JPH02286647A - Production of (3,5-dihydroxy-2-methylenecyclohexylidene) acetic acid esters - Google Patents

Abstract

PURPOSE:To easily produce the subject compound on an industrial scale in high yield at a low cost by using 5,7-dihydroxy-8-nonen-2-ynoic acids which are novel compounds derived from an easily and industrially available starting raw material and cyclizing the acids in the presence of a palladium compound. CONSTITUTION:The objective compound of formula n useful as a synthetic intermediate for 1 alpha-hydroxyvitamin D can be produced by cyclizing novel 5,7-dihydroxy-8-nonen-2-ynoic acids of formula I [R<1> and R<2> are tri(1-7C) hydrocarbon-silyl, 1-7C hydrocarbonsilyl or form acetal bond together with O of OH: R<3> is H or 1-4C alkyl] at 0-100 deg.C for 10min to 100hr in a solvent (e.g. benzene) in the presence of a palladium compound such as palladium(II) compound derived from bis(triphenylphosphine)-palladium(II) acetate and triphenylphosphine, etc.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is directed to the production of (3,5-dihydroxy-2-methylenecyclohexylidene) acetic acid esters that can be used as intermediates for the synthesis of 1α-droxyvitamin Ds. The present invention relates to a production method and an intermediate for producing the ester.

[Prior Art] Conventionally, regarding the production method of (3,5-dihydroxy-2-methylenecyclohexylidene) acetic acid esters represented by the following formula [■]', which are intermediates for the A-ring synthesis of active vitamin D3s. , the synthesis method shown in the reaction process diagram below has been proposed (the
Journal of the Orcanic Chemistry (
J, OrQ, Chenl, ) 1986, 51 (16
), 3098-3108) The method of the above reaction step is to convert [3S (IB, 3
α, 5β)'] -[3,'5-bis[[I1dimethylethyl)dimethylsilyl]oxy]-2methylenecyclohexylidene]acetic acid ethyl ester is synthesized6 [Problem to be solved by the invention] Bu In the above conventional method, the beam step and number of processes are long, fa)→(
During step b), an oxidative cleavage reaction using the toxic Os oa; during steps (b)→(C), a Beyer-Billiger reaction using potentially explosive 90% H2<)□; Furthermore, during the step (C) → (d), expensive bis[2,2,2-)refluoro-1phenyl-1-
It involved a dehydration reaction using (trifluoromethyl)ethoxy]diphenylsulfuran, and there were problems with its use in industrial large-scale synthesis. [Means for Solving the Problems] The present inventors focused on the above-mentioned problems and developed a method for producing (3,5-dihydroxy-2-methylenecyclohexylidene) acetic acid esters that can be industrially synthesized in large quantities. As a result of intensive research to find out, we have arrived at the present invention.

That is, the present invention is characterized in that 5,7-dihydroxy-8-nonene-2-ynoic acids represented by the following formula [I] are cyclized in the presence of a palladium compound. 3,5-dihydroxy-2-methycin-cyclohexylitine) acetic acid Nisder 6'' - In the description [-■] 11, R2 is the same or different, hydrogen atom, 1-(C1-C7 ) Does not represent a group that forms an acetal bond with a hydrocarbon silyl group, a C1-C7 hydrocarbon acyl group, or the oxygen atom of a hydroxyl group.

Examples of the (C1-C7) hydrocarbon silyl group include 1-trimethylsilyl group, 1-ethylsilyl group, triisopropylsilyl group, and tri(C1-Ca)alkylsilyl group such as -butyldimethylsilyl group; - diphenyl such as butyldiphenylsilyl group (C1~Ca
) Alkylsilyl groups; di(C1-C4)alkylphenylsilyl groups such as dimethylphenylsilyl groups; and tribenzylsilyl groups. Among these, a tri(C1-Ca)alkylsilyl group, a 7-diphenyl(C+-Ca)alkylsilyl group, and a phenyldiCC1-C4)alkylsilyl group are preferred, and a -butyldiphenylsilyl group is particularly preferred.

Examples of C1-C7 hydrocarbon acyl groups include acedel, propionyl, and butyryl groups (C1-Ca
) Examples include acyl groups and benzoyl groups derived from aliphatic saturated monocarboxylic acids. Among them, an acetyl group is preferred.

In addition, examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include a methoxymethyl group, a 1-hydroxyethyl group, a 2-methoxy-2-11':l pyr group, and a 2-methoxy-2-11':l pyl group.
Mention may be made of -ethoxy-2-propyl group, (2-ethoxy-1-oxy)methyl group, pencyloxymethyl group, 2-te)-lahydrobiranyl group, or 2-tetrahydrofuranyl group.

Among them, 2-tetrahydrofuranyl group is preferred.

In the above formula [I], R3 does not represent a hydrogen atom or a C1-C4 alkyl group. Examples of the C1-C4 alkyl group include methyl group, ethyl group, propyl group, butyl group, isopropyl group, 5ec-butyl group, and t-butyl group. Among them, ethyl group is particularly preferred.

5,7-dihydroholecy 8- represented by the above formula [I]
Nonene-2-ynoic acid esters can be obtained by the production method shown in the two-step diagram below.

■ In addition, 3,1-0-isopropylidene-3,4-dihydroxybutanal (1), which is the starting material in the above process diagram.
For example, Tetrahedron
) 1979, 35.933-940: Journal of Organic Chemistry (J, Org, Chel
), 198348, 4427-4430. Tetrahedron Letts ('1etrahedron Letts)
) 1982.23.4883-4886; Journal of the American Chemical Society (J,C
, S), 1978.100, 1942-1943.
Journal of the American Chemical Society (J, C, S), 1971.93.1490-1
It can be synthesized by the method described in the literature such as 491.

In the present invention, by cyclizing 5,7-dihydroxy-8-nonene-2-ynoic acid ester represented by the above formula [i] (8 or U) in the presence of a palladium compound, (3,5-dihydroxy-2-methylenecyclohexylidene) acetic acid esters are prepared.

Examples of the palladium compound of the present invention include Tetrahedron (Tetrahedron > 1986.42.
(16).

4361-4401, Accounts of Chemical
Research (8 counts of Cheli)
cal rlesearch) 198013,
(11), 385-393; and 'organic
5ynthesisWith Pa1radiu11
Coipounds”J, Tsuji, Springe
Various palladium complexes described by r-Verlag (1980) can be used. Preferably, palladium acetate, bis(triphenylphosphine)palladium(II) acedate, bis(tri-o-tolylphosphine)palladium(II) acetate, palladium chloride,
Bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(n)talolide, or tetrakis(1-rifhenylposphine)palladium(0), 1-lith(dibenzylideneacetyl) Examples include palladium compounds prepared in advance in a reaction vessel by adding a carboxylic acid such as #acid or propionic acid to cibaradium (0) or the like. However, the palladium compound of the present invention is not limited to these compounds. The amount of such palladium compound used is 5,7-dihydroxy-8 represented by the above formula [I].
-o, ooi for nonene-2-ynoic acid Nisderians
-1 equivalent, preferably 0.01-0.2 equivalent.

The reaction temperature during cyclization depends on the solvent used, and ranges from 0°C to 1°C.
00°C is preferred. Preferably it is 20°C to 80°C. The reaction time is 10 minutes to 100 hours, preferably 1 hour to 24 hours. The reaction is carried out in an organic solvent, and examples of the solvent include hydrocarbon solvents such as hexane and benzene, and ether solvents such as ether, tetrahydrofuran, and dioxane.

methanol, ethanol, propyl alcohol.

Alcohol solvents such as t-butanol, and others such as acetonyl-1-lyl, dimedylpolamide, dimethyl sulfoxide, and chloroform are used.

Preferably, tetrahydrofuran, benzene, and a mixed solvent of ethanol and benzene are used.

The reaction solution thus obtained is passed through a column chromatograph using florisil to remove solvent-insoluble solids such as palladium compounds, and the organic solvent is further removed under reduced pressure to obtain a crude product. The product can be purified by purification means such as column chromatography, thin layer chromatography, liquid chromatography, etc., if desired.

In this way, the (3,5-dihydroxy-2-methylenecyclohexylidene)acetic acid ester represented by the formula (n) can be obtained.

Preferred specific examples of the (3,5-dihydroxy-2-methylenecyclohexylidene) acetate represented by the above formula [I1] provided in the present invention include the compounds shown below.

+11 [33-(IE, 3α, 5β)]-[]3,
5-dihydroxy-2-methylenecyclohexylidene)acetic acid ethyl ester [2+ [38-(IE, 3α, 5β)]-[3,5
Bis[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methylenecyclohexylidene]acetic acid ethyl ester +31 [3S-(FE, 3α, 5β) ] −[3
,,5-diacetoxy-2-methylenecyclohexylidene)# acid ethyl ester (4) [BS-(IE, 3α, 5β)]-[3,5
His(2-tetrahydropyranoxy)-2-methylenecyclohexylidene]ethyl acetate [5] Stereoisomers of the asymmetric carbon atoms at the 3- and 5-positions of the compounds m to (4) Thus, the above formula [ff] The manufacturing method of the present invention for obtaining (3,5 dihydroxy-2-methylenecyclohexylidene) acetic acid esters represented by (1) can be manufactured from industrially easily available starting materials.

(2) It can be used industrially without using highly toxic reagents.

(3) It can be used industrially without using reagent 1 reactions that have a high risk of causing explosions.

It has the following advantages.

The present invention will be explained in more detail below using Reference Examples and Examples.6 Reference Example (1) 1N vinyl magnesium bromide dissolved in tetrahydrofuran (7,32 ml) was dissolved in tetrahydrofuran (
20 ml) and add 3.4-0 isopropylidene-3,4-dihydroxybutanal (1) to the solution.
A solution of 88 g in tetrahydrofuran (10 ml) was added dropwise.

After stirring for about 1 hour after the dropwise addition, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the product was then extracted with ethyl acetate. The extracted product was washed with saturated brine and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure and purified using a silica gel column to obtain 0.61 g of 1,2-0-isopropylidene-5-hexene-1,2,4-triol (2).The spectral data of the product was as follows. It was as follows.

IHNMR (CDCF3.90) δ 1.36
(s, 311) 1,. 13 (s, 311) 1.6-1.9 (■, 211) 3.58 (t, J=7.01lz, 1N) 4.0-
4.5 (IIl, 3H) 5.0-5.4 1m, 211) 5.7-6.2 (+3111) (+) 1,2-0-isopropylidene 5-hexene 1,2 .3.05 g of 4-triol (2) and 3.01 g of imidazole were dissolved in dimethylformamide (20 m
1), and t-butyldiphenylsilyl chloride (6.90ml) was added at about 0°C. This at room temperature is about 1
The mixture was stirred for 2 hours, then hexane and 1.7 ml of water were added, and the organic layer was taken out. The aqueous layer was extracted with ethyl acetate, and the extract was combined with the organic layer. Wash the organic layer with water and saturated saline, and then dry with magnesium sulfate. Concentrate the solvent under reduced pressure and purify with a silica gel column to obtain 6.99g
1.2-0-isopropylidene-4-[[I,1-dimethylethyl)diphenylsilyl]oxy-5-hexene 1.2-diol (3:R' = SiPh2''Bu
) was obtained. The spectral data of this product were as follows.

18 NHR (CDCF, 901　Z) δ 1.
06 (s, 9H) 1.27 (s, 6N) 1.6-2.0 m, 2!1 3.1-3.5 11III 3.8-4.4 m 3t1 4.7-5.2 1n, 21-1! 1.5-6.1 ml 7.2-7.8 m, 1011) (t) 4-1[I,1-dimethylethyl)diphenylsilyl]oxy-5-hexene-1,2-diol (n
) obtained in 1, 2. -0-Impropylidene 4- [
(1,1-dimethylethyl)diphenylsilyl]oxy-5-hexene-1,2-diol (3; R125iP
h2 nu) 6.99g in methanol (150ml)
Pyridinium para-toluene sulfonate (2
0■) was added and stirred at room temperature for 12 hours.

Tetralim hydrogen carbonate was added, and the mixture was stirred for 1 hour, and solids were removed by filtration.

After concentrating the solvent under reduced pressure, ethyl acetate and water were added, and the product was extracted into an organic layer. After drying the organic layer with magnesium sulfate, the solvent was concentrated under reduced pressure. Purified with a silica gel column, 4.5 g of 4-[(1,1-dimethylethyl)diphenylsilyl]oxy-5-hexene-1,2-
A diol (4:R1=SiPh2Bu) was obtained. The spectral data of this product were as follows.

ill NHli (CDCF3.90H1lz
) δ 1.07 (s, 9N) 1.09 (s, 9H) 1.3 -1.7 (l, 2H) 3.2 -3.6 (n+, 211) 3.7 1.1
(m, 111) 4.3 -4.6 (Jil+) 4.8 -5.2 (Ill, 211) 5.6 -6
．． 1 (1,IN) 7.2-7.8 (l,l0H) (to) 4-[(1,1-dimethylethyl) which cannot be obtained with 3-[(Ll-dimethylethyl)diphenylsite(t)
diphenylsilyl]oxy-5-hexene 1,2-diol (4: R1=S i Ph2 tBu ) 1.3
Tetra 2g, dolofuran (30ml), methanol (
15 ml) of a mixed solvent, and an aqueous solution (15 ml) containing 1.35 g of sodium periodate was added thereto.
Stirred for 3 hours. Stirring water was added, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine and dried over magnesium sulfate.

After concentrating the solvent under reduced pressure, it was purified using a silica gel column.
10t of 3-[(1,1-dimethylethyl)diphenylsilyl]oxy-4-pentenal (5:R1=SiP
hz tBu) was obtained. The spectral data of this product were as follows.

1tl N14R<CD (J3.90MHz) δ 1
．． 06 (s, 9H) 2.49 (dd, J=2.6 & 5.4Hz, 21
1) 4.65 (Q, J=5.5Hz, IN) 4.9
-5.3 (Ill, 211) 5.7-6.1 (
1,01) 7.2-7.8 (m, 10H) 9.69 (t, J=2.5117,1ll) IR(n
eat) 2970.2950.2870.1725.
15901425, 1110.820, 735, 7
00 c+n-'(v) 6-[(1,1-dimethylethyl)diphenylsilyl]oxy~7-octene-1
-yne-4■ 3-[(1,1-dimethylethyl)diphenylsilyl]oxy-4-pentenal (
5: R”=S i Phz tBu ) 1.04
g was dissolved in dolofuran (16 ml), and propargyl bromide (16 ml) and saturated aqueous ammonia chloride (64 ml) were added thereto. This solution was stirred and 1.2 g of zinc powder was added. After stirring at room temperature for 1 hour, the target product was extracted with ethyl acetate. 6. The extracted organic layer was washed with saturated brine, and then dried over magnesium sulfate. 6. The solvent was concentrated under reduced pressure, and purified with a silica gel column to obtain 1. .13 g of 6-[(1,1 dimethylethyl)diphenylsilyl]
Oxy-7-octen-1-yn-4-ol (Dan: R1
-3iPh2tBu) was obtained. Note that diastereomers based on the asymmetric carbon atoms at the roots of the hydroxyl and silyloxy groups could be easily separated using the column. The spectral data for the two diastereomers are as follows.

・Diastereomer [A]...Low polarity IHNHR (C
DC&'3, 90H1lz) δ 1.08 (s,
911) 1.7-1.9 (III, 2h 1.9-2.1 (m, IN 2.2-2.4 (m, 2N 3.10 (d, J=211z, 1ff3.9-4 .2
(+n 1l1 4.5-4.7 (n IH 4,9-5,2(m 2f1 5.6-6.1 (Llll 7.3-7.8 (++, 1011) IR(neat
) 3500.3310.2950.28θ01590
, 1470.1/125.1110°920, 820
．． 740 700 Diastereomer [B]...High polarity 111 Old (R
(CDC9390M1IZ) δ 1.07 (S,
911 > 1.7-1.9 (Ill, 2N) n -1 1,9-2,1 (III, Ill) 2.2 ~ 2.5 (m, 311) 3.7 -4.1 (+u , 1ll) 4.3 -4.
6 (Il, 111) 4.8-5.1 (III,
2) 1) 5.6 -6.0 (m, 1fl) 7.3-7.8 (nl, 10H) II (neat) 3450. 3300. 29
50. 2860. 21101585.1470,1
425,1110,1070920 820 74
0, 700 (7)-1fyf) 35 ~ bis tti
, i-dimethylethyl)diphenylsilyl]ogish-7
-6-[(1,1
-dimethylethyl)diphenylsilyl]oxy-7-octen-1yn-4-ol (6:R” = SiPhz
tBl''> 624 ffIg and imidazole (1,6
8ir) was dissolved in dimethylformamide (15 ml), and t-butyldiphenylsilyl chloride (3,
86 ml) was added. After stirring at room temperature for 12 hours, water and hexane were added, and the desired product was extracted into the organic layer. The extracted organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure and purified using a silica gel column to obtain 1.02 g of 3.5-his[(1,1-dimethylethyl)diphenylsilyl]oxy-7-octyne-
1-ene (7:RIR2=S i Ph2tBu ) was obtained. The spectral data of this product is as follows.

ill NMI (CI) C20, 90 + Z ) δ 0.98 (s, 9H) 1.01 (III, 911) 1.3-1.7 (III, 2H 1,7-2,2 (m, 311 3.7-4.0 (III 111 4.0-4.4 (n+ 111 4.5-4.9 (III 2t1 5.2-5.8 (III Il 7.2-7.8 (m, 201+) IR (neat) 3320.2950.2870.1
590.1430 Reference Example (2) 6-r(1,1-dimethylethyl)diphenylsilyl]
Oxy-7-octen-1-yne-4-obis(2-detrahydropyranoxy)-7octyn-1-ene□□□
Synthesis (1) 1-octen-7-yne-3,5-diol Synthesis Reference Example (1) 6-[fLl-dimethylethyl)diphenylsilyl]oxy-7-octene-1 synthesized in (v) -yn-4-ol (Dan: R1=Si Ph,,
B11) 768 my in methanol (100ml
), 20 μm of para-toluenesulfonic acid was added thereto, and the mixture was stirred at room temperature for 12 hours. After that, add sodium hydrogen carbonate and stir for 30 minutes. The mixture was filtered for 1 hour to remove insoluble matter. Then, the solvent was concentrated under reduced pressure and purified with a silica gel column to obtain 2
50 μm of 1-octene-fin-3,5-diol@ was obtained. The spectral data of this product is as follows.

1) I NMR (CDC23,908)12)δ
1.7 -1.9 (n+, 2H)2.0 -2.2
(n+, IH) 2.3 -2.5 (l, 2tl) 3.9 -4.3 (l, 111) 4.2 -4.7 (III, 111>5.0 -5
．． 5 (+++, 2tl)5.6 -6.2 (t
a, 111) (n) Synthesis of 3.5--his(2-tetrahydropyranoxy)T) (P) (1-octen-7-yne-3,5-diol 0241■ obtained in D (IGOm+) was dissolved, 3,4-dihydropyran (0.35 ml) and pyridinium para-toluenesulfonate (20 ml) were added thereto, and the mixture was stirred at room temperature for 7 hours. Potassium carbonate was then added and stirred for 30 minutes. The insoluble matter was removed by filtration.The solvent was concentrated under reduced pressure and purified with a silica gel column to obtain 3,5 of 396
-bis(2-tetrahydropyranoxy)-7-octyn-1-ene (10:R12R2=THP) was obtained. The spectral data of this product is as follows.

IHNHR (CDCffi3.90HH7) δ 1.3
-2.2 (m, 13H) 2.3-2.7 (l,
2+1) 3.3-3.6 (IIl, 2tl) 3.7-4.4
(In, 4 old 4.5-4.9 (m, 2tl) 4.9-5.4 (In 2t ri 5.4-6.2 (II, 1ll) IR (neat) 3330.2970.2130. 1
440.1350°1200, 1130.1080.1
020 an-” Example (1) 5.7-pis[(1,1-dimethylethyl)diphenylsilyl]oxy-8-nonen-2-ynoic acid diR3=Et
) Synthesis of 3,5-bis((1,1-dimethylethyl)diphenylsilyl)oxy-7octyne synthesized in Reference Example (1)
1-ene (ヱ: R” =R2=S 1Ph2tBu
) was dissolved in tetrahydrofuran (5 ml) and cooled to -78°C. This solution contains 1.54N n-
Butyl lithium/hexane solution (1.3 ml) was slowly added dropwise at 6-78°C, and after stirring for 30 minutes, the solution was mixed into a solution of ethyl chloroformate (0.32 ml) in tetrahydrofuran (5 ml) (-78°C). dripped into. After the addition, the reaction solution was stirred for 2 hours while gradually increasing the cooling temperature to room temperature. After that, the reaction solution was mixed with 5% phosphoric acid 1
The mixture was poured into an aqueous sodium solution, from which the target product was extracted with ether. The extracted organic layer was washed with saturated saline solution at °C.
Dry with magnesium sulfate. Concentrate the solvent under reduced pressure,
Purified with a silica gel column to obtain 1.02 g of ethyl 5,7-bis[(1,1-dimethylethyl)diphenylsilylcooxy-8-nonen-2-ynoate (I=dan:R1=R
, 2SiPhz tBu, R3=Et) were obtained. The spectral data of this product is as follows.

1HNHR(CD(Js, 90HH7)δ 0
．． 97 (S, 9N) 1.00 (s, 911) 1.28 (t, J=7.0Hz, 3 old 1.7 -2.
1 (tit, 2tl) 2.1-2.3 (n+,
2 old 3.7” 4.3 (m, 211) 4, 19 (t
, J-7,01lz', 211) 4.5 -4
．． 9 (III, 211) 5.2 -5.8 (I
ll 1N) IR(neat) 2970. 29
40. 28?0゜1590.1425,1250゜820 735, 700 2240.1?15゜1110 1070゜can' Example (2) [3,5-His[(1,1-dimethylethyl)diphenylsilyl]oxy] -2-methylenecyclohexylidene] acetic acid ethyl ester (II: R1 = bis(triphenylphosphine) palladium (■) acetate (40■)
and triphenylphosphine (14) to benzene (10
ml) and ethanol (1 ml), stirred at room temperature for 0 minutes, and then added 5,7bis[(1,1-dimethylethyl)diphenyl]oxy-8-nonene synthesized in Example (1). -2-Ethyl yoate (18:
R1=R2=S i Ph2 tBIJ, R3=I'.

t) Dissolve (183+w) in benzene (5 ml) f
::The 6 reaction mixture to which the solution was added was heated to 60'C and stirred for 4 hours. After the reaction solution was cooled to room temperature, insoluble materials were removed using a Florisil column. If the solvent under reduced pressure! 4 m
Purified using L silica gel column to obtain 138 mg of [3,
54::S[[[I,1-dimethylethyl)diphenylsilyl]oxyco-2-methylenecyclohexylidene]
Ethyl acetate (II: R1=R2=Si Ph2tB
u, R3=Et) was obtained. The diastereomer based on the asymmetric carbon atoms of the two silyloxy groups is l-11.
) It was separated by LC. The spectral cheater of the two diastereomers is 1-L.

・Diastereomer [A]...Low polarity 111-N old t
(CDC93, 90H1lZ) δ 0.97
(s 911) 1.0/l (S, 9N) 1.22 (t, J=7.HIZ, 311) 1.5-2
．． 4 (m, 4H) 3.7-4.2 (m, 2tl) 4.07 (Q J=7.Ko z, 211) 5.1-5.
2 (n, IH) 5.3-5.4 (m, IH) 5.7-5.8 (m, 111) 7.1-7.7 (11, 2 leaves) IR (neat) 3080.3060 .2980.2
9501715 1640 1590, 1470°14
30 1370 1180, 1110°910 885
820, 735° Diastereomer [B]... Highly polar' H-Ht4
t1. (CDCl3,908)1z)δ 0.
94 (s, 9N) 1460°1080°700■-1 0, 96 (S, 9H) 1.25 (t, J=7.Koz, 3N) 1, 83 (t
, J=5.1tlz, 2N)2.9 -3.1
(m 2tl)4.12 (q, J=7.3Hz,
2N) 4.0 -4.4 (m, 1ff) 4.5 -4.8 (In, IN) 4.93 (d, J=10.3Hz, 2N) 5.83
(s, IH) 7.1-7.7 in 20 old IR (neat) 3070, 3050, 2960287
0 1765.1715°735, 700 (7)-Process 1635°1105°2900° 3,5-bis(2-tetrahydropyranoxy)-7-octen-1-ene synthesized in Example Reference Example (2) (10: R
1=R2="l"T(P) (302■) was dissolved in tetrahydrofuran (5 ml) and cooled to -78°C. A 1.54N n-butyllithium/hexane solution (0.95ml) was slowly added dropwise to this solution. -78
The solution was stirred for 30 minutes at
ml) solution (-78°C).After the dropwise addition, the temperature of the reaction solution was gradually raised to room temperature and stirred for 2 hours.6Then, the reaction solution was poured into a 5% monosodium phosphate aqueous solution, and ether was added from there. The target product was extracted. The extracted organic layer was washed with saturated brine and dried over magnesium sulfate.
Reduced concentration (concentrate the molasses and purify with a silica gel column, 1
94 mg of ethyl 5.7-bis(2-tetrahyto-1-fubilanoxy)-8-nonen-2-ynoate (11:R'=Dingke22Tl(P,R3=Et) was obtained.The spectral data of this was It is as follows.

” H-NHR (CDCF 3 , 908H2) δ
1.31 (t, J=7.1Hz, 311) 1.4
-2.0 (l'Il, 14H)2.3 -2.6
(III, 2H) 3.3 -3.7 (n+, 2
N) 3.7 -4.0 (n+, 2H) 4.0 -4.4 (n+, 2tl) 4.24 (Q
, J=7.2H7,2H)4.5-5.0 (n,2
Old 5.0 -5.4 (Ill, 2N) 5.4 -6.
0 (n+, Itl)IR(neat) 2970.
2230.1755.1?15. 1630°1440
, 1370. 1260. 1205. 11001
020 am-' Synthesis of Example Et) Bis(triphenylphosphine)palladium(n) acetate (40,4+++g) and triphenylphosphine (14,1■) were dissolved in benzene (10ml) and ethanol (
1 ml) of a mixed solvent, stirred at room temperature for 10 minutes, and then added 5,7-bis(2
-tetrahydropyranoxy)=ethyl 8-nonen-2-ynoate (I=11: RIR2=THP, R3=Et)
A solution of 103 mt in benzene (5 ml) was added. This solution was heated to 60° C. and stirred for 5 hours to react. After the reaction solution was cooled to room temperature, insoluble materials were removed using a Florisil column. Concentrate the solvent under reduced pressure and purify with a silica gel column to obtain 15μ of [3,5-bis(2-tetrahydropyranoxy)-2-methylenecyclohexylidene]
Acetic acid ethyl ester (■: R1=R2=THP, R3=
F, t) was obtained. The spectral data of this product is as follows.

'H-14HR (CDCR3, 90HllZ) δ
1.26 (t, J=7.0IIz, 3H) 1.3-2
．． 0 (n+, 14N) 2.4 -2.7 (III, 211>3.3 -3
．． 7 (l, 1N) 3.8-4゜1 (n, IN) 4.16 (Q, J=7.011Z, 21+) 4.3-
5.0 (L21+) 5.4 -5.7 (l, 2H) 5.9 -6.1 (II, IH)

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[I
] In the formula, R^1 and R^2 are the same or different, a hydrogen atom, a tri(C_1-C_7) hydrocarbon silyl group, C_1-
Represents a group that forms an acetal bond with the hydrocarbon acyl group of C_7 or the oxygen atom of the hydroxyl group; R^3 represents a hydrogen atom or an alkyl group of C_1 to C_4. 5,7-dihydroxy-8-nonene-2- represented by
The following formula [II] is characterized by cyclizing ino acids in the presence of a palladium compound. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[II] ^2 and R^3 are the same as defined in the above formula [I]. ] A method for producing (3,5-dihydroxy-2-methylenecyclohexylidene) acetic acid esters represented by: 2, R^1, R^2 are the same or different, hydrogen atom, t
-butyldiphenylsilyl group, acetyl group or 2-tetrahydropyranyl group (3,5-
A method for producing dihydroxy-2-methylenecyclohexylidene) acetic acid esters. 3. (3) according to claim 1 or 2, wherein R^3 is an ethyl group.
, 5-dihydroxy-2-methylenecyclohexylidene) acetic acid ester. 4. The method for producing (3,5-dihydroxy-2-methylenecyclohexylidene) acetic acid esters according to any one of claims 1 to 3, wherein the palladium compound is a palladium (II) compound. 5. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・［I
] In the formula, R^1 and R^2 are the same or different, a hydrogen atom, a tri(C_1-C_7) hydrocarbon silyl group, C_1-
Represents a group that forms an acetal bond with the hydrocarbon acyl group of C_7 or the oxygen atom of the hydroxyl group; R^3 represents a hydrogen atom or an alkyl group of C_1 to C_4. 5,7-dihydroxy-8-nonene-2- represented by
Inic acid esters. 6, R^1 and R^2 are the same or different, hydrogen atom,
t-butyldiphenylsilyl group, acetyl group or 2-
5,7- according to claim 5, which is a tetrahydropyranyl group.
Dihydroxy-8-nonene-2-ynoic acid esters. 7. 5, according to claim 5 or 6, wherein R^3 is an ethyl group;
7-dihydroxy-8-nonen-2-ynoic acid esters.