JPS584786A - Method for producing dioxabicyclo-[3.2.1]-octanes - Google Patents

Abstract

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

Description

Detailed Description of the Invention The present invention provides (/RB, 4t8R, JRB)-4-(3-hydroxypropyl )-Cumethyl-/-alkoxy-3,t-dioxabicyclo-[3,r,i]-octanes.

Specifically, the present invention has high activity as a contraceptive (/R
B, 4tSR, J-BS)-4-(K,/-dimethyl-!-hydroxy-7-nonenyl)-gumethyl-3,
? -Dioxabicyclo[3°-0/]-Octane-/
-Acetic acid [A] (U.S. Patent No. 9./θ-1 and 7f, No. 4t, 2/!f
, θg No. 1 specification v! The general formula (...) is an important intermediate for the total synthesis of (/Re, &SR).

JR8)=gu(3-hydroxypropyl)-gumethyl-/-alkoxy-31r-dioxabicyclo-[3
0,;z,i ]-It relates to a method for producing octanes.

The compound of the present invention represented by the general formula (It) is -2-
nonenyl)-gumethyl-3,? -Dioxabicyclo [3°, 2. / :]-]Octane-/-can lead to vinegar.

3-1 The inventors have prepared an important intermediate (//
Re, daSR, JR8)-gu(3-hydroxypropyl)-4-methyl-7-flucoxy3. As a result of extensive research into an extremely advantageous method for producing mono-dioxabicyclo[31,2,l]-octanes, the present invention has been achieved. That is, the gist of the present invention is (/R8, SR, JR8)-4-(,2-carbalkoxyethyl)-, which is represented by the general formula (1) (in the formula, R and kN' represent a low-butyric alkyl group). Goomethyl-/-alkoxy-3,
! - Dimexabishik q - [j.

-8/]-Reducing octanes, represented by the general formula (I[) (in the formula, R' represents a lower alkyl group) (/
Re, @SR, J-R8) -g-(j-hydroxypropyl)-gumethyl-/-alkoxy-,3f-dioxabicyclo-[3,2,i]-octane production method VC exists.

The present invention will be explained below.

The reducing agent used in the method of the present invention is lithium aluminum high silicide LIAtH4.
Monosodium hydride bis(comethoxychetoxy) 7
Rumi = fy A: NaAzH2(00)! ,,
+3H200H, )2, etc. are used, and especially the latter is industrially safe and suitably resistant. The amount of the reducing agent to be used is about 7 to a slight excess relative to the compound of general formula (1).

As a solvent, toluene, benzene, tetrahydrofuran ether, etc. are used.

The reaction temperature is 00-10[theta]C, usually 70-60[deg.]C. The reaction time is about 70 minutes to several hours, usually about 30 minutes to λ hours.

After the reaction, neutralize, remove inorganic substances, wash, and
The target product, general formula (II), is extracted by extraction, distillation of the ingot, etc.
can be obtained.

The compound of general formula (U) obtained in this way has a sufficiently high purity and can be used as is in the next step, but if it is safe, it can be purified by distillation or column chromatography. You can also do that.

The compound of general formula (1), which is a raw material for the method of the present invention, can be synthesized by the reaction route of the following formula.

H2) Sea. 7 The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the following examples, which do not go beyond the gist of the invention.

8- Reference example/ Magnesium 7.79 (0,32mode) f In addition to tetrahydrone run 3θθme, iodine! θ■
Add and stir dibromoethane θ,j−. When the color of iodine disappears, cool to -7θ℃ and add prenyl chloride, 3
A solution of 0 f (0, J/7rnol θ) in tetrahydrofuran (760 yd) is added under stirring. The dropping rate is adjusted so that the reaction temperature does not exceed -1°C. After stirring and reacting for 30 minutes, this was
Ruhydrin, 26. s f (θ1.2 J' 7
mole ) and iodide fine-pot! I-,6F (2 mm0t8) was added to a mixture of tetrahydrofuran 10θ+nt' under stirring while controlling the dropping rate so that the reaction temperature did not exceed 110°C. After stirring for another 30 minutes, acetic acid/7. t,/(θ, -22moze) was added, and the mixture was further stirred for 30 minutes and the solvent was distilled off under reduced pressure. Add saturated ammonium chloride water bath solution (200 d) and water (10 d) to the residual sound.
Add o, z) and stir for 3 hours. Separate the organic layer and add water I
- is extracted three times with ethyl acetate (/θ0-). This ethyl acetate layer was combined with the previous organic layer, washed with water, dried, concentrated, and distilled under reduced pressure to obtain 7-chloro-6-methyl-j-hebutene-
1-ol (j 6,2 f, purity, !?39, NET
yield 6j%) bp (s j −61”C(,2Nl
lllHg) is obtained.

Chlorohydrin (/-chloro-6-methyl-J-heptene-cool 600 mg, pure suspension? θ%, containing -64
10 rng,! , 3.2 mmo7) and 2.3-dihydrobilane (37θ~, 41.Y2rnmoz)
is dissolved in 0.6 ml of ethyl acetate, several quarts of p-toluenesulfonic acid are added thereto, and after the exotherm has subsided, triethylamine is added to neutralize. The mixture was moved under reduced pressure to dissolve the residual sound in 7 ml of methylene chloride, and 63614 sodium bicarbonate was added. To this, add % m-chloroperbenzoic acid (purity? θ%, 7419■, 3, ay mm
oz) a little at a time while stirring over an ice-water bath. Furthermore, after stirring for 30 minutes, disappearance of the raw material was confirmed112
Add saturated sodium orosulfite aqueous solution/me and water solution to the dough and stir for 7 hours. Separate the organic layer, extract the aqueous layer with methylene chloride, combine with the organic layer, wash with water, dry,
After concentrating and subjecting the residual sound to silica gel column chromatography, the desired epoxy compound (/-chloro-6-methyl-!, 6-Eboxy-heptyl-tetrahydropyran-coyl ether, +00t,ri7
．． j%) will be lost.

Dissolve the epoxy compound (/-chloro-!, epoxy-6-methyl-cohebutyl-tetrahydropyran-yl ether, /, gjf%s, scommoze) in toluene 10%, and add the alkali to this. Add triisopropoxide (/, /rf, jJ mmote) and heat under reflux for 6 hours. After cooling, add λ specified local acid water J
After adding tnl and stirring for 7 hours, the organic layer is separated.

This organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate, then water, dried (Mg504), and condensed. 2/)), allyl alcohol=methylene-λ-butyl-tetrahydrobylan-1-yl ether, i,, i jy, s.i gmm0t
e, 23%).

Allyl alcohol B (/-chloro-j-hydro 1,000 C 6
-Methi 1/--heptyl-tetrahydropyran--yl ether, /. /￥v1 g. 3ri mrnozθ
) to triethyl orthoacetate (41.2 1%.2 6
mmole), 7 drops of propionic acid are added thereto, and the produced ethanol is distilled off while heating and stirring in an oil bath at irio°C. After 7 hours, excess triethyl orthoacetate and propionic acid were distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution: hexane: ethyl acetate (7:/)).
a then the desired ester (/-chloro-6-carboethoxyethyl-!-hepten-yltetrahydrobilan-2-yl ether/..3 / 9,9,3
θmInole, 22%).

Ester (/-chloro-6-carfoethoxyethyl-j-hepten-yl-tetrahydropyran-yl ether.i.or.

A mixture of a normal sodium hydroxide aqueous solution (a.-twll) and methanol (jml) is stirred at room temperature for a period of time to react. After removing most of the methanol from the reaction mixture under reduced pressure, water
In addition, it was washed with n-hexane, and acidified (p
H=/) and [2 Extract the organic matter with ethyl acetate. The obtained ethyl acetate layer was washed with water, dried, and concentrated to give carboxylic acid (/-10-6-carboxyethyl-j-hepten-y-tetrahydropyran-coyl ether,
Tag θ■, tag %) can be obtained.

OTHP OH hyranyl ether (/-10-6-carpoxyethyl!-heptene--yl-tetrahydrobyran-coyl ether, ri, da θ2.3.θ!Pmmoze)
Tetrahuman 07 run (ri θ-) and λ normal hydrochloric acid (30t
After intoxicating in a mixed solvent of ne) and leaving it at room temperature for 2y hours,
Most of the tetrahydrofuran is distilled off under reduced pressure.

This is extracted with ethyl acetate, and the resulting organic layer is washed with water, dried, and the residual sound produced by mcondensation is silicaed into a chlorohydrin compound (terchloro-!-hydroxy-goomethyl-goonone: 'acid% 6.l') θV% tag%) can be obtained.

Chlorohydrin (t-chloro-?-hydroxy-goomethyl-gunonenoic acid, t2 = 15- ~.3.in'+moze) in acetone (7mz)
K@dissolve, and while stirring on a water cooling bath in a nitrogen stream, Jones's reagent (accumulated active acid specified) (3,3111/)
was added dropwise over a period of 1j, and after the addition was completed, the mixture was stirred and reacted for an additional 3 hours under the same conditions.

After 30 minutes of adding Improper Tools (θ, ma-) and finger pressing, the acetone was distilled off under reduced pressure, and the remaining i was added with ether and water, and organic l
- is separated, washing and drying of this mound layer (Mg5O,),
The residual sound obtained from concentration is purified by silica gel column chromatography (γ)
-hexane:ethyl acetate (2:/) L, the desired chloroketone body (2-chloro-!-oxo-gourmet now!rudernonenoic acid, jdata~, ?-2%) is obtained.

Chloride 1 of nonenoic acid, J34ty, /θ, 7 mmot)
Cool on a bath at 6-°C, mix well, and add m-chloroperbenzoic acid (degree ? θ%, 3f, / 0.
It takes about 7 minutes to add and react. After the addition, the bath was changed to an ice water bath and stirred for an additional 3 hours. Add OJN hydrochloric acid aqueous solution (/imt) and stir for 7 hours. Saturated sulfite solution) IJium aqueous solution (
r3. After boiling with t) for a further 7 hours, methylene chloride and water are added respectively and the co-layers are separated. The aqueous layer was further extracted with methylene chloride, dissolved in a mixture of 6(/jmgx, 2) methyl chloride(/, 7s y), and a catalytic amount of 1)
-) Start the reaction by adding the luenesulfone solution.

After 2 hours at room temperature, a saturated sodium carbonate aqueous solution (/d) was added to the reaction mixture to stop the reaction, and ethyl acetate (is
, Ix! )Extract.

This organic layer was further treated with a saturated aqueous sodium bicarbonate solution (
-t, zx, z) washed 7, dried (MgSO4) and concentrated to give a product consisting of two closely spaced λ spots.

This crude product was subjected to column chromatography, and n-
When developed with hexane:ethyl acetate (j;, 2), the lactone (2-chloromethyl-1-methoxy-s-[λ-
(,2-methyl-j-oquine-detrahydrofuranyl)
]] - λ stereopromoted products of tetrahydrofuran (nonpolar: /, 0/f, physical properties: θ, ≦2v% 67.3%) are obtained.

Cochloromethyl-methoxyj-[-1(-1methyl-5-oxotetrahydrofuranyl)]-tetrahydrofuran (1 ¥6f%22.θ111110119
) f/0% (V/V) dimethyl sulfoxide (
/z, j7), and potassium hydroxide (trs
% purely! ,3.22,! Add 0.41 mmole) and heat the mixture in an oil bath at 2oC for 1 hour to react.

Then, the mixture was cooled on an ice-water bath and diluted with normal aqueous hydrochloric acid (−
Gradually add 2-tme) and acetone (/Ome), stir for a while while cooling, and extract with ethyl acetate (60me x 3). The obtained organic layer is washed with water (3×2) and extracted with a saturated aqueous sodium bicarbonate solution (jθme, 2.t, zx, z) to separate acidic products and neutral products.

From ethyl acetate, drying (Mg"On) and concentration produced a lactone [λ-chloromethyl--hydroxy-s-
(2-(,2-methyl-j-oxy-tetrahydrofuranyl)"-tetrahydrofuran 1.:z, t ty
) is collected. From the aqueous layer, acidic (4N hydrochloric acid solution)
After that, ethyl acetate extraction (3θ, /X,?)
Bicyclocarboxylic acid ((/RIE, gR8, JR8) = a-(2
-carboxyethyl)-coumethyl-/-methoxy~-
[9- C3. ? -dioxabicyclo[3,a,/:]-octane, 3.02t, 6ri, f%) is obtained.

mp, 70-76℃ Engineering R (KBr disk) cm-'; 3
'pt3θ, 3/fO, 2ri60°/736. /
, 210. /10θ, 10θ, f,? , 2θPMR (
0DOz,, /θoMHz) δppm; /, 33
(B.

jH,-(,!OH,), 2.4141 (adci
, ,2H,J=10.6. and-0) 1aHbO
-), 3,7.2(jH,J-//Hz, -C!H
aHbO−), 3, J”? (jH, d, J=j+H
z, -0HO-)(/R8, daSR, JRS)-&
-(,2-carboxyethyl)-7-methoxydermethyl-9. and-dioxabicyclo[3,2,/:]octane, z, o o y (complete, 7θ mmol)! Dissolve methanol in /jrnlK, add / and % hydrogen chloride methanol solution, 2 tnl, methyl chlortoformate, 20-λ, θ-(/! mmol), and heat under reflux for 7 hours.

After cooling, triethylamine λ,O-(/K, ¥mmol) is added to neutralize, and methanol is distilled off under reduced pressure. Add ethyl etherg θ- to this and saturated saline solution (10ml x
After washing with 2), drying with anhydrous magnesium sulfate, and concentrating under reduced pressure, 2. //3f#') (/RB, ¥BR, JRs
)-1g-(a-methoxycarbonylethyl A, )-
/-Methoxy-gumethyl-3,tr-dioxabicyclo[30,2,7]octane is obtained (yield 2 ta,j
Nine).

Example / (/Re, Dani R, JR8)-gu(,2-methoxycarbonylethyl)-/-methoxy-gumethyl-3, and-dioxabicyclo(3,x,/:]octane/J,
J y (sθ mmol) dissolved in toluene jθ,
Scary, sodium bis(methoxyethoxy)aluminum hydride [NaAzH2(OOH20H200
2θ% ton solution of H, ), ] / j, 5r (
sr mmol) is added dropwise to a toluene 7θdK solution [/7 minutes]. (At this time, the temperature rises to 56℃.)! After stirring for θ minutes, the mixture is heated to 1θ° C. and further stirred for 30 minutes. Cool to below 30°C and add dilute sulfuric acid (C, H2SO,
,λ,7,t d +H20,? ,2 ,t ,1
) was added dropwise, 36-methanol was added, and the mixture was heated under reflux for 7 hours. After cooling, the white madder is separated in a furnace, combined with a toluene-methanol mixed solvent (2j, z + i Dar Guco wash liquid F and the washing liquid tube, and concentrated under reduced pressure.To this, toluene 7θ resistance is added and concentrated under reduced pressure, Furthermore, 10-ethyl acetate was added to remove insoluble matter, and the mixture was concentrated under reduced pressure to obtain /0.≦6f (/R
8,4tSR,JR8)-cou(3-hydroxypropyl)-/-methoxy-coumethyl-3,? -Dioxabicyclo[3,2,7]octane is obtained as a colorless oil. Yield ♂, 7% IR(Neat, v(yB-')3ri/θ,
+2 rijθ, 2za7θ, /+20θ, /100
．． /θ 01106θ, /θ20°NMR (δppm, CDCl3./θOMHz)OH.

/,4t -co,λ (crH,m, methylene proton)Lt/ (,2H,t,
Hoe■2-) Example λ Ester ((,7R8,gSR,,tR8)-dar-(
,2-carbomethoxyethyl)-gumethyl-/-methoxy-3,? -Dioxabicyclo[3,2,7]-octane, 3.2? , / 2. o mmol) t-mSottiK, dissolve lithium aluminum oxide (de'LiA) while stirring with ice water.
Add IH4 (&j OW, / /, J' mmot) and react. After 7 hours, the disappearance of the raw material was confirmed, and the crude product obtained by decomposing the excess reducing agent, filtering, drying, and concentrating the resulting salt was purified by silica gel column chromatography (developing solution, n-hexane: ethyl acetate (developing solution, n-hexane: ethyl acetate). /:/)) Then pure alcohol ((/R8,4tSR,JR8)-@-(
j-hydroxyglovir)-gumethyl-7-medoxy3. ! -dioxabicyclo-[30,2,/]-octane, 3. 2%, 3.0%) is obtained.

Claims (1)

[Claims] (1) (/Re, 4tSR, JRB)-Q-(,2
-carbalkoxyethyl)-termethyl-7-alkoxy-3,? -dioxabicyclo-[3,,2,i]
-Reducing octanes, represented by the general formula (It) (in the formula, R' represents a lower alkyl group) (/
R8,4tSR,JRB)-gu(3-hydroxypropyl)-termethyl-7-alkoxy-3,♂-dioxabicyclo=[3°λ,/]-ocooctane Method