the solvent under reduced pressure and remove the residue.
Distillate with ether and saturated sodium bicarbonate solution
Add. Separate each layer and remove the ether layer with carbonated water.
Wash with sodium solution and then with magnesium sulfate.
Dry and remove the solvent under reduced pressure to obtain a yellow oil.
Ru. Chromatograph this on silica gel 60 (110 g).
Added to graphite and ether/petroleum ether
The compound of title B obtained by elution was left to stand.
crystallize. On silica gel, ether/petroleum
TLC (UV and UV) using ether (1:1)
Rf0.33 (visualized with vanillin and vanillin). move quickly
Substance (R _f 0.45) 0.410g (27%) was isolated and
It was identified as an isomer with a double bond. C [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-4-(2-methylphenylene
)-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of methyl ester (fast migrating isomer)
Preparation: - 0.930 g (2.33 mmol) of the compound of item B above
and cerous chloride 7.6 hydrate 0.896ml
(2.33 mmol) with 25 ml of methanol and 4 ml of THF
dissolve in After cooling to 0-5℃, hydrogenated fluoride
Add 0.088 g (2.33 mmol) of sodium uron.
Add in portions in 30 seconds. Remove the ice bath and pour the mixture into
Stir for 10 min, add saturated ammonium chloride solution 175
Pour into ml. The product was diluted with ethyl acetate (50 ml x 5
2 times) and dried over magnesium sulfate to reduce
The solvent is removed under pressure to obtain an oil. Siri this
On Kagel 60 (110g), attached to chromatography
and eluted with ether-petroleum ether (3:2).
Fast-migrating isomer of the compound of title C
0.479g (51%) and 0.184g of the slower migrating isomer
(20%). On silica gel, ether-stone
With oil ether (3:2) and vanillin
R of TLC _f value 0.39 (faster migrating isomer) and
0.21 (slow migrating isomer). D [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-4-(2-methylphenylene
)-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of (fast-migrating isomer): - Methyl ester of item C above under argon atmosphere
Le isomer (fast moving isomer) 0.479g (1.2mm
mol) in 60 ml of THF and 11 ml of water. 1N water
Add 12.0 ml of lithium oxide solution to this mixture.
Stir at room temperature for 6 hours. Add saturated oxalic acid solution to this
Add liquid to adjust the pH to 3, and add the mixture to 450ml of water.
pour. Extract the product with ether (200ml x 3).
Combine the ether extract and add water (200ml x 3
times) Saturated sodium chloride solution (200ml x 1 time)
and dried over magnesium sulfate under reduced pressure.
Exclude solvent. The resulting oil was dissolved in silica gel 60
(50g) was subjected to chromatography and chlorinated.
Purified by elution with 3% methanol in methylene,
0.2965 g (64%) of the title compound was obtained. Shirikage
5% methanol and buffer in methylene chloride
TLC R with Nilin _f Value 0.24. Elemental analysis, C _{twenty four} H ₃₂ O _Four Calculated value: C, 74.97%; H, 8.39%; Actual value: C, 74.91%; H, 8.63%. Example 47 [1β, 2α (5Z), 3α (1E, 3β), 4β]-7-[3
−
[3-hydroxy-4-(2-methylphenyl)
-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of (slowly migrating isomer): - Slowly migrating isomer under argon atmosphere:
[1β, 2α (5Z), 3α (1E, 3β), 4β] −7 − [3
−[3
-Hydroxy-4-(2-methylphenyl)-1-
Butenyl]-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester
(Compound described in Example 46) 0.184 g (0.46 mmol)
Dissolve 1N hydroxide in 25ml of THF and 4ml of water.
Treat with 4.6 ml of tium solution. 6.5 Mixture at room temperature
Stir for an hour and add saturated solution of oxalic acid to pH 3.
Adjust. Pour this solution into 150ml of water to remove the product.
Extract with ether (7 ml x 3). Ether drawing
Combine the extracts and add water (75ml x 3 times) and saturated sodium chloride.
Wash with 75 ml of thorium solution and dry with magnesium sulfate.
Dry and remove the solvent under reduced pressure to form a viscous oil.
0.165 g (93%) of the title compound was obtained. Shirikage
5% methanol in methylene chloride and vanilla
TLC R with Phosphorus _f Value 0.17. Elemental analysis, C _{twenty four} H ₃₂ O _Four Calculated value: C, 74.97%; H, 8.39%; Actual value: C, 74.91%; H, 8.56%. Example 48 [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-[3
−
[3-hydroxy-4-(3-methylphenyl)
-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
(Fast migrating isomer): - A 2-oxo-3-(3-methylphenyl)
Preparation of lopyldimethylphosphonate:- In 130 ml of distilled THF under argon atmosphere,
Dimethyl methylphosphonate after distillation 9.1ml
(10.5 g, 77 mmol) solution cooled to -78°C
70ml of 1.15N n-butyllithium in hexane
(80 mmol) solution was added dropwise over 30 minutes.
After the addition was complete, stir the mixture at -78°C for 30 min.
Ru. Then m-tolyl acetic acid methyl ester 6.56
g (40 mmol) in 7 ml of THF over 15 minutes.
Add it dropwise. After stirring at −78℃ for 3.5 hours, remove the cold bath.
Remove and stir the mixture for an additional 60 minutes. Add acetic acid
The reaction is stopped by adjusting the pH to 6.
Ru. Remove the solvent under reduced pressure and add 70 ml of water to the residue.
Ru. Pour the product in methylene chloride (100ml x 3 times)
Extract. The extracts were combined, washed once with water, and washed with sulfuric acid macerate.
Dry with magnesium and remove the solvent under reduced pressure. Residue
Distill the distillate under reduced pressure to obtain a boiling point of 133-135℃/0.1mmHg
5.6g of phosphonate compound of heading A as a fraction of
(55%). B [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-oxo-4-(3-methylphenyl)-
1-Butenyl]-7-oxabicyclo[2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Preparation of stell: - Sodium hydride 0.201 under argon atmosphere
g (4.18 mmol, 50% in mineral oil) was distilled
Suspend in dimethoxyethane. Phosphate in Section A above
1.46 g (5.7 mmol) of phonate dissolved in 7 ml of DME
Add liquid. The mixture will be almost transparent and will look like cotton.
Ciliary solids begin to crystallize. Stir for 90 minutes at room temperature
After, [1β, 2α (5Z), 3α, 4β]-7-[3-formi
Ru-7-oxabicyclo[2.2.1]hept-2
-yl]-5-heptenoic acid methyl ester 1.031
g (3.8 mmol) in 5 ml of DME is added.
After the mixture was stirred at room temperature overnight, 0.5 ml of glacial acetic acid was added.
to stop the reaction. Remove solvent under reduced pressure.
The residue contains ether and saturated sodium bicarbonate.
Add the solution. Separate each layer to create ether layer
Wash once with sodium bicarbonate solution and rinse with sulfuric acid macerate.
Dry with magnesium, remove solvent under reduced pressure, and remove yellow
A colored oil is obtained. Add this to silica gel 60 (110g)
Top, chromatographed, ether-stone
Elution with oil ether (1:2) gave a colorless oil.
1.009 g (67%) of the title compound of Section B is obtained.
On silica gel, ether-petroleum ether (1:
1) and R of TLC with vanillin _f Value 0.34. Ma
A substance that moves faster than this (R _f value 0.42)
0.262 g (17%) was isolated and this material was
It was identified as a double bond isomer. C [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-4-(3-methylphenylene)
)-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of methyl ester: - 1.005 g (2.5 mmol) of the compound of item B above
and cerous chloride 7.6 hydrate 0.968g (2.5
mmol) in 25 ml of methanol and 2 ml of THF.
do. Cool the solution on an ice bath and dilute with borohydride.
0.0955g (2.5 mmol) of lium in small doses of 30
Add in seconds. Stir the mixture for 8 minutes without the ice bath.
After that, pour into 200ml of saturated ammonium chloride solution.
ingredient. Extract the product with ethyl acetate (50ml x 5 times)
, dry and remove the solvent under reduced pressure. residual oil
Chromatography on silica gel 60 (110 g)
ether-petroleum ether (1:1),
Then the isomer that migrates faster eluting with (3:2)
body 0.634g (63%) and slower migrating isomer 0.210
g (21%). On silica gel, ether
with petroleum ether (3:2) and vanillin
R of TLC _f value 0.35 (faster migrating isomer) and
0.15 (slow migrating isomer). D [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-4-(3-methylphenylene)
)-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of (fast-migrating isomer): - Methyl ester of item C above under argon atmosphere
isomer (fast moving isomer) 0.634 g (1.59 mi)
Limol) was dissolved in 75 ml of distilled THF and 14 ml of water.
Understand. Solution 15.9ml of 1N lithium hydroxide solution
and stir at room temperature for 6 hours. Oxalate saturation
Add Japanese solution to adjust the pH to 3, and add the solution to 450ml of water.
Pour into. Product with ether (200ml x 3 times)
Extract, combine the ether extracts and add water (200ml x
3 times) and saturated sodium chloride solution (200ml
x 1 time) and dried with magnesium sulfate.
The solvent was removed under reduced pressure to obtain a colorless oil. this
Chromatography on silica gel 60 (50 g)
and dissolved in 3% methanol in methylene chloride.
0.513 g of the title product as a colorless oil
(8.4%). Methylene chloride on silica gel
TLC with 5% methanol and vanillin in medium
R of _f Value 0.27. Elemental analysis, C _{twenty four} H ₃₂ O _Four As, Calculated value: C, 74.97%; H, 8.39%, Actual value: C, 74.98%; H, 8.42%. Example 49 [1β, 2α (5Z), 3α (1E, 3β), 4β]-7-[3
−
[3-hydroxy-4-(3-methylphenyl)
-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of (slow moving isomer): - prepared in Example 48, Section C under argon atmosphere.
The methyl ester (slow moving isomer)
That is [1β, 2α (5Z), 3α (1E, 3β), 4β] −7−
[3
-[3-hydroxy-4-(3-methylphenyl)
-1-Butenyl]-7-oxabicyclo[2.2.1]
Hept-2-yl]-5-heptenoic acid methyl ester
0.210 g (0.53 mmol) of THF and 5 ml of water
Dissolve in ml. Add 1N lithium hydroxide solution 5.3 to this
ml and the mixture is stirred at room temperature for 6.5 hours. Tired
After adjusting the pH to 3 by adding oxalic acid solution, the solution
Pour into 150ml of water. The product was mixed with ether (75ml×
3 times) Extract. Combine the extracts and add water (75ml x 3)
times) and washed with 75 ml of saturated sodium chloride solution,
Dry over magnesium sulfate and remove solvent under reduced pressure.
0.191 g (94%) of the title product as a colorless oil
I got it. 5% meth in methylene chloride on silica gel
R of TLC with nol and vanillin _f Value 0.18. Elemental analysis, C _{twenty four} H ₃₂ O _Four As, Calculated value: C, 74.97%; H, 8.39%, Actual value: C, 75.09%; H, 8.39%. Example 50 [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-[3
−
[3-hydroxy-4-methyl-phenyl-1
-Pentenyl]-7-oxabicyclo[2.2.1]
hept-2-yl]-5-heptenoic acid (quickly transferred)
Production of (moving isomer): - A 2-oxo-3-methyl-3-phenylbutylene
Preparation of dimethylphosphonate: - Sodium hydride 0.3744 g (7.8 mmol,
50% in mineral oil) with 5 ml of freshly distilled THF.
and suspend in 78ml of THF. In this, 2-oxo
-3-phenylbutyldimethylphosphonate
(Produced as described in Example 43, Section B.)
2.0 g (7.8 mmol) are added dropwise at 0°C. mixture
The mixture was stirred at room temperature for 1 h and then cooled to −78 °C.
n-butyllithium 1.7M solution in hexane
Treat with 4.85 ml (7.8 mmol). mixture
Stir at -78°C for 15 minutes and at 0°C for 1 hour. You
Add 1.5 ml (24 mmol) of methyl chloride to the mixture
After stirring at 0°C for 1 hour, glacial acetic acid was added to terminate the reaction.
make it stop. Carefully pour the reaction mixture into saturated carbonated water.
and the product in ethyl acetate.
(150ml x 3 times). Combine the extracts
Saturated sodium bicarbonate solution and saturated sodium chloride solution
Wash with thorium solution and dry with sodium sulfate.
The solvent was removed under reduced pressure to obtain a brown oil. child
Distilled using a kugelroh
and the title A as a distillate with a boiling point of 170℃/0.15mmHg
1.9 g (92%) of the phosphonate of No. 2 is obtained. B [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-(3-oxo-4-methyl-4-phenyl-
1-pentenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of methyl ester: − Under argon atmosphere, sodium hydride 0.201
g (4.18 mmol, 50% in mineral oil)
Suspend in 70 ml of methoxyethane. Section A above
1.54 g (5.7 mmol) of sulfonate in 7 ml of DME
Add the solution and stir the mixture for 90 minutes at room temperature.
To this, [1β, 2α (5Z), 3α, 4β]-7-[3-ho
lumil-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester
Add 1.031 g (3.8 mmol) of DME in 5 ml,
The mixture is stirred at room temperature overnight. 0.5ml of glacial acetic acid
to stop the reaction, and remove the solvent under reduced pressure.
The residue was dissolved in ether and saturated sodium bicarbonate.
Add liquid. Separate each layer and saturate the ether layer
Wash once with sodium bicarbonate solution and use sulfuric acid mug.
Dry over nesium and remove the solvent under reduced pressure to give a yellow color.
Obtain an oily substance. Apply this on silica gel 60, Chroma
Ether/petroleum ether
Compound 1.0 of section B was eluted as an oil.
g (64%). On silica gel, ether/
TLC (vanillin) using petroleum ether (1:1)
R _f Value 0.48. C [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-[
3-
(3-hydroxy-4-methyl-4-phenyl
-1-pentenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of methyl ester (fast migrating isomer)
Structure: - 1.0g (2.43 mmol) of the ketone body of item B above
and cerous chloride 7.6 hydrate 0.932ml
(2.43 mmol) in 25 ml of methanol.
After cooling the solution in an ice bath, add sodium borohydride.
0.092g (2.43 mmol) of um in small portions for 30 seconds
Add with Remove the ice bath and stir the mixture for 8 minutes.
and pour into 200 ml of saturated ammonium chloride solution.
Extract the product with ethyl acetate (50ml x 5 times)
and dry with magnesium sulfate and remove the solvent under reduced pressure.
to obtain an oily substance. Add this to silica gel 60
(60g) was subjected to chromatography and
Elution with petroleum-petroleum ether (2:3) gave title C.
0.690 g of the fast-migrating isomer of the compound in term (69
%) and 0.97 g (9.7%) of the slower migrating isomer.
obtain. On silica gel, ether-petroleum ether
R of TLC using (3:2) and vanillin _f value
0.46 (faster migrating isomer) and 0.32 (slower migrating isomer)
moving isomers). D [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-(3-hydroxy-4-methyl-4-phenylene
)-1-pentenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of (fast-migrating isomer): - Methyl ester of item C above (fast-migrating isomer)
0.680 g (1.67 mmol) of 75 ml of THF and water
Dissolve in 15ml. 1N lithium hydroxide solution 16.7ml
is added and the mixture is stirred at room temperature for 7 hours. child
Add saturated oxalic acid solution to the solution to adjust the pH to 3.
Pour the liquid into 450ml of water. Pour the product in ether (200ml
x 3 times), and combine the ether extracts with water.
(200ml x 3 times), saturated sodium chloride solution (200ml
x 1 time) and dried with magnesium sulfate.
Remove the solvent under pressure. The resulting oil is fused to silica gel.
60 (40g), subjected to chromatography, and chlorinated.
Elution with 3% methanol in methylene yielded the title compound.
0.545g (82%) was obtained. On silica gel, chloride
With 5% methanol and vanillin in tyrene
R of TLC _f Value 0.32. Elemental analysis, C _{twenty four} H ₃₅ O _Four As, Calculated value: C, 75.34%; H, 8.60%, Actual value: C, 75.07%; H, 8.37%. Example 51 [1β, 2α (5Z), 3α (1E, 3β), 4β]-7-[3
−
[3-hydroxy-4-methyl-4-phenyl
-1-pentenyl)-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of (slowly migrating isomer): - Slowly migrating isomer prepared in Example 50, Section C above.
Methyl ester: [1β, 2α (5Z), 3α (1E, 3β)
，
4β]-7-[3-(3-hydroxy-4-methyl-
4-phenyl-1-pentenyl)-7-oxabi
cyclo[2.2.1]hept-2-yl]-5-hepte
0.095 g (0.23 mmol) of acid methyl ester
Dissolved in 12 ml of THF and 2 ml of water, 1N lithium hydroxide
Add 2.3 ml of solution and stir the mixture for 6.5 hours at room temperature.
and adjust the pH to 3 by adding a saturated solution of oxalic acid,
Pour this solution into 100 ml of water and dilute the product with ether.
Extract (50ml x 3 times). Combine the ether extracts
water (50 ml x 3 times) and saturated sodium chloride solution.
(50ml x 1 time) Wash and dry with magnesium sulfate.
The solvent was removed under reduced pressure to obtain the title compound as an oil.
Obtained 0.091g (99%). On silica gel, chloride
Using 5% methanol and vanillin in tyrene
R of TLC _f Value 0.2. Elemental analysis, C _{twenty five} H ₃₄ O _Four As, Calculated value: C, 75.34%; H, 8.60%, Actual value: C, 75.64%; H, 8.44%. Example 52 [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-[3
−
[3-hydroxy-3-(1-methylcyclohexyl
sil)-1-propenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of (fast migrating isomer): - A 2-oxo-2-(1-methylcyclohexy
) Production of dimethylphosphonate: 9.1 ml of distilled dimethyl methylphosphonate
(10.5 g, 77 mmol) in 130 ml of THF (−
78°C) in hexane with stirring.
Butyllithium (1.15M) solution 70ml (80mmol)
Add dropwise. Stirring was continued for 30 minutes at −78°C.
After that, 1-methyl-1-cyclohexanecarbonate
6.24 g (40 mmol) of acid methyl ester
Add 8 ml of THF solution dropwise over 15 minutes. mixture
Stir at -78°C for 3.5 hours, then at room temperature for 2 hours.
Stir. Add acetic acid to adjust the pH to equivalent to 6.
to stop the reaction. Remove solvent under reduced pressure
Add 70ml of water to the residue. The product is converted into methylene chloride.
(100 ml x 3 times) and combine the extracts.
Wash once with water and dry with magnesium sulfate.
The solvent is removed under pressure to obtain an oil. distill this
It is specified as a fraction with a boiling point of 120-122℃/0.2mmHg.
6.0 g (60.5%) of the above compound are obtained. B [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-oxo-3-(1-methylcyclohexy
)-1-propenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Preparation of methyl ester: − Under argon atmosphere, sodium hydride 0.201
g (4.18 mmol, 50% in mineral oil)
Suspend in 70 ml of methoxyethane and
1.42 g (5.7 mmol) of phonate dissolved in 7 ml of DME
Add liquid. The mixture is stirred at room temperature for 90 minutes.
To this, [1β, 2α (5Z), 3α, 4β]-7-[3-ho
lumil-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester
Add 1.031 g (3.8 mmol) of DME in 5 ml,
The mixture is stirred at room temperature overnight. 0.5ml of glacial acetic acid
to stop the reaction, and remove the solvent under reduced pressure.
The residue was dissolved in ether and saturated sodium bicarbonate.
Add liquid and separate each layer. carbonate the ether layer
Wash once with sodium hydrogen solution and rinse with magnesium sulfate.
The solvent was removed under reduced pressure to form a yellow oil.
get something Place this on silica gel 60 (110g) and
romatographed, ether/petroleum ether
The compound of title B was eluted as an oil.
Obtain 1.241g. On silica gel, ether/petroleum ether
TLC using (1:1) (visualized with vanillin)
R of _f Value 0.48. Also, substances that move quickly (R _f value
0.050g (3%) of cis-2
It was identified as a heavy bond isomer. C [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-3-(1-methylcyclohexane)
xyl)-1-propenyl]-7-oxabisic
B[2.2.1]Hept-2-yl]-5-heptene
Preparation of acid methyl ester (fast migrating isomer)
Preparation: - 1.226 g (3.1 mmol) of the compound of item B above
and 1.18 g (3.1
mmol) in 30 ml of methanol and 2 ml of THF.
do. After cooling this solution on an ice bath, hydrogenation
Add 0.117g (3.1 mmol) of sodium boron.
Add in portions in 30 seconds. Remove the ice bath and pour the mixture into
Stir for 8 minutes and add 175 ml of saturated ammonium chloride solution.
Pour into ml. The product was diluted with ethyl acetate (50 ml x 5
(times), dry and remove the solvent under reduced pressure.
1.22 g of oil is obtained. Add this to silica gel 60 (80
g) The above was subjected to chromatography and ether
- eluted with petroleum ether (1:1) and obtained the title C.
Substances rich in fast-moving isomers of compounds 0.930
g and 0.142 g (12%) of the slower migrating isomer were obtained.
Ru. ether-petroleum ether (3:2) and
R of TLC with vanillin _f Value 0.41 (move faster)
isomer) and 0.2 (slow-migrating isomer).
The fast-migrating isomer was then sampled again on silica gel 60.
Romatographed with 10% acetic acid in benzene.
Clear compound of title C when eluted with ethyl
Obtain 0.602g (50%). D [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-3-methylcyclohexy
)-1-propenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of (fast-migrating isomer): - Methyl ester of item C above under argon atmosphere
isomer (fast moving isomer) 0.602 g (1.54 mi)
Dissolve rimol) in 75 ml of THF and 14 ml of water, and add 1N water.
Add 15.4 ml of lithium oxide solution. this mixture
Stir at room temperature for 6.5 hours. I'm so saturated with this
Add an acid solution to adjust the pH to 3, and add the solution to 450ml of water.
Pour into. Product with ether (200ml x 3 times)
Extract, combine the ether extracts and add water (200ml x
3 times) and saturated sodium chloride solution (200ml
x 1 time), dry and remove the solvent under reduced pressure.
to obtain 0.574 g of oil. Add this to silica gel
60 (40g), subjected to chromatography, salt
Eluted with 3% methanol in dichloromethane, colorless oil.
0.479 g (83%) of the title product was obtained as a solid.
5% methanol in methylene chloride on silica gel
and R of TLC with vanillin _f Value 0.56. Elemental analysis, C _{twenty three} H ₃₆ O _Four Calculated value: C, 73.37%; H, 9.64%, actual value: C, 73.06%; H, 9.70%. Example 53 [1β, 2α (5Z), 3α (1E, 3β), 4β]-7-[3
−
[3-hydroxy-3-(1-methylcyclohexyl
sil)-1-propenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
(Slowly migrating isomer): - Slowly migrating isomer prepared in Example 52, Section C above.
Methyl esters, namely [1β, 2α (5Z), 3α
(1E, 3β), 4β]-7-[3-[3-hydroxy-3
-(1-methylcyclohexyl)-1-propeny
]-7-oxabicyclo[2.2.1]hept-2-
yl]-5-heptenoic acid methyl ester 0.142g
(0.36 mmol) in THF18ml under argon atmosphere
and dissolve in 3.2ml of water. Add this solution to 1N lithium hydroxide.
3.6 ml of solution and the mixture was kept at room temperature for 6.5 hours.
Stir and adjust the pH to 3 by adding a saturated solution of oxalic acid.
and pour the mixture into 150ml of water. Ether the product
(75ml x 3 times). Combine ether extract
water (75 ml x 3 times, saturated sodium chloride solution 75
ml, dried over magnesium sulfate, and vacuumed.
Remove the solvent at the bottom to obtain 0.132 g of an oil. this
For chromatography on silica gel 60 (15 g)
and eluted with 3% methanol in methylene chloride.
0.097 g (72%) of the title compound was obtained. silica gel
Top, 5% methanol and vanillin in methylene chloride
R of TLC using _f Value 0.18. Elemental analysis, C _{twenty three} H ₃₅ O _Four As, Calculated value: C, 73.37%; H, 9.64%, Actual value: C, 73.24%; H, 9.67%. Example 54 [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-[3
−
[3-hydroxy-4-(4-methylphenyl)
-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
(Fast migrating isomer): -A 2-oxo-3-(4-methylphenyl)
Preparation of lopyl dimethyl phosphonate: - Methyl phosphonate distilled under argon atmosphere.
Steaming 5.6 ml (6.44 g, 47 mmol) of dimethyl acid
The distilled THF 80ml solution was cooled to -78℃ and
30ml of 1.65Mn-butyllithium solution in Sun (49
mmol) solution dropwise over 30 minutes. dripping
After completion, the mixture is stirred at −78° C. for 30 minutes. p
-Tolylacetic acid methyl ester 4.025g (24.5ml)
Add 5 ml of THF solution of -
After stirring for 3.5 h at 78 °C, remove the cold bath and remove the mixture.
Stir for an additional hour. Add acetic acid to adjust pH to 6
The reaction is stopped by Dissolve under reduced pressure
Remove the medium, add 75 ml of water to the residue, and salt the product.
Extract with methylene chloride (75 ml x 3). extract
Combine once with 75 ml of saturated sodium bicarbonate,
Wash once with 75ml of water and dry with magnesium sulfate.
The solvent was removed under reduced pressure to obtain an oil. reduce this
Distilled under pressure to obtain 3.06 g (49
%). Boiling point 132-134℃/0.1mmHg. B [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-oxo-4-(4-methylphenyl)-
1-Butenyl]-7-oxabicyclo[2.2.1]
hept-2-yl]-5-heptenoic acid methyl ester
Preparation of stell: - Sodium hydride 0.201 under argon atmosphere
g (4.18 mmol, 50% in mineral oil)
Suspend in 70 ml of methoxyethane. Section A above
1.46 g (5.7 mmol) of sulfonate in 7 ml of DME
Add solution. A fluffy solid precipitates. blend
Stir for 90 minutes at room temperature. To this [1β, 2α
(5Z), 3α, 4β]-7-[3-formyl-7-o
xabicyclo[2.2.1]hept-2-yl]-5
- Heptenoic acid methyl ester 1.03g (3.8ml)
Add 5 ml of DME solution (mol). Bring the mixture to room temperature
Stir overnight, then add 0.5 ml of glacial acetic acid and incubate.
stop responding. Remove the solvent and the residue under reduced pressure
Add ether and saturated sodium bicarbonate solution to
I can do it. Separate each layer and dilute the organic layer with sodium bicarbonate.
Wash once with magnesium sulfate solution and dry with magnesium sulfate.
and remove the solvent under reduced pressure to obtain the product (if left standing)
and crystallize). Place this on silica gel 60 and
romatographed, ether/petroleum ether
The title column B obtained by elution with tel (1:3)
1.064g (70%) of the compound was left to crystallize.
Ru. On silica gel, ether/petroleum ether
TLC using (1:1) (visualized with vanillin)
R of _f 0.36. Also, substances that move quickly (R _f 0.43)
0.228g (15%) was isolated and the cis-double bond was isolated.
It was identified as an isomer with C [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-4-(4-methylphenylene)
)-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of methyl ester: - 1.06 g (2.66 mmol) of the compound of item B above
and cerous chloride heptahydrate 1.02g (2.66
mmol) in 25 ml of methanol and 2 ml of THF.
do. Cool the solution on an ice bath and dilute with sodium borohydride.
Thorium 0.101g (2.66 mmol) in small amounts
Add in 30 seconds. Remove the ice bath and leave the mixture for 10 minutes.
Stir and pour into 175 ml of saturated ammonium chloride solution.
ingredient. Extract the product with ethyl acetate (50ml x 5 times)
and dry with magnesium sulfate and remove the solvent under reduced pressure.
to obtain an oily substance. Add this to silica gel
(100g) was subjected to chromatography.
Elution with ter-petroleum ether (3:2) gave title C.
Compound (fast moving isomer) 0.602g
(57%) and the slower migrating isomer 0.185g (17%)
get. On silica gel, ether-petroleum ether
of TLC using Le (3:2) and vanillin.
R _f Values 0.35 (fast moving isomer) and 0.12 (slow moving isomer)
(isomers that move more quickly). D [1β, 2α (5Z), 3α (1E, 3α), 4β]-7-
[3
-[3-hydroxy-4-(4-methylphenylene)
)-1-butenyl]-7-oxabicyclo
[2.2.1]Hept-2-yl]-5-heptenoic acid
Production of (fast-migrating isomer): - Methyl ester of item C above under argon atmosphere
Le isomer (fast moving isomer) 0.602g (1.5mm
mol) in 75 ml of THF and 14 ml of water. 1N water
Add 15 ml of lithium oxide solution and bring the mixture to room temperature.
Stir at room temperature for 7 hours. Add saturated oxalic acid solution to this
Adjust the pH to 3 by adding and pour the solution into 450ml of water.
The product was extracted with ether (200 ml x 3),
Combine the ether extracts and add water (200ml x 3 times).
and saturated sodium chloride solution (200ml x 1 time)
Washed, dried over magnesium sulfate and under reduced pressure.
Exclude solvent. Remove residual oil with silica gel 60 (50g)
The top was chromatographed with methylene chloride.
Eluted with 3% methanol as a colorless oil.
0.416 g (72%) of clear title product was obtained. S
5% methanol in methylene chloride on lyca gel
R of TLC with and vanillin _f Value 0.30. Elemental analysis, C _{twenty four} H ₃₂ O _Four As, Calculated value: C, 74.97%; H, 8.39%, Actual value: C, 75.08%; H, 8.48%. Example 55 [1β, 2α (5Z), 3α (1E, 3β), 4β]-7-[3
−
[3-hydroxy-4-(4-methylphenyl)
-1-butenyl]-7-oxabicyclo
[2.2.1] Hept-2-yl-5-heptenoic acid
(slowly migrating isomer):- Production of the methyl ester (slowly migrating isomer) of Example 54, Section B above.
0.185 g (0.46 mmol) of migrating isomer)
Dissolved in 25 ml of THF and 4 ml of water under Rougon atmosphere
do. Add 4.6ml of 1N lithium hydroxide solution to this.
and stir the mixture at room temperature for 7 hours. saturated scene
Add an acid solution to adjust the pH to 3, and add this solution to 150% water.
Pour into ml. Extract the product with ether (75 ml x 3).
Combine the extracts and add water (75 ml x 3 times) and saturated
Wash with sodium chloride solution (75ml) and sulfuric acid mug.
Dry over nesium and remove the solvent under reduced pressure to form a colorless oil.
0.177 g (99%) of the title product was obtained as a solid.
5% methanol in methylene chloride on silica gel
R of TLC with and vanillin _f Value 0.23. Elemental analysis, C _{twenty four} H ₃₂ O _Four As, Calculated value: C, 74.97%; H, 8.39%, Actual value: C, 74.80%; H, 8.08%. Example 56 [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β]-7-
[3-(3-hydroxy-4-phenyl-1-he
xenyl)-7-oxabicyclo[2.2.1]hep
[t-2-yl]-5-heptenoic acid (quickly moving)
Production of -A oxo-3-phenylpentyldimethylphos
Preparation of phonate: - 12.8 ml of distilled dimethyl methylphosphonate.
(14.75g, 108mmol) of THF (distilled) 180ml
The solution was cooled to −78 °C under an argon atmosphere,
1.65Mn-butylene in hexane while stirring.
68 ml (112.4 mmol) solution of lulithium for 30 minutes
Apply additional processing over time. The mixture was heated to -78°C.
Stir for 30 minutes, then add methyl 2-phenylbutyrate.
ester 10.0g (56.2 mmol) in THF 15ml
Add the solution dropwise over 15 minutes. Stir at -78℃ for 3.5 hours
After that, remove the cold bath and add glacial acetic acid after 75 minutes to adjust the pH to 6.
Adjust to Remove most of the solvent under reduced pressure and remove the remaining
Add 100ml of water to the distillate. The product is converted into methylene chloride.
Extract with a tube (125 ml x 3 times). Combine the extracts
1 time with 100 ml of saturated sodium bicarbonate, 100 ml of water
Wash once with ml and dry with magnesium sulfate.
Remove the solvent under pressure. Distill the residue to obtain the title phosphor.
10.5 g (69%) of nate is obtained. Boiling point 134-136
°C/0.1mmHg. B [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β] −
7
-[3-(3-oxo-4-phenyl-1-hex
Cenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid methyl ester
Production of: - 0.201 g of sodium hydride under argon atmosphere
(4.18 mmol, 50% in mineral oil) in distilled
Suspend in 70 ml of methoxyethane. Section A above
1.54 g (5.7 mmol) of sulfonate in 7 ml of DME
solution and the mixture was stirred at room temperature for 90 min.
To [1β, 2α (5Z), 3α, 4β]-7-[3-hor
Mil-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid methyl ester
Add 1.031 g (3.8 mmol) of DME 5 ml solution.
Ru. The mixture was stirred at room temperature overnight, then glacial acetic acid
Add 0.5 ml to stop the reaction. Dissolve under reduced pressure
The solvent is removed and the residue is mixed with ether and saturated sodium bicarbonate.
Add thorium solution. Separate each layer and
Wash the layer once with sodium bicarbonate solution and sulfurize.
Dry with magnesium acid and remove the solvent under reduced pressure.
to obtain an oily substance. This was subjected to HPLC, then silica
Gel 60 (100g), attached to chromatography
and eluted with ether/petroleum ether (1:3).
1.130g (72%) of the title compound as an oil
get. On silica gel, ether/petroleum ether
TLC (UV and Vanilla) using 1:1
R of R (visualized with phosphorus) _f 0.43. C [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β] −
7
-[3-[3-hydroxy-4-phenyl-1-
hexenyl]-7-oxabicyclo[2.2.1]
Methylbut-2-yl]-5-heptenoate
Production of tel:- 1.125 g (2.73 mmol) of the compound of item B above.
and cerous chloride heptahydrate 1.047ml
(2.73 mmol) in methane under an argon atmosphere.
Dissolve in 25ml of water. Chill the solution on an ice bath with water.
Sodium borohydride 0.104g (2.73 mmol)
Add in small portions over 20 seconds. Remove ice bath and mix
After stirring for 8 minutes, add saturated ammonium chloride solution.
Pour into 175ml. The product was diluted with ethyl acetate (50ml x
5 times) and dried with magnesium sulfate.
Remove the solvent under reduced pressure. Remove residual oil with silica gel
60 (100g), subjected to chromatography,
Eluted with ether-petroleum ether (55:45) and labeled
0.660 g of the fast-migrating isomer of compound C
(58%) and the slower migrating isomer 0.186 g (16.5
%). Ether - petroleum ether (3:
2) R of TLC using _f Value 0.51 (fast moving difference)
(isomer) and 0.24 (slow-migrating isomer). D [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β] −
7
-[3-(3-hydroxy-4-phenyl-1-
hexenyl)-7-oxabicyclo[2.2.1]
[but-2-yl]-5-heptenoic acid (fast moving
Production of isomer): - Under argon atmosphere, the above C term moves quickly.
0.655 g (14 mmol) of isomer in 75 ml of THF and water
Dissolve in 14ml and 15.8ml of 1N lithium hydroxide solution
Add. This mixture was stirred at room temperature for 6.5 hours,
Next, add saturated oxalic acid solution to this to adjust the pH to 3.
Adjust. After pouring the mixture into 450ml of water, the product
Extract the substance with ether (200ml x 3 times),
Combine the extracts and add water (200ml x 3 times) and
Wash with 200 ml of saturated sodium chloride solution and rinse with sulfuric acid solution.
Dry with magnesium and remove the solvent under reduced pressure. Residue
Distillate oil on silica gel, 5% methanol/salt
methylene chloride, R by TLC with vanillin _f 0.49 (early
Isomers A) and R that move _f 0.40 (move faster)
The two main spots consisting of isomer B) are shown. this
Chromatography on silica gel 60 (80 g)
and dissolved in 3% methanol in methylene chloride.
0.238 g very rich in title isomer A, mixed
0.114 g of compound and 0.194 fractions enriched in isomer B
Obtained 3 pieces (total amount 0.546g (86.7%).
The fraction rich in isomer A was placed on silica gel 60 (40 g).
Chromatographed again and methylene chloride
revealed by TLC eluting with 2% methanol in
0.1801 g of the title isomer A, which was observed in the following manner, was obtained. Elemental analysis, C _{twenty five} H ₃₄ O _Four As, Calculated value: C, 75.34%; H, 8.60%, Actual value: C, 75.53%; H, 8.61%. After standing, this material becomes a waxy solid. Example 57 [1β, 2α (5Z), 3α (1E, 3α, 4β), 4β]-7-
[3-[3-hydroxy-4-phenyl-1-he
xenyl)-7-oxabicyclo[2.2.1]hep
[t-2-yl]-5-heptenoic acid (quickly moving)
Production of isomer B): - as a substance enriched in isomer B, as described in Example 56, section D.
0.194g of the loaded fraction was placed on silica gel 60 (30g) again.
chromatographed in methylene chloride.
Elution with 2.5% methanol yielded 0.0954 g of the title isomer.
(fast migrating isomer B) was obtained. This substance is pure
95% or more (impurities are of isomer A described in Example 56)
That's it. ) was shown by TLC to be
Ru. On silica gel, 5% methanol/methylene chloride
R of TLC with vanillin and vanillin _f 0.40 (0.49 (opposite sex)
including trace amounts in the body A)). Elemental analysis, C _{twenty five} H ₃₄ O _Four As, Calculated value: C, 75.34%; H, 8.60%, Actual value: C, 75.28%; H, 8.36%. Example 58 [1β, 2α (5Z), 3α (1E, 3β), 4β]-7-[3
−
(3-hydroxy-4-phenyl-1-hepte
Nyl)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid (a fast-migrating compound)
- Preparation of the slow migrating isomer as described in Example 56, Section C above.
0.182 g (0.44 mmol) of body under argon atmosphere,
Dissolved in 25 ml of THF and 4 ml of water, 1N lithium hydroxide
Treat with 4.4 ml of solution. Stir this at room temperature for 7 hours.
Afterwards, add saturated oxalic acid solution to adjust the pH to 3.
Pour the mixture into 150 ml of water and dilute with ether (75 ml x 3
times) extract. Combine the ether extracts and add water (75ml
x 3 times) and 75 ml of saturated sodium chloride solution.
dry over magnesium sulfate and remove the solvent under reduced pressure.
Removed to obtain 0.172 g of oil. On silica gel, 5
% methanol/methylene chloride and vanillin
With TLC, major spots R _f 0.34 (isomer B) and
very small spots R _f 0.42 (isomer A of Example 56)
shows. This oil was poured onto silica gel 60 (30g),
Chromatographed 3% in methylene chloride
Elutes with methanol and is labeled as a wax-like solid.
0.1006 g (57%) of product was obtained. on silica gel,
7% methanol and vanillin in methylene chloride
By TLC R _f 0.34(B) and R _f 0.42 (isomer A low
amount). The content of this substance is estimated to be 95% isomer B
Ru. Additionally, 0.026g of substance rich in isomer A was extracted from the column.
and mixtures (substances with a higher content of B)
Obtain 0.021g. Elemental analysis, C _{twenty five} H ₃₄ O _Four As, Calculated value: C, 75.34%; H, 8.60%, Actual value: C, 75.37%; H, 8.50%. Example 59 [1β, 2α (5Z), 3α (1E), 4β]-7-[3-[3
-Hydroxy-3-(1,2,3,4-tetra
Hydro-1-naphthalenyl)-1-propenyl]
-7-Oxabicyclo[2.2.1]hept-2-
Production of [yl]-5-heptenoic acid (isomer B):
− Formula: Methyl ester of isomer B represented by
(see Example 60) 0.466 g (1.1 mmol)
Dissolve in 50 ml of THF and 9 ml of water under Rougon atmosphere.
Add 11 ml of 1N sodium hydroxide solution and stir the mixture.
Stir at room temperature for 7.5 hours. Add saturated oxalic acid solution to this
Add liquid to adjust the pH to 3 and pour the mixture into 300ml of water.
ingredient. The product was extracted with ether (125 ml x 3),
Combine the ether extracts and add water (125 ml x 3 times) and
and saturated sodium chloride solution (1 x 125 ml).
dry over magnesium sulfate and remove the solvent under reduced pressure.
except. Pour 0.470 g of residual oil onto silica gel 60.
romatographed with 3% methane in methylene chloride.
0.2409 g (53%) of the title compound eluted with tanol.
I got it. 5% meth in methylene chloride on silica gel
R of TLC with nol and vanillin _f Value 0.27. Elemental analysis, C ₂₆ H ₃₄ O _Four ・0.25H ₂ As O, calculated value: C, 75.24%; H, 8.38%, actual value: C, 75.25%; H, 8.38%. Example 60 [1β, 2α (5Z), 3α (1E), 4β]-7-[3-[3
-Hydroxy-3-(1,2,3,4-tetra
Hydro-1-naphthalenyl)-1-propenyl]
-7-Oxabicyclo[2.2.1]hept-2-
Production of [yl]-5-heptenoic acid (isomer A):
− Formula: Production of the compound shown by: - Add a dropping funnel (150ml
ml), comes with condenser and acetylene gas inlet tube
do. This system is dried by fire under a nitrogen stream. system
3M Methyl Bromide Magneto in Ether, cooled to room temperature.
Add 100 ml (300 mmol) of Si to the dropping funnel.
Put 200ml of THF into the three-necked flask. THF
-78°C trap and concentrated sulfur with magnetic stirring at room temperature.
Acetylene gas passed through an acid trap is converted into THF.
Let it foam. THF with acetylene for 10 minutes
saturate, then add a small amount of methylmagnesium bromide
Add in portions (equivalent to 5 ml at a time) at room temperature. This attachment
Continue the addition for 2.5 hours (the mixture will turn dark green).
(becomes a cloudy liquid). After the addition is complete, leave the mixture for an additional hour.
Stir. Used for methylmagnesium bromide
Add 62 ml of THF to the dropping funnel under an argon atmosphere.
Drop solution containing 38 ml (0.287 mmol) of medium tetralone
Replace with Cool the mixture to 0°C for 45 minutes
The above tetralone is added dropwise over a period of time. mixture
Warm to room temperature, stir overnight, and add ice-containing saturated ammonium chloride.
(200ml + 100ml). Separate THF layer
Separate and extract the aqueous layer with ether (300ml x 4 times).
Ru. Combine the organic (THF and ether) layers and add water.
Wash (200ml x 2) and dry with magnesium sulfate.
do. After this, the solvent was evaporated to obtain
Separate 45 g of brown oil. 82~90℃/0.3mmHg
The fractionation is the fraction enriched with the desired compound (contaminated with starting material).
dyed). This fraction was further
Purified by elution with ethyl acetate/ethyl acetate (5:1).
20 g (0.12 mol, 42%) of pure colorless oil product
obtain. formula: Preparation of the compound represented by: - alcohol form () in 20 ml of dry methylene chloride
3.4g (20mmol) and 2.8ml triethylamine
(20 mmol) of dry chloride solution (at 0°C).
3.1 g diethyl chlorophosphite in 7.2 ml tyrene (20
mmol) dropwise. Leave the mixture at 0°C for 1 hour.
Stir at room temperature for 1 hour, then pour into 50 ml of saline solution.
and extract the product with chloroform (50 ml x 3).
put out Combine the chloroform layers and wash with 40ml of saline.
and dry with magnesium sulfate. solvent
was evaporated, and 6.5 g of the yellow oil obtained was evaporated into silica.
(Silica) 60 (175g) on column, petroleum ether/
1000 ml of ethyl acetate (9/1) and methylene chloride
Purified by elution with methanol/methanol (93/7).
4.96 g (17 mm) of slightly brownish oily product
le, 85%). formula: Manufacture of the compound represented by: - 3.76 g of phosphonate () in 12 ml of methanol
(12.8 mmol) diethylamine 24 at room temperature
g (328 mmol). Mixture at room temperature
Stir for 96 hours and concentrate under reduced pressure to obtain a brown oil.
120g of silica column (Silic AR.CC-7)
Top, eluted with 1-2% methanol in methylene chloride.
purified as a slightly brownish oil3.89
g (10.68 mmol, 83%). formula: Production of the compound shown by: - 2.9 g (7.9 mmol) of enamine body ()
Dissolved in 120ml THF, 25ml water and 25ml TFA,
Heat at gentle reflux temperature for 24 hours. reduce this
Concentrate under pressure and dissolve the residue in 80 ml of ethyl acetate.
and wash with saturated sodium bicarbonate. acetic acid for the aqueous layer
Re-extract with 80ml of ethyl and combine the ethyl acetate layers.
Wash with salt water and dry with sodium sulfate. past
The solvent was evaporated, resulting in 2.4 g of a tan oil.
on the column (about 80 g of Silic AR.CC-7),
Purify by eluting with tyrene 1% methanol. major
Purified by fractionated Kugelrohr distillation to form a yellow oil.
Approximately 1.96 g (6.32 mmol, 80%) of the product is obtained. 225
Desired product as fraction with bath temperature of °C/0.03 mmHg
get. formula: Preparation of a compound of: - 0.201 g (4.18 mmol) of sodium hydride.
50% NaH in oil)) and distilled dry dimethoxyethane
70 ml of the suspension was stirred under an argon atmosphere.
Phosphonate () 1.77 g (5.7 mmol)
Add 7ml DME solution. Mixture at room temperature for 100 minutes
Stir. Then the formula: 1.03 g (3.8 mmol) of aldehyde represented by
Add 5 ml of DME solution and stir the mixture overnight at room temperature.
Ru. Add 0.5 ml of glacial acetic acid to stop the reaction, and reduce the pressure.
Remove the solvent at the bottom. The residue is saturated charcoal dissolved in ether
Wash twice with sodium hydroxide solution, then rinse with magnesium sulfate solution.
and remove the solvent under reduced pressure. yellow oily raw
Chromatograph the product on silica gel 60 (140 g).
Compound ()1.33 as anhydrous oil
g (83%). On silica gel, ether-stone
Oil ether (1:1) and UV + iodine
R of TLC _f Value 0.35. Also cis double bond isomer
0.099g (6%, R _f 0.46) was also obtained. formula: Manufacture of the compound represented by: - 1.33 g (3.15 mmol) of compound () and chloride
1.21 g (3.15 mmol) of monocerium heptahydrate
Dissolve in 25 ml of methanol under argon atmosphere.
Cool the solution in an ice bath and add borohydride while stirring.
Sodium 0.119g (3.15mmol) in small portions
Add in 30 seconds. Remove the cold bath and stir the mixture for 8 minutes.
After stirring, pour into 200ml of saturated ammonium chloride solution.
ingredient. Extract the product with ethyl acetate (50ml x 5 times)
dried over magnesium sulfate and removed the solvent under reduced pressure.
Remove to obtain 1.33 g of oil. Add this to silica gel 60
(100g) was subjected to chromatography and
Elute with petroleum ether (1:1). silica
On the gel, ether-petroleum ether (3:2) and
The following three isomers were obtained by TLC with vanillin and vanillin.
Ru. Isomer A0.479g (36%), R _f 0.40; isomer
B0.620g (47%), R _f 0.29 (see Example 59); and
and isomer C0.154g (11.5%), R _f 0.20. each isomer
Subjected to chromatography again to remove small amounts of impurities.
except. Production of the title compound (Example 60): - Methyl ester () under argon atmosphere
(Above isomer A) 0.381g (0.9 mmol)
Dissolved in 40 ml of THF and 8 ml of water, 1N lithium hydroxide
Treat with 9.0 ml of solution. Stir the mixture at room temperature for 7 hours.
After stirring, adjust the pH to 3-4 with saturated oxalic acid solution.
Pour the solution into 250 ml of water and dilute with ether (100 ml x 3
times) extract. Combine the ether extracts and add water (100%
ml x 3 times) and 100 ml of saturated sodium chloride solution
Wash with water, dry with magnesium sulfate and dissolve under reduced pressure.
Remove the medium to obtain an oil. Add this to silica gel 60
(50g) was subjected to chromatography and
Elution with 3% methanol in tyrene yielded the title compound.
(G947025) was obtained. On silica gel, methylene chloride
R of TLC with vanillin and vanillin _f Value 0.35. Elemental analysis, C ₂₆ H ₃₄ O _Four ・0.4H ₂ As O, calculated value: C, 77.75%; H, 8.40%, actual value: C, 74.71%; H, 8.34%. Example 61 [1β, 2α (5Z), 3α (1E), 4β]-7-[3-(4
-cyclohexyl-3-hydroxy-1-pene
thenyl)-7-oxabicyclo[2.2.1]hept
-2-yl]-5-heptenoic acid (slowly migrating
Production of isomer): - Formula: Production of the compound represented by: - 2-phenylpropionic acid methyl ester 5.15
Dissolve g (31.4 mmol) in 100 ml of glacial acetic acid,
Treat with 0.2g of platinum chloride. At pressures not exceeding 53psi
Hydrogenate the above mixture overnight (completely in 5.5 hours).
Absorbs hydrogen. ). Separate the catalyst and add acetic acid under reduced pressure.
except for most of the. Dissolve the residue in ether and saturate
Wash twice with sodium bicarbonate solution and soak with magne sulfate.
Dry with cium. After removing the solvent, distill
4.55 g of product (85
%). formula: Preparation of a compound of: - Methylphosphonic acid distilled under an argon atmosphere.
5.86 ml (6.74 g, 49 mmol) of dimethyl was distilled
Dissolve in 80 ml of THF and cool to -78°C. stirring
While n-butyllithium solution in hexane
(1.65M) dropwise over 30 minutes. Do this for another 30 minutes
After stirring for a while, 4.36 g (25.6 mmol) of compound ()
Add 5 ml of THF solution dropwise over 10 minutes. Mixture -
Stir at 78℃ for 3.5 hours, then remove the cold bath and stir for 1 hour.
Continue. Add glacial acetic acid to adjust the pH to 6 and under reduced pressure.
Remove most of the solvent and add 75 ml of water. product
was extracted with methylene chloride (75 ml x 3 times), and the extract
Combine 75 ml of saturated sodium bicarbonate solution and
Wash with 75ml of water. After drying with magnesium sulfate, reduce pressure
Distill to remove the solvent, boiling point 122-124℃/0.01
Product () 4.55g (68%) as mmHg fraction
get. formula: Preparation of the compound represented by: - 0.201 g of sodium hydride under argon atmosphere
(4.18 mmol, 50% in mineral oil) was distilled from
Suspend the phosphonate in 70 ml of toxyethane.
() Add 1.49 g (5.7 mmol) of DME 7 ml solution.
I can do it. The mixture was stirred at room temperature for 90 minutes and then the formula: 1.03 g (3.8 mmol) of aldehyde represented by
Add 5ml of DME. After stirring overnight at room temperature, acetic acid 0.5
ml to stop the reaction and remove the solvent under reduced pressure.
Ku. The residue was dissolved in ether and saturated sodium bicarbonate.
Dissolve in solution. Separate each layer and saturate the ether layer.
Wash once with Japanese sodium bicarbonate solution, sulfuric acid mug
Dry over nesium and evaporate to dryness under reduced pressure. obtained
Chromatograph the oil on silica gel 60 (140 g).
Ether-petroleum ether (1:
3) eluted as an oil with compound () 1.181
g (77%). On silica gel, ether-stone
Oil ether (1:1) and UV light and vanillin
By TLC R _f Value 0.45. formula: Production of the compound represented by: - 1.176 g of ketone body () under argon atmosphere
(2.91 mmol) and cerous chloride/7.6 water
Dissolve 1.116 g (2.91 mmol) of the compound in methanol.
Dissolve, cool the solution to 0°C and dilute with sodium borohydride.
0.111g (2.91 mmol) of um in small amounts in 20 seconds
Added. After stirring the mixture for 8 minutes without the ice bath,
Pour into 175 ml of saturated ammonium chloride solution. product
Extract with ethyl acetate (50 ml x 5 times) and place in a sulfuric acid mug.
Dry over nesium and evaporate to dryness under reduced pressure. residual oily
Chromatograph the material on silica gel 60 (100 g).
with ether-petroleum ether (55:45)
0.708 g (60%) of the fast-moving isomer
Obtained 0.258 g (22%) of the slower migrating isomer ()
Ru. On silica gel, ether-petroleum ether
(3:2) and TLC R with vanillin _f value 0.24
(slow moving isomer) and 0.47 (fast moving isomer)
isomers). The slow moving isomer is a single isomer.
It is thought that Preparation of the title compound (Example 61): - Slowly migrating isomer of methyl ester ()
0.253 g (0.62 mmol) under argon atmosphere,
Dissolved in 30 ml of THF and 5 ml of water, 1N lithium hydroxide
Treat with 6.2 ml of solution. After stirring at room temperature for 7 hours,
Add oxalic acid solution to adjust the pH to 3. This melt
Pour the liquid into 200 ml of water and mix the product with ether (100 ml
×3 times) Extract. Combine the extracts and add water (100ml x
3 times) and 100 ml of saturated sodium chloride solution.
dry over magnesium sulfate and remove the solvent under reduced pressure.
except. Pour the residual oil onto silica gel 60 (25 g).
romatographed with 3% methane in methylene chloride.
Desired compound 0.1786 obtained by elution with tanol
g (74%) becomes a wax-like solid on standing. S
5% methanol in methylene chloride and
R of TLC with vanillin and vanillin _f Value 0.27. This substance is
TLC and ¹³ Single isomer by C NMR
Show that. Elemental analysis, C _{twenty four} H ₃₈ O _Four As, Calculated value: C, 73.81%; H, 9.81%, Actual value: C, 73.70%; H, 9.55%. Example 62 [1β, 2α (5Z), 3α (1E), 4β]-7-[3-(4
-cyclohexyl-3-hydroxy-1-pene
(chill)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid (a fast-migrating compound)
Preparation of methyl esters A and B):- Fast transfer of the methyl ester as described in Example 61 above.
0.480 g (1.12 mmol) of the moving isomer was added to the Argo
Dissolve in 60 ml of THF and 10 ml of water under a dark atmosphere. child
Add 11.2ml of 1N lithium hydroxide solution to this and mix.
Stir the mixture at room temperature for 6.5 hours in a saturated oxalic acid solution.
Adjust the pH to 3 by adding and pour the mixture into 375ml of water.
The product is extracted with ether (3 x 175 ml).
Combine the ether extracts and add water (175ml x 3 times) and
Wash with 175 ml of saturated sodium chloride solution, rinse with sulfuric acid
Dry with magnesium and remove the solvent under reduced pressure to form an oil.
Obtain 0.486g of substance. A large amount of free acid (equivalent to 0.460 g) was added to silica gel 60
(55 g) was subjected to chromatography and
Main fraction eluted with 2.5% methanol in tyrene
0.3115g and a small amount of post-fractionation 0.0449g were obtained (total yield
77%). Both have single spots (silicage) on TLC
5% methanol/methylene chloride and vanilla
R due to the use of phosphorus _f value 0.41). Elemental analysis, C _{twenty four} H ₃₈ O _Four As, Calculated value: C, 73.81%; H, 9.81%, Actual value: (G653186) C, 73.58%; H, 9.48
%.

Claims (1)

[Claims] 1 Formula: [In the formula, A and B may be the same or different, A is CH=CH or (CH ₂ ) ₂ , B is CH=
CH, C≡C or (CH ₂ ) ₂ , m is 1 to 8, X is OH; [Formula] CO ₂ R ¹ (where R ¹ is H or lower alkyl); or [Formula] (where Z is H, lower alkyl, aryl, SO ₂ -Q
(Q is lower alkyl or aryl), [Formula] or OR ² (R ² is H)), Y is aryl (lower) alkyl; alkenyl;
alkynyl; aryl; pyridyl; pyridyl (lower) alkyl; substituted pyridyl; thienyl; thienyl alkyl; substituted thienyl; cycloalkyl; substituted cycloalkyl; cycloalkylalkyl; , Y may be alkyl), 〓 is a single bond or a double bond (provided that when 〓 is a double bond, A is CH=CH,
B represents CH=CH or (CH ₂ ) ₂ and Y is alkenyl or a group other than alkynyl] or a stereoisomer thereof. 2 formula: The compound according to claim 1, which is represented by: 3 formula: The compound according to claim 1, which is represented by: 4 A is (CH ₂ ) ₂ or CH=CH, B is (CH ₂ ) ₂
or CH═CH, the compound according to claim 2. 5. The compound according to claim 4, wherein X is CO ₂ R ¹ , [Formula] or [Formula] Q is phenyl or lower alkyl. 6 Y is phenylalkyl, thienylalkyl,
A compound according to claim 1 which is cycloalkyl or cycloalkylalkyl. 7. The compound according to claim 1, wherein X is OH, [Formula] or [Formula]. 8. The compound according to claim 1, wherein Y is [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] or [Formula]. 9 [1β, 2β (5Z), 3α (1H, 3S*), 4β] −7−
[3-(3-cyclohexyl-3-hydroxy-1
-propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or [1β,
2β (5Z), 3α (1E, 3R*), 4β]-7-[3-(3
−
cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo[2.2.1]hept-2-
The compound according to claim 1, which is yl]-5-heptenoic acid or methyl esters thereof. 10 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −6
-[3-(3-hydroxy-3-cyclohexyl-
1-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-1-(1H-tetrazol-5
-yl)-4-hexene or [1β,2β(5Z),3α
(1E, 3R*), 4β]-6-[3-(3-hydroxy-
3-cyclohexyl-1-propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-1-
The compound according to claim 1, which is (1H-tetrazol-5-yl)-4-hexene. 11 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(4-cyclopentyl-3-hydroxy-
1-butenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or [1β,
2β (5Z), 3α (1E, 3R*), 4β]-7-[3-(4
−
cyclopentyl-3-hydroxy-1-butenyl)-7-oxabicyclo[2.2.1]hept-2-
The compound according to claim 1, which is yl]-5-heptenoic acid or methyl esters thereof. 12 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-hydroxy-4-phenyl-1-butenyl)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid or [1β,2β
(5Z),3α(1E,3R*),4β]-7-[3-(3-hydroxy-4-phenyl-1-butenyl)-7-
Oxabicyclo[2.2.1]hept-2-yl]-5
- The compound according to claim 1, which is heptenoic acid or a methyl ester thereof. 13 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-cyclopentyl-3-hydroxy-
1-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid or [1β,2β(5Z),3α(1E,3R*),4β]-7-[3
−
(3-cyclopentyl-3-hydroxy-1-propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or methyl esters thereof as described in claim 1 compound. 14 [1β, 2β (5Z), 3α (1E, 3S*), 4β] - N
-acetyl-7-[3-(3-cyclohexyl-3
The compound according to claim 1, which is -hydroxy-1-propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenamide. 15 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-cyclohexyl-3-hydroxy-
1-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-N-(phenylsulfonyl)
-5-heptenamide Claim 1
Compounds described in Section. 16 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-cyclohexyl-3-hydroxy-
1-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-N-(methylsulfonyl)-
The compound according to claim 1, which is 5-heptenamide. 17 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-cyclohexyl-3-hydroxy-
1-propenyl)-7-oxabicyclo [2.2.1]
The compound according to claim 1, which is hept-2-yl]-5-heptenoic acid. 18 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-cycloheptyl-3-hydroxy-
1-propenyl)-7-oxabicyclo [2.2.1]
hept-2-yl]-5-heptenoic acid or [1β,2β(5Z),3α(1E,3R*),4β]-7-[3
−
(3-Cycloheptyl-3-hydroxy-1-propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or methyl esters thereof Claim 1 Compounds described. 19 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-(4-cyclohexyl-3-hydroxy-
1-butenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or [1β,
2β (5Z), 3α (1E, 3R*), 4β]-7-[3-(4
−
cyclohexyl-3-hydroxy-1-butenyl)-7-oxabicyclo[2.2.1]hept-2-
The compound according to claim 1, which is yl]-5-heptenoic acid or methyl esters thereof. 20 [1β, 2β (5Z), 3α (1E, 3S*), 4β] −7
-[3-[3-hydroxy-4-(3-thienyl)-
1-butenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or [1β,
2β (5Z), 3α (1E, 3R*), 4β]-7-[3-[3
−
Hydroxy-4-(3-thienyl)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-
2. The compound according to claim 1, which is a compound having the name yl]-5-heptenoic acid or their respective methyl esters. 21 [1β, 2α (5Z), 3α (1E, 3S*), 4β] −7
-[3-[3-hydroxy-4-(3-thienyl)-
1-butenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or [1β,
2β (5Z), 3α (1E, 3R*), 4β]-7-[3-[3
−
Hydroxy-4-(3-thienyl)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-
The compound according to claim 1, which is yl]-5-heptenoic acid or methyl esters thereof. 22 [1β, 2α (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-hydroxy-4-phenoxy-1-
butenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or [1β,2α
(5Z),3α(1E,3R*),4β]-7-[3-(3-hydroxy-4-phenoxy-1-butenyl)-7
-Oxabicyclo[2.2.1]hept-2-yl]-
The compound according to claim 1, which is 5-heptenoic acid or a methyl ester thereof. 23 [1β, 2α (5Z), 3α (1E, 3S*), 4β] −7
-[3-(3-hydroxy-4-phenyl-1-butenyl)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid or its methyl esters. 24 [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β]
−
7-[3-(3-hydroxy-4-phenyl-1-
pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer A); [1β, 2α (5Z), 3α (1E, 3α), 4β
]−
7-[3-(3-hydroxy-4-phenyl-1-
pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer B); or [1β,2α(5Z),3α(1E,3β)
，
4β]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (slow-migrating isomer) or The compound according to claim 1, which is a methyl ester thereof. 25 [1β, 2α (5Z), 3α (1E, 3α), 4β] −7
−
[3-(3-hydroxy-4-(2-methylphenyl)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer) or [ 1β, 2α (5Z), 3α
(1E,3β),4β]-7-[3-(3-hydroxy-4
-(2-methylphenyl)-1-butenyl]-7-
Oxabicyclo[2.2.1]hept-2-yl]-5
- Heptenoic acid (slowly migrating isomer) or its methyl esters. 26 [1β, 2α (5Z), 3α (1E, 3α), 4β] −7
−
[3-(3-hydroxy-4-(3-methylphenyl)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer) or [ 1β, 2α (5Z), 3α
(1E,3β),4β]-7-[3-[3-hydroxy-4
-(3-methylphenyl)-1-butenyl]-7-
Oxabicyclo[2.2.1]hept-2-yl]-5
- Heptenoic acid (slowly migrating isomer) or its methyl esters. 27 [1β, 2α (5Z), 3α (1E, 3α), 4β] −7
−
[3-[3-hydroxy-4-methyl-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer) or [ 1β, 2α (5Z), 3α
(1E,3β),4β]-7-[3-(3-hydroxy-4
-methyl-4-phenyl-1-pentenyl)-7
-Oxabicyclo[2.2.1]hept-2-yl]-
A compound according to claim 1 which is 5-heptenoic acid (slow migrating isomer) or its methyl esters. 28 [1β, 2α (5Z), 3α (1E, 3β), 4β] −7
−
[3-[3-hydroxy-3-(1-methylcyclohexyl)-1-propenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer) or [1β, 2α (5Z), 3α
(1E,3β),4β]-7-[3-[3-hydroxy-3
-(1-methylcyclohexyl)-1-propenyl]-7-oxabicyclo[2.2.1]hept-2-
yl]-5-heptenoic acid (slow migrating isomer)
or a methyl ester thereof. 29 [1β, 2α (5Z), 3α (1E, 3α), 4β] −7
−
[3-[3-hydroxy-4-(4-methylphenyl)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer) or [ 1β, 2α (5Z), 3α
(1E,3β),4β]-7-[3-[3-hydroxy-4
-(4-methylphenyl)-1-butenyl]-7-
Oxabicyclo[2.2.1]hept-2-yl]-5
- Heptenoic acid (slowly migrating isomer) or its methyl esters. 30 [1β, 2α (5Z), 3α (1E, 3α, 4α), 4β]
−
7-[3-(3-hydroxy-4-phenyl-1-
hexenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer); [1β, 2α (5Z), 3α (1E, 3α, 4β), 4
β]
-7-[3-(3-hydroxy-4-phenyl-1
-hexenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast migrating isomer B); or [1β,2β(5Z),3α(1E,
3β),4β]-7-[3-(3-hydroxy-4-phenyl-1-heptenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (slow-migrating isomer 2. The compound according to claim 1, which is a methyl ester thereof.