JPS6287539A - Production of 3,6,7-trisubstituted bicyclo-(3.3.0)-2-octene - Google Patents

Abstract

PURPOSE:To produce the titled compound, by reacting 6,7-disubstituted-2- hydroxy-3-methylenebicyclo [3.3.0]-ocuanes with an organolithium, then with cuprous iodide and further with an organolithium compound in the presence of a specific reactant. CONSTITUTION:6,7-Cisubstituted-2-hydroxy-3-methylenebicyclo-[3.3.0] octanes expressed by formula I (R<21> and R<31> represent trihydrocarbonsilyl, etc.; R<4> represents H, methyl, etc.; R<5> represents alkyl, etc.; n is 0 or 1) (containing its enanthiomer or mixture thereof) are reacted with an organolithium in an organic solvent, and then with cuprous iodide. Then the resultant is reacted with an organolithium compound expressed by formula II (R<11> represents H, hydrocarbyl, etc.; m is 0-6) in the presence of N,N-methylphenyl- aminotributylphosphonium iodide and, as necessary, subjected to deprotection, hydrolysis and/or salt formation reaction to obtain a compound expressed by formula III (R<1> represents H, hydrocarbon, etc.; R<2> and R<3> represent H, trihydrocarbonsilyl, etc.). USE:An antithrombotic agent, etc.

Description

Detailed Description of the Invention <Technical Field> The present invention relates to 3.6.7-trisubstituted vinclo[3,3,0]-
]Relating to a method for producing 2-ocdene. For more details on history (
0 no meta/-halo (9 levous meclanone class 11: 3,6.7-trisubstituted hisoku (3,3゜UJ-
2-7r Krahn class 6,7-two conversion-2-hituroyano~3-me+renbi/ri1](3-3,U)]4-kutano-ruikira et al. Nko Seki - [Ro.

<Prior art> Lilha Taiclin is inside the L body' [1 month cleansing the proboscis]!
bru prostaclandin (PG and 16^self-'kotoru;a6) It (PGIt) ii, 9-ii
4 oxygen atoms are 1 tyrene A4; te [substituted brosume Z funjin l, a-conjugate, natural prosmeglandin 11' which has a partial structure of dinol ether in tana thousand yen't, It is also a chemically stable compound that can be used as an anti-inflammatory drug after filtration for 5 hours, and can be used as a medicinal drug. Life, 2M of Carbacycline, I'm longing for a sexual body bar, 7, ro 1
7-phosphorus, -4', i.e., 9LO)-meta/
It has been discovered that -Δ6(9a)-prostaglandin l, has the most effective inhibitory effect on platelet and JL functions among these homologs, and VKN is expected to be applied as a medical product. [Ikegami et al., Atraheton-on-Letters (
Tetrahedron Letters), 3
3, 3493 and: J) 497 (1983) r
L l-)Hitc44i11i45”J-1374
45 and 59-210044.

Hitherto, several methods have been known for the production of 9(0)-methano-Δ(](9α)-prostaclandin 11 (incarbacycline), and the safety and use of the method have been reported.
Compile 11, 6 synthesis intermediates, and report t 9
11. (1) Narukami Raya Tetofuhed 1J N Renose <
T@trahedron Letters ) + 24
+ A493 (19813) and Gumistry Letters +
19144, l 069 di-key intermediate
Incarbana-1 Kri/lel Narijou, Natrahe 7 Tron Letters (1'eLrahedron
Letters ) + 24.34 ”j 7(1
983): a intermediate〇h incarno (su17rin131 a top, di1'-nal・1)・→J-siζril nsaieti, riζcal kosaichi 1 nikenyo
(J, Chem, Soc, + Chem+c;t
l CummunIca-wons, ++ 19
84 , + 6 Rii Two-key intermediate A, C5.
．． ．． B11-'-199゜1(4) Shibasaki et al., Tetrahetq/・Lettersl (Tet
rahedron Letters)+25
, 5087i (1184): Key Intermediate 01-1 tJ)l Incalvary 1 Crine (5) Shibasaki et al., Tetrahedron Letters ('11
etrahedron Letters L 25,
1067 (1984): Key Intermediate 4 Nocarbasa 1 Clint 6) Small M Ra, Cumical & Furman You Nile Zlete (7 (Chem, Pharm, B
un, )+32.2866 (1984): Key Intermediate (O4)-Incarbacycline (7) Kojima et al., JP-A-60-28943: Method 7.

Among these seven methods, there are 10,000 methods and methods (
5)) J(a:) is taken as the starting IfA family, and after several steps
The process leads to a key intermediate and then goes through several more steps to obtain the desired product, incarbacycline, so it cannot be described as a flexible manufacturing method. In addition, method (2) and method (3) will eventually reduce the cost of the multi-step process from expensive Corey lactone to obtain the corresponding starting materials and pure intermediates, and also reduce the calculated yield of +T31. However, the problem is that it cannot necessarily be said to be an advantageous method for industry.

In addition, method tt31 t;
is an out of the question method.

Finally, in method (4), the starting material is optically oily (R)-4-hydroquine-2-7 prepared by the method of the present inventors.
Not only can it be easily obtained from coupenanone (Japanese Patent Application Laid-open No. 57-155116), but the derivation of the key intermediate from the starting material poses no problems for industrial V-1 (it is a method that can produce A. However, the key intermediate In the step of transferring from the body to the final incarb→l゛<41), the use of organic mercury compounds, loss of regiospecificity, and
The major drawback is that the overall yield is low due to a number of problems such as the contamination of by-products, making it impossible to use as a practical or industrial production method.

1.1 9(U) l p 7
- △ti (9cc) - Booster crandin l, M (incarbacycline knowledge) 3,617-Miokikyohinoku ρ (3,3,Ll 1-2-Sai1in class industrial J
We present a modern manufacturing method that can delay the production of A.
(It's about doing.

In view of the above-mentioned points, the inventors of the present invention (4 compositions and effects of the present invention) have prepared 9(U)-methanomero(9(U)-methanomerol)(9(U)-methanomerol)(9(U)-methanomerol)(9(U)-methanomerol), kl(1-nocarba) Practical t of cyclin classes
J [After extensive research to find a method for cracking, we have arrived at the present invention. Well, in this invention,
compound represented by the formula 1, l] and its enantiomer, or a mixture of their ratios, fi, 7-2-directly converted-2-hytroya 7-3-7,000 lenohink 1 (3,3 , 03 noncutanes to +f in a conspiracy body, lithiums, together with iodized steel and /lX reaction 1 sushi.

After 7, the following formula [1■] Li −(CI,)m-R'' --L 11)
By reacting the naum compound represented by the formula in the presence of N+N-menalphenylaminotribnalphosphonium-codite, a hydrolysis reaction,
and/or a salt-forming reaction. a (3,3,LJ J-2-r Kudens are provided and the above formula (1
) is represented by the above formula (13 stereochemical construction formula), and the following 1 generation is obtained by obtaining one of the adjuncts and their trap images or their ratios, represented by the stereochemical construction formula of the above formula (13). 6.7 - Sancho P - 2 - Draw death no 3
- Menarenohi 7 no Kuchi (3, 3, OJ octane is a known, -r product, and the inventors separately worked for 10,000 V
This is 7L.

That's right! -, cited references (beam materials, 7r trahedron let's)
ters), 25+5υ87 (198.1)
6, produced by method S or a method based thereon;
7-2V (Kyo-2j-Hitokinome Senrupine 7 rJ
L 3. ：L"-2-Departing from Okuan tomb and L(
It is a raw material for the method of the present invention, and it is a compound that can be used as a material for the method of the present invention.

The above dα formula (in IJ, X Next.

(C, ~Ct) hydrocarbon silyl group, or (C, ~C,)alkylsilyl group, such as (C, ~Ct) hydrocarbon silyl group, tongue,
t-Fnaldiphenylunril') J: 5 Nasifenyl U, ~C2) Di(c, -e, J alkylphenyl)kr f or tribene/ru/ I would like to mention one preferable group such as a lyl group. Tori (C, ~(
:, ,+Aryalsilyl, diphenyl (C+~C,)
Furkyl/lyl, noenyldi(C+-C4)al, 7-rulyl groups are preferred, and fr-7:1, but t-punaldime, 1000-rulyl groups, and trimenalsilyl groups are sometimes preferred.

An example of a group that forms a tar bond at the core with the oxygen atom of a hydroxyl group is a met→menal group.

1-Eng)-? Cylinal group, 2-methyne-2-propyl group, 2-ethene-2-propyl group.

(2-methofonetov-nramethyl, pennruokinemethyl group, 2-tetrahydro7phnyl group.

2-tetrachorfuranyl AI or 6,6-cymethyl-3-:fyasa-2-A゛1,000 nonbicyclo3゜1.0
] Name the hex-4-yl group. 2-detofhyto p-pyranyl lk, 2-tetrahydro 7-phenyl, 1-j-l 4-enal, 2-ethoh←cy2-7
'lopyl, (2-methocyce)-+no)methyl, 6.6
-Nomethyl-3-Osensu-2-Oyanbinkuro (J,
1.0) 4-al, Qr+; preferred for %. Among them, 62-natofuhytroviranil is T+! preferred for f.

It should be understood that these noryl groups and the acemer bond forming group are protecting groups for water groups. These protecting groups are easily removed with a weak (from useful to neutral J-) hydroxyl group in the final product, making it useful as a free σ) hydroxyl group and -C. It's coming out. Gakatsu ℃
Protecting groups of water groups having such a monomorphic form can be used as substitutes for the monolithic groups that form annryl, shield, or acetal combinations. .

Upper + iri formula (IJ v Kooi + t' is a hydrogen atom, menal group.

Or use a hinyl group.

The above formula [mouth odor element 1e] is a straight or branched C3-C, alkyl group containing an oxygen atom and having good temperature.

Argunyl group 4L<f Air 1,000, ≠; Argunyl group or unsubstituted 7-L-nyl group: Substituted 4) or unsubstituted phenol 4) or unsubstituted pheno-Cs;
C8゜incoualkyl group; rectangle f is C1-C, alkoxy group.

phenyl group which may be substituted or ℃, or *c, which may be substituted or ℃, -e, .inc+j directly replaced with t A straight chain or a branched line C5~CS representing an alkyl group or a straight chain or an oblique line C3~C,
2-7
−? In addition, there is no IJI nil, M, 7'-y-ru, ben+ru group, heyanole, and hefnal.

2-heyanlunotongue, 2-menaroo 2-heyanlujo.

2-menal/nal, i,'=,'l-methylbennal.

This can be done by adding the 2-methyl, 1,000, 4, i, 2-+, and so on groups. Funar, Bennar, Heyanru, -\/Naru, 2-Hekinru, ? &
, 2-menaroo 2-to 1,000/le 4+2-me, 1,000 ru still &,
2-I like the menalbennal layer.

Straight chain or branched chain Cs with good temperature when referring to bean atoms
-C, alkynyls include, for example, 1-7thylhinyl, 2-bouylallyl, 2-benanyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-h4-2yl, L4-dimethyl-13 - Bennard. 5-hefnanyl, l-menal-5-hex vinyl, 6-menal-5-
Preferred are hef'nanyl, 2,6-dimenal-5-hebutenyl, and the like.

Branched chain (straight chain or branched chain that includes children and is good for ℃)
fl (,:, ~C, Alyanil purchase and L″C are, for example, i
engineering, 2-]-nyl, 2-bennanyl, 3-penenyl.

■-Methyl-2-ben→-nyl, ■-methyl-3=pentynyl are better.

Substituted phenyl group. Substituted 7 Yamanosenshi group, or '-'s
= C + o substitution - t substituent of chloroalylic group, and °C is, for example, ~p gene atom, protected hydroxyl group (tl:j, enryl 7r, 1,000 cy group, C5 ~ C, alkoxy group, etc.),
Examples include 01-C4 alkyl groups.

C,-○,.・') Nkuar thousand ru 4 ugliness and Lt are 1 analogy (1, cyclopropyl eyebrows, tsukuben tingle 茫, nkroheyan l+/!, nkroheya y =! shi A chicken/ri 1 heptyl group, tsuku 0 = (ri Senru Kyou, Nukuifde/le leather, etc. can be graduated from rj.

A cyclohexyl group is preferred.

C1-C, alcoyane, substituted n (also optionally phenyl group, substituted 1-(7j-coconut group), or substituted C1-C1°/chloroaryal group There are 10 "1-< is a branched chain C1~C
In the s alkyl group, C9 to C6 alkone groups include, for example, metho-1-7 group, Etoya/group, Flohil-(
1,000 groups, 1 group to nbrovir T.

Notoseso 6. Examples include a t-butoyaso group and a hesyl-butoyaso group. phenyl group optionally substituted with ll1t,
[Changed (myoi)] ↓noxy group.

Alternatively, ℃ 1 is good 03 ~ CIQ nog [Fal thirty -group (') f conversion and c8 ~ c4 ゜ tsuku O -al -yal group, or the above -mentioned example and + AJ 1 can be ￥. . l! L region or branch g4C, ~C, al.
Hill group and L° C. are, for example, menal, &, ethyl group, furoyl group, isopropyl group, gunar, 1-notyl i +
See -7 tyl group, t-butyl group, benal group, etc. can be mentioned. Ka6 R' Totoshiro includes bunal, pentyl, hexyl/heptyl, 2-hexyl,
2-me+ru 2-hekinru.

2-Methylbutyl, 2-menalbenthyl, Schiff1nohenal, cyclohesocil, phenyl, phenoyan, cyclobenthylmyl, 2,6-cymethyl-5-hephanyl,
It is possible to cite cyclohenlume, 1,000, and the like as a preferred option υ).

Incidentally, the substituent group may be bonded to one position thereof.

In the above formula [1], Cn is 0 or l.

In addition, the compound represented by the above formula (1)
7 (3, 3, 0) : 't Cutan ring self-material and its hincro (3, 3, U J bond L" (Φg
! Substituent bond L-C Irocarbon has stereoisomers due to the small angle environment, but according to the present invention, it includes any stereoisomer, and also these stereoisomers of arbitrary assignment. A mixture is also acceptable. In addition, the compound represented by the formula tL refers to all of these stereoisomers and mixtures of these isomers in arbitrary proportions; Mosquitoes are also good things L''
C can be given.

Provided by the present invention is 6 represented by the above formula [l],
7-disubstituted-2~辷N (,,+ya7/-j-megolenebicyclo(3,3,tJ)'f Preferred y゛Specific examples of ctanes and R31 is a hydrogen atom Enumerate in the form of compounds - [And the following 5 oaths/konaro.

(1) Four examples (101) of compounds where n is 0 (I S , 5 S , 6 S ,
7 R) -2-hyroxy-3-methylene-b
((E +38)-3-Hitoja/-1-f Quanyl)
-7-Hitoroya/Hishi/ri”t3.:(,0]octane(102) (IS, 5S, 6S,
7 i7) -2-hydrothousand/-3-methylene-6-(-
<h2+38)-3-hydro-thousand-5-ethode-1-
pentenyl]-7-hytrose/hisoclo(,3,3,
U3:4-cumene (103) (lS,
5S, 6S, 7R) -2-human g-4
"So-3-methylene-6 ((E.

:iS) -3-hydroquine-5-phenoquino 1
-benzonyl]-7-human quinohink ρ(3,3+O
J octane (104J (l S , 5 S , 6 S
, 7K) -2-human p-? N-3-Mesenren-
6-((k:.

3S)-3-human 7-7-4-(riorJphenoquine-1-bunanyl)-7-human O xybicyclo(3,3
, υ] Octane ("υ5) (Is, 5S, 68.
7K)-2-hydroquine-3-methylene-6-((E.

:3S)-3-hydroxy-1-nonenyl"-7
-Hido+81-? cibicyclo(3,3,0)octane uuh) (IS, 5S, 6S, 7R) -2-human LJ thousand so 3-me+lene-6-((E.

3S) -3-hydroxy-1-decenyl]-7-
Hydrosenbiclo(3,:i,0)-xcumene(107)(lS, 5S, 6S,
7K) -2-hydroyasi-3-nona1/n-6
-[(E.

3S)-3-hydroquine-5-methyl-1-nonenyl]
-7-Hido 1,000 Cypin black (3,3,0) octane (1 (18) (l S, 5 S, 68, 7
1 road) -2-human c2 kin-3-7 thousand len-6-[(k
Sh.

3S, 5R)-3-1nido-c3,000-5-methyl-
1-/unyl]-7-human I:I thousand bicyclo(3,3
,0) :Octane (Is, 58,6S,7R)-2-
human 3-mesenshin-6-((h:.

38.5S)-3-human I:l-? Sea 5-Menaroo 1
-7Funyl]-7-Hydroxybisic o [3,3,O
J octane (110) (l S, 5 S, 6 S,
7K) -2-hydroyac-3-methylene-6-
((k;.

3S)-3-hytroyan-5,5-dimethyl-1-butenyl]-7-human 0,000-thenyl (3,:LO) (lsI5s, 6S17R)-2-hydro-3-menalene-6 −[(J!;.

3S)-3-human ayan-3-cyclobenal-1-bupbenyl]-7-hydroso/binculo(3,3,tJ
) Octane (112) (IS, 5S, 6S, 7
k) -2-human p+-3-menalene-6- [(E.

3S-1, 1-Human g-3-Cyclohane-1
-propenyl]-7-hydroyanvinculo L 3.3.
LJ) Octane (113) (ISj58,6S
, 7K) -2-hydrothousand 3-menaV:'-6((v
+38)-3-human 0-? 4-en cloben 1,000 ru 1-7 tenyl]-7-hydro 1,000 sibincμ(3,3,(
1) Octane (11・l) C10,5S, 6S, 71t)-2
-Hitojan-3-Menare7 6 [(k-+38)
-3-Hydroxy4-cyclohekyne-1-ph1nyl]-7-hydropyanhincro(3,3,tJ);octane(l15)(is,5S,LlS,7R)-
2-Hydroquine-3-menalene-6-L(E)-3-hydrocenyl:3-M+L-octenyl]-7-human GJ octenyl[,1:L(J]octane (116) (IS, 5S, 6S+7R) 2-Hitroyan-j-Mejushin-6-((j;)-3-Hitroyan-3-Me+Ru 5-Ethothen-1-Bennanyl]-
7-Human IJ Ya7 Bisik O1:4,3.03Nectane (117) (IS, 5S, 6S, 7R) -2-Hydro-1-3-Methylene-6-((E)-3- -3-me+ru-l-nonenyl]-7-hydroxyshink [2L 3,3゜OJ nonenyl (118) (l S, 5 S, 6 S
, 7)-2-hydroxy/-3-methylene-5-((
W)-3-hydro;
:nikutsu/ (111() (I Sl 5 S, 68, 7
R) -2-Hydrothenone-3-menalene-h L
(E +38)-3-hydro4-7-4-methyl-1-
octenyl)-7-hydroyajibicic I: +(3,,1
,0) ,r shoes/(121B (l S ,5
S, 6 S, 7 R) 2-Neat Lff Yassi 3-Methren-6-((E.

3S)-3-Hydroquine-4,4-dimethyl-1-octenyl]-7-human p. "C-3-methylene-6-((k:)-3-
Hydro7-3-hinyl-1-octenyl]-7-hydro-Okimbicyclo[3゜j, υ]octane (122) (Is, 5S+68,7k)-2-hytroyan-3-methylea6-((E)-3- Hydroxenyl 7-3-hinyl-l-nonenyl J-7-hitroya 7'bincro (:3.:s.

uJ, q shoes/ (123) (ls, 5.-i+68.7R)-2-
human-3-methylene/-6-t, (E)-3-human-3-hinyl-ξ)-7,000-1-nonenyl J
-7
-hi l-Ij goo-/-7-me+nod-1,,fi-f
Phtagenyl J-7-human 0yanhicyclo(3,3,0
];t shoes/(125)(Is, 5S, 68.7+4
)-2-, trotin-3-methin-6-[(IF;
.

3S)-: Hydroquine-8-Made-1-Rue 1.7-
7nadienyl]-7-hydro IJ ~ Novink I:l (3
, 3, υ] Fukuri no (126) (l S, 5
S, 6S, 7K) -2-Hitoroki/-
3-menane y b ((ih.

3S)-3-Human IJ Yang-9-M+L1,s-tecandienyl]-7-HydroyajibisikO(3,3,(J
) Octane (127) (lS -Hydroxyhincro[:(,3,0]octane (L) Specific example of a compound where n is 1 (21JIJ (Is, 5S, 6S, 71()-2-
1 Need O Dry Sea 3-Methylene-6-L(k;)-4-
Hydroxy-1-octenyl'-7=hydro-1-octenyl (:(,3,U) octane 202) (l S, 5 S! 6 S,
7 R) -2-hydroquine-3-methylene-6-(
(E)-4-Human "F; Key/-5-Nito? No 1-
pentenyl) -7-hytroyanobichu (3,:LU
J octane (2tJ3) (l S , 5 S , 6 S
, 7k) 2-hydroyac-3-methylene-f
i-((E)-4-human 0yan-5-nouenoyan-l-
Bennanil) -7-Ll-+Konanhi/Taro (:L3su) ten thousand cumene (2tJ4) (l S, 5 S, 6 S
, 7)-2-Human IJ Yano 3-Mesenren-6-
((EJ-4-human 1-/unyl 1-7-hydrobinoclo(3,3,tJ);I'cutane(2
L15) (lS, 5S, fiS, 7 butt no 2-hydroino 3-7 thousand len-6-((h:J-4-human p-?
N-1-Deseni・1・]-7-(-toC"Kinhinkuro(39,'1.υ";rTough2/(206n(l
s, 5S, 6s, 71ζ) -2-hydroyac-3-methylene-6-((E)-41-human-quino-5
-Menalu l-Nonenyl” -7-Hitroyanhinta τ
ノ(3,:3゜0)Ouctan (207) (l S, 5 S, 6 S,
7 iζ)-2-hydroquine-3-methylene-6-(
<1 = 4-human p Yang - 5,5-dime thousand Roux 1 = non-tenyl J-7-human p xybincro (3,3, OJ Octane (208) (l S , 5 S , 6 S
, 7 R) -2-hydrothene-3-methylene-6-
((E)-4-Hydroxy-4-Enterbenal-Pdenyl)-7-Hydrooxy-4-Nterbenal-Pdenyl [3,,3
,0] Okkun (209n (IS, 5S, 6S,
7 tt ,)-2-human pyannow 3-menalene-6
-[(E) -4-Hydroyan-4-Nkleheyasil-1-butenyl J-7-Hydroyanhi/Riu 13,3.
(J) octa/ (21uJ (+, S, is+bS+71c)2
7-63-menalene-6-(1)-4-methyl-1-octenyl]-7-hytroquinehycyclo[flame 3, U) octane (211) (IS , 5S, 6S, 717in-2-human I
j quin-3-methylene-6-((E.

4s)-4-Hydrosocy4-methyl-1-ocdenylJ-7-hydrobicyclo[:i, :number, 0'Jy
9 Men (212) (is, 5S, 68.7K) -2-Hitroya, -1 U-Menareno-6-1 (E14R) -4-
e-μyan-4-menaloo-1-4-ri-T-nil]-7-human rJ 1,000 yen piculo (3,3, OJ ectan (213) (xS, ss, 6S, 7xt) -2-
Human I: I-? sea3-menalen-ti-cca)-4
-Human c27-4-methyl-5-ethoxy/-1-benanyl]-7-human pYambisi70: 3,3. OJ octane (214) (ls, 5s, 6S, 7R)-2-human Ij-? -3-menalene-6-((E)-4-hydro-4-methyl-5-phinoxyi-benzonyl-7-human-poxybicyc-o (3,3,OJ Tcutano(215J (As, 5St6S, 7R )
2-Hydroxy-3-methylene-6-[(
Misaki-4-hydroquine-4-methyl-1-/nenyl]-7
-Human t:I 1,000 octane (3,3°0) octane (216) (LS, 5S, 6S, 7)
15-';'me-thousand-nonenyl'-7-hydroya/
Vinclo(3,j, (J J Octane (2+7) (IS, 5S, 68.7ft)-2-hydro(-no 3-methylene-6-L CE)-4-hydro:?/-5-methyl-1 -octenyl J-7-human O
Sennobi Tsukuro 1 5.0] Octane (218) (I S, 5 S, 6 S,
7 R) -2-human c7-1-c3-men+vn-
t;-((h:)-4-human p =1-cy4-nonal-4-ncroperu-1-7denylJ-7-humanc
Noyanbink O (3,: U, tJJt9 men (21)
(ls, 5s l 68, 7
Le )-2-hi) g-? No 3-Menalen-61 [(
E) -4-Hydro1/-4-MeF-4-72a Hekyn-1-7-tenyl]-7-Hydo-a Quinpink u [3,
3, υ] Octane (220) (l S, 5 S
, 68.7 K) -2-human 1,000/-3-menale/'-6-((E)-4-human 1,000,7-4-vinyl-
1-Otatenyl'-7-Hytroquine C3 (3゜3
．． 0] Oritan (221)
(IS, 5S, 6S, 7R)-2-Hitroyan-3-'
-methylene-6-((E) -4-humanC3-?So4
-vinyl-5-etquin-bentenyl J-7-human l
J: + Mbishiku [, U, 3. UJ Octane (222
) (is, 5S, 6S, 7R)-2-human O+7-
3-menalene-6-L(E)-4-human axy-1-
Vinyl-5-phenoquine'-1-pennanyl]-7-hydroxyvinculo[,3,3,t) :l Octane(
223) (l 8 , 5 S , 6 S , 7
K ) -2-Hydrothen-J-Me+Lene-h-L(
EJ-l-hydro-4-vinyl-1-)
-7-human GJ 84-mbicyl-I L 3,3゜0] Tcutane (224) (ls, 5s, 6S, 7R) -2-human-cai-3-menalene-6-[(E)- 4-Hydrochlorine 4-vinyl-5-menal-1-nonenyl]-7-
Humanoquinbintaro (3,3,O)octane (225) (IS, 5S, 6S, 7RJ-
2-Hydrocyclo-3-methylene-6-((E)-4-hydroxy-4-vinyl-4-cycubenal-1-bunanyl)-7-hydroxybicyclo(3,3,tJ)octane (226J (IS, 5 S, 68
, 7k) -2-human oyannow, 3-methine-
6-((E)-4-hytroyan-4-vinyl-4-chlorohefluorene-1-cutynyl)-7-hydrococonut di(3,3,0)octane (227) (ls+58
．． 6s, 7R) -2-Hytroloki/-3-methylene-6-
L (IE)-4-human qx'l-methyl-1,6
-ocmesienyl'-7-hydroacibisicou[3,3
, (J J Fmen (228) (l S , 5 S
, 6 S, 7 K) -2-Beatro 4-No, 3-7 thousand Ren-6-IIE) -lI-
Hitoro? No-8-methyl-1,7-nonagenyl”-
7-Human IJ Yanohi/Rig[3,3,S]1 Cumene (229) (i S, 5 S, 6 S,
7 R)-2-Human mouth-Vn-,
1 - Menu - (i - ((
I E )-4-: (-human gkin-9-fu 1,8-decanenyl J-7-hi)・1 coconut a
(3, 3, OJ Aucmen ℃ Represented by the above formula (1) 6,7-disubstituted-2-human 1kin-3-me + Renhinoku a [, U.

3.0): Specific examples of s-cumene include the above-mentioned R.
"and 1 (as a specific example where 31 is a hydrogen atom, R11 and R3' of the above mentioned compound are the above-mentioned R" and 1<
Examples include compounds protected with the protecting groups specifically exemplified as bases of 31°C, but are not limited thereto.

In the method of the present invention, the above-mentioned 1-61', the formula (I
1j, 7-disubstituted-2-hydrotine- substituted by J
3-Methyllenhincro(3,3,(J)octane) reacts with an organic compound in an organic medium, then reacts with cupric iodide, and then further reacts with an organic compound represented by the formula (if). The thylamine compound is reacted with N,N-methylphenylaminodripthylphosphonium iosite in the presence of thylphosphonium iosite, and if necessary, subjected to deprotection reaction, hydrolysis reaction, and/or salt formation reaction (also known as VC). More targeted expression c+it]
3,6,7-trisubstituted bicyclo (3,3,t
l) Derived from -2-ocdenes. The above reaction is basically based on Y. Tanigawa et al., Journal of the American Chemical Society, (J.
Am. Chem. Soe ■. 100. 1: Implemented according to the method of 4610 (1978).

That is, the fi IJ used in the above manufacturing method
For lithium and R4, n-butyllithium or methyllithium is preferably used. The amount used is 10.8 to 1 mole of 6,7-211-substituted-2-hydroxy-3-menalenbicyclo(3,3,υ)okukume represented by formula IIJ.
1.5 mole times, preferably 1. The reaction temperature was 8°C to 50°C (or -40°C to 25°C, and the reaction time was different from the reaction temperature). , for example, 2 LJ -C” (: is 3
The deviation of 61tL by about fJ is about 10. The process of the invention - (: is replaced by the formula [1] according to the step of interest, or 7-trisubstituted-2-hydroyasis 3-menasis/mbishi47..+ (;(,;3゜OJ: t Cumenes are f
7) There is 11,000 um of Arcoyasito and 1 Natsu.

Next, this bath plate was reacted with the primary iodide to form a Sazumata organic steel+Rum compound 1;4e. The cuprous iodide used is also represented by the formula (1): Vr, i'! l-”(
The reaction temperature is -100C to 50C1, preferably -78'C to 25C. The time differs depending on the reaction temperature, but at 20℃ it is 305+1'4
It is sufficient to react with Be.

In the method of the present invention, the above-mentioned 11 copper tin compound 11 thus obtained and the Fiid formula (11'IL+ -(
CH, )m −R”
--Llf) In formula 1, 1t11 is a hydrogen atom IC! ~
C6()) The reaction is carried out by adding an organic lithium compound represented by the sum of p, l or 1.

R'' in the formula (It) is a hydrogen atom, a C7-C1 saturated or unsaturated hydrocarbon group, a hydroxyl group, or 4-methyl-2,6,7-)oxabicyclo(2
,2,2]] oct-1-yl, and m represents an integer from O to 6. As a saturated or unsaturated hydrocarbon group of C, -C, (is an enal group or a vinyl group.

enanyl group, cyclopentyl group, cyclohexyl group, phenyl group, etc.
)-methano-to 6(9a)-prostaglandin l, M
In order to lead to (incarbacycline), a vinyl group is suitable for i and 1, and in this case m is preferably 2.

In addition, as the protected hydroxyl group, the above-mentioned 311 and >t
Hydroxyl groups protected by the groups listed in sl are preferred, and this is also 9
This is preferred because it can be easily guided. 4-methyl-2+ 6
+ '/- Triunion 2.2.2 J oct-1-yl group is a line-maintained ester group, and since the oxidation conditions are the same as the target product, 1 (among 11, the optimum group binding is In this case, m is preferably 3.

Such single lithium compounds can be prepared from the corresponding 7cJi and iosides, such as t-7tirinium and lithium anionine fusical baths (such as 1enaphthalene, 1-(N,
N-dimenalamino)-naphthalene, 4,4'-di-t-methylbiphenyl.

It can be easily obtained by reaction with ammonia etc.

The amount of violet of the organolithium compound used is 0.8 to 20.0 times the mole of the compound of formula (1), preferably 1.0 to 20.0 times, preferably f
The reaction temperature is preferably 1.2 to 5.0 mol, preferably 1.2 to 5.0 mol.
Preferably, fL< is carried out at -78°C to -40°C, and about 10 to 30 minutes is sufficient for 56 hours.

The reaction is carried out by addition of N,N-methylphenylaminotributylphosphonium iosite.

The method for synthesizing this reactant is described in Y above.

It is preferable to set the temperature to 48° C. for NlN-dimethylformazole when adding this anti-abrasive cutting to C16 as reported in the literature of Ranigawa et al.

Before using this reactant, the temperature of the compound vc of formula (1) was 0.8°C.
~5.0 times by mole, preferably 1.0 to 3.0 times by mole, preferably 1.1 to 2.0 times by mole for bamboo]1 is used, and the reaction temperature is -1t)'C~5υ゛C1 preferably -78
The temperature ranges from 25°C to 25°C, and a reaction time of several hours at 25°C is sufficient.

Such reactions take place in organic media from the first stage.

Such an organic medium is hexane.

Benzene, ether, tetrahydrofuran, dimethane, diosethane, menalene chloride.

1-, 1N-dimethylformamide, etc.
It is carried out in a medium system more than Dan, but hexane.

Tetrahydrofuran and N,N-dimethylformamide are particularly preferably used. It can be used as long as the reaction is smooth/C entraining, but it is a waste.

The concentration of the reactants is 1.0 to 100.0, preferably 5.0 to 50.0, and the reaction is carried out at a concentration of 1.0 to 100.0, preferably 5.0 to 50.0.
□ Or <Because of the reaction that resulted in Li]! ! What is the notification? □I'm ashamed of the way I handled it! 1
t゛・Relie" 1: Hesensan, Benmen, petroleum ether, ethyl ether. 1 ￥ Add 1,000 yen of ethyl water to the water and add the samurai's organic mixture to Ichichichi. 1
) 1st prize brine: etc., and after drying with a desiccant such as anhydrous maginolam sulfate, anhydrous waxy sodium, or anhydrous calcium chloride, the organic medium is removed under reduced pressure to obtain a crude product. Take the crude product and empty it according to your wishes.
□Mucroftography. Through purification methods such as Hironowa chromatography and liquid chromatography,
#1 - Can be made. :
(3, ti, 7- represented by the above formula (lit)
Trisubstituted bisic I: +(3,3,U)-2-octenes, R2 and Ro are preserved &! Moreover, + is the expression (
IJ: conversion of the raw material compound into the form 1 as it is 8
You can get things. In this method, the obtained product is further subjected to deprotection reaction and hydrolysis reaction if necessary.

and/or subjected to a salt-forming reaction to finally form a mixture of a compound represented by the following formula (IIIJ) and its enantiomer, or any of their enantiomers.
7-Three-Kyakuhinokuro L, i, : 3 and U J-2-Okunan's, 1 that is 9 (0) -A agate, l Muro (! ) is issued as a public bond.

Removal of the protecting group of the hydroxyl group can be carried out if the protecting group is a shield that forms an acetal bond with the atom of the hydroxyl group (for example, acetic acid, P-toluenesulfone 1 kind of viridinium salt ff
2 is positive 11-n father exasperation 4 nW valley as catalyst (-1 example f
j, water, lack of trahi l-'u]゛7/'.

This reaction is more conveniently carried out by using chemical ether, dioxic acid, acetone, ayatonitrile, etc. as a reaction medium. The reaction is carried out in a temperature range of -8-78'C to -h:iu'C for 1°C to 3B.

Further, when the protecting group is a (C, -Cy) hydrogen ash solyl group, for example, a fluoride, tetofuptylammonium fluorite, and a cephram fluoride.

141 (f
) are carried out in a bath medium at a similar temperature and for a similar period of time.

In addition, 4 to 11 is a 4-methyl-2,6,7-trionethyl group(2,2,2)oct-1-yl group.
(lit), under the above-mentioned deprotection conditions of the preserved hydroxyl group (for example, acetic acid, p-toluenesulfone 1
reaction under a catalyst such as a pyridinium salt or an ion-exchange resin), and the 11 is 2.2=bis(human l:l-
1"Nme 1,000) Prob-1-1" Coconut carbonyl group VCK? I can get it.

This 2.2-bis(humanofcymenal)prob-1-
The yloxycarbonyl group undergoes the usual hydrolysis reaction of an ester group, i.e., water? : Or linium hydroxide, sodium hydroxide, potassium hydroxide and -40C in a bath medium containing water.
-1(0°C, preferably 10'C to 50'C) by reacting for 10 minutes to 24 hours to convert 1(0 to a compound having a carboxy group).

According to the present invention, the compound having a carboxy group produced from the hydrolysis of anti-bVC as described above is optionally subjected to a salt-forming reaction to give the corresponding carbonic acid salt. The salt-forming reaction itself is known and includes 1. Rilphon rλ and approximately the same amount of potassium hydroxide, monolium hydroxide, sodium carbonate, etc.
N7nia, Trimenalamine, Sevenanoe% / -J+-
7: By carrying out a mid-phase reaction with 1 molpoline in the usual manner,
;a.

In addition, the adduct of formula IIJO in which R'' is a vinyl group can be expressed by the well-known 1h...
Awakening reaction at i
4 of them are asking for that ester, cuckoo!・Ask the A-ton rate cast body・Two togade? ! reactor.

The formula obtained in this way] is substituted by the former. Information 6.7-trisubstituted bic(ko(::S, :逼, l+) Specific examples of 3-2-octenes and L″′C are the starting point of the method of the present invention and (
- formula (represented by IJ, fl, 7-21d-2-)
Nido 0-? C3-menalenbicyclo(:i, :i,o
) xi' Kutakume specifically exemplified the products of chemical formula 11 (products obtained through deprotection, hydrolysis, and salt-forming reactions).

Is it like I explained it? The above formula (■6 represented by J,
7-disubstituted-2-human-quin-3-menalenbi/riO[
3,:3. υ" Octene 17 is used as a starting material and the 3,6゜7-trisubstituted bicyclo(3,3,0)-2-"octenes represented by the above formula [1nJ are converted into As for the method of crawling, (ll) is used in the above-mentioned manner.

(, 7j Hon'ble Shirikiun's f-bribe synthesis) L-body hihi 1 standing position) j! ; It lights up and the yield is also good.

(3) A practical production method such as 0, where the production of the product is easy, is specified by PF,
i is for people.
However, the present invention is not limited to these.

Example 1 (is, 2R8, 5S, 6S, 7)-2-human 1-
A-C, U-Menalen-6-CCE, :3S)-:U-wo 17,000 Rujimenalunriruoyashi-1-Furi τnil J
-7-t-gushirugimenarunril sr -t-7 hincro (3,3,0) octane (2,42y, 4,7
smmol) of tetrahydrofuran (x5g?)
Awakening to Alg by n-bunarulinaqum (1,5
6M.

3.65 at, 5.7 mmol) was added at 0°C and stirred at room temperature for 30 minutes. This fr4 reason is 178
Cupric iodide (1,36 & , 7,1
A suspension of 3 mmol) was heated to room temperature.
Stir for fJ minutes.

On the other hand, this originally contains naphthalene (7, (1,!+').

s 4.6 mmol) of tetrahydrofuraf (30
d) Metallic lithium (380Ihfl, 54.
6 mmol) f! : Added at room temperature, cooled to OC after layering, and continued stirring for 5 hours. 1 for 178C on this bathing armor
-(,3-butocohppropyl)-4-methyl-2,6,
7-Dolioxabicyclol: 2.2.2 ) octane (1.1.l- of 4-gulo-7bumenic acid) lis(hydro-7/mthyl)emene orthoester; h, s s Jl
+27.3 mrnol ) ')) Tetra c a fufun (1514) The bath solution was taken up and stirred at -78'C: for 5 minutes. 1'7 for the bath liquid that was prepared based on Korin Yokuken.
Boil overnight at 8'C and stir for 10 minutes at 100°C.
mmol ) of N,N-di) 1,000 ruphor A amide (2
A bath solution was added, the temperature was raised to 9°C under cooling, and the mixture was stirred at room temperature for 31 hours.

Reaction 1: Add saturated ammonium chloride to the batter in a water bath and extract with a trowel and hexane. After washing the obtained organic 1 with brine, dry over 72 tons of anhydrous sulfuric acid. , a side dish i
1L Matako-E paraboloid is a samurai. Column data rJ-
7 togufufu 1- () 11: r-thylamine-treated silica gel, heximension: ether-9:1)K
N L C(l S , 5 b , h
S*7K),'3
(4-(4-nonal-2.6.footly4-?sahishifuchi(2,2,2)octo-1-ia1.)methyl]-6-((h:,:u5)-1u- L-bunaldimenalsilyloxy-1-ectenyl) -7-t -
7'su, dimethylsilyloxybisigu (3-:3.
0) -2-octene (2,52M, 3JOm
mol, 8υ′) was also obtained.

NMR (CL) (1!, )tj:0.0:3(1
2Lt, s), f), 73 (31, s).

o, 8-1.0 (Z l il , m), i, u
~2.3 (2:hrL +mL3.74 (614,
s), 3.7-4.2(2)i, m).

5.136 (ltL, m), 5.2-5.4 (21
,m),.

Example 2 ′-) Obtained on stream side 1 (IS+ s S+ b
S + 7+<No:< -(4-(-↓-Me+Ru 2
．． 6.7-Dryoxabinc r-L 2,2,2 J-butyl]-6-((E, 38-no,
3-t-Punardimenarunril: 1-ocanyl) -7-t-Butylunmethylsilyl t-xypinocloro (3,3j): 1-2-Coldene (2, OiJ J
, :4. IJ 2 mmol) f(methanol (2υOmi) and 7 toluene sulfonate (10U19) at J℃'!Ii temperature 18
Stir for a while. Remove methanol under reduced pressure, add 100 ml of salt, add brine, dry with anhydrous sulfuric acid Maginorm, and add It's a bone. Tonomo)) was added to Sirinofuge I Rekara μ Riromado Craphy (Hayasan 2 total 4 enal 3:l).
(9(O)-meta/-mufi(FJa)-pursugegrandin L+ 2.2-bis(ht'rlJ7sime7yl) 7' a hill ester 11°15-bis(t-
Pusenruji, Menarthorir) Ether (1,871+
〇NMR (2.75 mmol, 91%)
CIJC/', )6: 0.03 (12H, s), 0.7 ~ 0.9 (2
4H+m) -1, (J~2.5(23H,m),
3,1J7(21i+bsL3.40(41(, b
s, l, 3.98(2)1. s).

3.3-4.1 (2H, m), 5.06 (
l H+ m J +5.2~5.4 (2ji,
m),,11R(e,l12)2342Ll,3t14su+17(5,172u,125
5゜1115.1050,970.8J5,77U(z
'−',.

Example 3 9 obtained in Example 2 (0)-methane~, 6('a mirrorprostafsodinl, 2.2-bis(?1.t(J1,000 dimethyl)), flobyl ester 11. 15-his(t-7' methyldimethylsilyl) ether (Hibiki,
87 &, 2.7 mmol)
Set 0 tril fi00m/
) To the mixture was added hydrogen fluoride-pyridine (4 ml) to a mixture of pyridine (Zyr&) and stirred at room temperature for 5 hours. Add 1J of sodium bicarbonate to the reaction solution and
This solution was subjected to enal extraction, brine, drying with anhydrous chloride, and reduced IE condensation to obtain a crude product. This σ) thing is silica gel strength chromatography 1
-(hexane:ff1Etfflethyl=l:4) attached to L"(9(0)-meme/-halo(9°-pursugegrandin 1, 2,2-bis(human-quinmethyl)propyl ester (t), 877 jl* 1.94 mmo
NMR (CI) Ce3) δ: 0.84 (6H, m), 1.0-3.1 (27H+
m).

3.4(+(4H,ns), 4.00(2i(,s).

3.3~4.1 (2f(,m), 5.06 (IH
, m).

5.2-5.4 (211+m).

Example 4 CM.

Husband 111x%ll 3 Te 4 Lareta 9 (LJ) -,
j may-7-), “a)-pursugelandin l,
2.2-bis(human ρ xime thousand lufbu pvir L stel ((J, 877, V.

1.94 mmol) was added to Natracitronoff 7 (31J
:tu).

l Tal/-tal (15a/,), water (15fit) (41',,; Dissolved in % medium, 1,000 hydroxide on the instep...Water 41) (o, s4y+ 20mmol
) and stirred at room temperature for 18 hours. After adding Anyyani chloride 7 to the reaction solution, the vC solvent was distilled off under reduced pressure,
The resulting bath solution was made acidic by adding diluted hydrochloric acid, extracted with vinegar, washed with brine, and dried over anhydrous sulfuric acid solution (after drying with anhydrous sulfuric acid solution) to obtain a assembled product. 7υ force gel force rum chromatography fee
2) 1 sun' (9(0)-meme/-mufi(9a)-
Prostakura/Jinin L (o, t'i 55 &.

1.80 mmol, 9:3%) was obtained. Ko0
) also coincided with the synthesized specimen and the light sound.

NMR (CI) Cl, ) J: 0.83 (3H, m), 1.0~3-3 (23M
, m).

3.3~4.3 (2H, m), 5.20 (11(
, bs).

5.25-5.5 (211, m), 5.97 (jl, b
a).

IR (K!L membrane): 3350.3050. l710,109su,970α-
1, ゛, A4 size 1. P115 CH.

9(0)-Meta/-Muro(9) obtained in implementation tll 2
α)--prostacula/ginl, 2,2-bis(hydro427menal)buqviresnatL-11,15-
Hiss (t-butyrunme 1000 lenril)-ichisui shuku l
, 31 jJ, 1.93 mmol > 7 (6U ru), l//-
(3Q me), mixed with water (20 liters), mixed with water (1,
55 & ) and stirred for 2 hours (=f) at temperature. After adding the sulfuric anteptinium water mochi, the bath medium was depressurized 1.
11i! , -5 Cloth Salt
After that, extract with α-acid emol. Obtained RL, then dried it with a non-saline solution, dried it on a dry bed (SO in M), and contracted it'1
: A crude product was obtained. This material was subjected to column chromatography (hexane dioxic acid = l:2) [ML9 ((υ
- Methanol△0(!□j“Fufrosmeclandin l,
l 1 , l 5-bis(t-7raldimeryl)ether (1, U 59.1.) 32mmo
I served 98% of the staff.

NMi'l (CDC13)δ: 0.03(12)1. s), 0.8-1.0 (2uH)
.

1, C1-1.6 (12 quantity 4.m), 1.7-3.1 (
llH, m).

3.3-4.1 (2H, m), 5. lJ7 (1M, m)
.

5.2-5.4 (2H+m), 9.73 (IH, bs)
.

11 yen (film formation): 304 (J, 3υ0s, 1710, 1255.1115
゜970.851J, 835. 7751-1゜Example 6 Husband〃) 9(O)-Meta/-Muro (9") prepared for 11 hours in Example 5
)-prostacula/gin 11 i l l 15-his(t-funaldimethylunryl)neal (1,05L
L, 82 mmol) was subjected to a deprotection reaction using a hydrogen fluoride-pyridine complex under the same reaction conditions as in Example 3, and the same post-treatment was performed to convert 9(0)-methane to 6(9" )
-Prostacula/Zin L (0,5U &.

1. 44 rnmol, 79%). This was carried out and completely coincided with the product obtained in 11.1.

Example 7 Example 41f This is obtained in Example 6 (υ)-Meta 7
-Mu 1i (9ctJ-Solosmekura: / 7; / L,
(u, 5°1, 1.44 mmol) 'x ether (5, o) y co-MD' was added to room temperature as an air bath of methane. At the end of the reaction, when the seedlings are grown, they are almost pure 9 (0,1-methane-1
) (9a-1) [] Stakrange 71. Mail+Russj
le (lJ, 52, V, 1,41 jmmol, 9
9%) were given 14 results. This 1/) also matched perfectly with the standard product made by L').

NMR ((,:lJcg, )δ: U, 83 (311+m) 11.l~d,l (25M
1m).

3.65 (3H,s), 3.9~4.3 (21
-1, m).

5, J, 3 (lli, bs), 5. ,'(5
~5.55 (214, m).

IR (liquid glands): 3350, 1740 ctg-'.

Example 8 9 (Lj) − obtained in Example 1 or Example 6
Methano-△6(9")-Frosmecla/Zin 1.((1
, 35g + 1. U r + unol ) eta/-
(3Qm6) and 0.0% at 0°C. IN water bath solution (10, fJml, 1.0 mmol
), stirred for 30 minutes, and lyophilized under reduced pressure at 11C.
9 (OJ-methano-△6 (“p-prostaglandin I
, sodium salt (L37 ,!/, 1.Ommo
l) was obtained.

Example 9 Similar to the procedure of Example 1, L C(Is, 2R8, 5S1
68.7R) -2-human pya7'-3-me・shi/'-6
((h+as) 3 t-7tilsime(-l-octenyl)-7-t-bunaldimenalsilyl T:?Nhinku a (3+; U, 0): rcumene (1,80jW + 3.54 +11mol )
``Tet'' 7 people ``Kofura 7 (5u me) n to melting
-Nosen Rurisen “Tsum U) # T :/S Q (1,
S 6 M, 2.72 II〆, 4.24 mmol
) was added at 0°C and stirred at room temperature for 30 minutes.

This bath water was cooled to 178°C and the tertiary steel (1,0
1&, 5. J l mmol) v) Onsokug
7 (Additionally, the mixture was heated to room temperature and stirred for 30 minutes.

- force, followed by naphthalene (6-41, y.

5 (J, Ommol) of tetrahuman (J)77(5
tld) f4m all over the area (3501hfl,
5L), Ommol) were added at room temperature, and the mixture was cooled to a temperature of 500 mL and stirred for 5 hours. this#? 1st enemy
4-gu7-1-pufun (31, i 87
1, 25.0 mmul) of tetrahydrofuran (50 roots) di'rrJTL, stirred for 5 min at -78 °C L
-c2. This solution was added dropwise at 178 U to a solution prepared using LC, and stirred for a while.
10. A solution of N, 1'J-dimenalforemamide (3Qm/) was added thereto, the cooling bath was removed, the temperature was raised to 3°C, and the mixture was stirred at room temperature for 3 hours.

After the reaction, the cells were sensitized and separated on the column in the same manner as in 1 on the leaflet side.
Is, 5S, 6S, 7tt)-3-(4-pentenyl)
' ((h,, 3b> 3 t-bunaldimenalunryl tki7-1-ocanyl J-7-t-7'naldimethylsilylohya/bi/chloro(:S.

A, OJ-2--r ctene (1,161, 2,12m
mol.

60% yield was obtained.

NMR (CF) (J,)a: 0.03 (12H, sJ, 0.83 (21j1.m).

1, O~3.1 (21it, m), 3.1~4
．． 2 (2H, rn).

4.6-6. U(6H+mJ.

Example 1O Hs, 2hS, ss in the same shellfish as in Example 1.9.

6S, 71ζ)-2-Hitoroyashi: 3-Metenn-6
-(c1!;13S)-3-t-2naldimenal/lylox-1-ocdenyll-7-t-7±ludimenalunliluoyanhinkury (3,:LtJ J”tcumene (1,19&+ 2.34 mmol )J)rto-
yy Hexton ma (1,56M, 1.65 mg,
2.57r+unol) was added at U'C and 41L was added at room temperature for 30 minutes.

This bath liquid was IC-cooled to -78' and then cooled to a temperature of -78'.
0,49,! /, 2.57 mmol) of dt
Q Add to Q and heat to room temperature, stir and press for 30 minutes.

Because of this bath, we also added n-Funa I Rerina C Num 1,000-inch bath a (1,56 to 1, 1.65 ml, 2.5
7 mrnol) at -78C and stirred for 10 minutes. Last ICN, N-Mesenrufe [, Ami/Trifunalphosphoni "Humyount (1,12Vy, 2.5
7 mmol) of N, N-di) 1,000 lforma=t'
(iuy) Add a bath, remove the cooling bath and raise the temperature to 1°C.
Stirred at room temperature for 3 hours.

After the reaction, post-treatment was performed in the same manner as in Example 1.9.
(E,:U5)-3-t-7chirujime 1,000 ru/surshi)r
2r'/ltJ-7t-butylnmethylnriruoya/bishikua (3,3,OJ-2-octene (0,82/, 1.50rnmol, 64
%) obtained.

NMIζ(cI)c6. N δ: 0, (J3 (12H, s), 0.85 (24H, m).

1.0-1.6 (14H, m), 1.7-3.2
(9n, m).

3.55 (LH, dt, J=2 and 7 Fiz) +'
, +, 7-+4.1 (IH+m), 5.0b (lH+
m).

5.2-5.4 (2n+m).

It value (liquid film): 304υ, 1255.1115, 1000, 970°8
55+835+775cIn-'.

Implementation - Ill ~ 18'4 M In the same manner as in Fil 1, a prayer for the transformation of an arrow was synthesized.

Example 11: (ls, 5s, 6s, 7RJ-3-(4-(4-me thousand ru 2. l'i, 7- Tori clove nabinkuu (2,2,
2J oct-1-yl)butyl J-6-((k;,3
8゜5R) -3-t-7,000 runs, 1,000 runs, dry sea 5
-Nonal-1-nonenyl]-Fu1-Punaldimethylunril4-? Chibishiku c+ (3, 3, IJ J-2-'
: Nictene (73Lyo), Example 12: (xs, 5S, 6S, 7R)-3-(4-(4-methyl-2,6,7-trioyasabiciclj[2,2,23oct-1-yl ) 7,000 ru J-6-(1;, :xs.

5S)-3-t-7' Thousand Luzimenal/Lil T Yang-5-
Methyl-1-nonenyl)-7-t-bunardimenalunliluozenpinkulo(3,3,Ll)-2-octene (75%).

Example 13: (IS, 5S, FIS, 7RJ-3-(4-(4-menalou2.6.7-)rioxabicyclo(2,2,23
T-9t-1-yl) Boo) 6 ((h:
, 3s)-: (-t-butyldimethylsilyloxy-3-/p-pentyl-1-buvenyl J-7-t-butyldimethylsilyloxyhincro(3,3,υ)-2-
Sai Kuan (9%).

Example 14: (IS, 5S, 6S, 7R) -3-(4-(4-Menaloo 2 + 1), 7h Rio Chisu Bisicou L 2
．． 2,2) oct-1-yl)butyl)-6-((E
,3S)-3-1-butyldimethylsilyl3-
1-7'a-benyl)-7-t-nordimethylrinryl-quinpink. (3,3,OJ-2-
5" (77%).

Example 15: (ls, 5S, 6s, 7R)-3-(4-(4-nonal-2.6.futlio-bicyclo(2,2,2)oct-1-.1l)butyl) -6 -((1!;)-4-
t-butyldimenalsilyl f? N-1-Me 1,000 Rui 1
-Octenyl J-7-t-:7Tyldimethylnriruo 1,000 Sibisic I:! L 3. :(,υ〕−2−nonctene(6
4%).

Example 16: (Is, 5S, 6S, 7)-3-(4-(4-Methyl-2,6,7-trioxabincroL2.2.23oct-1-yl)butyl)- 6-((a:No 4-t
-Putyldimesenrunril f+C・1-vinyl-1-
octenyl)-7-t-y+rudimethylsilyl oyashibinc R(3,3,U)-2-octene (67%).

Example I7: (iS,5S,tiS,7R)-3-(4-(4-methyl-2,6,7-trioxabinculo(2,2,2Joct''-1-iluns,100)- 6-CCE)-3-t
-butyldimethylsilyloxy, 3-methyl-1-ophanyl)-7-tert-butyldimethylsilyl quinpin (3,3,0) -2-octene (78%).

Example 18: (lS, 5s+fi8.7K)-3-(4-(4-methy/l-2+b+7-dryoxabicicμ(2,2
,2) oct-1-yl)butyl)-6-((g)3-
t-/'naldimenalsilyl to palm-4,4-dimethyl-1-octenyl)-7-t-butyldimethylsilyl octenyl O(3,3,0)-2-zctene (65%
).

The characteristic spectral data of these compounds are listed in Table 1.

Examples 19-26 In the same manner as in Example 2, a compound having a temperature of L° C. was synthesized.

Example 19: 17 (It), 21J-dimethyl-9(0)-meta/-△6(''-7'aS7>n1.L2
-bis(hydroxymethyl)furoyl ester 11゜1
5-His(t-butyl dimenalinol ether (9
3%),,1 Example 20: 17(S),20-dimethyl-9(0)-methane-Δ6
(”' yu sp y' y 79 nI,
212 2 Su(hydroxymethyl)furoyl ester 11゜15-bis(t-7' tyldimethyllinurine ether (96%).

Example 21: 16117118.19.20-benmetru15-ben+ru9(O)-methano-halo(9'')-prostaglandin i, 2,2-bis(hydroacymethylnobropyl ester 11 .15-bis(t-2,000 lua-tylnoryl) ether (89%).

Example 22: th1i71islt912o-pentanol-15-7
Chloheyanlu-9(0)-methano-muro(9cr)-prostaglandin, 2,2-bis(hydroxymethyltinylphyl ester (t-dutyldimethylmonlyl))nyal (92%).

Example 23: 15-deoxy-16-hydroA-C16-menal-9(0)-meta/-Δti(9aJ-prostaglandin l, 2,2-bis(human a-r dimethyl)furobyl ester 11 .15-bis(1-butylunmethylunryl)ether (90%).

Example 24: 15-thioxy-16-hytroquine-16-hinyl-9
(<,))-Mekno△6(ja)-Prostaglandin I, 2.2-bis(hydroxymethyl)propyl ester 11.15-bis(t-7' tildimethylsilyl) ether (86%).

Example 25: 1 5 ) + Roux 9 (0) l P /
Q6 (9cL) 7' rostaglandin I, 2.2-
Bis(hydroxymethyl)furoyl ester 11,
15-His(t-,y' methyldimethylsilyl)ether (94%).

Example 26: 16,16-dimethyl-9(0)-methano-Δ6(9“
nobros taglandin l, 2,2-bis(hydrothousandimethyl)propyl ester lit15-bis(t-
Butyldinalsilyl)ether (81%).

The % hostile spectrum cheaters of these compounds are listed in Table 2. The compounds obtained in Examples 19 to 26 were obtained by the same hydrolysis reaction as in Example 5 to convert the corresponding carbon 1 of bis(t-butyldimenal 7lyl) ether.
4 was introduced into the visiting conductor, and then the corresponding 9(0)-methano-Δ6(9'')-prostaglandins were introduced by the same decontamination procedure 6 as in Example 5.

Examples 27-34 Hisa's compound was synthesized in the same manner as in Example 3.

Example 27: 17(R,7,20-dimethyl-9(0)-mecnorme6(9")-prostaglandin I, 2,2-bis(hydoxymethyl)furobyl ester (75%).

Example 28: 17(Sn, 20-dimethyl-9(0)-meta/-△6
(9a)-boostaglandin I, 2.2-bis(
Hydrocoir methyl) propyl ester (74%).

Example 29: 16.17.1 g, 19.20-benme/ru 15-cycloben-ru 9 (0)-methanol 6 69%).

Example 30: 16.17, 18.19.2L)-pentanol-15-
Cyclohexyl-9(O)-mekno△fi (9a nob p staglandin l, 2.2-bis(human Ij)
? dimethyl)propyl ester (76%).

Example 31: 15-deoxy-16-hydroxy-16-methyl-9
(0)-menno to 6('1-but p-staglandin l,
2.2-bis(hydroxy7menalumbrovir) (81%).

Example 32 215-deo 16-hidoh 1f5-methyl-
9(0-methanome6(9a)-prostaglandin I, 2,2-his(hydroxymethyl)furovir ester (73%),.

Example, 13: 15-Methyl-9(O)-methano-Δ6 (9-booster taglandin l, 2,2-bis(hydroxymethyl)propyl ester (76%).

Example 34: 1(i, 16-dime 1,000 rou 9(O)-meta/-, , 6(
9a) j a metano' 5 ndi 7 L 2
! 2-His (human aq-methyl) fluorescein (67%).

The % spectral data of these compounds are listed in Table 3. The fossilized antiquities obtained in Examples 27 to j4 were 7n
The same hydrolysis reaction as in Example 4 led to 9(0)-mek/-muro(a)-prostaglandins.

Table 13-(4-(4-methyl-2,6,7-tri>+-
4-Dimensional a(2,2,23-nonct-1-yl)methyl) Vinclo(3,3゜0)-2-octenes a2 9(OJ-Meyi-△6(9c')-Fos z
Cransin l.

2,2-His(Hydroquinemethyl)propyl Sb”
11.15 (or 16)-his(t-pnaldimethylsilyl) ether 39(0)-methano-Δ6(9a)-fupstaZlandin i.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, R^2^1 and R^3^1 are the same or different, and (C_1 to C_7) represents a hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R^4 represents a hydrogen atom, a methyl group, or a vinyl group, and R^5 contains an oxygen atom. a straight-chain or branched C_3-C_9 alkyl group, alkenyl group, or alkynyl group; a substituted or unsubstituted phenyl group; a substituted or unsubstituted phenoxy group; a substituted or unsubstituted C_3-C_1_0 cycloalkyl group; Or C_1~
Straight chain or branched chain C_1 to C_7 alkyl group substituted with a C_6 alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C_3 to C_1_0 cycloalkyl group , and n represents 0 or 1. ] 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3,3,0]octanes, which are the compound represented by the formula and its enantiomer or a mixture thereof in any proportion, are combined with organolithium in an organic medium. , then reacted with cuprous iodide, and then further reacted with the following formula [II] Li-(CH_2)_m-R^1^1...[II] [where R^1^1 is hydrogen] atoms, C_2 to C_6 saturated or unsaturated hydrocarbon groups, protected hydroxyl groups, or 4-
Methyl-2,6,7-trioxabicyclo [2.2.2
] represents an oct-1-yl group, and m represents an integer of 0 to 6. ] is reacted with the organolithium compound represented by N,N-methylphenylaminotributylphosphonium iodide in the presence of iodide, and if necessary, a deprotection reaction, a hydrolysis reaction,
and/or the following formula [III] characterized by being subjected to a salt-forming reaction ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III] [In the formula, R^1 is a hydrogen atom, saturated or unsaturated carbonization of C_2 to C_6 Hydrogen group, 4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl group, 2,2
-Represents a bis(hydroxymethyl)prop-1-yloxycarbonyl group, a carboxy group, or a carboxylate group, R^2 and R^3 are the same or different, and represent a hydrogen atom, a tri(C_1 to C_7) hydrocarbon silyl group , or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R^4, R^5, n, and m are the same as defined above. A method for producing 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes, which are a compound represented by the above formula, its enantiomer, or a mixture thereof in any proportion. 2. 3,6,7-trisubstituted bicyclo [3.3.
0]-2-Octene production method. 3. 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes according to claim 1 or 2, wherein the organolithium is n-butyllithium or methyllithium. Manufacturing method. 4. 3,6,7-trisubstituted bicyclo [3.3.0] according to any one of claims 1 to 3, wherein R^1^1 is a vinyl group and m is 2. -A method for producing 2-octenes. 5. Claims 1 to 3, wherein R^1^1 is a 4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl group, and m is 3. A method for producing 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes according to any one of the above items. 6. R^2^1 and R^3^1 are the same or different and represent a tri(C_1-C_4) alkylsilyl group, diphenyl(
C_1-C_4) alkylsilyl group, phenyldi(C_
1-C_4) Alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, or 6,6- dimethyl-3-
Oxa-2-oxobicyclo[3.1.0]hex-4
The 3,6,7-trisubstituted bicyclo [3.3.0
] Method for producing 2-octenes. 7. 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes according to any one of claims 1 to 6, wherein R^4 is a hydrogen atom. Manufacturing method. 8, 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes according to any one of claims 1 to 6, wherein R^4 is a methyl group. Manufacturing method. 9, 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes according to any one of claims 1 to 6, wherein R^4 is a vinyl group. Manufacturing method. 10, R^3 is a butyl group, a bentyl group, a hexyl group, a heptyl group, a 2-hexyl group, a 2-methyl-2-hexyl group, a 2-methylbutyl group, a 2-methylbentyl group, a cyclobentyl group, a cyclohexyl group, Phenyl group, phenoxy group, cyclobentylmethyl, 2,6-dimethyl-5
-heptenyl or cyclohexylmethyl group according to any one of claims 1 to 9.
, 7-trisubstituted bicyclo[3.3.0]-2-octenes. 11, 3,6,7-trisubstituted bicyclo [3.
3.0] Octanes. 12, 3,6,7-trisubstituted bicyclo [3.
3.0] Method for producing -2-octenes. 13. 3,6,7-trisubstituted bicyclo [3. 3.
0] Method for producing -2-octanes. 14. 3, 6, 7 according to any one of claims 1 to 13, wherein the reaction temperature is -100°C to 50°C.
- A method for producing trisubstituted bicyclo[3.3.0]-2-octanes.