JPS58150583A - Novel halogenated prostacyclins, their preparations, and pharmaceutical compositions comprising them as active ingredients - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formulaI the bond between the 13-position and the 14-position is a single bond, double bond or triple bond; R<1> is H, alkyl, (substituted)phenyl, etc. ; R<2> and R<3> are H, or halogen; R<4> is H, methyl, ethynyl, etc.; R<5> is (substituted)alkyl, (substituted)alicyclic group; R<6> and R<7> are acyl, tri(1-7C) hydrocarbon silyl, etc. and a compound shown by the formula II (with the proviso that R<3> is not H when R<2> is H or F). EXAMPLE:5-Bromo-DELTA<6>-PGI1metyl ester 11,15-bis-t-butyldimethylsilyl ether. USE:A drug for breast pang, vasodilator, hypotensor, etc., stabler than natural PGI2, having biological activities equal to those of it, showing improved selective activities. PROCESS:A compound shown by the formula III is reacted with an electrophilic halogenating reagent shown by the formula X-Q (Q is nucleophilic residue; X is Cl, etc.), to give a compound shown by the formula IV(R<12> is as shown for R<1> other than H; R<42> is as shown for R<4> other than ethynyl; R<62> and R<72> are as shown for R<6> other than H).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel norogenated prostacyclins, processes for their production and pharmaceutical compositions containing them as active ingredients.

Prostaglandin (hereinafter referred to as PGIt) is a known compound represented by the following acid II.

PGIt is mainly released from the vascular endothelium, has the effect of suppressing platelet aggregation, and has a blood pressure lowering effect based on the effect of relaxing and breaking the smooth muscle of the muscles (轡-昭S*-13).
(Refer to Publication No. 1-1) Therefore, it is an important ritual item that is expected to be applied to medicines. (If you keep J, R, Van
s et al'Pr0staoyclin.

Raven Pleas, N,! , 1G71: J
, Med, Ohem, Vol 23゜number@r 6
．． Juns, 19110. pages 59
1 N593).

However, the PG engineer has a nominative pHK$P.

The half-life of the drug's activity is only a few minutes, and there are problems with its stability as a drug. PG engineering, anxiety is chemically Δ
This is thought to be due to the fact that the vinyl ether structure containing a double bond is easily hydrated and converted to 6-Okitsubrosta Grandi 7, which is quickly metabolized by the ls position hydrogen element in the parent body. ing. On the other hand, the am action of PG drugs is considered to be inferior in action selectivity as a pharmaceutical, as the platelet aggregation inhibiting action and blood pressure lowering action are almost the same at different doses. For this reason, great efforts are being made both domestically and internationally to synthesize PGIts and compensate for the above-mentioned shortcomings of PGX (for example, 89M).

ROb@rt-et al., Chemistry, Bioche
Mistry & Pharmaoological
tivity of Prastanoids.

Pergamon Press, Oxforl, 1
9711). In particular, list the conventionally known PGI proverbs that stabilize enol ether: (1) @, @-imino trout conductor (G, L, Bund
yd;w+k.

Tetrahadron L@tters, 1371
0117・)) +2) 6.11-Cheer-conductor (
K, O, N1aolaou 5ae-h.

J, mer, chem, 8oc, 1@0.21S@
7(1.78): M, 8h4basaki et al.? @tr
ahsdron Letters.

559 (1117$): Y, Ar&i G2
(See 0h@m, Lett@rs, 1375 (11178)).

(3) 6.11-Calva trout conductor (K, o, N1ao
laou et al.

Ch@m', Oommun,, 10$7 (11171
1): Kiojima et al.

Tetrahedron L@tt@rv, 3743(
19711): M, Bhibagaki et al., 1b14
,433(x@7@): Y, Kontshi et al., O
Mm, L@tt@rs, 143? (197G): D, R
, Morton et al., J, Org, OMm, 44JII
O (1979)).

(4) 5-o middle trout conductor (11, llishiyama
and others.

T. trahodron Letters, 34$1 (
(1979)).

Detective) 7-Okino $ is one axis (European Patent Association @31
, 42 @ Sanki).

(@) 5-cyano haze conductor (US dA Patent No. 4J19,4
(See Mei No. 79).

+7) 5-phenylthio-conductor (Troru et al.

T@trahedron Letters, 2539 (
5980) 1(s) s,9-aza-5-thia-conductor (W, Bartmann et al.

mngew, oh@m, nt, Id, lngl, 11
1.8111 (198G)).

Recently, Gloster Cycle IJ Building 1, which has the following structural formula, is located at 04~On! I (rim 4) 1.・, 4. '4 +, 5
+, t, t -, I Q, I O-O is substituted with fluorine and claims nine-fluorinated prostacyclins (Claim 3) No. 110
Publication No. 1G02 was published.

In the above device 11i111 publication, it is clear from the above structural formula that the
GMm* is listed, not too much, ^6-prosta t
Icrin compatibility, ie Δ-PGI+IIIa, is not described at all.

In addition, the structural feature of the Δ-glostaniculin vote described in the above MS general report is that if any of the 4th, 7th, or 10th positions are fluorinated, those positions are always fluorinated. Fluorinated (g@m-aiflrorina
t@l) point.

These 77-fluorinated 9-pal stannitalins can be prepared without using PGMm as a starting material.
*It is disclosed that it is produced by concentrating m II as a starting material.

The biological activity of these fluorinated prostaniphrins is
The company report does not contain any specific data at all. Isosho known to the present inventors, among the fluorinated prostaniphrines having the above structural formula, the compound whose biological activity has been specifically demonstrated is I O,1G-difluoro-
1 for 14-dehydroglostasta italin i.e. Of! Only. That is, JJR, 1ecL, who is the author of the above T's application, and their researchers have submitted 10-
Difluoro-13,14-prostacyclin has vasodilatory effects, platelet aggregation inhibiting effects, and chemical stability (pH 7,
4) etc. (J.

Mea, Ohem, 1980, Snow 3 Snow B'l-Snow I
I, ProcJatl, Mucad.

8e1. σ8mu7? , nott, 5st6~asi
o, t*ao).

Therefore, it is an object of the present invention to provide novel halogenated brostanitalins, ie, halogenated PGXIs and halogenated PG compounds.

Another object of the present invention is to provide a novel mono- or dihalogenated gross compound which is mono-halogenated at the 5th or 1st position or dihalogenated at the 5th and 7th positions. It is in.

Another object of the present invention is the novel Nanomatasha dichlorination (
or oxidized or iodinated) prostacyclins.

l of the present invention! Another objective is to provide a stabilized halogenated glostanyl chloride/all with natural PGI repellents.

Yet another object of the present invention is to provide a halogenated glostanitalline steel having a biological activity approximately comparable to natural PGI and a selective activity superior to natural PG II. be.

The purpose of koji is to control the operation of the vascular system.

Suppression of malignant tumor metastasis, aS transplantation, vascular skin or extracorporeal circulation m101111011! Kawa, we offer halogenated glostanitalline steel for 09.1clr.

An object of the present invention is to provide a novel prostacyclin intermediate useful for producing the halogenated glostaline compounds of the present invention having the above-mentioned desirable properties.

I of the present invention! Another objective is to provide a novel process for producing novel halogenated glostanitalline steels.
be.

Further objects and advantages of the invention will become apparent from the description below.

According to the present invention, the objects and advantages of this book 4i are as follows:
This is achieved by a halogenated prostacyclin selected from the group consisting of halogenated pGI compounds represented by
deceive

10genated PGIII represented by the above formula (5l)
and nologonized PGI represented by the above formula (mu)
For the stereoisomerism of *llll, K11m should be determined as follows.

In the formulas (M,) and (Mt), the four bonds coming out of the cyclopentane ring are directed downward (into the paper) relative to the cyclopentane ring as shown in the formula. The three bonding hands (to the back side of) are sticking out (...
) and 1 extending upward (toward the back of the page)
It consists of a book bond (indicated by 4m).

Therefore, the stereoisomerism of the compounds represented by formulas (M1) ν and (At 2 ) is specified in terms of the four bonds coming out of the cyclopentane ring.

In addition, when R1 bonded to the carbon atom at the 5th position is a halogen atom, the PGXw of formula (M1) can be attached to the carbon atom at the S position (asymmetric carbon atom) to form a zero-center stereoisomer. It also includes three stereoisomers regarding the asymmetric carbon atom at the K18 position.

PGL@l in (m) above therefore includes one of these stereoisomers or a mixture of 1 or more of these stereoisomers.
should be understood. Furthermore, the PG work of 1 above (mu 1),
S is %. When the bond between the carbon atoms at the 13th and 14th positions is a double bond, it should be understood to include the cis form or trans form or a mixture thereof with respect to the double bond.

First, in the PGX snow group of the above formula (Muyuki), when Ha bonded to the carbon atom at the 7th position is a halogen atom, two types of carbon atoms are secretly attached to the carbon atom at the -1st position (asymmetric carbon atom). It includes stereoisomers, and even if the asymmetric carbon atom KII at the Bcts position includes two stereoisomers.

The PGI snow class of the above Ie (Muyuki) has a double bond between the carbon atoms at the 5th and 6th positions, and a double bond between the carbon atoms at the 13th and 14th positions. and includes cis or trans forms, as well as mixtures thereof.

The above (mut) PG engineering group is one of these stereoisomers.
It should be understood to include the species or species.

In the above formula (At3 and (Muyuki), the 13th and 14th
The symbol between the two positions represents a koto bond, a double bond, or a triple bond.

R1 is a hydrogen atom, an alkyl group of O+-0+, or an unsubstituted phenyl group, a substituted or unsubstituted oi+i
r Muji group, substituted or unsubstituted O phenyl (Os =
Os ) An alkyl group or a cation whose salt is a pharmaceutically acceptable salt.

Examples of the alkyl group of 0INO+・ include methyl,
Ethyl, n-probyl. 1-0-gu api k.

0-butyl, -.C-butyl, tart-butyl, n
-pentyl, n-hexyl, n-heptyl, n-octyl. Mention may be made of linear or branched 040 such as n-nonyl and n-decyl.

Examples of the substituted or unsubstituted phenyl group ot* group include a halogen atom and a hydroxy group.

01-Cg acyloxy group, OI-C6 alkyl group optionally substituted with a halogen atom, 0.01-Cg optionally substituted with a /10 gun atom; ~C4 alkyl group.

A nitrile group, carboxyl group, (0B-Os)alkoxycarnyl group, etc. are preferred. The atom is preferably monofluorine or chlorine, such as fluorine, chlorine or bromine. 0. Examples of the radical include acetoxy and propionyloxy.

n-butylyloxy, 1-O-1tyryloxy.

n-valeryloxy, 1so-valeryloxy.

Mention may be made of cabroyl, enantyloxy or penzoyl.

Examples of the C1-C4 alkyl group which may be substituted with a radical include methyl, ethyl, n-propyl, iao
Preferred examples include -j-propyl, n-propyl, chloromethyl, dichloromethyl and trifluoromethyl. C3 which may be substituted with halogen
Examples of the C, alkoxy group include metho, ethoxy, n-propo, 1so-prop, and n-butoxy.

Examples of preferred examples include chloromethane, dichloromethoxy, and fluoromethane. (
01-0.) As the alkoxycarbonyl group, for example, methoxycarmenyl, ethoxycarmenyl, ethoxycarmenyl, butyl
Examples include carbonyl, dicarbonyl, carbonyl, and the like.

The substituted phenyl group can have one to three substituents, preferably one, as described above.

Substituted or unsubstituted 31111 formula groups include those substituted with the same substituents as above or unsubstituted O%ji
i sum or not jl! C1~CI of I spider, preferably C@~
Os, 41 is preferably an O@ group, such as cyclopentyl, cyclohexyl, cyclohexenyl.

Examples include cyclohagetyl and fuculooctyl.

Substituted or unsubstituted phenyl (cl-Ct) alkyl groups include those in which the phenyl group is substituted with the same substituents as above or unsubstituted phenyl groups, a-7
Examples include enethyl and β-7 enethyl.

Examples of monoequivalent cations include NH4, detomethylammonium, monomethylammonium, dimethylammonium, trimethylammonium, benzylammonium, 7enethylammonium, 4. An-percentium cations such as ruphorinium cations, monoethanolamine cations, piperidinium cations, alkali metal cations such as Ha, IC: h Oa” + 'A
'g''+.

14Zn□+. Tsuramu tm+ Can list three metal cations, four or three.

R1 is preferably a hydrogen atom, an at-eta alkyl group, or a cation equivalent to a pharmaceutically acceptable salt thereof.

R1 and R''F1 are the same or different water bulk atoms or halogen atoms.The halogen atoms are.

Mention may be made of a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

R4 is hydrogen atom, methyl group, ethynyl M (-0=OH)
Or it is a secured ethynyl group. Preferred examples of the protected nine-ethynyl group include trimethylsilylethynyl and t-butyldimethylsilylethynyl groups. Among these, a hydrogen atom or a methyl group is preferred.

R1 is an unsubstituted O@~Os alkyl group; an optionally substituted phenyl group, phenoxy group, 01~O@alkoxy group 4L< is substituted with an O~0.cycloalkyl group and I is a substituted 0 ．． ~C-alkyl group; or a substituted or unsubstituted alicyclic group. The unsubstituted alkyl group of 01 to C. may be linear or branched, such as n-pentyl, n-hexyl, 2-methyl-
1-hexyl, 2-methyl-snow-hexyl, n-heptyl, n-octyl, etc., preferably n-pentyl.

n-hexyl! -Methyl-5-hexyl, 2-methyl-2-hexyl and the like. Replacement 0+~O
The I alkyl group may be linear or branched, such as methyl, ethyl, n-propyl,
1soap building.

Examples include n-butyl, 5ea-butyl, t-butyl, n-pentyl and the like. These substituted alkyl groups are phenyl group; phenol group; methoxy, methoxy)'? /
, n-propoxy, lso-propoxy, n-butoxy, 180-butoxy.

Nidiclopentyl, an aI to 0.alco group, such as t-buto, n-bent, n-hex, etc.

It is substituted with a Cs~0·cycloalyl group such as cyclohexyl. These substituents may be further substituted with nine substituents as substituents for the KR'ot-substituted phenyl group.

Examples of the substituted Ot -O@aryl group include fluorine atom, chlorine atom, methyl, and ethyl. An alkyl group, or globoxymethyl, ethoxyethyl, propoxyethyl.

Butoxymethyl, methoxypropyl, 2-ethoxy-1
, 1-dimethylethyl, globoxydimethylmethyl, or cyclohechusylmethyl, cyclohechusylethyl, cyclohedPtaldimethylmethyl,! -cyclohexyl 1
．． 1-dimethylethyl and the like are preferred.

Substituted or unsubstituted alicyclic groups include 9-
The same thing can be mentioned.

R @ is n-pentyl, n- to 1? Tal.

2-methyl-1-hexyl, 2-methyl-2-cyclopentyl or cyclohexyl groups are preferred.

R1 and R' are the same but significantly different and are hydrogen atoms.

It is a group that forms an acetal bond with an 0s-Ov acyl group, a tri(0,-%-C)hydrocarbon-silyl group, or an oxygen atom of a hydroxyl group.

Examples of the C-C maacyl group include acetyl.

Propionyl, n-butyryl, 1-O-butyryl.

n-/(leryl, 1-O-pa-V-lyl, caproyl.

Enantyl, benzoyl, etc. can be mentioned.

Among these, preferred are 0~aS@aliphatic acyl groups such as acetyl, n- or igo-butyryl, caproyl, or benzoyl.

Examples of the at-ay hydrocarbon silyl group include trimethylsilyl and triethylsilyl.

Tri(C+-04) such as t-butyldimethylcryl group
Preferred examples include diphenyl(0@-04)alkylsilyl or tribenzylsilyl groups such as rusilyl in alkali, t-butyldiphenylsilyl group, and the like.

Groups that form an acetal bond with the oxygen atom of a hydroxyl group include, for example, methoxydimethyl, methoxyglobin, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, penzyl-dimethyl .

2-tetrahydropyranyl. Mention may be made of the s-4-yl group in 2-deto2hydro7ranyl or 6,6-dimethyl-1-oxa-2-o (a, s, o). Among these, 2-tetrahydrovinyl,
2-detrahydro7tool-1-ethoxyethyl, 2-methoxyethyl, 2-pucvir, (2-methoxyethoxy)methyl or 6,6-dimethyl-3-ol to 2-oxobicyclo[a,r,o] A kiss-4-yl group is preferred for 41.

These silyl groups, acyl groups, and groups forming an acetal bond are to be understood as holding groups for hydroxyl groups. These silyl groups or groups forming acetal bonds are easily removed under acidic to neutral conditions.

The t+ acyl group is removed into the container under basic conditions.

Among these, R@ or R1 is a hydrogen atom.

Rusilyl group in tri(OI-Oa)alum, diphenyl(
0+-(3*)alkylchloride group, 2-deto-2hydropinyl group, 2-tetrahydrofuranyl group.

A diethyl group in l-eth, a 2-propyl group in 2-eth, and a methyl group in (2-meth).

-2-oxobicyclo[3,1,0]hex-4-yl group, acetyl group or benzoyl group are preferred.

The halogenated brostanitalins of the present invention are a group of compounds (F
It can be conveniently divided into a group of compounds having a double bond between the 5th and 6th positions (PGI-s, At).

The definitions of each singel in the above formulas (Al) and (M1) are as described above, but the halogenated brostanitalins of the present invention have R1 and R1 both hydrogen atoms in the above formula (M+). PGI, class and above formula (is)
When R1 is a hydrogen atom or a fluorine atom, it does not include PGMs steel in which R1 is a water bulk atom.

PG I in which in the above formula (AI) or (mut), there is a trans-double bond or triple bond between the 13th and 14th positions;
The r-series or PGI compounds form a preferred group of compounds within the nitogenated prosthetic italins of the present invention.

In addition, as pGItll of the above formula (Muyuki), even if there is a double bond between the 5th and 6th positions, a bond in which the carbon atom at the 5th position of the double bond is bonded to the carbon atom at the 4th position. It is preferable that the carbon atom at position 6 of the double bond is in a cis relationship with the bond bonding to the oxygen atom.

According to the present invention, among the halogenated brostanitalins, halogenated PG I+ g s represented by the following formula (AI)-1R#IOR111 and halogenated PGI- represented by the following formula are particularly suitable for administration form a group of compounds desirable as

A group of compounds in which the bond between the 13th and 14th positions in the above formula (Mu,)-* or (Mus)-2 I is a trans-double bond or triple bond have an activity that is biologically superior in %. more preferable. 9, in the above formula (mu-)-I, the bond in which the carbon atom at the 5th position of the double bond between the 5th and 6th positions is united with the O carbon atom at the 4th position, and the 6th position of the double bond. A compound in which the O carbon atom is bonded to the oxygen atom and the relationship between the two and the two is paulownia λ is l! For convenience, a specific compound of the halogenated compound of the present invention is represented by the above formula (AI) (formula (M1)=1
Compounds of formula (including formula (-)-1) and compounds of formula (-)-1 are listed below.

Compound (11H) of the above formula (I), G-7k-Δ-PGIs (l
・1), 7-fluor-Δ-PGX* *(SO snow),
s-riH-ru th-PGXt #(103),
7-taloru Δ-PG engineering 1° (104), h-brome-Δ-PG engineering,.

(10s), 'I-PHA-Δ-PGI1゜(1
0g), 6-so-do Δ-pa 2゜(1G?)
, 7-W-doΔ-PGL.

(tos), s, y-Schiff to a-Δ-PGII
.

(tto), s, y-JikC1 & -Δ-PGI
1° (11ri, s, t-jib (1mu-Δ-PGIt
e(114), l! ,? -ji■-do∆-PG
Engineering l.

(fill), S-chloro-7-fluora-Δ-
PG engineering.

(tts), s-pDA-7-7A/o-Δ-
PGI, (1110), 7-Fluoro-5-Yellow Δ-PG Engineering I.

(122), 7-7 OA/-8-7k t Q -Δ
-PGL.

(124), 7-bromo-S-chloro-Δ-PG-1(tzs), s-fluoro-13,14-dehydro-(128), 5-10-IS, l4
-dehydro-Δ-PGL m (lio), 5-pHA-13.14-dehydro-Δ-PGI.

(xaz), 5.7-difluta-13,l 4-
Dehydro-Δ-PG engineering turtle.

(134), 51? -dichlor-t i,t 4
-dehydro-Δ-PGL* (13 g), 7-bromo-5-chloro-13,14-dehydro-to'-PGL.

(1m8), 5-fluoro-13,14-dihydro-Δ-PG Kufu.

(14G), S-9Qk-13,14-dihydro-Δ-PGI.

(142), 5-bromo-7-chloro-13,14
-dihydro-Δ'-PGI1° (144), 5-fluora-17(R), 20-dimethyl-Δ-PGII.

(145), y-7s, 0-17-2o-dimethyl-Δ-PGxI.

(14 g), s-tuo#-17@, 20-dimethyl-Δ-paI nose.

(14@), S-pua A-17@, 2 @-
Dimethyl-Δ-PGIs.

(tso), s, y-jikuok -17@, 20
-dimethyl-Δ-pe engineering turtle.

(1!i2), S-7ktO-1'l@, 20-dimethyl-Δ-PGL* (153), Is-7kI0-17@, 20-dimethyl-Δ-PGMs.

(1!14), Is-riQ k -17@, 2
0-dimethyl-Δ-PGI.

(156), l1t-puGA-17@),! 0-dimethyl-Δ-PGXm − (15 g), 5,7-difluoro a-17@) *
” '-dimethyl-Δ'-PGI1 (l brocade), 1!i-cyclopentyl-5, -fluoro-
1.,l 7,11. I II! 0-PentanoruΔ
-PG engineering 1゜(l・(1), 1!s-cyclohexyl-!1-fluoro 1 @, 17,111.l 9,20-pentanol-Δ-PGMs * (IU), 15-cyclobenthyl 7- Fluoro-
t s, ty, t s, t o, zo-pentanol-Δ-PGIL.

(tO), S-chloro-Is-cyclohexyl-11+
,17,1 a,1 @,2 G-”tnfi/
A'-Δ'-PG engineering, 1 (1183), 5-riI20-15-fuclopentyl-14, l7,11,1@, 20-pentanol-Δ6-PGI,.

(1g4), 1! ! -'/lcxheqVk-5-
! -)' -141,17,111,111,20-pentanol-6-PGL- (t6s), 7-chloro-15-cyclopentyl-
111,1? , l II, l @, 20-pentanol-Δ6-PGIt.

(leg), 5-chloro-15-citalohexyl? -Full 10-16.17,111,19.20-Pentanol Δ4- PG engineering.

(tsy), s, t-Schiff and otx-20-methyl-Δ-PGX* + (1g8), ! -Fluoro Snow O-Methyl-Δ-G
L I (le・),! I-promo IS-cyclopentyl-
t s, ty, t 's, t・, snow O-pentanol-Δ6-PGIt * (rho), h-rio rho Z G-methyl-Δ
-PGl list.

(171), S-cyclopentyl-
t s, t 7,111. 6-PG engineering to L20-pentanol.

(x7z), 7-fluoro-20-methyl-Δ-PGMs + (174), 5-fluoro-15-methyl-Δ-P
GIs*(tta), s-chloro-Ls-methyl-4-PG
l.

(tys), s-fluoro-7-it-do IB
-Methyl-Δ-PGIt.

(1so), s-fluoro-16,l@-dimethyl-Δ'-PGIt.

(rsz), s-ri1:1ru1@, 1g-dimethyl-Δ-PGIt.

(lJ14), Is-riOk-7-M-dot
g, t's-dimethyl-Δ-PGI+.

'(lsg), t s-cyclo to middle 5. ? −
Difluoro-*t, *1,111. Goose O-detranoru Δ-PG engineering i.

(xay), s-y fluoro tS-cyclohexyl-16,1? , 1 Lu, l hui, 20-pentanol Δ-P
Gl1゜(lSS), 1m-cyclohexyl-5,7-cyclo-16.17,11,19. ! 0-pentanol-Δ-PG engineering.

(too), S-bromo-15-cyclohexyl-
111,17,18,111j O-pentanol Δ6
- PGl1゜(190), 5-fluoro-1@-phenoxy-t
ytstezo-pentanolΔ-PG engineering.

(l・2), s-ri a rule @ (p+7j%zophenomoshi) -17,18,19,20-tetra true Δ
-PGI+.

(1114), S,? -difluoroCl-16 (a
t-) fluoromethylphenol) -17,18°19.26-detranol-Δ-PGI electron.

(10), 1 g -(p-chlorophenoxy)-
5.? -Ji l a k -1? , 111. l 9,20
-Δ'-PGIt.

(iss), s, y-dibuam-is-(m-methylphenol Schiff-17,1,8,19,20-pe/tanoru Δ-PG engineering 1 (Snow OS), S-fluoro-1@ -phenyl-17
゜151.1・, s e-tetra true Δ-PGI+
.

(zoz), s-chloro-ts-(m-fluorophenoxy)-17,11,t@,2G-tetratrueΔ-PGMs.

(H4), S, 1-dichloro-xs-(Im-)
Riff A/ Oh Mechi A/ 7 工 x A/ ) -1?
, l s, t Q.

2G-tetratrue Δ'-pGIII (zoo), s-p*A-ts-(p-riOlphenyl)-7-M-do17.1 jl 9,20-tetratrueΔ-PG 1゜(gos) , s-pHA-ti-(o-methyl7enyl)-17,111,l9,20-tetratrueΔ-PGL.

(210), 5-fluoro-Δ-18-oxerPGI+m (21ri, !-chloro-Δ-18-oxer-PGI+m).

(214), S,? -Schiff ni O-Δ-17-Okisu-PGXs * (216), S,? -Dichlororu20-Methyl-Δ-18-Omer-PGI+ + (2151), ? -Kuroru 5-51-Do 16.
I III -dimethyl-Δ-17-O-container PG engineering I
.

(2111),! -7k o 0-16. I II-
Dimethyl-Δ-PG engineering.

Methyl ester of (gzo), (too).

Methyl ester of (221), (lot).

(222), methyl ester of (ts2).

(2ZS), (50m) methyl ester.

(224), (104) (D methyl ester.

(225), methyl ester of (iso).

Methyl ester of (2!@), (1011).

(!2?), (tU) methyl ester.

(2!11), methyl ester of (108).

(!!11), (1@l) Tsumethyl X, Xfk.

(130), methyl ester of (120).

(m), (145) mechi k X , X f k
.

(1m2), (ts2) O Ethyl X Stell.

(!33), (lli methyl ester.

(134), (114) O methyl ester.

(05), (14G) methyl ester.

(236), methyl ester of (116).

(23?), (lie) methyl ester.

(gas), (tts) 0 methyl ester.

(was), (562) methyl ester.

(z4o), (t2o) o methyl ester.

(2413, n-butyl ester of (148).

(j42)-(122) f) Ethyl ester.

(24m), (18 Phantom n-butylnisder.

Ethyl ester of (zn), (ts4).

(245), butyl ester of (144).

number (!46), (l Tsuru) n-propylnisdel.

(2nd y), n-butyl ester of (4yuki).

' (24@), n-butyl ester of (lull).

(249), methyl ester of (ts・).

(no), n-pentyl ester of (ts2).

(262), n-hexyl ester of (134).

(2s4), (1ss) O methylnisder.

(21@), (140) methyl nisdel.

Methyl ester of (!511), (144).

(25G), butyl ester of (144).

Ethyl ester of (0), (1411).

(262), n-octyl X X tyl of (1!i0).

(2sn), (tsz) ethyl ester.

(!811), methyl ester of (154).

(a6y), (13G) n-butyl varnish, del.

(268), (tss) On-decyl ester.

(zae), (gas) n-decyl ZX del.

(!TO), (In) methyl ester.

(zyt), (lee) n-decyl ester.

(27ri, (HIri methyl ester.

(Methyl ester of snow 713. (21.).

(Mushroom 4), (141@) 0 Phenyl ester.

(!?!ri, (1・?) On-Dital Ester.

Methyl ester of (us), (tss).

(!711), p-methylphenyl ester of (170).

(no), p-fluoro7 enyl ester of (174).

Ethyl ester of (3all), (l)・).

(u2), benzyl ester of (IN).

(ts4), (iso) phenethyl ester.

Methyl ester of (as) (t@yuki).

(!117), methyl ester of (21G).

(zss), (Snow 20) Ol 1. I It-diacetate.

(2811), (228) 011. I G-diacetate.

4zso), (us) Ot 1,1! I-Diacetate.

(2111), (gas) v t 1,1 s-
Diacetate.

(292), (sat) to 11,1 s-diacetate.

(293), 11,11-diacetate of (gzt).

(1194), t 1 of (224). IS-Diacetate.

(296), 11,1 of (!4・)! ! -Diacetate.

(2as), 11.15-diacetate of (gas).

(Full 90), (Snow 24) t t, gas-diacetate.

(3oo), (Snow 80's 11.I S-Diacetate.

'(sow), (ttt) 11. IS-Diacetate.

(103), i 1,1 s-diacetate of (Rei 73).

(104), 11,1 B-diacetate of (ays).

(10@), (Goose@?)'s 11. IS-Diacetate.

(Sol), 11,111+-diacetate of (two).

(so・), (gas)'s t 1.1 s-bi x(
t-butyldimethylglyl) ether.

(310), (2B8) Ol 1. IS-bis-(t-butyldimethylsilyl)ether.

(all), (zz・)OLL, Is-bis-(t
-butyldimethylsilyl)ether.

(312), (2m?) 11. I K-bis-(
t-butyldimethylsilyl)ether.

(314), 11.1 of (24111)! ! -bis(t-butyldimethylsilyl) ester.

(315), (26@) 11,1! ! - Bisou (t
-butyldimethylsilyl) needle.

(311), 11 of (235). I m-bi x-
(t-butyldimethylsilyl)ether.

($17), (!41) t 1,1 s-bis-(t
-butyldimethylsilyl)ether.

(3111), (2B) 11. I m-bi x-(
t-butyldimethylsilyl)ether.

(32G), <224) t t, t+s-bi x
-(t-butyldimethylsilyl)ether.

(01), (2511) 11. I S-1'X
-(t-)fldimethylsilyl)ether.

(szU, sodium salt of (tow).

(32il), the sodium salt of (159).

(324), sodium salt of (fil).

4zxs), (tst) o sodium salt.

Sodium salt of (us), On).

(328), sodium salt of (12.).

Sodium salt of (340), (1117).

(34ri, sodium salt of (101).

(344), sodium salt of (145).

(34@), sodium salt of (219).

(3451), sodium salt of (100).

(sso), potassium salt of (103).

(u2), (toll) sodium salt.

Sodium salt of (354), (110).

Calsulam salt of (ass), (tt.).

(3 brocade), (XU) magnesinium salt.

Compound of the above formula (A!) (soo), s-chlor-PGIt.

(Sol), 'I-Fluoro PGI*.

(so Tomi), S-PHA-PGIt 1 (so
s), y-ria sr-PGIt + (5G4)
, S-:il-doPGIte(sos),
y-BEI A-PGII + (so・), 5
．． 7-ji7nio-PGIt*(son), J
T-jikuak-PGMs @(ate), s,
T-jib EI A-PGI family.

(stg, t-p*A”!! -7k #O-
PGIm.

(sll), 5. ? -Jimou-Do PG Kousetsu.

(sta), s-ri Ok-7-51-do PGIm
.

(5143,5-chloro-7-fluoro-PGIt.

(81!ri, 5-brom-1-ria Roux PGI
t.

(sts), t-riOk-g -7koQ-PG
II.

(SIT), t-rit:1 k-! i-M-
Doped PGMm+(ill), 5-doped OA-7-
7k O-PGIt.

(sts), ? -bromo5-rol, -PGIt
.

(no), rt-riah-ts, t4-dehydro-PGIt.

(S snowl), 5-chloro-13,14-dehydro-PG
It.

(02), S,'I-Zikualu 1 ft, l
4-Dehydro-PGIt,'.

(03), 7-7 kO El-13,14-dehydro-PGIt.

(Sha), S,? -difluoro13.14-dehydro -PGI f1, (s2s), s-butlA-7-7kjQ-13,14
-Dehydro-WaX嘗.

(5263,5-chloro-13,14-dihydro-PG
It.

(527), 7-7ktQ-5-a-t-t 3,
14-dihydro-PGIt.

(Ha), 5.7-difluora-ts,t4
-dihydro-PGIt.

(011), 7-fluoro-13,14-dihydro-pa-t.

(53G), S -F O Lu 15-1 +
Lou PGII.

(531), 7-fluoro-15-methyl-PGIt.

(5 companies), s,y-difluoro-11! -Methyl-
PG proverb.

(533),! -1a roux? -ylta-13,1
4-Dehydoku PG! elephant.

(534), i-chloro-7-fluoro-ls-methyl-PGI proverb.

(63B), 5-ri Hk -1? @), 2
@-diIfh-PGI* # (sag), s-chloro-ls-methyl-18,14dihydro-PGIt.

(537), 7-Thruo0-1fu@,! 0-dimethyl-PGI so.

(sss), ? -Ok -11+ -7kO0-
17 (0-17(dimethyl-PCkX*.

(53•), 'l-fluoro17@, snow O-dimethyl-PGIm.

(54G), ! -PHA-7-Fluo' -i t
@) O-dimethyl-PGIme ($41), 7-chloro-5-fluoro-t'
@) +20-dimethyl-PGL.

(!iD), i-riah-1@, 1@-dimethyl-
PGIm.

(s4g), s-ri O Luo? @,! @-dimethyl-PGIm.

(144),! ,? -difluoro t s, t s
-dimethyl-PGI official.

(IS45), I-Kukuru! -116-Simethyl-PGI.

(54•), 'I-7kO-16,111-dimethyl-PGIm.

(!1411), l 5-cyclo to sil-5-chloro-1., l 7,1 jl., 20-pentanol-PGIm.

(149), 'I-Fluoro-15-cyclohexyl-ts,t7.1s,to,2o-pentanol-PGIm.

(55G), 8. ? -difluoro15-sikuo)
Nakasil-16,1ts,tL20-pentanol PGIm.

(sas);

(552), S-7k O-1-OP HA-1!
I-cyclohexyl-t s, t 7,111. l s
, t o -pentanol PG engineering 1° (S51), ? -ria a -I S-cyclopentyl-t s, i y, t s, t., 20-pentanol-PGIm.

(554), h-tukuru 16-cyc a hexyl-
t 7,1 s, t s, snow--tetrano-k-PGI
m.

(sss), i-ta 0h-1 @-siku a to medium 7-fluo ci-1? , Ko 1,1sha, 20-tetraturu-PGXI t (ssa), Is, 7-difluoro-1-cyclohexyl-11,l, 1j, Yuki O-detotonoru PG
x snow.

(157), i-ta-oa-ts-cyclopentyl-
−? , 11.1・,! -Pentanolu PGIm.

(sss), s, t-difluoro a-1@-phenonoshi 1? ,l 1,1 @,2
0-PGIm.

(sss), t-pro-1s-7 talopentyl 1 @, l? , l., 1.11.-pentanol-PG
Xm.

(sso), s-poum-1-phenyl-17゜l, 1-9-tetraturylumi x number.

(ssu), 1. -11-do#@1 [-cyclobentolu-凰・-7,1jl @,20-pentanol-PG engineering
.

(562), , S,? -JikuOh-1g-Pheny-17,111,l 11,1 G-Tetra True P
dIt *(564), 7-7 Luo C1-19-
Pheno middle sea 1? , 1 g, 1 @, 20-tetratrue kidnapping.

(sas), t-fluoro-t@-(p-yfluorophenol'/ ) -17,111,111,! O
-Deto Tsunolu PG Koen.

(08), J? -difluoro-16-(m-trifluoromethylphenoxy)-17,ilB.

! Society, 20-Detranoroo PGI Proverbs.

(57G), 'I-Fluo a-16-(m-) Refluor, lomethyl 7 stone now)' -17, I Jl turtle 30-detranol paI spirit.

(57ri, 7-fluoro-16-(p-chlorphenol)-1?, l 1,1 m, 2ot true PG factory.

(574),! ll7-difluoro-141-(p
-ri.

rufenoxy)-17, 11m, 111. ! 6-? Tratrue PGI - (its), s-bromo-16-(trifluoromethylphenyl)-17,11,19,20-detranol-PG1° (sem), s, t-dichloro-5a-( p-chlorophenyl) -1? , 111. t., 20-Tetra True PGM Tomi.

(sio), s-react-Ill-(o-methylphenyl)-1? , l II, 19. ! 0-detranol-PGIt-(Ill2), S-ria #-20-Methi-P
G-engineering ■.

(684), Is-bromo-20-methy#-PG
lll(S...), 5-W-do-yuki O-methik-PG
Mm.

(58 Hatake), s,r-difluoroH-20-methyl-PGI.

(sso), t-Full Nakaguchi-17-O Nakasu-PGh
l(S・2), S,? -Schiff kIO-1? -Ochuner PGI Yuki.

(594), 5-chlor-17-o#? -PG
It.

(sss), s-puo A -7-7ko0-1?
-Omeina PGM Lightning.

(sea), 7-fluoro-5-iodo-18-oxa-PGIt.

(goo), s, t-difluoro-18-oxa-
P.G.It.

(602), 'I-bromo-5-chloro-III-
Okina PG Eng.

(604), S,? -Jik Ok -I II -t
*t-PGII.

(606), 5.7-Jik O# -20-Methi ni 1'II-O Chuna PG Kousetsu.

(6011), S,? -Difluoro*-20-methyl-・16-okizu-PGr snow.

(UO), ! I-bromo-20-methyl-5--
OdP! -PGI* 5 (612), ! I-ta C1 & -2 (1-methi-
18-Okizu-PG Kodake.

(1114), ? ? -fluoro t s, t s
- Dimethyl - 11-year-old middle school PGI meeting.

(4!013. 's'-Ji y Luo a-l@, 16-
Dimethyl-1 fuosu-PGM deprivation.

(61・), 5-brome-? - Fluoro 11. l
#-Dimethyl-17-Okina PGM Snow.

(82G), 7-fluoro-O-methyl-PGI
t*(6223,5-bromo-1-fluoro0-20-
Methyl-PGI Mayuzumi.

(@24), ! -riHA/-7-7/l/o-
IQ-Methyl-PGIt.

(szs), 7-fluoro-118,1@-dimethyl-PGI*.

(ass), s-pro^-7-fluoro-1@, 1
6-dimethyl-PGX* e (630), S-chloro-7-poA-1@, 1l
I-dimethyl-PGIt.

(@32), S,? -Difluoro H-1'@, l@-
Dimethyl-P(hXs # (jar), s, t-dibrome-11i, l
11-dimethyl-PGIt.

(ass), (s4t) o methyl ester.

(6311), methyl ester of (500).

(+l37), methyl ester of (501).

(ss@), methyl ester of (502).

(634m), methyl ester of (503).

(@40), methyl ester of (sos).

(1141), methyl ester of (54Jl).

(@42), (Sell) methyl ester.

(643), (szs) methyl nisdel.

(644), (8111) OI Chill! J?
k.

(4B45), (sao)'s mechi k 1 X naru.

(64g), ethyl ester of (522).

(@4?), (ll+0@) methyl ester.

Ethyl ester of (184@) and (52@).

(64G), methyl ester of (508).

(sso), (sso)'s methi sr x stell.

Methyl ester of (・51), (64?).

(sst), (soo) propyl ester.

(663), methyl ester of (SI?).

Propyl ester of (ss4), (sow).

(655), (53?) Methyl 1Xfk.

Propyl ester of (656), (50111).

(@s?), methyl ester of (535).

(sss), (sho) propyl ester.

(6603, butyl ester of (500).

(sss), (545) Buchi k 1 X del.

(si2), (sot) butyl ester.

(664), (St(1) Buchi A/Z Stell.

(665), butyl ester of (523).

(ssi), (51g) ()butyl ester.

(667), butyl ester of (543).

(sias), (514) pentyl ester.

(s7o), (szo) pentyl ester.

Methyl ester of (sll), (st@).

(・72), (szz) 0 pentyl ester.

(1173), (sll) mechi k x x?
k.

Octyl ester of (O74), (626).

(・75), methyl ester of (Slit).

(6711), n-decyl ester of (53G).

(@7?), n-decyl ester of (520).

Phenyl ester of (O783, (53@).

(67.), n-decyl ester of (si.).

(6803, p-methylphenyl ester of (54G).

(ass), butyl ester of (53G).

(ssz), (si phantom p-methylphenyl ester.

(sag), (sts) methyl ester.

(6114), p-fluorophenyl ester of (554).

(68@), (soo) sodium salt.

(687), sodium salt of (516).

(sss), sodium salt of (s).

(641G), sodium salt of (502).

(18110), sodium salt of (504).

(sag, the sodium salt of (say).

(6 [stock] 2), sodium salt of (SO8).

(6113), sodium salt of (sza).

(694), sodium salt of (2121).

(1195), sodium salt of (549).

(1196), sodium salt of (5!9).

(697), sodium salt of (547).

(sss), (rtm) sodium salt.

(ass), (s4p) sodium salt.

(yoo), (soo) potassium salt.

Sodium salt of (731), (535).

Potassium salt of (tow), (soi).

(703), sodium salt of (530).

(7G4) Sodium salt of (sow).

(705), sodium salt of (5041).

(7011), potassium salt of (601).

(7G?), (567) sodium salt.

(7ou), (soo) ammonium salt.

(7(Hl), sodium salt of (501).

(710), ammonium salt of (sot).

(712), ammonium salt of (554).

(714), ammonium salt of (!156).

(wig), (sss) ammonium salt.

(Till), ethanol ammonium salt of (500).

(7mG), ethanol ammonium salt of (SQL).

(To), (soo) 11. I B-bis(t-
butyldimethylsilyl) ether.

(724), (501) 11.11-bis(t
-butyldimethylsilyl)ether.

(726), 11,11-bis(t-
butyldimethylsilyl) ether.

(7211), (Nishiki 2) Turtle 1. I! - Bi x (t
-butyldimethylsilyl)ether.

(?3o), (seo) 11.15-bis(t
-butyldimethylsilyl)ether.

(7m2), (50G) of 11.15-bis(2-natrahydropyranyl)ether.

'(734), 11 of (50). l! -Bis(2
-detrahydropyranyl) ether.

(73@), 11 of (1G). IS-Bis(2
-detrahydropyranyl) ether.

(7111), 11,1 of (Ul)! ! −Bis(
2-Buto2hydropyranyl)ether- (f4a), 11,15-diacetate of (630).

(?4ij), (6311) 11. IS-Diacetate.

(743), t 1.1 g-diacetate of (64G).

(744),, (645) 11. IS-Diacetate.

(745), tt,3s-diacetate of (683).

(74@), 3t of (s, ay), 5s-bis(t
-butyldiphenylsilyl) ether.

(rat), (si3) l tit s-bi x (t-
butyldimethylsilyl) ether.

(7411), lI of (a'l'l), l 5-bis(
t-butyldimethylsilyl)ether.

(7so), <647) () s t, l m
-Hx (t-butyldimethylcryl)ether.

(752), (63g) of 11,1 i-bi x(t
-butyldimethylsilyl)ether.

(754), (679) 1! , 16-diacetate.

('156), 11,1 m-diacetate of (637).

(757), (673)011. II-'/7-? -).

(758), (637) Noll, Is-HiX(t
-butyldimethylcryl)ether.

(780), (63g) O11,1K -Hix
(t-butyldimethylsilyl)ether.

(71i2), (642) 11.凰S-Bis(t
-butyldimethylcryl)ether.

(763), (ss?) 11. I m-bix(t-butyldimethylsilyl)ether.

(764), (651) O11, IS-J7SE? -).

(T166), (881) l l, l m-bix(t-butyldimethylsilyl) engineering del.

(768), t t,is-diacetate of (671).

(770), 11.15-diacetate of (675).

The method for producing I-logy prostacytalins according to the fourth invention will be described in detail below.

Among the halogenated glostanitalins of the present invention, in the general formula (M) or (M), R snow and ptm are a hydrogen atom or a fluorine atom other than a fluorine atom, and at least one of them is A group of compounds in which is a halogen atom other than a fluorine atom can be produced according to skis AI and 2 below.

Scheme 1 (Bl) (Mu)-
1 Scheme 2 (B+) (Mu)-
2 In Scheme I, the PG polycarbonate represented by the general formula (Bl) is reacted with an electrophilic halogenating reagent represented by the general formula (0) in an inert organic solvent, if necessary in the presence of a basic compound. A halogenation reaction is carried out. The reaction product is a must! The compound is then subjected to a disassociating reaction and a salt-forming reaction to give the halogenated glostanitalins represented by the above general formula (i)-i.

The above formula (Ih) representing PGIII (starting material)
, the symbolic opening between the ti-position and the 14-position and R1
The definition of is the same as the above formula (mut)K&.

Also, all, all, R@I sPj and R”
Definitions of the above formulas (MUHO) OR' and R', respectively.
, R. and R1 are defined as follows: H4* is an alkyl group 11 of O+ to c1. or an unsubstituted phenyl group.

Mono-substituted or unsubstituted aliphatic lateral group or substituted or unsubstituted phenyl (0+ to am) alkyl group, 14m
is a hydrogen atom, a methyl group, or a protected 9-ethynyl group;
3w acyl group, tri-(O1~at)jl hydrogenide system-
A group that forms an acetal bond with the oxygen atom of a silyl group or hydroxyl group.

PGl and lI represented by the above formula (B) are G. Manufactured by known methods from staglandin IP (1111116S 2-95644
(see publication). Specific examples of such PGI electronic distribution include the following.

! :54 (bond) R"R"It'
R” R” double bond OHs H0sl
s+ TBDM81 teBDM8iTHP
TIP OHsOO0HaCO # Q, li, # #
TeBI) M81 TeBDM81' Ot・
fill I I C Zheng H1101111 # 2-Mep 5 Re # 0tHs Hl, 4' OHs H cyclohexynol
l triple bond ” (sou 0HsOOO0
HsOO monomer I # In the above formula (0) representing the electrophilic halogenating reagent which is the other starting material, I is a chlorine atom.

It is a bromine atom or an iodine atom, and Q is a nucleophilic residue.

Preferred examples of such electrophilic halogenating reagents include chlorine, bromine, iodine, 1M-bromosuccinimide, 1. - OA succinic acid, 1M-iodosuccinimide, M-promophthalenimide, N-chloroheptalimide.

Dioquinane dipromide, dichlorohydantoin, dibromodimethylhydantoin, trichloroisocyanuric acid, t-butylhypochloride.

Examples include t-butylhybob Qmite or pyridinium γ hydropromitoperbromide.

The reaction of the starting compounds represented by the above formulas (Bl), (0) and K is carried out in an inert organic solvent, necessarily in the presence of a compound more basic than IEK.

Examples of inert organic solvents include dichloromethane, chloroform, viA carbon chloride, 1.2-')? Halogenated hydrocarbons such as lorethane; ether compounds such as ethyl ether, tetrahydrofuran, and diquinane; benzene, toluene, and silane.

Aromatic hydrocarbons such as hyanosine; hexane. Aliphatic hydrocarbons such as pentane and cyclohexane; esters such as ethyl acetate; aprotic polar solvents such as dimethylformamide, dimethylsulfonate, and hexamethylphosphoramide are preferably used.

PGGa4, which is represented by the above formula (&) of the raw material, is neutral to
Due to the instability of the vinyl ether bond, which is easily broken by hydrolysis under acidic conditions, the above reaction can be carried out using, for example, triethylamine pyridine, sodium bicarbonate,
This is preferably carried out in the presence of a basic compound such as soda carbonate.

The reaction temperature is from -100°C to 60°C, preferably from -0°C to l·°C. The reaction time varies depending on the reaction temperature, the reagent used, the amount of +1 medium, etc., but is usually 0.1 to 1.
48 hours Ii direct is preferred, more preferably o, t
-20 hours Ill is recommended.

In the above halogenation reaction, PG
w) Electrophilic halogenation reagent @ (0) of 0.9 to 1. When used at a ratio of s4, the compound of formula (M)-1 in which R'' is a hydrogen atom (- is a double bond between the 6th and 7th positions) is mainly produced, and PGI@(Bt) t mole of electrophilic halogenating reagent (
0) in a proportion of i, 14 mol, preferably 2 to S mol, the #i product is the formula (mu)-- in which R1 is X.
Compound 1 (a compound in which X and Ram are the same I.rogen atom and a double bond exists between the 5th and 6th positions) is mainly produced.

Separation of the reaction product from the resulting reaction mixture (7) can be carried out by adding an aqueous solution of sodium carbonate or the like to the reaction solvent and washing it to separate the organic layer, if the reaction solvent is water-insoluble, or by separating the organic layer if the reaction solvent is water-soluble. After condensation, an aqueous sodium bicarbonate solution and a water-insoluble solvent are added thereto, followed by washing and extraction to separate the organic layer.

The nine organic layers obtained are dried and then combined to give the desired product.

Examples of the target products include silica gel column chroma dog 2-fee, silica gel column chroma dog 2-fee, and florisil column chromatography.

It can be purified by means such as high performance liquid chromatography. Such loading means may also be directly applied to the reaction mixture obtained.

In some cases, a base such as triethylamine having a strength of KO, 01-1 may be added to the additives used in these processes.

The silane produced by the above halogenation reaction is then subjected to a salt-forming reaction, which is removed by the halogenation reaction.

The deprotection reaction can also be carried out in a reaction mixture after the halogenation reaction is completed, or it can be carried out in a single reaction mixture as described above.
) Removal of the holding group (R・1 and /l or R1) of the hydroxyl group can also be carried out on the target product when the holding group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group. , using a catalyst such as acetic acid, a pyridinium salt of p-)luenesulfonic acid, or a cation exchange resin, and using water as a catalyst.

This reaction is suitably carried out using detrahydride 07ran, ethyl ether, dioquinane, acetone, acetonitrile, or the like as a reaction solvent. The reaction is generally carried out at a temperature range of -78°C to +30°C for about 10 minutes to 3 days. In addition, when the holding group is ) (0°-〇·)hydrocarbohydrate-silyl group, for example, acetic acid, detofuptylaminofluorozide.

cesium fluoride, etc., preferably in the presence of a basic compound such as triethylamine, in the presence of a reaction solvent such as
(preferably a reaction solvent other than water) at similar temperatures and for similar times.

When the protecting group is an acyl group, #i, for example, caustic soda, gastric potash, calcium hydroxide water #1 moat or water -
Alcohol warm S* or sodium methoxide,
This can be carried out by hydrolysis in a methanol or ethanol solution containing potassium methoxide or sodium oxide.

The removal of the carboxylic group O-retaining group (R11) can be carried out using an enzyme such as River, for example, using water or a water-containing 1 [1 medium 10'' ~ + @ 'C'il' degree Ii #l So 14
Yangdu is performed for 1 minute to 34 hours.

According to the present invention, a compound having 9 carxyl groups produced by the above-mentioned protective group removal reaction must then have 1 m! The carpone salt is subjected to a salt-forming reaction and is then phased out. The salt-forming reaction is itself omniscient;
phosphoric acid, almost a voluminous amount of sodium hydroxide, and potassium hydroxide.

A basic compound such as sodium carbonate, or ammonia, trimethylamine, 4-ethanolamine, 1-morpholine is subjected to a neutralization reaction using an overcharge method.

Thus, the above s life-5 IK is shown and s? A halogenated prostacytallin represented by the following formula (M)-1 is obtained.

According to the reaction according to Scheme IK above, by controlling the amount of electrophilic halogenating reagent (0) used, seven- and dihalogenated prostanitalins (monohalogenated PGX*@ and dihalogenated PGIts) can be produced. This is a halogen atom beam meaning 0 dihalogenated PG technology.

In the life-^I, pG represented by the general formula (Bl)
X*WA is an electrophilic halogenated test compound represented by the general formula (0) and a halogenated brostanyl reacted in the same manner as gold (IK). Give talins.

PGIII (Starting material, 's*) a%pa
PGI+g @l can be produced by the omniscient method (R, Mu, Johns
on et al., J, m@r, ohem.

Boa,, 100. 711HI (凰・71):
K, Bhimoji et al., 1t)i(1,.

■Mu spirit! 47(11?I)).

Examples of such PGZ and common odor bodies will become clear from the above-mentioned RK example of the nine PGIt manifestations.

According to the above method, halogenated brostanitalins represented by the following formula (M)-F are produced.

In the formula -18, it is difficult to produce any of the above monohalogenated prostanitalin and dihalogenated prostanitalin *<monohalogenated PG-treated heavy compounds and dihalogenated PGh compounds). This dihalogenated PG engineering.

The halogen atoms in SO snow are the same. "Among the halogenated brostanitalins of the present invention, K R" and Ra are hydrogen atoms or halogen atoms other than fluorine atoms, and at least 4, one of which is a halogen atom other than fluorine atoms. A group of compounds is obtained from 97-halogenated PGI@1lI(mu-)-a obtained according to the method in step 3 above to dihalogenated PGIa according to steps 3 and 4 in the following step, respectively.
llI ((At)-at) and dihalogenated PGX ((Aj)-1Lt), and nine mono-I-logonated PGxs ((Aj)-1Lt) obtained according to 53 of the above
(Mu,)-a) to Gino Logonization PGXII11 ((Mu,)-1L,
) and monohalogenated PGIII ((mu,)-
Manufactured as &,,).

Life 3 (Mu,)-a' (Mukan)-m.

In the above formula, 11 is a chloride atom, a bromine atom, or an iodine atom (hereinafter referred to as -).

Scheme 4 Scheme - The above schemes 1 and 5ort are the same as scheme 1 and Oka 1.
It can be carried out with 1K.

In the above reaction, monohalogenated PGI*111 represented by (M1)-1 is treated in a solvent containing protons OIF to convert the O double bond at the 6th position to the double bond at the 1st position. isomerization and then, if necessary, by subjecting the compound to a transfer reaction and/or a transfer reaction). The obtained product is monohalogenated PGIdll represented by the above formula (M)-1.

The above-mentioned isomerization reaction acid (~ by means of a catalytic protonic acid or an organic sulfanoacic acid pidazine salt in an inert aprotic solvent, as required) in the presence of a dehydrating agent sequentially or simultaneously. At the very least, let Asahi ■ or (moan) in a protic solvent with a protic amount of O protic acid! 1
J611L is then heated in aprotic sS.

In the above-mentioned -)O procedure, examples of the inert phosphoric SIs include benzene and toluene.

Nakasilane, chlorobenzene, hexa/, hentane, citarohenan, methylene chloride, chloroform, carbon tetrachloride, l-cycloethane, ether, tetotsuhydro7fun, diochusan, dimethanoethane, dimethyl sulfoxide, dimethyl Formalde and the like and warm solvents thereof are preferably used.

As a catalyst, for example, 12 mm, hydrochloric acid, hydrobromic acid,
Perchlorine 11H, O mineral acids or p-)ruethyl sulfonic acid, trifluoroacetic acid, methanesulfonic acid, trifluorometacisulfonic acid, organic sulfonic acids, and pyridium p-)ruethyl sulfone)@0 organic sulfonic acid O
One example is salt tatami. Sulfuric acid is preferably used for *.

Temperature change is 11! (1~+100℃, 411K-1
It is preferable to carry out the reaction at a temperature of ＠ to +90°C. Kaiho Jito differs depending on the location, the catalyst used, etc., but it usually takes about 4 seconds to 4 seconds.
The time shift is stormy, and the best time to steal is from 3 seconds to 1 hour.
It is I degree.

The treatment includes sequentially or simultaneously the presence of a dehydrating agent,
It can be carried out. That is, treatment with a protic acid or an organic pyridine salt containing a dehydrating agent such as madanesium dihydrofuran sulfate or dihydropyran, or treatment with a protic acid or organic pyridine salt in the presence of a dehydrating agent. It can be treated with salt.

In the above 1e (tJ 0 hand 1), as the protic solvent, for example, methanol, ethanol, and 1s〇-globyl alcohol l1fi are preferably used.

All due to protonic acid is -? 0', +10oC
, preferably one! It is carried out at @'-+i・℃. The partial layer time is preferably from 1 minute to 4 hours, preferably from 1 minute to 3 hours. After such mlie, the reaction product is then heated in an aprotic medium.

Preferably, such heating is applied to a single reaction product. As the aprotic wetting agent, an aprotic 41ki11 medium such as a 0% 01 bottle or a methyl nephthalate can be used as mentioned in the above-mentioned procedure 111. Heating is usually carried out at a temperature of so' to 2.0°C, preferably 120' to 180°C. The reaction time is from over S minutes to 24 hours.

Purification of the target product from the reaction mixture thus obtained can be carried out in the same manner as described for Step-5 IK above. 9, the obtained 9 reactions must be about 1
The disassociation reaction and/or salt formation reaction that are often carried out in Step 1 can also be carried out in the same manner as described in Step 5.1 and Step 9 above.

Thus, according to the above order-54, the above formula (mu I) -
A halogenated PG industrial electrical appliance represented by 1LI is obtained. These monohalogenated PGIs differ from the starting material monohalogenated PGs in the position of the double bond.

The reaction of the above Suimaichi ^6 is to heat the PGX, which is represented by (MU5)-a, in the habitual hatch where the Oka IIK proton exists, and to place the 2nd place O double bunker. isomerize into a double bond and then must! Disengagement by and/
K is then subjected to a salt-forming reaction. The isomerization reaction is carried out in the same manner as the procedure (a) or (110) above for the reaction of Sum 4.

The resulting products are monohalogenated PGIs represented by the above formula (M+)-am. These O compounds differ from the starting material, monohalogenated PGI mushrooms, in the position of the double bond.

According to the reaction of the above-mentioned sugou-goo--, the halogenated prostacytalin llIC formula (n) or (mudo) of the present invention
) out of! l'' and R8 are the same or different atoms, each of which is a hydrogen atom or a halogen atom other than a fluorine atom (however, R1 and R1 cannot both be hydrogen atoms), mono- or dihalogenated PGIs@l and It is understood that mono- or dihalogenated pGI*III can be produced.

Among the halogenated polymers of the present invention, compounds in which at least one of a'sP and Rs is a fluorine atom in the general formula (Mu) or (Muyuki) are defined by the following formula. 7 to 13.

According to the above-mentioned Step 7, the hexanovucinated Glosta-Italin compound represented by the above formula (MU) is produced. That is, monochlorination (i.e., monochlorination, monobromination, or monooxygenation) of formula (M+;)-a) PG engineering I
PGI
No matter which type of O is used as a starting material, s-fluoroPG engineering t! I and 7-FluoEI PGIII
(Compound of the above formula (M)-set) is produced.

The reaction of frame 1 in the above scheme is carried out in an aprotic inert organic solvent.
) or mono/SQ-genated PGMs ((mu,,)7a)
is subjected to a fluorination reaction with a fluorinating agent, and then, if necessary, subjected to a debinding reaction and/or a salt formation reaction.
It is embroidered.

As the above-mentioned fluorinating agent, various fluorinating agents that can be used in a fluorination reaction in which a chlorine atom, a bromine atom, or an iodine atom is replaced by a fluorine atom can be used. Such fluorinating agents are omniscient, and examples include #f7 silver tsulfide, cesium heptatide, potassium heptatide, sodium fluoride, mercury heptatide, and borofluoride. Examples include silver or tetoptylammonium fluoride. Among these, silver heptadide is preferably used in 11%/-h of 4IK.

Examples of the aprotic inert organic radish include a7tonitrile and dimethylformad.

Dimethyl sulfate, to dPt methyl phosphoric acid, polar combination; benzene, toluene, xylene O
Water-based addictive agents; dichloromethane, chloroform,
II Tarolized hydrogen mortar such as carbon chloride; ether;
Tetrahydrofuran. Ether solvents such as diethylene glycol dimethyl ether are used. Among these, acetonitrile in the nonapolar ttI medium mentioned above is particularly preferably used. For example, a crown ether chain such as 18-curacun-. may be used as a ζOII fluorinating agent.

[
S can be used.

In the fluorine substitution reaction, the overcharge is 0-! O・℃, preferably sO
It is carried out at 0-160°C. The reaction time ranges from several minutes to 1 hour, but 48 hours is usually sufficient.

In reaction 0111, it is preferable that triethylamine, potassium hydrogen carbonate or sodium hydroxide, potassium carbonate or sodium hydroxide, etc. be present in the reaction system.

The above-mentioned Fluorination Reaction Co., Ltd., preferably 77 as a priming agent.
Silver tsunide is exfoliated at -10 to sec for several minutes to 4 hours.

The OI target product can be isolated and purified from the obtained reaction chamber by writing the system IK and performing it at Marutooka 11K. However, the tS removal reaction or salt conversion reaction to be carried out on the obtained round compound must be carried out in the same manner as described above. (Otori) O human ■ life cipustacycline is S
-HydroxyPG engineering 5ell or 1-human aqS/P
Represents any of the GIm classes.

According to S-Mei-5, any of these human I2 cyprostacyta q and q can be used as a starting material, S-fluor-PG4sllk and 1-fluoro PGIs.
M ((mu)-al compound) #IImk-JtL! .

The above-mentioned life-5 $O reaction is carried out by converting the above-mentioned human acypus stacytalins into luadenolgFm in di(at~0.)alcohol.
, bis[di(o+~Os) alcohol lua ζノ]-87,,
4# $rif-81s or 0FaOHP M (Owls
The reaction is carried out in an aprotic inert organic solvent.

For example, dimethylamino-llFm, diethyl A-
11Fm.

Examples include Diprovira ζ No 8h and Dipentylar Ashi-811.

Bis [di(0,~Os) alcohol lua ζノ] -8'! *
For example, bis(dimethylaζ))-81■
.

Bis(diethylami))-81 Yuki, Bis(diglopyruaζ))-8FI * Bis(dibutylami))-8
11, Bi^(Diventilua Z))-81 So et al.

Examples of the aprotic inert organic solvent include di/almethane, taroform, ffl chlorinated carbon, and! , 8
- Dichloroethane, etc.; ether, tetrahydro, dimethane, etc.; benzene, toluene.

Hydrogen am hydride such as silane is used. Preferably, hacyclomethane, chloroform, etc. are used.

The above-mentioned bulking agent can be used in an amount of 1 to 1 times the amount of the starting material.

The reaction temperature is -! ...℃~IOC, but preferably -
The temperature is between 1.°C and 3.°C. What is the reaction time?

This may be true depending on the reaction l1IIl, the test system used, the amount of O, etc., but... W411i1 when 1 to 4 dollars! is preferable, and more preferably ・jN111 time Ill station.

The isolation and purification of the target product from the reaction product that could be obtained is described in Scheme 1 and can be carried out in the same machine as Scheme 1. The des*si reaction or the salt scavenging reaction to be carried out as necessary for the purpose of obtaining the desired product is also described in Term I, and can be described in the same manner as in 9.

The starting material represented by the above formula (1), ie, the starting material, is a compound of ζ-dolyl, p-stat, and italin.

According to the research of the present invention, the above-mentioned hydroxyprostalins can be synthesized from the following enzymes or BKs from PGhs or PGIsM, respectively.

Sume-mu (1)-Lm (())-amsuo-5 B In the above scheme 5, the first O starting substance PGIJII
a tr, f allylsulfinyl chloride (mur
-B-OL (where Mr is an aryl group such as phenyl or tolyl) and triethylamine.

Pyridine, 4-M, M-dimer-minopyridine.

3. Snow, . . . - It can be produced by reacting in the presence of an O basic compound such as ν in the presence of an aprotic inert organic solvent. The reaction is -s
It is advantageously carried out at temperatures between o'' and +SO°C.

The i-resulfuel-PGIs represented by the above formula (1) can be isolated from the reaction mixture by the same method as described above.

Next? s s-allylsulfenyl-PGLl@a
, Kaku-chloroperbenzoic acid (m-OPBm), and Suishin d&
Compatible organic solvent and sodium hydrogen carbonate or potassium O
The reaction is carried out in an aqueous solution and an O3 phase solvent system.

Examples of water-immiscible organic heating medium include dichloromethane,
Taroroform, i! Carbon chloride, dichloroethane, benzene, toluene, 4PV lene, ethyl ether and the like are preferably used. The reaction is preferably carried out o-1otOs directly.

In this way, S-allylsulfinyl-'1'GXi represented by the above formula (G)-a+ is produced. The ζO compound can be isolated from the reaction mixture in the same manner as above.

Then, 2-allylsulfinyl-pGLs a, a-s
In the presence of MO, 6 ml of the reagent such as diethyl amine, methyl phosphide or methyl phosphite was added to the solution.

Examples of organic solvents include methanol and ethanol.

1so-faA)-ruoml low 11 alcohol; ether, tetrahydrofuran, dioquinane, dimethoxyVethane O#IQ self-ethers, etc. are preferably used.

The reaction is carried out at -400 to +1.0°C, more preferably from 0°C to -
Performed at 0°C.

Thus, the above formula (]ri-ms expressed as 1-
PGxssI in human cI constitutes a part of hydroxyprostaniphrine of the above formula.

According to S-511, if we take the above-mentioned S-Mm Kjm from the first mountain-ridge material MI- class, we can obtain the formula (ν
) '-am's 1-allylmelphenyl PGIm fist! 7-arylsulfinyl 'I'GXs of the formula (G)-am
Via @, S-hydroxypaX*-1 of formula (ν)-
fi manufactured. ζo s -E droxy PGX*@ is the above (1) -am97-hydroxy V pGI
The mixture forms the cyprostase and italin group of the above formula (1).

Examples of the cibrostanitalin chain in the above formula (1) include the following: ? -H)' a Q V -PGM@methyl ester-tt, ts-bis(t-butyldimethylsilyl) ether.

1-Human PGI Ethyl Ester-11,II-bis(t-butyldimethylsilyl)ether.

Mahcht*Q'/-PGIs-knob-pyl ester-11,,II-bis(t7-butyldimethylV1) ether.

7-Hydroxy-PGI butylnisder-tt, is-bis(3-detrahydropyrael) ether.

1-human o*V-PGMm syl ester-11. ji-bis(2-tetohydro-pinyl) ether.

7-hydrodP-PGIt decyl ester-11,Xi-bis(t-butyldimethylsilyl)ether.

1-V in hydro-PCkX dew Methyl ester-11,15-diacetate.

1- and doroya sea 11.14-dehyde a-pe engineering.

Methyl ester-11,1s-bis(1,-butyldimethylsilyl)ether.

7-Hydroxy-tm, t4-dihydro-PG-dimethylester-11,lj-bis(t-butyldimethylcryl)ether.

1-Hydroxy-■-methyl-PGI ethyl ester-x5tj-bis(=-detothydropyzyl) needle.

7-Hydroxy-17(2)-dimethyl-PG-methyl ester-11,1-bis(t-1-dimethylsilyl) ether.

V-111,lj-dimethyl-PGII in γ-human c1
Butyl ester -tt,t+s-his(t-)fldimethylsilyl)ether.

1-Hydrof.l., 17. II, 111.20-pentanol-IS-citalohexyl-PGI*methyl ester-11,Is-bis(t-butyldimethylsilyl)
ether.

1-Hydroxy-57,111,1iljO-detonol-lj-phenyl-PG.

Methyl ester-11,II-bis(t-)f-dimethylsilyl)ether.

5-HydroxyΔ-PG X I methyl ester-11,11-bis(t-prodimethylsilyl)ether.

S-ship Droxy Δ-PGI.

Ethyl ester-11,1'S-bis(t-p-dimethylthalyl)ether.

s-1 hydroxy-Δ-PGIt decyl ester-11,Is-bis(mushroom-ditrahydrovinyl) ether.

Easy-hydro-11,14-dehydro-Δ6-GXI methyl ester-it, ts-bis(t-butyldimethylsilyl)ether.

S-human od? CIS-methyl-Δ-PGL ethyl ester-tt, ti-bis(t-butyldimethylcryl)ether.

Bu-Hydro Nakashi 11(2), Yuki O-dimethyl-Δ6-
1'GIs methyl ester-11,Is-diacetate.

纂-Hydro Life Sea 1@, l-dimethyl-Δ-R)It
tt ester-11,II-bis(t-butyldimethylsilyl)ether.

S-human c1 life v -ts, ly, ts, lj@-pentanol-1s-cytalohe-midsilu-Δ-PGXI methylnisdel-11,11-t's(i-butyldimethylcryl) ether.

17.18,1·, snow O-detranol-I-(p-y fluorophenoxy)-Δ6-PGI+ methyl ester-tt, Is-bis(t-butyldimethylsilyl) ether.

5-Human 0 Medium Sea IT, 18. II,! 0-deto2 true 16-(p-)lifluoromethylphenoxy)-Δ-
PGMs Methyl ester-11,ll5-bis(t-butyldimethylsilyl)ney, del.

Life - 5 - The cibrostanitalins of formula (D) above are:

S-Mesyl (or trifluoromesyl, or tosyl) oxy PGIt represents either $1 or 1-metal (or trifluoromesyl, or tosyl) oxy PGI.

According to IK, 4,5-fluoroPG and 4,5-fluoroPGIm ((mu)
-a, 0 version) is the number that is created.

In this reaction, the above-mentioned cibrostanitalline chain is subjected to a fluorination reaction with a fluorinating agent in an aprotic aprotic organic solvent, and then, if necessary, subjected to an unbinding reaction and/or a salt formation reaction. KotoK Yosho will be carried out.

As the fluorinating agent and the aprotic inert organic solvent, those described in the above-mentioned 57 and the same threshold as 9 can be used. The reaction conditions are also Sum 1 and Gang Yu. However, the reaction time is 1 to 16 hours, preferably 4 to 46 hours.

A method for single-graining a target object from a sumi-shamono,
The disassociation reaction and/or salt formation reaction that may be carried out on the target product if necessary can be carried out in the same manner as described in Section 9 for Life IK.

The above formula (n)
It is regulated ethics. 5-O middle PG Engineering 5Jll and 11 O middle Sea PGIm ticket is the above formula (Otori)-1 hydro PGI+llI or the above formula (Oni)-a, hydroxy va sulfonyl chloride,
It can be produced by O reaction with tolylsulfonyl chloride or trifluoromethylsulfonyl chloride.

This reaction is carried out in the presence of a basic compound O in an aprotic inert organic bath medium.

As the basic compound, organic bases such as pyridine and triethylamine are preferably used.

Examples of protic inert organic solvents include 0-chloride solvents such as dichloromethane, taloloform, and carbon tetrachloride:
Ether type SM such as ether, detotsuhidoku7fun:
Pen-in. toluene.

Dimethyl formamide, dimethyl sulfonate, hedPt methyl phosphorita triamide, etc. are used. Preferred examples include dichloromethane and taloloform. In the case of another 01 machine, pyridine or triethylamine O-like organic base can also be used as SM.

Surneel talolide as described above can be present in an amount of 1 molar to 1 molar to cyprostane in the starting material, hydrochloride.

Reaction Source II Company-1e @~10°C, preferably -10~3°C for 1 hour.Reaction time may vary depending on the reaction conditions, but 1-4 hours or more. Actually, it's 8~! It's an hour.

The above formula (D) produced in this manner was not isolated from the reaction mixture but was present in the above reaction mixture.
Mu・O reaction 0Jfi can be used as a fake substance.

According to Part 1 to Part 1 of the above, among the herodan ibiprostanitalin Ia of the present invention, s-fluoro tetraPG knee chain (formula (mu 1)-1 below) and 7-fluoro PGIs steel (formula (mu 1)-1 below) It is assumed that the formula (M)-1L,) is produced.

The reaction in the above scheme 1O is the reaction of the above-mentioned scheme 4 and 1 and the eclipse. It costs $11.

According to step 16 above, the starting material is the formula
-107-Fluo OPGM- with different double bond O position 7-Fluo tetraPGI*]II ((mu,)-1L,)
is obtained.

Scheme 11 (Mu)-a4 Su-5 12 (A,)-Kin (Mu)-a4 The above formula (5)-a, 0 glue-Aluoro PGI11ll and (Mu's)-1s 1-Fluoro PGK gooseberry can be purified from the reaction product obtained in any of the reactions described in (5)-57 to 9 above by various chromatography methods such as those described above.

In the above scheme, reactions 11 and 180 are both expressed by the above formula (0
) and an electrophilic halogenating reagent represented by
In the middle of the day, definitely! The halogenation reaction is carried out in the presence of a fairly basic compound, followed by an unbinding reaction and/or a salt formation reaction.

As the electronic halogenation reagent, those described in Sumei-51 and 940 and Kangjitun can be used. These can be used in proportions of 0.9 to 1,000 S, per mole of starting material. As the electrophilicity/%Q gunning reagent, t-butyl hybota-a-tite, t-butyl hybota-mitite, or Natsu-zenichi dostashin ion is preferably used.

As the inert organic am and the basified metal used if necessary, Hirosu Mei-5 IK is described, and the same one as in 9 is used.

The halogenation reaction and optionally carried out purulent removal reaction and/or salt formation reaction are also described in Section 9-1 and can be carried out in exactly the same manner as Section 9.

According to the above Part 11 and 13, among the halogenated brostanitalins of this G & Beak, one of R and R'0 is a fluorine atom) and the other is a halogen atom other than a fluorine atom. Hardware is manufactured.

-mu 凰1 (mu)-a, (mu)-am
In the above formula (mu)-a=,! and Y' are the same or different 1k> Fluorine atom, chlorine atom, bromine atom or iodine atom, To3, slightly! and! ′ cannot both be fluorine atoms, and! When is a fluorine atom, the 5th and ・oea
is a double bond), Y' is a fluorine atom O and 1, Hiro position and 1
Position OIi is a double bond.

The halogenated brostanitalins represented by the above formula (M)-a are therefore the compounds of the above formula (M)-1t) 01
Part, (mu)-! O Kakin 01 Department, (Mukai)-at O
Compound, (Mu ■)-O Compound, (Mu,)-a O
Compound.

It is composed of (Mu1)-a-metallic compounds, (Musuga)-aao compounds and (Ayu)-aS O compounds.

The above step-5 ISO reaction can be carried out in the same manner as the step-step 10 reaction described above.

According to the Sumo-110 reaction, the difluorinated prostamine represented by the above formula (M)-1La having a double bond in the same position as the halogenated prostanitalins ((M)-1), which are ASII substances, No. Italin products are manufactured. In other words, if the starting material is halogenated PGMs, the product will be a difluorinated PGIt chain, whereas if the starting material is a difluorinated pez+Jm, the product will be a difluorinated PGXa chain.
It becomes a chain.

Thus, by producing all of the above formulas (mul) and (A,) provided by the above formulas (mul) and (A,), it is possible to Ru.

According to this research, among the compounds provided by the above formula (mu)-1 or (mu-)-, It has been revealed that the compound represented by S has 41 excellent activities, for example, an activity for controlling the operation of the vascular system.

Therefore, according to Ippondo@, halogenated PG engineering type 1 represented by the following formula (Ayu)-1 and the following formula (A
I)-1 A four-gented goose that will meet you! Vascular system preparation containing italin as an active ingredient together with a pharmaceutically acceptable carrier.
Pharmaceutical compositions are provided for controlling.

The above halogenated Glosta-Italin 4 [((mu1)-1
) and ((Mueg)-1) are more stabilized than natural PGMs (sP), and have comparable biological activity to natural PGMs and are superior to natural PO2 as well. It is unique in that it exhibits clinical activity.

The active compounds of the present invention may be administered orally or rectally,
It can be administered subcutaneously, intravenously, intravenously, etc.

Although the active compound of the present invention exhibits higher stability in vivo than PGIt when administered parenterally, *Ks
4[K11O& can also be given as smam.

The present pseudo@Or8 drug compound is administered alone as the above-mentioned pharmaceutical composition, previously as a tumor agent in unit dosage form.

The dosage of activated metal O varies depending on the type of active compound, the patient receiving the drug, the patient's condition, the Tokyo Metropolitan Government ordinance, gender, body weight, administration route, etc., but it is usually 0.02 sf to about 100 g. /~
It can be administered in an amount equivalent to one body weight per 7 days. Such dosages may range from 1 to several 11, e.g. 2 to
It can also be administered separately.

The active compounds of the invention are essential for controlling vascular system movement.
It can be administered to certain warm-blooded animals, such as humans or non-human animals. The active compounds of this invention can be administered prophylactically or therapeutically to warm-blooded animals in need of vascular system control.

The active compounds of the invention can be used in patients for example for antipincerosis, vasodilation, hypotension, antithrombosis, antiarteriosclerosis.

Pile angina pectoris, anti-myocardial μ infarction, anti-pulmonary arterial hypertension, anti-stroke, anti-transient infarction (transi・atIsch@mio)
Attack), antithrombocytopenic purpura.

It can be administered for anti-deep vein hemorrhage or anti-distal vasculopathy disease. Furthermore, the active compounds of the invention can also be administered to inhibit the metastasis of malignant tumors. The compounds of the invention can also be used in mk, i*a transplantation, vascular surgery or extracorporeal circulation. For example, mariofluid, blood-producing proboscis.

Blood substitutes, and 70*0 isolated body parts (for example, four axillary mesopectasia; even if attached to the former O body, it may be separated and stored or prepared for transplantation or Artificial extracorporeal circulation (including cases where it is attached to a new body)
jP and Ill [can be used as additives in the fluids used in the flow. Such calculus and m*#PK, condensed blood I
[Tends to occlude the emetic vessels and the circulatory system.]

The active compound O** of the present invention eliminates this occlusion. For this purpose, the active compound was added to kK or 1
place or number [K, circulating blood, blood i++
us offering O blood] 1 to the body Φ - part attached to the recipient or social theory), or these O out of O or to the social part, o, in? -* st / KI single weight 7
Continuous infusion in minutes.

Certain compounds of the invention, such as 5-chloroPG It
Alternatively, 1-fluoro PGX has a high activity of inhibiting blood aggregation, but a low blood pressure lowering effect. Such selective l5
The active compounds of the present invention having lltfi properties can be advantageously used in the above-mentioned in vitro administration.

For oral administration, K can be formulated into a wetting agent or a casing formulation. Examples of wetting agents include tablets and round steel.

There are powders and granules. In such solid preparations, one or more active substances are present at least 41'
) It is mixed with a pharmaceutically acceptable carrier, such as commonly used sodium bicarbonate, calcium carbonate, mannitol, dicarboxylic methylcellulose, etc. The preparation is carried out according to conventional methods, but may contain additives other than those mentioned above, such as lubricants such as calcium stearate, magnesium stearate, and glycerin.

Oral administration 〇 Liquid preparations, such as emulsions.

11 Liquid preparations Contains cloudy agents, syrups, or xyl agents. These formulations include commonly used pharmaceutically acceptable carriers such as water or liquid paraffin.

For oral administration, O Enteric Coated Formulation Co., Ltd., 1! i%m
mK % e.g. cellulose acetate phthalate, hydrolifecyl acetate phthalate, phylmethylcellulose q-sphthalate), holjhinyl alcohol 7-thaletate.

It is manufactured by applying an enteric coating by spraying an organic or aqueous solution of a lI #l substance such as a styrene monohydric maleic acid copolymer or a methalyl saline-methalyl sapon-methyl copolymer O. Powders, -granules, etc.0g1ll1
Form preparations can also be encapsulated.

The pharmaceutically acceptable carrier in this book includes other adjuvants commonly used in Australia.

Contains fragrances, stabilizers, or preservatives.

However, this liquid preparation may be made of an absorbable substance such as Latin-O and placed in a container.

In addition, the prostacytalyphs of the present invention can be administered intranasally, and nasal solutions for intranasal administration include a, a, ttr,
Siglovir cellulose in hydro.

Preferably used is a mixture of a base such as lactose and a prosthetic italin, or a solution or emulsion of a prosthetic italin in a saline solution or a superior grape velvet solution.

Intrarectal administration Formulations include herbal medicines containing one or more active substances and prepared by methods known per se.

Parenterally administered oils are given as solid aqueous or non-aqueous solutions*' II cloudy agents, or emulsions. Non-aqueous SSS opaque agents include, for example, Provirda Licol, Polyethylene glycol t*, vegetable oils such as olive oil, and injectable organic esters such as oleic acid ethyl O in a pharmaceutically acceptable carrier. shall be. Such preparations may contain adjuvants such as fillers, preservatives, wetting agents, emulsifying agents, dispersing agents, and stabilizers. These solutions, s
I clouding agents and emulsifying agents can be used, for example, by passing through a bacteria retention filter, blending Hfl agents, or by irradiation6.
By appropriately performing mm1, it is possible to speed up the process of eliminating 1. Also no 1
It is possible to produce a solid preparation and use Naoso KIIA Sodium Sodium as an m-plane hot medium for injection.

In addition, the active compound can also be contained as an inclusion compound with Ktitethistrin, as is well known in Todoroki Techniques.

Hereinafter, the present invention will be explained with reference to Example II. Specific kIt@
do.

How many pal scale medemethyl esters are carried out?1. l S-bis-t-butyldimethylsilyl ether 30 tsp Methyl chloride vy o
, amKlltli, '-Promoco/acid (<de) was added at 0°C and allowed to react for 1 hour. Then, column chromatography (silica gel, 7-chlorohexane/acetate-ethyl; 99:1) was performed. triethylamine, o, s
7 volumes of z-promo Δ-PG I
+Methyl ester 11.11! -Bis-t-butyl dimethyl 7lyl ether is obtained.

The properties of this product were as follows.

MMR spectrum (ODOm)-2349 (SR,s), 3.71-4.1s (zii
, a).

a, s - a, * (IH, It), 8.02
(l H, (1, Jm! Hg).

SJ (2H, m).

Mass spectrum (10·v): 674, @? Snow (-), sty, its.

611! ,! 17? , S@l, 535,311゜Example! PG excrement methyl ester 51,1 s-bisub-t-buf
kjiIf#&sk,r,-? k l S
q2 (0,0!!+amot) and triethylamine 1
Add 0.68 dlc of methylene chloride, cool to -14°C, add bromine chloride solution (6.02 m mm)
Drop A) into a circle. After the dripping is finished, give your friend koji Kazushige no water l-
After extraction with methylene chloride and drying, the same procedure as in Example 1 was carried out to obtain S# 5-butyl-Δ'-PG, methyl ester t1,1 s-bis-t-butyldimethylsilyl ether. I got it.

Example 3 Synthesis of S-por Δ-por1 methyl ester 11°15-
Bis-t-butyldimethylsilyl ether 7# was dissolved in tetrahydrofuran 0. Snow-Kl! Understand.

Tetraptylammonium fluorozide toll under water cooling
Add detohydride tetrafuran solution 011d of
Stir for a while. Florisil column chromatography (
v Taro to medium nano/6ml ethyl; s: t, o
,5-5% of snow #b
Bromo-∆-PG-1 methyl ester (!24) was obtained.

MMRX vector (ODOA*) ' 3J II
(S H, a), 1.75-4.2 (Spirit H*
l') *4.1-4.・(Yuki II, ma)
, 5.04 (LH, 6, Jm2HM).

S,! $(2M,!l).

Example 4 17m)-Methyl-.-HomoPG engineering methyl ester 1
1,15-bis-t-butyldiphenylsilyl ether l@■7tetrachloride carbon 0. Dissolve ldK and at room temperature M, M-
Add dibromo-5,S-dimethylhydantoin sq and stir for sO minutes. It was treated in the same manner as in Example 1 to obtain sq of the desired product.

nmr (100Mlim a 0DOLs): 0
．． 5 (311), 1.63 (14M), 1.0-2.
'1 (21H).

L@-31 (IH), 1.6j (311).

3.70-5.00 (4H), 4.・5 (txt).

140 (2M), 7J-7,? (1011).

Example 5 PGI-rich methyl ester diacede)! 00# was dissolved in carbon tetrachloride (e-6c@), 13 um (94 ml) of carbonate was added, and then 94 um of carbonate was added, and the mixture was stirred at room temperature for 1 hour. Saturated 11aHOO @ Add water and then
Extract 3 m with ether and wash the needle layer with water. After IIL drying with IamljOa, the solvent was removed, and the resulting residue was separated with 7o lysyl katsumukutsumatogerahui.
The target product of the bathing part xtsy sheet was obtained.

no+r (J ODOtm): tIse (sg, s), goose, 02 (l Ht
@) *z, s -s, s (breath 11.br),
1.・a(Ill, s).

4.4　z　(t　H, t　,　J謔?Hm).

4, @-5,3 (41, m), 5.4-5.6 (!d,
m).

Example 6 PGX methyl esderdiacede)! 01flC) 82 pL of ethylamine and then 1 lIj of ether were added, and the mixture was cooled to -70 CK under an argon atmosphere. Geochunanjipromide l! After stirring for an hour at 0℃~r, t, add saturated M&HQOs water and add 3g of ether!
After extraction, cells #3 were washed with MaOA water. After drying with MfB04, it was evaporated and the resulting residue was separated with TLO (Is whisper oolt-benzene) to give (1 sap (yield 2%) O6
-bromo-Δ-PGIt methyl nistert 1,1 B-
Diacetate was obtained. The ζO value of 00 was similar to that of 4 shown in Example SK.

Example 7 PG engineered methyl ester l 1,15-diacetate 8
0.0 ml of methylene chloride was dissolved in 0.3 ml of methylene chloride, and t-butylhybob cI mite was added at -78°C, followed by reaction for 30 minutes. Pour into 5 liters of methylene chloride and saturated aqueous sodium bicarbonate solution, separate, wash the organic layer with saturated brine, dry over 11 g of potassium carbonate-sulfur, and leave under reduced pressure to obtain a crude product. The product was purified to 11 times the same as in Example S to obtain a 12-inch product.

Example S PG Engineering Methyl Ester Diacede) 1 (IIIK) Liechium 5.sL, then Needle l@li added Argon 11IIl! The mixture was cooled to −7° C. under 1 atmosphere. Pyridinium bitrob 0! Add idperbromide 2s-
After stirring for 2 hours at -TO°C to -go°C, saturated MILI (
After adding OOa water and extracting zfgl with ether, extract phase M&
Washed 2WA with OL water. After drying with MfEiOa, the solvent was removed by IIIJIIL, and the resulting nine residues were separated by TLC (t
5-AcOIt-benzene), then 7. OW (Yield:
! 01G) 2-PoA-1h-PGI+methyl ester was obtained. ζK)4ht)O Physical Properties Company Example 5
It was the same as shown in .

Example 9 1 T R,ji O-dimethyl pGIwn n-butyl ester l 1,15-bis-t-butyldimethylsilyl ether 40119 was dissolved in 5 mKg of ether, and triethylamine & OsL were added. Add y-bromosuccinimide 12Q, stir for minutes at room temperature under SO, and purify with 7m lysyl chromatography to obtain 23 inches (contains ethylamine) of 0,19k lythylamine. ) of 5-brome-1?
[,! 0-dimethyl-Δ6-PGI+butyl ester
1,16-bis-t-butyldimethylsilyl ether was obtained.

oar (J ODO & ): o, a torture (1
8M, m), L7-4.1 (411, is).

4.4g1 (IH, t, J-IHg).

4.7-1. l(!if, *a), 5.4-5,6(1
! 11. m).

lI! Koji Example 10 Synthesis 1 @,l @-Dimethyl PGMmMethyl ester diacedate 0 tsp was dissolved in +171- m and triether amine 5-m, and then cooled to -40C. Next, add 7 tablespoons of t-butyl hypopromite and stir at -40C for 1 hour, then add saturated 11aHOO@water and dilute with ether!
- After washing with saturated saline, dry with MtaOa. # After removing the filtrate under reduced pressure, the residue f
m 4k Ac0ICt-benzene) Then 7w (collection vehicle 30-) of 5-proﾇ6,1-dimethyl-Δ-PG
Industrial methyl needle t 1,1 m-diacetate was obtained.

nmr (ξODOLm): 1M (11!, g), 1113 (miI, s).

Ll? (3jl,・), 4.43 (111
,t,,T■$■1).

4.? -Lm(4H,ma),s,s-6,7(2H
, m).

Example 11 *nee ti-sita 0 to pm Vk -1@, l? , 1 jl @
.

10-Detotonoru PG engineering 1n-decyl ester 11#
1 G-Diacete)4! Dissolve qp into cyclomethane 3-#I, add 13 inches of N-process tacine, and make one 0
Stir at room temperature for 2 hours. Saturated carbonated water and sodium chloride solution # were added, and after extraction with ether for 2Fm, the mixture was washed with Naowa saline. After drying with magnesium sulfate, concentrate the solvent and
The resulting 9 residue was separated using 70 lysyl kafmutaromatog 2-fee to give 2-promo-15-cyclohexyl-18
, 17, 11, 1 book, 30-pentanol-Δ-PG1.
n-decyl ester ii, t s-Siaryu date 2s
Misaki (collection vehicle: S snowman can be obtained.

rsllr (100MHN, a IJ) Om): Tomi, 01 (SR, I) + 1°04 (lit, s).

4.61(!H,t,;T-11111).

4.41 (IH, t, J-IHg).

4.6-! *j (4II, m), 18
@ (! H, m).

Example 1z 13.14-dehyde" PGXs n-butyl ester 11.1 m-diacetate 30s sodium carbonate A2
- Added 1sIJ of cyclocumethane and then 1sIJ of cyclocumethane.

1jl-dibromo-5,5-dimethylhydantoin group 8
After stirring at room temperature for 1 hour, add saturated NaHOOs water, extract 21g with ether, and then add Maruwahai aOA.
Washed with water. After tIII with MtaOa, the solvent was concentrated and the resulting residue was separated by TLO (10% colt-benzene) to give %5-promo-13.14-dehydro-
12 ■ of Δ-PGI+fl-butyl ester t 1,1 s-diacetate were obtained.

nmr (#CD01*): CI>1) (3!!, l# is also 6! (311, a).

4.0'1 (tH, t, T-6Mm).

4.41 (lit, t, J-IH fable).

n, s-s, *(4H, l.

Example 1m tys, go-dimethyl PG methyl ester 11,
30 t-butyldiphenylsilyl ether was dissolved in l-carbon chloride, and 2.
Added da. M-bromosuccinimide? After adding qp and stirring at room temperature for 10 minutes, Maruwa carbonate solution and sodium hydroxide solution were added, followed by extraction with ether for 8 times, and then washing with saturated brine. The obtained Jiufen product was separated by TLO (＄憾mucolt-
Hekinano) Then, S-boumo Δ-PGII methyl ester t t,is-bis-(t-butyl 7-enylsilyl edel) 1-da ([4!, 4*1) was obtained. This 4DO physical property value is also 9, which is the same as that obtained in Example 4.

Example 14 Synthesis of Ni Δ-PGIs Methyl Nisterol, l S-bis-monobutyl dimethylsilyl ether l@s #41; Needle 1
- Understand the I-pu four-sucsin-i ζ-do-san. The mixture was stirred at room temperature for 10 minutes, and 9 bags were treated in the same manner as in Example 1 to obtain S Soo O (750).

nmr (160MH1l a 0DOAs
): 0.18 (21R), IJ-Lit (181
).

Lou, 5s (3H), 3.80 (III), 4.08 (1
m).

a, s s (I II), 44 * (l H
), 4.15 (s m ).

s, sz (xH).

Example 1 Is PG methyl ester t 1,1 s-bis-t-butyldimethylsilyl ether xxwg was dissolved in ethyl chloride and 5 sdKil, and ice-cooled to give I20 succinimide 4. Se2 was added. After stirring for 1 hour at 1IIIL, the -medium was distilled off.

Immediately purify using a 70 lysyl column (ow) by lithography (Schiff/Ethyl acetate; 99:1゜o, i-) ethylamine), then evaporate into a dark ji-/OEl.
-th -PG engineering 1 methyl ester ILls-bis-
t-Butyldimethylsilyl ether (gos) was obtained.

I am (ODOmu) a: o, ss (ztm, s), t, 1-tBtyi).

2, II-12 (IH, m), LSI (III, #).

3.7- a, t (3 rins ”) e 4-4・(
t ii t xa ) +tt-s, o (t yt
, wr ), 5.00 (IH, (1, J-311
1! +).

s, so (2N, Otori).

Mass spectrum (to・ma): ago, 6 Sekiro (M), se3itm, its.

SS0 How many times to perform - Synthesis: - 5-l 00- Δ-PCkX* l f k 1 X
? k11.

II-Bis-butyldimethylsilyl ether 1! ql was dissolved in 87ml of detrahydride, 2ydK, 1ml of detoptylammonic fluorozide and 7ml of detrahydride was added under water cooling, and stirred at a desired temperature for 4 hours.

Purified by 7o lysyl column chromatography (citalohequinane/ethyl acetate; 3:7, 0.5 triethylamine) to obtain the target product of 4QF S-chloroΔ-P
G, methyl ester (22) was obtained.

MMlt spectrum (ODOj!s) a:0.
11 (3H, m), 1.1-LM (1711, a)
.

m, @-1,1 (11, m), 3.111 (1M, @)
.

I7-4.1 & (1M, Otori).

4.31 (AH, t, J-718).

5.04 (III, d, J-3Hfi).

4J-! jj(IH,a),! 143 (snow 11.m).

Example 17 Synthetic knee 5-ri q rho Δ-PG X*methyl ester ssl at 1
Stir in 0.1-M caustic soda water and 0.1-M ethanol at room temperature for 3 hours, and add black-chlorine Δ'-PG monosodium salt O alkaline water-ethanol #I case.

Example 1 Lu 15-91 a to dPY Lu 16.1? , I Jl
, IQ.

O-pentanol-PGX*methyl ester 11ti-
Bis-t-butyldimethylsilyl ether xiη and triethylanne IIβt are combined with carbon tetrachloride o, 5IIjK@
Illustrated, Iris Chlorostasis Kendo 911# 1lIII
IK tea, stirred for 1 hour Example IS and i41
1km IIL? , 1 sq+oi equivalent nmr (10mMHM a 0DOta)
:0.11(III), 1.0-2. @ (21m).

z, a − s, x (tw), s, mm (
a II).

3.7-4.1 (11), 4JI (1M), 4JI (
IH).

4.7-5.1(11), jl@(IH).

Example 1 15-methyl PGII/chills fk l 1. I
m-diacede)! @1llp to methylene chloride 0.2
The mixture was dissolved in m1K, and added with an electric wire to react for 3 hours. KIJ same as solid line fl15
& I got 11 objectives.

nmr (10@MHz a ODOLm): 04
-1.8 (!7H),! , @O(IH).

Lm & (3H), 4.40 (th 1144-
$4 (IM), @, 5 (1H).

Example 20 ``'(s)ex e-dimethyl-PGI methyl ester t 1.is P bis-t-butyldimethylsilyl ether to 0 ml of methylene chloride, Ihmk dissolving y-chlorosuccine ind 4v And the same as implementation 815!
1611L,IIIC)5-eveningclEI-17(8)
, 20-'/methyl-PG, methyl ester t t,
i s-bis-t-butyldimethylsilyl ether<3
15) Wow 48 friends. Then, a silylation reaction was carried out according to the IIK theory in Example 3, and 31q (36) was converted into II9.

nmr (10gIMHg #ODOAm
): o, 5(sit-), t, o-z, 5B
si).

Snow, s s -s, s (eye 1), Li2 (311[)
.

3.7-4.3ji(1if), 4.48(1)1).

4, @i-s, t(sit), s, go(za).

Example 31 tr@, to-dimethyl-pa korei n-butylnisderl 1,1 ! ! -Bis-t-butyldiphenylsilyl ether 2-ml was treated with methylene chloride LdK@114 and OC
Tric-10 isocyanuric acid tSS@ was added to the mixture, and the mixture was allowed to react for 3 hours at Oka Atsushi. Nidel sodium was added, saturated carbonate was added), washed with water, dried over potassium carbonate-magnesium sulfate, sodium carbonate, and magnesium sulfate, filtered, and evaporated under reduced pressure. Oily - column taromatogukufi (7 o lysyl, cyclo to life / vinegar 1 l ethyl 991.) 1 ethylamine (0.1%
) ) to obtain 26 inches of the desired product.

! 1llr (ODOta, #ODOmu) :O0
Meeting (IH), 1.0i (IIH).

1.0-spirit, -(meaning 5 H), 18 S -3,3(
IH).

1.17 (31), m,'F-4,8 (411).

4.4 (eyes, 441!-11 (IH).

! 5.41(IIH), 7.1-7. ? (!01l)
.

Example! Snow 11.14-dehy)” o PGIm de'/ rue x del it.

tS-bis-t-butyldimethylsilyl ether kI S
qj was dissolved in ether o, zmllcflj, t-butylhypochloride 419 was added at -7@C, and reacted with SO for 1 minute. Purified in the same way as Example 1s, 5qo
Get the ta thing.

nmr (100Mill, J ODO & )
:o, s-s, = (isl, m, s-i, 5(in)
.

4.7-5.0 (11I).

Example = s 13, 4-dihydro RPG industry methyl ester 11゜1
s-bis-t-butyldimethylsilyl ether (1) was purified with 0.2d1Kg of methylene chloride,
Hydantoin S was stirred in the dark at room temperature with SO for minutes, and then passed through KIJ as in Example 11 to obtain 4111F01.

nmr (loOMHg a 0DOAs)
:0.81(!1it), 1.0-1.6(21H).

Lm-IJ (11), 111 (31).

3.? -a, s (snow if), 4.31 (lit).

Lm @ (I H), 4. ? -11(lH)
.

Embroidery example 4 S-ri-Q-low 16-6-dimethyl PGIm n-butyl ester diacetate xsq and carbonic acid)
wg was added and stirred for 1 m at room temperature. It was processed in the same manner as in Example S to obtain 5ssIItI)kl.

nmr (50 (1MHg a ODQLm)
:0, il-Lm (33H), 1! ,? -3
, 2 (I H).

! , O(s H) , 4.2! l (2H),
a, ao (eye 1°4.6, - Lm (3H),
Lm G (2H).

Example 5 Δ-PG 1 methyl ester 11.11-diacede-)
18111f was reacted with 4 caps of N-tac10 succinimide in methylene chloride, swl in the same manner as the practical inversion S to obtain INIIO (74m).

tuar(1・oMHwaanazs) :0Ji(3
M), 1.0-0-111 (24°a, 6m (3H)
, 4.1-84 (4H), L! ! 0 (meaning 11).

11[1f4za PG engineering 1 methyl ester L L, 1 s-diacetate 1 1 4F (0,034m1m0J KK嘗00
Add s mQ (0,01Iho mot), 00
Mu I@JK and Kasu. Alpun atmosphere 1 M-! -XI
Add Schiff 4 (Fljl+9 (0.0 m5 mmoj) and stir at room temperature for 5 hours. After the reaction, place it in a florisil column and add 200 ml of sulfuric acid.
0.1'41tsMK was bathed out to obtain the target product, $-en-do Δ'-PG41 methyl ester jl, II-diacetate 4.9.

11MR (JODOL Lu): 3.6f (11,1), 4.6-5.1 (4H,m).

15~$, 7 (2H, m).

Mass (!O@', II/@) :17@(M
), m1m, 450,4411゜see, s@s, ss
o, sss, ass.

114, 1 meeting t, l ・3
.

Example 3 Form 1i - Form Δ'-PGI, methyl ester bis-
t-Butyldimethylsilyl ether II) lIPwoku*
Add concentrated sulfuric acid to 11 ml of W $ km with a micro screw while stirring thoroughly. After stirring at room temperature for 8 minutes, add 1 ml of sulfuric acid and 1 ml of water. Extracted with σride (1osiJx 2 ). The organic layer was washed with jl1110 sodium bicarbonate solution (sag), dried with magnesium sulfate and saponified potassium, and the resulting oil was mixed with 4 layers of silica gel/aw) g')7
Separation and purification using 4-(S* medium, nod vinegar, ethyl hequinane) yielded two oily compounds.

・Compound 1 (1ess polar & compound) (I
I)-5-p114 PGl, methylesterkll.

ti-bis-t-butyldimethylsilyl ether: 1.0 inches Mass (70 mm, 1/2): @74.
@72. @17.藝Is, 1s93゜ss
i.

0DOAs.

MMR (10 (IMM earthquake-).

7M8 s+, as ~s, si (sg, m) s4.51-4.
as (t1!4) mL@%〜4J@(snow 1j
e”) *3.11@(3H,s), OJ@(2
111, a).

・Compound 4 (more polar compound)i
(Z)-5-Flomo PG Industry Methyl Ester 11゜1B
-Bis-t-butyldimethylsilyl ether: 1.2 mass (7 (IeV, !l/11): @74,
6? Snow, 1? , @Is, 1sI2゜SaW.

MMR (100MHm, aOD""): 7M8! 1.41! ~i,・s (x u * sa )
t4.6% ~4.10 (II!, ++a).

3.65~i, s s (Yuki H1 Otori), s, 5s (sa
+s)*O0[1 snow 11. s).

Example 2 Synthesis of $s-bis-t-butyldimethylsilyl ether 1.0
119 was treated as 11 as in Example 3, and (in)-5
-P o 4 PGIm Methyl Nisder (@1@) 0.
I lost 5119.

Mass (TO@V, Oboro/・): Shi II, 4
44,4! I, 420,410°40・ , $4
7゜Execution 儒鵞・(sz)-i-puEx 4 PGIt Ichi @Xfk
lLti-bis-t-butyldimethylsilyl ether 1
．． Two scoops were treated in the same manner as in Example S and S (SZ>-5-PQ 4 PGI, 31 f k Z X f k (
1,! -118) 0.1! I got q.

Mass (TO・Ma, m/・): 44., 444. 418. 4!・、　45O.

401.14? .

Example 3 Synthesis of ni(II)-5-pro7PGImJ'thyl ester.2
Add 0.1 d of aqueous sodium hydroxide solution and 0.2 d of ethanol and stir at room temperature for 10 hours to obtain the desired o(sc)-s-po% PGMs Ia (4111
) jJ[O wave was obtained.

Example 1 凰(SR)-@-bromoPGI food methyl ester.51
Add 0.1 m of 0.1 summer sodium hydroxide water electrolyte and 0.8 m of ethanol to 1 and stir at room temperature for 10 hours.
D (mM)-6-7'*4 PGrsMIL
A solution for salt (stfl) was obtained.

夷111f4st l-riglowΔ-PGL methyl ester 11゜lz-bis-t-butyldimethylsilyl ether 31■ori c1
Dissolve the solution in a 0.5-gram solution, add one drop of amic acid with a microsyringe while stirring vigorously, and stir with an electric current for 1 minute.9. Saturated 1 water S- was added directly to the mixture and extracted with methylenetalolide (i@5lxz). After washing the organic layer with saturated sodium bicarbonate solution (・d), sulfuric acid! Daneshikmu potassium carbonate,
Dry in a vacuum tube, remove the medium under reduced pressure, and remove the resulting oil.
Separation and purification using lO-ethyl acetate-helamine) gave an oily compound.

・Compound 1 (1@ma polar lk compound)
(1 ml) -5-chlorotetraPGI*methylnisder-i 1,1 s-bis-t-butyldimethylsilyl ether = 4.9 pieces Mags (?・@V, ml/@): ago,
@Goose @, $73. 571. Gas.

0DOA・): (100MIII, a, M8 L41 (!11.m), 4.41 (LH, m).

4.0 @ (INI, m), 3.14 (IH, ma).

s, 5s (all, @), o, a・(sn+5LO1・
-(IIH,s).

・Compound 2 (mar@pol&r compound) (5
z) -5-RegloPGIm methyl ester ILl&-bis-t-butyldimethylsilyl ether: -17 Mass (TOeV, m/*): @10. @2@, 6cho8. 571. 131°0DOL sudden.

(100MH1,a) - 1M8 S, 47 (lii, m), 4.70 (IH, m).

4.01(IH,l), 3.94(凰H+ll)+mJ
? (111,s), (1,11G(911,a).

0.81 (@if, *).

Example 33 0go1ni(-1)-rio a P(k
,5S-bis-t--If dimethylsilyl ether 4
．． 9 tablespoons of detrahydrofuran IIIJK was dissolved, and triethyl alcohol OsL was added. There, tetrabutylammonium fluoride hydrate (nBallP-3Ht
o) After adding 48 liters of water and stirring at room temperature for 4 hours, *one portion of aqueous sodium bicarbonate solution was added, and xB was extracted with ethyl acetate of 1 dollar. The organic layer was washed with saturated saline (xsm) and then with water (toms), and the solvent was distilled off under pressure with magnesium sulfate-potassium carbonate. , Vinegar 11 Ethyl Ruben (N - 5 = 1) then =, ・ 啼の(83 RI ichiban - Chloro PGI
Snow methyl ester (@1・) was obtained.

mass (20@V, m/・): 401 400, $84,111,11@.

3・413・I, 147° ODOmu.

MMR (100MH@,a).

7M8 1%8 (IH, in), 4.51f ~4.7
Is(lj(,m).

s, es ~ tz (xH, m).

3.7-4. o (IH, Otori), 3.611 (
3H, I).

Example 34 PGxs methyl ester 11゜IS-bis-t-butyldimethylsilyl ether 8.7 increase was layered in the same manner as Example 3 and 3.8 dark 0
(iz)-s-riC' Q PGIs methyl ester (
SZ-6s・) was obtained.

Mags (word OeV, m/e): 40! ,
400,1114,382,31111゜3@4,8@
5,347°0DOLa.

NMR (breath 0 (IMHII, J).

M5 8JI (2H, ia), 4,6~4JS to).

4.0-4J (11f, m), 3.7-w4,0 (11
,a).

s, 5y (su, s).

Example is O synthesis ni(Im)-1-rio a pGXm methyl esde k1.
@QK% 0.1 M* Sodium oxide water extinction 0.1
Stir the reaction of sl and ethanol O0s at mold temperature for 6 hours and check the electrometry to confirm that the hydrolysis of Nissdel and Nisdel has completely progressed, and obtain the desired (am)-s-tarolo PG process. I got the prayer liquid from Feguru M1 Salt (@ssj).

Example 3. (sz)-s-Taro Shimi Den Methyl Ester Snow, 04e
c@, lit* Sodium oxide solution II o, 1- and ethanol@j MJ were stirred for 6 minutes at a temperature of Kamimaro, and the purpose was 0 (II Ri-1-ri t” 'PGIt 1la( 1z
-@@Naru) Obtained II moat of Ii.

Example 1 - 5-riao-Δ-PGI-enriched methyl ester-bis-1-butyldimethylsilyl ether obtained in Example 18!
Dissolve Tm1IP in benzene 111JK, add viricinicum P-) luenesulfonate 4QF & - after stirring overnight,
Add anhydrous magnesium sulfate-0 (1 tbsp) and heat for 3 hours Rf
After 2 hours, saturated sodium bicarbonate solution #1 was added, extracted with ethyl acetate, and washed with saline. The resulting crude product was fractionated using 'rXJo' to obtain the desired product as shown below.

(sH)-! l-Chloro PG engineering snow methyl nisdel 1LI
I-bis-t-butyldimethylsilyl ether (yield @
(sz), -s-chloroOPG engineering methyl nysdel 11゜11-bis-t-7' tyldimethylgril ether (yield $＄).

The physical property values of these items are the same as those shown in Example 5xvc.

Example S @ S-Taro IS-Shitarohe Medium Tar-16゜1? ,l
1,1 jl @-Pentazuru Δ-PGXs methyl ester t 1,11-bis-t-butyldimethylsilyl ether II was rearranged in the same manner as in Example 37, and then desilylated to a threshold value as in Example 1133. React, s
#0 Obtain (s4t).

nar (50 (IMIII jODO4m)
:l, o-*, 5(ssi*), a, si(sg).

s3-4.1 (0 m), 1.41 (3 g).

Example 31 1s-cyclo to medium-16,1? , I Jl 9゜7
20-Pentazuru PG work, methyl ester 2 dark for 20s
When the mixture was reacted with t01 M sodium hydroxide rice cake solution in 30-liter ethanol at room temperature for 3 hours, the spot of the raw material completely disappeared. i-kroll-! Win - cyclohexyl 1 (1?.

A solution of 111, l@, 20-pentatyl pGr 嘗sodium salt (see) was thus f14Ilk.

Example 40 (1) 5-talol-5-, 1@-dimethyl-Δ-PGM
s n-butyl ester 11.15-diacetate 31
A rearrangement reaction of Example 37 and Example 61 was carried out to obtain (in)-Kageta-alo1 (16-dimethyl-PGImn-butyl ester ii, is-Siaryuday) 1%ql.

(1) This compound was cooled to -40CK for 1s,
Dry 3@IO memetal containing 16 mmoLO natamine methoxyl was added and left open at -20°C for 16 hours. Aqueous sodium bicarbonate solution (1.-) was added, extracted with ethyl acetate (tO+++jxz), and washed with water (8-). After drying with magnesium sulfate-kalic carbonate^, remove the solvent under reduced pressure! @Shizuku's (in)-s-Tarolu 1 to 16-dimethyl-PG, -n-butyl ester (@-1) was obtained.

na+r (100Mi1m, aODOLm):
0.8-14 (i[i), 3.7-7-44 (4°4.
4-4.1 (Meri, S, 1! (III).

Example 41 (1) 5-chloro-15-methyl-Δ'-pe, methyl ester 11.1 Add # and stir for 1 day to prepare Kuyu, Penin O,
After adding S-, 500 liters of anhydrous magnesium sulfate was added and heated under reflux for 3 hours. Processed in the same manner as in Example 3 to obtain 3 scoops of (sm)-s-ricIQ-I S-19k.
PGI Methyl Ester 11.11! - Shear Dragon Day)
(?44) and S, S 噌0(sz)-s-chloro-tS
-Methyl PGI methyl ester 11. Is-Shear Dragon Day) (!1Z-744) obtained 9.

[) The compounds obtained above were mixed with Example 441 and sodium 9.9% in methanol, respectively. ^ Treat it with Methonide,
Deacetylated to i, sw and snow, sso0, respectively.
Obtained the object.

(am)-s-talol-15-methylPG engineering methylnisder (14!i) nmr (1G+)Milg, #ODQmu): *, a
-z, s (z I H), L@ ・ (s
H) *4.0-4. Meaning (mouth [), 4.85-4.
1 (IH).

S, S win (IH).

(lZ)-1-riaa-18-methylPσ, methyl ester (8 to 141) nmr (106MIIIg, $01) Om): o,
s-t, 5(siiu), m, @5(sn).

+, o-tti (1, ii), n, 1o-n, Lu (t
l.

s, ii (sm).

(1030)1111 was obtained by converting the S layer-5-kukyl-1i-methyl-PG Kosuga methyl ester of Example 4'l1# into Example ss 14111KMMl.

Example 43 5-ri 0-low 1? ($3), 10-dimethyl-Δ-P
GI*Methyl ester! 1.16-bis-t-butyldimethylsilyl ether hzz was treated with pyridinium p-toluenesulfonate in pen/cene and then with magnesium sulfate in the same manner as in Example s7 to obtain the crylic ether form of sag (7.3). Ta. Then, similarly to Example s3,
Perform a desilylation reaction to obtain L and S 0 (61!?).

nor (#ODOjm): Ol・1(11ri, 1.0-11.!i(!411).

s, 5y (sn), s, go (tl.

Example 44 51-1-chloro-17(19),! (1-Dimethyl-PG engineering ruthyl ester!) was treated to 1 m in the same manner as in Example ss to obtain (701) 0#IE.

Example 4s Medium S-ri0low1t@,z@-dimethyl-Δ6-
PGMs n-butyl ester 1. I IS-BI x
-t-butyl di7-ethyl ether zsq was dissolved in benzene with p-ynium p-toluenesulfonate and anhydrous magnesium in the same manner as in Example 31,
0(III)- and 7<NZ)-011,1m-
Obtain bix-t-butyldiphenylsilyl ether.

(1m) - i - evening a cm -1? QQ-1ftb -
・-Homo PGI Raishi-butyl ester l 1. l m-
Bis-(IIMHm a 0DOAa) :
O,S-%-1,1 (snow 4M),! , 1 ~ 8.4 (Yi Lu u) + 3.19 ~ 4.1 (4M), i, lo (211
).

7.1-7.7 (!6).

(The nmr spectrum of the whole was also similar to that of baldness.

゛(-) The compound obtained in (1) above was treated with detoptylammoeum alotide in the same manner as in Example ss to perform a desilylation reaction, and the corresponding compound, namely 1 wIIO(In?
) and 81190 (SZ-@・7). These On+
The mr subetator was almost the same as that obtained in the above except for the silyl group.

Example 4 @ medium 5-ri o o -11 @ l 4-dehyde opGX
w decyl ester11. Is- was reacted with 'su-t-1 methyldimethylsilyl ether II in exactly the same manner as in Example S, and tv@o(sm) (74 g) and hqo<sz
>Obtain (y4s Z).

α) This was desilylated in the same manner as in Example 38, and sqP (@7?) and 3dark (
・Get 112).

(I??)'s nmr (1@lMl1g, #ODOmu): (1,11-L Yuki (441), L7-4.3
(41[).

a, s -4,7 (eye 1゜(iz-・)?) Onmr is essentially the same as (@7?) as well.

Example f141 Di-chloro-11,14-dihydro-Δ-PG 1 methyl ester 1 i,i s-bis-t-7' tildimethylsilyl ether 4119 was treated in the same manner as in Example s, and a 3-in. Obtained a mN unit (14 m), then processed it into a Yoshi IIIA example 33 and an r4 machine, and put it under social insurance! ■Object (14)
3) was obtained.

nmr (100MilII, #ODCmu) :o
, 5Bsii), t, o-goose, s(!@H)131, @
I (I II), 3. Mar 4.3 (Picture 11)
14.4-4.7 (Item 1゜II Theory Example 4I 7-chloro-PC) Is methyl ester l 1,1 !
7 volumes of i-diacetate were dissolved in 2 volumes of chloroform, 1 #1 of sulfuric acid was added from a capillary, and the same procedure as in Example S was carried out to obtain zslo (xso).

nmr (1@lMHs, JODOM): o, s s
(s vI), t, o-yuki, @(six)+3.
67 (3 old, 4.5-14 (SH), !, 1i5 (Snow H).

夷11114a* PGI snow methyl ester t i,t s-bis-t-butyldimethylcidal edel l l After dissolving All in dichloromethane o, 5mK111, under argon atmosphere -7@
CK was cooled and triethylamine $μtt was added. Add t-butylhypochloride 3$#t to it, -7
After stirring at 0°C for 40 minutes, saturated aqueous hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with salt solution, dried over magnesium sulfate, and the solvent was distilled off. Sun) f 4 to I,? -Si I a a PGI
Somedemethyl ester 111-bis-t-butyldimethylsilyl ether and its Δ-heavy bond isomer (sz)-set-dichloroCI PGI snow methyl ester 1. Three compounds of IS-bis-t-butyldimethylcryl ether were obtained.

1oss poxar & compound (compound) yield; 1
．． 8■ (Yield 141II> Tll0 Nijiri Kagel Rf -0,411 (10 ethyl acetate-henan) Mass spectrum; (Yield/・)@01.@・S.

syt, sss.

11MR (ODOAs) a: o, 5s (su, s), o, 5t (sII, s).

L@7 (l II, @), 3. @~44
(2H, ma).

4.110t, s), 4.1-1. l (t
! ! ,br).

i, rtsHn, m).

mor@polar Compound (compound B) yield in 1:
m, o we (Shumotofu SIs>Tll0 Niji 1J Kagel, Rf -0,4 (to-ethyl acetate) mass spectrum; (m/・)to7.go!I.

syt, sas.

MMR (ODOAs) a: 0.11 (@I, #), 0.10 (・
I m g ) eL@7 (IH, @ ), L@
~4J (111, m).

4.79(xu, s), ts~s, t(ta, or).

s, s　s　(t　m　　, 鳳).

Example S (1) Compound M1.11 obtained in l1m Example 4
was dissolved into detrahydrofuran, 2-, and 10.1 mg of detrahydrofuran (111, 111, 111, 2, 1, 2, 3, 3, 3, 3, 3, 4, 3, 4, 3, 3, 3, 3, 3, 3, and 4, were added under ice-cooling, and after stirring at room temperature for 5 hours, the mixture was immediately dissolved). The residue was purified by seal column chromatography [ethyl acetate/hexane-1; 1 (0,111) ethylamine)] to obtain 1.0 scoops (yield - 1 bag) of O compound C.

Mass spectrum;
Ikai, 343.341.325.323.

MMR (ODOAs) a: L@7 (3H, s), 3. -~4.2 (Rose H
1 grave).

44 @(IM, #), 4. Hatake ~ 5.1
(1'H,'br).

LSI (111, Grave).

(1) 1.8 inches of Compound B obtained in Example 4 was reacted in the same manner as in (1) above, and purified by Florisil column chromatography [ethyl acetate/Hemesan-1: t
(o, t-) riechilua (/)] then 1.011(
A compound with a yield of S S was obtained.

Mass spectrum; (hase／・)3? il, 177.3・t
mllll, 343,341,3ri4 s33.

, MMR (ODOA crow) 1 ;s, s t
(s w , s ), s, s~4. meaning (3■-1
゜a, t s (纂H, s), 4.11~S, 1 (IH
,br).

S, S S (Tomi H9 Otori).

Compound 0. Compounds are one or the other! 1.7-
')l OW PGI-methyl ester and other 1
2) On the other hand, force/ΔS - double binding isomer (iz) -
5, γ-diqQpσh methyl ester.

Example 111s1 (1) Compound 01. obtained in Example st. @qp! Iris Kasei soda water...! - and stirred in 0.1 m of ethanol at room temperature for 3 hours, and compound 0 disappeared in TE LQ),
Make sure that compounds with high polarity O are converted into Kll.

(1) React the compound DIJq obtained in Example s1 in the same reactor as in (1) above.

Either one of the solutions obtained in Example 11 (1) and [) is a S,7-dichloroOPGM-sodium salt solution, and one of 4ii1 is a Δ-heavy bond isomer (sz)
-s,y-dichloroEI PGM, sodium salt.

Example s = “-6-promo Δ-PGX + methyl ester l l
.

1s-diacetate 1.1llK) ethyl anne @,
'1sLttlAL, t-butylhypochloride 16
Add 4t and heat to 40℃ for 1. After stirring for S hours, Example 111
When the residue obtained by post-treatment in the same manner as in 1 was separated by TELO, the above-mentioned target compounds (1·-polar 1 compound and ll0r@pollLr compound) were obtained as shown below.

1ssst polar compound (compound expletive) Rf (
0sils: TobitoAo m 1cho: l):
0.51Mass (meaning 0@V, 11/@): 11
,664, S snow 8°1! @, 164. Si2.4@l
, 44? .

444.44! ,408,4011.3111゜327
.

MMR (CDOLs) -20.11 (311), 14-1.7 (14
H).

2.0A-3,1 (6!@), L3~3.0 (4
1°141 (S 1), 4.7? (l H
, s).

4.1~s,a (sI), s,lss~s,t
(xw).

Otori ors polar @ compound (compound 1) 11f (
OsMs: 1toAe = 1 7:
l): 0.44 Ma@s (Snow 11e
IF, m/@): s6@, 1@4
, 62.

62@, m*@, 104, I (1,483.

447.4 @ 1,407,381,881゜341.1
44.821, Tomi 27.

MMR (CDOLs) a: 0, II (1 m long, IJ ~ 1.1 (1411).

t, si ~z, x (sm), z, mg, a (4m)
.

141 (a H, l), '4.11 (item 11)
.

4.7-14 (II), i, i? ~5.7
3 (!II,s).

1@l Theory Example 1s (Il-!I-Promo7-riQ CI PGI*Methyl Ester 11.I
Treatment of 11-diacetate with it in methanol as in Example 4 yields the corresponding target compound (compound Gl). and compound E) can be obtained.

Compound-G IIMR (ODOAs) a: O1$ 1 (1, 1..~z, 5 (ton).

1.113H), 1.7-4.3([).

a, yy (xii), 4.6-4.9 (eye 1°S, 55
~Lj (l irises).

Compound H NMR (ODOM) J: e, B(an), t, o~v, Bgog).

3, @I (I K), L? ~4.2 (Snow ■).

4. a l (l H), 44-4.9
(IM).

Ll　K　～4. ? @ (2M).

Example S4 Hiron-chloroΔ-PG4t methyl ester l 1゜1s
-Diacede) 114 in 3 mK11 of dichloromethane, add 100 mK of anhydrous potassium carbonate, and add violet while stirring.
I added the 9-piece jig 0 Romethan Island-Totan, and added Yuki and Jikan in the warm weather. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ether. Extract the aqueous layer with ether, combine the organic layers, and wash with Marowa saline. -Water 1
11a v/4v 9a ftlkm, filtration 1ea L, force 2m Chromatodarahui (florisil 3
f, 4P nano to the exuding moist area *Saponethyl: triethyl ζ
too:to:・, 1) to obtain 1-polymerized OOPGI methyl ester t i,t s-diacetate (1・#@poxar compound-14η, yield 3
8%: more polar compound 1010
Obtain 1l# yield of 58 g.

1@lia polILr compound nf (pen<y/1toic-a/x, silicab k)-
0R Hatake MMIt (ODOAs) J: <L, 8 tons (t, 1it), 1.0~1.8 (xa l
"H) +x, 5s(s, sl, s, os(s, sl
.

Breath, Hatake~s, t (m, tax), 3. ? @(@, I
II).

a, 54(s, xi), 4. s ~s, s(m, sa)
.

1.4~L’l (im, III).

mar@pol&r compound ur (benzene/expletive C■4/l)-0JMass(
0@V, ml/@): III, SO2, i@
! .

SO4, SO2, 1!0will, 484,484°4@! ,
1@4,3・2゜11MR(ODOAa)a:o,sBt,
sa), t, ot, ・(II, II).

1.11 (@, iM),! , @4 (@, 3H).

1. Easy ~ 3. O (Otori, 1・Tsubasa) + 8m” (' m
1H) m4.1@(@, II), 4.6-54(m,
III).

14~m,’l (m,!H).

Example 5S z-brome-Δ-PG 1 methyl ester 11° 1ll
- Dry 1 tablespoon of bis-t-butyldimethylsilyl ether in acetonitrile x mKIIj1L, potassium carbonate 10
In the presence of a spoon, silver fluoride SO was added and stirred at mold temperature for 1 hour. Add methylene chloride to the reaction system and add celite to the reaction system.
After filtering with a glass filter and washing with methylene chloride, remove 1 methylene chloride. A very powerful item was obtained. When it was separated by silica gel thin layer chromatography (extracted with 10% ethyl acetate-hequinane as solvent), the following zero O compound was obtained.

7-Full t OPG Kokai lf Ruesdel 1. IS
-Bis-t-butyldimethylsilyl ether: Yield: s
, oq (yield 3・-) Teoo: xt -o, am (Exhibition 111HI:
1 o@ethyl acetate-hexane) Mass Spectrum Otori/・: @1! (M”), im Tomi, imil,!!3!!.

MMR (100MHg, ODO Mue Pp Zen)
:0.11・H,s), 0.90(・H,II).

! 4@(3H,s), 1.7-4. ! l(!H, m*)
.

4.6-4.9 (11m) * n, 7t (eyes!, t,, Tms? HII).

4.111 (III, l,, T-5ling).

Sound, S! (!H,m).

1-Fluoro-Δ-PGx layer methyl ester 11°! S
-Bis-t-butyldimethylsilyl ether; Yield: 11. OQF (yield 14) TLO: xt-
1), 43 (Tenma i1 @: 1o vinegar sapon ethyl kirikiri mass spectrometer /...: a s z (m), 5llz, sss.

11MR (100MHg, 01) Ojv, ppm
): O, SS (・■, s), 0.19 (會Ht') e snow, y~s, x (tit,
br), s, @ a (“L”)+1, @ ~4
．． 1 (11.ml of snow), 4. i〜藝、x(in、mL
1! , 4 y (! H, Peng).

Example 56 S-brome-Δ-PGL methyl ester l 1゜1s-
Dry diacetate, ylf, k) Nitrile 1s
Add silver fluoride solution and stir at room temperature for 1 hour. Methylene chloride was added to the reaction system, the mixture was washed with methylene chloride twice through a Dallas filter, and methylene/chloride was distilled off to obtain tsq of crude product. When it was separated using silica gel thin-layer chromadog 9F (Example 1II11 medium: 1S-ethyl acetate-pen(n)), the following two compounds were obtained.

7-Fluoro-PGM rich methyl ester i 1,1 s
-Diacetate) (751); Yield: i, 5sIF (yield 174I) TLO: Rf-0,45 (developing solvent = 15-ethyl acetate-benzene) 448,4 (IS, 3118,14
1゜3■.

11MR(100Mllffi, 0DOLa, P
I) Otori): Yuki, at (sm, s), IJ4 (3!i, s
).

3, @@ (3H, @ ), 4.77 (lft,
t, J-? H+g).

4.75~ls, 1(1(IH, 11).

4.114 (IH, d, J-$411).

s, s-s, m s (3He m) @l m 7
k O*-Δ-PGXI methylnisdel 1t1s-diacetate (so Hatake); Yield; 1.・W (yield 1y%) TeLO: *t-・, 41 (extraction solvent: 111G vinegar 1
11 Ethyl-Benzene) Mass Spectrum Feng/・: 4@@(M”), 441.408.388.141.

■Hatake.

1M1t (凰6@M1m, 0DOA spring,
pp Otori) :t, sBsg, s), い, oBsi, s)
.

t, 9~m, goose (III, br),! ,・7(III,
@).

4. Fuji~i, s (sw, oboro).

s, as ~ i, 5i (sit, m).

Example! 11 5-chloro-Δ-PGIs methyl ester 51゜ts-
py7day) Dry 18 tablespoons of Aryu Tonitrile KIII
Add L, N-〇triethylamine, and then silver fluoride 8.
I heard the sound of a sound and stirred the circle with electric power.

After the post-treatment in Example S6 and Example 11, separation by silica gel thin layer chromatography (developing medium: 15% acetic acid and ethyl benzene) resulted in 1-fluoro-PG methyl ester, the product of Example 2. 1, 14 grams of fluoro-S-diacetate (15.
Δ-PGI+methyl ester l 1,1 i-diacede) (30.) KaO0.QF (IIc rate, regret) was obtained.

Example 1 1-FluoEI PG Kodenden Methyl Ester 11. I
Cool S-Diacetate 3 in the dark to -40°C, O Snow 3
w*rrroL () O9 containing cyto in sodium meth
- Add dry methanol and leave at L-3°C for 1 hour. Aqueous sodium hydrogen carbonate solution (L@d)t+a
After extracting with ethyl acetate (1.-x3), wash with water (diluted). Dry with Madanesium sulfate and potassium carbonate 11f
fl, the solvent was distilled off under reduced pressure ◆, and 11519 (yield 7s-
) of 7-Full I OPGIa j fRuesdel(s
sy) is obtained.

? LO (silica gel; dichloromethane/acetate-7
/ *) If -0,4Imass(2(1@V,
11/@) ; N @ 4(M”), m・@
,a@4゜14@,all,317゜snow■.

MMR (10@Mlig, 0DOj!s, ppm
): m, 5y (si, s), s, s ~4.2 (IH
, va).

4, @I (11, t, J horse mackerel 1 ■ building).

4.7~S, ・(t H, b r ) 14.11(I
II, l, J-1@l1fi).

``43~L? (Goose H, 1m).

Example 19 0 Synthetic Ni-i-Fluoro-Δ-PG11 Methyl Ester IL1s-
Diacetate I * K @, Q Yukit mwot□
Add dry methanol containing sodium methane, -
After leaving the mixture in XOC for 144 hours, a dilute carbonate solution (1@511) was added. After extraction with ethyl acetate (LOMXS), it was washed with water (@d) and then dried over magnesium sulfate and potassium carbonate. When am is distilled off under reduced pressure, 2.
1 ■ (Collection book 1-) OS -7kt O-Δ”F PG
l, Jl fkx, X chill (zzo) can be obtained.

TeLO (silica gel: dichloromethane/acetone =
y/s ) at-(1,4sMars (z
oev, III/11): xsn(m”), s@
s, s・4all, 33m, 31? .

36th grade.

MMR (106MHsi, 0DOLs, pp
m) :1.11! i ~3.2 (111, br
), L@Kore (s Hl) 134! ~i, Bs
g, m).

4,・t (l H, broad doublet,
J m4 @Hg).

4.1~s4 (Snow H9 position).

! 1.41-5. -(mean■, 臘).

Example 0 1-Fluoro PGX * methyl ester l l, 11-bis-t-butyldimethylsilyl ether 1 piece (0,0a
18 mmoLa), 02 M n-detraptylammoeupentafluorotuide triethylamine (S:
t (mol It)] of detrahydrofutun 1 m (
Add 0.03 oz.oL・) and react with electricity for 24 hours. After the reaction, the medium was distilled off, and extracted with aqueous sodium chloride solution containing a small amount of triethylamine and ethyl acetate. The organic layer was washed with water and treated according to a method) to obtain the desired 1-
Fluoro PGI-methyl ester (-3 cho)・、S (
81).

Example 1 Weni 1-FluoD FGII methyl ester lJ# was mixed with ethanol o and 5slKfl, to which were added KO and 1M sodium hydroxide solution @@o, 15ml, and left at room temperature for 13 hours. The reaction was detected using thin-layer chromatography (silica gel; dichloromethane/7 setone-7/3), and the results confirmed that ester hydrolysis had proceeded completely.
Obtain the desired 1-fluoro PGXm Wa salt OII case.

Example @I O synthesis knee ll-7 o -A -PGxs Methi k X
Add lI sodium hydroxide aqueous solution 0,31- and leave at room temperature! I left it for a while. Electron detection of the reaction with a thin layer of Qmatoda 9F (silica gel; dichloromethane/acetone-t/S) confirmed that ester hydrolysis had progressed completely, and the objective 8-7 was confirmed. sr oa-Δ-
Get PGIs M1 salt habit fluid.

Example 3 The 91-fluor* PGIm methyl nitride 1 obtained in Example 6 was converted into methanol o, s wbl K fl
it jl lk.

11.1N Sodium Hydroxide Water - Add a box and SW, stir overnight at room temperature, wrap, add water and ethyl acetate, and transfer to a distribution funnel. A lot of liquid.

While shaking the dispensing funnel, adjust the pH of the aqueous layer to approximately IK.
After that, the organic layer was dried with ILA B04, and the solvent was removed under reduced pressure vl* to give 1 # (
) @ You can get healing. Add Rin mW ether, add diazomethane ether Sat, and stir for 10 minutes with electric current, then add one coat of m medium. LOK〉min - When purified, 5 sloy -
It is possible to obtain Aluo OPGM methyl ester.
1-Fluo OPGM will be successful--Ichishimaru.

Example 4 After dissolving the Maru S-Fluo p-Δ6-PGXs methyl ester l@sobtained in Example 5 with methanol ohwJKIN,
11 Add Arashi Sodium Hydroxide 9M Water III Solution, Temperature-, and after stirring at room temperature for 6 hours, apply it to the same solution as Example 1. When the residue of S-hydroxide containing 5-fluoro-Δ-PGL is added. I found relief. When the residue was methyl esterified in the same manner as in Example 3, 3.3 tons of S-fluoro-Δ-PGL methylnisder was obtained.
It was confirmed that Is was generated.

Example @2 2-pro^-17R, which was formed in Example-, O-dimethyl-Δ-= PGMs butyl ester bis-butyldimethylsilyl ether IS dark and acetonitrile aJ
K#1IIL, 1 ml of sodium carbonate, and then 3 ml of silver fluoride were added, and after stirring at room temperature for 8 hours, post-treatment was carried out in the same manner as in Example IS. No residue left! Separated with IIa (1゛・
-mu colt -n - to middle number) Then - the punctuation mark can be written as follows.

oh-fluora-1714-dimethyl-Δ6-PG
Is butyk Z

4', s -i, +* (s irises 1 fold).

i, 4-Il, (Shigeshige, Otori).

・7-7 rut I” -i? (III) e 1
0-SiJ' f PGI1 phthyl ester l 1,1
-bis-t-butyldimethylsilyl ether (station 11
7111) nmr (JODO4,): @48 (all, I), 1. ? -w4
j (411111L4.6~i, 薯(im, m).

s, s ~ i, m5 (s*, m).

Example-1 9s-y Luollow 11R9 snow-dimethyl-Δ-PGIs butyl ester 1Lis-bis- obtained in Example @S
1-Butyldimethylsilyl ether 3.3 darkness
Desilylation was carried out in the same manner as for O by treatment with detraptylaminocarboxylic acid and five fluoride detriethylamine in detoxhydrofuran, and 1. ! Obtain 40M compound.

nmr (#0DOAs): 17-4.1 (4mI, m), 4.6-@, B (11
[, m).

s, 4-s, s (*m, Otori).

Example @7 Nine-mer fluoro-tytt obtained in Example S.

! @-N methyl 'I'GXs phthyl ester pith
-butyldimethylsilyl ether 8.1m# Example 6
・From K to X-like Kit silylation, target object 3.・
Get a spoon.

n1llr (#0DO4): 3.7-44 (411, m), 4.6-Lm (31!
, m).

s, +s -IJ s (Goose 1. Otori).

Example・− Exposure-fluorescence-17(2) obtained in Example 6●.

3.-Dimethyl-Δ-PGII Butyl Ester @Yuki and the same aircraft KII & So, the objective moat was obtained.

Example-9 hl-7,1-ow-xyOoe3 obtained in Example-2
・-Dimethyl Pqx-methyl ester in Example-2 and l
Ii! When the IIKM ring is used, the objective-011 liquid can be obtained.

Example 1 Nine S-bromo obtained in Example 1! @-6-dimethyl-Δ-PGMs methyl ester 11-Sumiichi diacede)
Dissolve 74 in 6.1110 acetonitrile, add 1 opt of triethylamine, and add 1 m of silver fluoride.
t, after stirring for 3 hours at room temperature.

As in Example 6, the desired product was obtained by reducing K11II and separating the obtained product using 90% LO (cont-benzene).

・S-fluoro-t s, t s-dimethyl-Δ6-r
G1. Methyl esde k l 1. I K-diacetate (yield 3 sachets) mar (JODOjs): 1.11 * (III
, a).

x, o4 (in, a), snow, -1, meaning (111, br
).

3J? (IM, #), 4. i-! 1j (III, m).

5.46- IJ Bu (Yuki H, Zen).

e7-Fluo W-1-1! --Dimethyk PGX snow methylnisdelt 1,11-diacetate (yield All)
nmr (JODOAs): LOI (3m!, s), Lgall (II, @).

lJt (III, s), 44 G (lJt,
J=? ll5).

4.7l-IJI) (411, m).

i, s Ns, si (Snow H, ml.

Example 15 S-Fluo aXS--dimethyl-Δ-PGXg methyl ester 11.1 m-diacetate Tomiso obtained in Example 70 is your example! I11! : #1IIK Deacetylated by treatment with sodium methoxide in methanol, 1. - Obtained one prize.

mar (loOMIIm, #ODOm): meaning,'
a-1j (III, br), 347 (31, @).

s, t ~ tz (snow H, m), 4.5 Ni2
(3111, m).

j, 41~i, 1JI (!II, m).

Example 1 Snow 91-Fluoro-1@ obtained in Example 7.

1. Dimethyl PGM-methyl ester 11. 1 ml of diacetate) in methanol in the same manner as in Example s9,
Nat IJ9 Mumet 1? The product was deacetylated with J611 using SUID to obtain L snow al101.

vrmr (106MHz, #ODOM) :s,a
s(sit, s), s, y-i, BsM, m).

4.6~i, +1 (III, Otori).

IJ-1, @1 (lH, m).

Example 13 1.6 inches of 9S-fluoro-16゜1-dimethyl-Δ-PGI+methyl ester obtained in Example 71 was added to Example 1.
Obtain a solution of J611t and l with sodium meth+1 in methanol-water on the same machine.

Example 14 4 obtained in Example 7 words? -Fluoro-1@.

16-dimethyl PGMm methyl ester! 1 ml was passed through Examples 3 and 41 in methanol-water over sodium methane to give 1 ml of sodium chloride.

Example 1S and 0t-y Ruolol 1s-cyclohexyl-〇 Acid-containing knee 9S-pu$14-18-shikuo He48' Jk-ri@** 1 aL s, t s
, s O-hey 1 True Δ-PGMs f S' Dissolve ester diacetate 119 in acetonide, add sodium carbonate, then add 12 tsp of 7-chloride, and heat to 11 at mold temperature. After stirring, the same method as in Example SS was carried out. The resulting nine residues were separated using TELO (l@cyst colt-
When you pen (n), you get the object and a friend.

・S-Arole ll-1m-8/ria hedp sill 16° 11.1 Lu, 1 race!・＾Pentano-Δ-PGMs de2yl ester 1l-s-Siaryudate (yield S) MMR (10gIMiig, JODOM): t, I
I (II, s), Goose, 01 (311, s).

Snow...~1. ! 1 (AI, 1zr).

4.07 (3M, t, J■@lam).

4, i ~ Lm (114).

1.4l-LSI (!II, Otori).

111-Fluoro-1s-Schiff Q to Naka Shiru 1 Crane 1?
, l 1,11. ! @-Pentazuru PGI*Decyl Ester 11.1 m-Xialong Qi) (IE amount s, sqy
) MMR (100MHg, JODOM): s, e
o (Hatake 1, s), L・4 (am, 5) s4
,@? (11,t, J■・Hg).

4.6-m, 8 (i H, m), i, i~
i, s(aM, m).

Example 71 FluoroEl-11-sikOhekiVk-14,l obtained in Example 71? , l jl・, i0-tet2 true Δ4- PG engineering, Decylnisdel i 1,1 i-
When cyanotate S# is passed through Example S and M in methanol with sodium methane II and 4
You can't get it.

nmr (1...Mug, a ODOmu): meaning,
・~1J (111, br), 3.7~4J (411,
m).

a, s ~ s, s (sm, ym).

Violent, 4 SM ink, SS (Yuki H, Peng).

Example 71 1-Fluof-11-Citaro S obtained in Example 7I
-7k middle school -16,1? ,l.,11. Snow @-Pentazuru PGMs De V Luester l'l, II-Sia Seven Chi)
When #8 was treated with sodium methoxide in methanol in the same manner as in Example s9, the desired product could be easily obtained.

nhor (i0@Mis, aODom) :s,
v ~ a, x (a H, m ), 44 ~ 1.1 (
31! , m).

S, S ~ S, 6i (III, m).

Example 78 9m-Fluo lm-ll-cytalohene obtained in Example 1S -1.,l? , 1 j5-, 8--pentanol-Δ-PG needle ester ii, t s-diacetate 4# was dissolved in 1 dK of ethanol, 0.01N hydroxide was added, 1 U of water was added, Example 68
and w411k and violent-fluoro1s-yria hedp
Vk l @, 1? , 11,1 j20-pentanol-Δ-PGL-nato dark sulfate was obtained.

Further, uniformly from the 9-fluoro 11-V chloride obtained in Example γS, 1-Fluoro-凰S-
Sita I11 to middle sill-t s, t 7, 11, 11j
.

- A solution of pentatulu PGIm sodium salt was obtained.

Example γ9 Middle 95-promo Δ-PGI methyl ester obtained in Example 13 11.11-bis-t-butyldi7-enylsilyl ether was dissolved in acetoethryl, and 111 m of triethyl acene was added to it. Then, after stirring fluoride silver snow and soybean at Hosomi room temperature for t*aa*, Example S
Separate with S and same 11 post-processing @Ki%T1af3 (!! @
A601t-n-hen+nance) and 31fOI-
Fluoro-凰7 (b).

20-dimethylΔ-PGM, methyl ester 1! ,
l 1li-bis-t-butyldiphenyl Vskl-del and 4. m dark 01-7 and o a-1? (80-dimethyl P()1 methyl ester IL1s-bis-t-butyldiphenylsilyl ether was obtained.

1) The good compounds obtained above were desilylated by treatment with detoptylaminylfluorotite F-)IJ ethylamine in detoxhydrolrane, respectively, in the same manner as in Example SO. O-O-O-Bou-Fluor-11g, Goose/
-dimethyl-Δ6- PGM, methyl ester and 3
．． 0 tablespoons of fluoro-118, type O-dimethyl PG Xs
A methyl ester was obtained.

, s-fluor a-tyg, so-dimethyl-Δ6-P
G Engineering 1 Methyl Ester MMR (#0DOA*): -L, 5 (111,br), $4@(SH,s)
.

1.? -'4'j (Tomomi, 臘) #4. I-1,3
(II, Peng).

1.41-1. il (ll1m).

Lower Fluoff-171,t O-dimethyl PGI methyl nysdel MMR (aanom); ml@(IH,s), 1.7-44(!H,m).

4.6-5.1 (m M, Otori).

i, s-M, @i (Snow H, m).

Example-O Example 6
As in 3, use KJ6i1L to obtain a solution of the target substance.

Example S5 7-fluoro-17゜-dimethyl PGX* methyl ester 2.0111 obtained in Example 79 was converted into Example 63.
Process in the same way as the target object OI! l1li1k was obtained.

Example■ O synthetic knee (1) 1 m of S-Boomo obtained in Example 1.

14-dehydro-Δ-PGXIn-butyl ester
1,1 m-diacetate)1! +119 to acetonidosyl 0. IdKllllllL, sodium carbonate! Next, 8 tsp of silver fluoride was added, and the mixture was stirred at room temperature. 1 methylene chloride was added as before, and the mixture was passed through Celite. #I After plastering the dust! Separation of 11 moat with TeLQ yields Yukisho OS-fluoro-13,14-fe draw Δ-PGIsll-butyl ester 11°1s-cya heptadate and S#7-fluoro-13,14-dehydro-PGXm ! ll-butyl ester 1,11-diacetate was obtained.

(1) The good compounds obtained above were acetylated by treatment with sodium methquinide in Example S and 111ml 1K methanol, respectively, to give t, i and z, respectively.
Obtained the objective of Cape S.

・lj-fluoro-11,14-dehydro-Δ-PGM
s n-butyl ester nmr (jODom): L1-4J (4H, m), 4. m ~ m, 3(
8kl, vm).

Ol-fluoro-11,14-dehydro-PGItn-
Butyl ester mar (JODolm): 3, f ~ 44
(41, wa), 4.6-51 (III, m)
.

Example $3 Example I 95-Fluoro-13゜1a-dehydro-^-PGXs butyl ester L, S obtained from Yuki was dissolved in methanol, m5lK@, and then dissolved in Ol.s style with sodium saponide. Add 0.1-liter of moat and stir at room temperature for 8 hours.
By measuring the reaction voltage, it was confirmed that a solution of the target product was obtained.

Example 84 97-Fluoro-13゜14-dehydro-PG, butyl ester 2.0 # obtained in Example Iz was dissolved in ethanol O, smK@, and then 615 ml of o, os standard sodium saponide aqueous solution was dissolved. In addition, the same procedure as in Example 62 was carried out for 11K to obtain a solution of the target product.

Example $5 1-bromo-PGI*methyl ester l 1,1 M
- 18 tsp of bis-t-butyldimethylsilyl ether in 3-m of acetonitrile, conduct silver fluoride SO■i#1ss
s, s qo (ysa) and s
, s # of (3111) was obtained.

Real 114 synthetic knee (1)? -yh operation, butyl ester l 1,
15-bis-t-butyldimethylsilyl ether to
Decompose sg into pyridinium-
p-) After stirring overnight, add luenesulfonate.
200 inches of anhydrous magnesium sulfate was added and refluxed for S hours.
'-PG engineering turtle methyl ester l 1,1! - bissu t
- Obtain butyldimethylsilyl ether.

(1) The compound obtained in (1) above was prepared in the same manner as in Example 60.
By silylation with lK, 7-fluoro-Δ
'-PG engineering 1 methyl ester 2.8 dark was obtained.

nmr (a ODOmu): ! , 9-34 (lkl, br), 3. @7(:III,
s).

3.7-4.2 (2H, m), 4.7-1.0 (IH
,br).

h, s-8,7 (211, m).

Example +17 T-7A/tO-Δ obtained with synthetic knee 111iN s-
'-PGI + methyl ester meaning Example 8s and SI
The desired product, #I solution, was obtained.

Example 8S 7-fluoro-171°20- obtained in Example 6s
Dimethyl PG1. Methyl ester l l, 5-5-p-t-butyldimethylsilyl ether 10 pieces Example 37
The target bis-t of 4 and 2 staves obtained by uniformly processing
-butyldimethylsilylninal from Example 60 and pi+
3. Desilylate the target product to ai. I got an OQ.

nmr (#0DOts): 2J-3,2(lit,br), L@
γ(* H18j e3, ta, 2(sm, *),
4+7-6.0 (IH, br) 15.5-5.7 (2
II, m).

Example 91411 When 1.0 inch of 7-fluoro-171°20-dimethyl-Δ-PGI+methyl ester obtained in Example 88 was treated with Example SS and 14IIK, the desired S fatigue was obtained.

Example 90 Adult knee 5-Fluo a-Δ-PG! , methyl ester ILtS-
10sfK) 10st of ethylamine was added to dissolve methylene chloride ImK. -46CK After cold R, add t-butyl hypochloride l hsL,
Stir at -40C for 40 minutes, then bring to KFll temperature for 30 minutes. Saturated MaliOO and water were added, washed with ether and brine, dried over K-Mf8, and the solvent was distilled off. The obtained residue was separated by -TLO (tsl-colt-benzene) to obtain the target compound as shown below.

Yield 2 N (1 sga polar) iaes (m
/*): 504, 5 G2(M).

nmr (aODOM): 3.417 (31, s), 4.6-5.3 (4H, ml
).

5.5 NL@l (2H, tts).

Collection i14 Q (ador@polar)Mass(m
/e) : @ @ 4, 50 g (M”)
.

nmr (J0DOAs): 3.6? (111, s), 4. 4J (4H, mj.

s, s ~s,? (2M, wm).

Example I (S)-7-chloro-'a-fluoroPGI methyl ester 11.15-diacetate and (!1z)-7
-/RORO S-Fluoro PGI sodium carbonate methyl ester 11.
The desired product 40#I liquid was obtained by hydrolyzing I M-diacetate using the method of Example 8s.

Example 92 Ill-fluoro-Δ-taxs methyl ester 11°1s-diacetate was dissolved in methylene chloride, a small amount of triethyl 72 was added, and the mixture was cooled to -40C and t-
Butylhypoglomite is added, stirred at 0°C to room temperature, and treated in the same manner as Jmi117 to obtain the desired product.

Fruit 103 7-promo 5-fluoroPG engineering methyl ester l
When 1,15-diacetate is subjected to 77 elementation with silver 77ide in the same manner as in Example 55, the K-yoscinic target product is obtained.

O Synthesis 5.7-Difluoro PGI*Methyl Ester 11゜15
- The above-mentioned target product was obtained by treating cyanodate with sodium chloride in methanol in the same manner as in Example 58.

Synthesis of 37-) Fluo-Q PGI Snow Medemethyl Ester 94
When treated with 13 um (hydroxylated in ethanol-water as in @L), a solution of the above target compound is obtained.

Synthesis of Example 94 (1), PG poultry methyl ester l 1,11i-
Bis-t-butyldimethylsilyl ether 5611 (O
OSImmot) and triethylamine 304 (030m
moj) benzene solution! A benzene solution containing 14 tm of benzenesul-2enyl chloride (o, rt) was added dropwise into the solution at oo-s°C. After the reaction, an aqueous solution of Q rum was added, extracted with hexane, the extract was dried with anhydrous magnesium sulfate, then anhydrous potassium carbonate, and treated in a conventional manner to obtain the product 11xa.
Got o4. This was then purified using 4Pt (containing 0,1-triethylamine) on a silica gel column) to obtain S-phenylthio-Δ-PGI fish methyl ester-11. IS-bis-t-butyldimethylsilyl needle 38119 (yield 60-) was obtained.

TLO (silica gel: benzene/hexane-47a.

Rf OJO mass (20@V, m/e) under ammonia atmosphere; 702 (
M”) nmr (OOAa, ppm); o, o
s(t2g, be), o, 9(zta, be).

s, t ~ z, a (l all ), s, 6G (
3H,s).

3.7 (III, m), 4.1 (IH, m).

4, O5 (IH, d, J-IHg).

4.7 & (l H, m), 5.43 (2H,
m).

7.1-7.1 (Is iris 9m).

(ii), @@ s -y engineering diruthio-PG engineering 1 methyl ester - 11.15-bis-t-butyldimethylsilyl ether 110 q (0,1241 mmo
A) as NIIHOO*i alj (0, OS M )
and methylene chloride 5w1K@ were dissolved, and to this K m -p-perbenzoic acid 24s9 (0,14nuaoA) was added with vigorous stirring, and the reaction was allowed to proceed for 0 minutes. The organic layer was separated, the aqueous layer was extracted with methylene chloride, and the organic layer was
Wash the organic layer twice with saturated ammonium sulfate water.
si triethylamine was added, dried over *hydrosulfuric magnesium potassium chloride, and purified by a conventional method to obtain crude 5-phenylsulfinyl-Δ-PG It methyl ester-11,1! i-bis-t-phthyldimethylsilyl ether @Q (0,123 mmoA, @yield,
ss%) was obtained.

TLO (pen: ethyl acetate 8:2; silica gel)
2Rf-0,40,0,45 MMR (O014m m OMHg): 0, O5
(l Tomi H), 0.11 (2111).

IJ (12H), 1.6~z, 5(aH)+3~3.6
(III), 3.6 (3m1.a).

n, o(ta, bg), a, t ~+, e(gu, WA
)+S, 45 (2M, m), 7.5 (511, bs).

Mass (20@V, m/s): @ @
2 (M”-1111)C11,5-sulfinyl-Δ
-PG4. Methyl ester i 1. t s-bis t-butyldimethylsilyl ether 96 ■ (0,113 mm
The reaction mixture was diluted with saturated ammonium sulfate containing a small amount of triethyl. The crude product 11' was obtained by pouring into water and extracting with ethyl acetate.
Refine with l ethyl@/2 ammonia water 2-) to obtain the desired 7-w droxy-PGX methyl ester l 1,15
-bis t-butyldimethylsilyl ether (SOO)s
xq (0, @ I z watnot, yield 349
6) was obtained.

at -o, as (silica gel; benzene/ethyl acetate!+8/day n1ar (OOI4r i)P”) '3.6O(
3H, m), 34-4.0 (2H).

4.80 (LH, t, J-'Ik1M).

4.01 (llI, bs), 4.7 (lfl, m).

5.45 (2H, +a).

mass (zo@v, m/・) sxo (m) analysis value: 0uHssO@81s (kl-HmO) calculation value 5 Q l! , 3 So II 2*-value ! 1112
．． 3981 1i set f4mM 5-sulfinyl-Δ-PG, methyl ester 11.
11! -Diacetate 118 s (0,49 mmo
ts) t'ld detrahydrofuran 11% followed by diethylamino 0. II @ d (8, i mmoAe)
After stirring overnight with Xuangin, saturated NaHOO Hatake solution 5S
Added JI7f.

Extract twice with ethyl acetate (20dX2). The organic layer was extracted with water and dried over potassium magnesium sulfate penta-carbonate for 3 d (t Od x s). When the solvent is distilled off, 2
A crude product of s9 Todoroki 2 was obtained. When this was separated and purified by 7Q reseal column chromatography, the target 7-hydro PG1. Methyl ester 11゜15-to sheer? -) 111119 (yield SS
Many) were obtained.

Rf-0,43 (silica gel; benzene/ethyl acetate-6/4 NMR (ODQLs, pPIa): 3, @@ (1M, s), 4.28 (111, a).

two (tii, t, y Zheng 7Hg).

4.7-5.4 (R11, broad).

! 1.4-6.7 (IH, m).

Mass (20@V, m/e); 4@@ (
M) Example 5S 7-PGIs Methyl Ester in Hydrogen 1. IS
-44 scoops of diacetate to 4TIJ of dichloromethane
76 sL of diethylaminosulfur trifluoride was added while cooling to -40°C. This reaction crystal compound was stirred at -20°C for 1 hour and then left at -20°C for 14 hours. Add saturated aqueous sodium bicarbonate solution (LED), extract with ethyl acetate (io+ajx2), wash with water (20aJX2), and dry over magnesium sulfate-potassium carbonate. The solvent was distilled off under reduced pressure, and the resulting crude product (45%) was separated by silica gel chromatography.

Two types of compounds were obtained. (Solvent: ben(n/ethyl acetate-85/I S (o, s-) ethylamine)
) 7-Fluo OPG, methyl ester 1. IS
-diacetate) (75g); yield 1111q (yield 1
8) TLO (silica gel: benzene/ethyl acetate-@
s7'is) Rf -0,45mass (2oe
v, m/e); 4 mm (M”)e 44”
*408.3118,34JI.

SZS.

NMR (100MHM, 0DOAs, ppm):
! , 01 (3H, #), LO4 (3B, @
).

s, as(sl, a)s 4.77 (lit, t, J-s7Hg).

4.75-5.30 (31i, m).

4.114 (IH, d, J=g5@Hg).

S, S ~54 & (21, m).

5-fluoro-Δ-pG I+methyl ester 11゜1
5-DiI cedate (ITS) Yield: 12■ (Yield: 21%)
l! /11) Rf-0,41Mass(!OeV,
m/e): 4@8 (M”), 448, 408
.

388.348,3211°MMR (1oomam, apem+ppm);t
, 5s (an, s), z, o4 (in, s).

L9~3. Snow (IH, t+r) 1 s, 5y (iH, a), 4. s ~ s, 5 (su, n)
.

5.45~S, Sm (2H, m).

Example 97 Synthesis of nee-1-hydroxy PGIm methyl ester l 1,15-
14 μm of bis-t-butyldimethylfuryl ether was dissolved in dry pyridine (osm), 1 G of meta/sulfoelk 0.5% was added, and the mixture was stirred at room temperature for 3 hours. Ether (ls d ) and saturated aqueous sodium bicarbonate solution (t
After shaking with a separating funnel, the aqueous layer was extracted again with a needle (15d). The ether layer is mixed with water (t2a
After washing with Jx3) and drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 7-methoxypropylene.

Crude product 14# containing methyl ester 11.15-1:'neat-7'f dimethylsilyl ether was obtained. The entire amount of the obtained product was dried with ace)nitrile (1-)
After stirring at room temperature for 1 hour, then at 60°C, then at room temperature for 2 days, remove No. 111 and distill off the solvent. I left. The obtained product was separated and loaded using 7-liquid thin-layer chromatography (developing solvent: n-hexane/ethyl acetate-9/1).
A, l, oq of 1-fluoroPG, methyl ester t1,1 s-bis-t-butyldimethylsilyl ether (7511) was obtained.

7Lc (silica gel; n-hexane/ethyl acetate-s
,"g) Rf-0,73 Mass (toeV, sa/e); Ill (M),
5112.855.

111, Sit, 4@O.

MMR(1(10MHg, 0DOAs*PPIE
l): O2 Hatake @ (Ill, s), 0.110 (11
H,s).

s, 5s (si, s), m, a ~4.4 (2) 1. b
r).

4.6~LO (snow if, la).

4, *S (5 H, IL, JswS, 4H
ta).

S, 45-54 (2H, 1m).

Example 8 (1) PG Kosetsu methyl ester 11.15-bis-
t-Butyldimethylsilyl needle 10.7119 was dissolved in methylene chloride (1.3 mK, and after purging with argon, 1.5 stt of triethyl aquine was added and cooled to -70°C. 22.6 sL of t-butyldimethylsilyl needle was dissolved in methylene chloride. After adding 50aL of a solution dissolved in 0.48C and stirring at -70℃ for 40 minutes, the crude product obtained by the same treatment as in Example 1 and 11 was separated by silica gel thin layer chromatography. , 10% ethyl acetate-hexane) 2.4 If (yield t9%) of 5-chloro-Δ-PGI+ I thyl ester l 1.I S -bis-t-butyldimethyl 7lyl ether was obtained.

Max x pect l'y: (m/e) 63 G +
62 II +59! , 573,571,515° MMR (QDO1*) a: o, as (eu, *), O; 9 o
(e H, ta).

2.85-34 (IH, m).

a, 5s (aH, s), s, t-4, z (zH, a).

4.40 (lH,in), 4.7-5.0
(lH,m).

s, o　o　(eye 1.d, J-!Hg).

s, 5o (ra, m).

<if) Pax* Methyl ester 11.11$-Bis- is dissolved in monobutyldimethylsilylneedlestqfn-hesosan O,5IIj, and triethylamine t2
After adding sL and purging with argon, the mixture was cooled to -7 (IcK).

There, t-butyl hypochloride number sμt was dissolved in 1 ml of n-hexane, 0.1-g of 9-molten water was added, and -YOU
After stirring for 26 minutes, the above solution was further added with SOSL and stirred at 1 γO 0 C for 30 minutes. After the same llK post-treatment as in Example 1, the obtained crude product was purified by 70 lysyl katsum chromatography to give o, s 1 ethyl acetate-n-hexane (o, iv I) ethyl acetate). Elution 1iK17.
lq (yield S 3%) (DS-chloro-Δ-P
GI+Methyl ester t 1.15-bis-t-butyldimethylsilyl ether was obtained.

Example 9I 0.02 M Sodium Dihydrogen Phosphate 6.54- and r/
o, o 11M Disodium hydrogen phosphate 29.0
When I checked the ajl and measured the pH with a pH meter, it was 7.4.
Met.

(am)-s-chloroPGX obtained in Example 3s IJ salt solution and 7'1aZ obtained in Example 36
)-! i-Chloro PG Sodium Salt Solution 7-Fluo Q PGM, sodium salt was added to the above mild solution and its UV spectrum was recorded over time at room temperature. 210H
Their half-lives were determined from the absorption values of m.

o(sm), -s-ri OEI PGI1o) Q4.
""MetIA'22aa(sz)-s-rio
o pG engineering sodium salt °half">"1 Example 1OO *s-cyclopentyl k-1 (17,111,l 9°20-pentanol-PGIs methyl ester 11°1s
- Diacede) 100 inches of carbon tetrachloride, 5 dKlll
Then, 441 g of irises-bromosuccinimide was added. After stirring for 30 minutes at room temperature, the same procedure as in Example 1 and 4! IIK and get the (295) of O strike.

nimr (#QDO1*): 凰、・會（
31! , @), Minoh, 01 (I H, a).

2.11- s, a (eye t, br), L・t(aH+
eL4.41 (III, t, J-?Hsi).

4.8-1ij (4H, m).

5.4-s, @(鵞■l”) e Example 101 S-promo tS-cyclopentyl-16,17,18,19,20-pentanolΔ obtained in Example 10G
-PGI + methyl ester l 1,15-Siaryudate 5olIF was dissolved in acetonitrile 1mlC@, and after adding triethylamine 4@at, fluorinated vIA140
Add ① and stir at room temperature for 3 hours.
Process in the same manner as above to obtain the desired object.

Rhocyclopentyl-5-fluoroQ-1417, l I
I, l@, 20-pentanol-Δ-PG-Kudzu methyl ester l 1,1 B-thia heptadate: Yield 12# MMR (a 0 DOts ): 1.118 (3H, a), s, oBsa, s).

2.9-3.3 (I H, b r ), a, 5
8(an, s).

4.6-L3 (5H, hazy).

! ,4　s　-s,@(birdH,!l).

Mass spectrum (2...'T1. m/s)': 4.
藝（M”）、44＠、4018.888.346゜1
5-cyclopentyl 1-7 to 1 oro 1 to 17.1
@, 1 *, 尤O-pentanol-PG4t methyl ester t3. -Diacetate: Yield ass5) MMR (a0DQL island): t, 91e (31, s), 2. all (31!, s).

3, @7 (3H,・).

4.7 'I (l H, t, J Mai?Hg).

4.74~S, 8@(81,m).

4.114 (1, d, J-10g).

s, s A-s, m s (寞H-1° mass spectrum (lo@v, m/・): 411g (M), 44@,
4 (Ml, 81111,3441゜Example 102 15-cycloben-7-fluoro0-1 obtained in Example 101 @, 17.1 g, 19.20-pentanol-PG Is methyl ester $ 1.I S- Diacetate) 2owI was treated with sodium methoxide in methanol to deacetylate it in the same manner as in Example 4o to obtain the desired product (1!?) 15■.

1HMR (aODOLm): n, 5Bsa, s), a, s ~ 4.2 (2H, m) 1
4, @II (IH, t, J-IHM).

4.? ~LO(IH,br).

4.111 (IH, d, J-55HIm).

! T,! i-V5.7 (IH, m).

Mass spectrum (20@V, m/・): 382 (Ml
), 3@4. ! I@m, 344゜Real 1-91103 15-Cyclobenchik-15 obtained in Example 1ot
-71, O0-111.1? , 1 a, I Jl 0
-hentanol-Δ-PGI*methyl ester 11.16
-Diacetate 10η was treated and acetylated with sodium methoxide in methanol in the same manner as in Example 40 to obtain the desired product (225) 7 #.

NMR (a QDOAs): 2.11 ~ a, z (t, br), a, gy (sit,
s).

3.6S ~4J (1!IIImm) 14.11s
(Eye 1, broIMl aoubxet, J
-4@if m).

41~Lm (nml, ++a), 5.45~5.6 (2
11, m).

Mass spectrum (snow o*v, m/e):ass(M
”) ass4,3@l!, 344.

Example 104 -7-FluoQ-16,1? , 111, 19. ! When 0-pentanol-PG engineering methyl ester was treated with Example 112 and Example 11, a solution of the target product (325) was obtained.

Example 105 ls-Cyclopentyl-5-fluoro0- I Jl obtained in Example 1O3? , 131 *, 2 G-pentanol-PGM, methyl ester was treated in the same manner as in Example 62 to obtain the desired product (32 if moats).

Fruit 1106 15-cyclopentyl-16.17.1 g, 19゜2
0-pentanol-Δ'-PGI*methylnisder11.
16-p-t-butyldimethylsilyl ether 10
0 ml and triethylamine 70βt with 1 liter of captured carbon chloride, 5
ajK@Hakashi-Kai-chlorosuccinimide snow powder was added at room temperature and stirred for 1 hour.

The purpose of 62 inches was obtained using the same method as in Example 1. NMR (# ODCjm): 2.8-3.2 (IH, br), 347 (3H, s).

3.7-4.8 (2H, br).

4.311 (II, t, 717111g).

4.911 (11!, 1.J-IHg).

4.7-5.1 (eye 1br).

5.4- s, @ (2H, m).

Example 107 S-Rio a -11-cyclopentyl-1s,l obtained in Example 106 7. t8. t 9.20-pentanol-Δ'-PG 3-methyl ester 11.1 M-
60 μ of bis-t-butyldimethylsilyl ether was rearranged in the same manner as in Example 37 to obtain the desired product (yiy) t
w q and (5Z-747) 20 N were obtained.

(8m)-! ! -Chloro 115-1/Clobenthru 16.17,111. l・j20-Pentaturu PGI
Snow methyl ester 11. Is-t-butyldimethylsilyl ether NMR (acDOLm): 3. @@ (3
H, s).

3.7-44 (3M, m), 4.65-4
．． 7 (IH, br).

L4-1. @ (IH, m).

Mass spectrum (!...ma, m/s): 62, 6
3@, S'll, 5@il, 1i33.

(sz)-s-chloro-111+-cyclopentyl-t
s, t 7,111.1-. 2 o-pentano#P
GX Domedemethyl Ester 1.11! -Bis-t-butyldimethylsilyl ether NMR (JODcm): Lll@(III, s), 17-44 (2H, a).

4.5&-4,7 (lit, br).

s, a -s, a (s I, Peng) Male spectrum (10@V, III/@): @! @,
@11@, i? l, S@I, 533゜Example ios Compound (747) obtained in Example toy 10■, (
5z-447) 20 The dark was treated in the same manner as the real 10s, and the silylation reaction was performed to form the compound (1151).
I, (8z-183) 12m# was obtained.

(lltl)-5-chloro-IS-cyclopentyl
@, l? , l 8,11. Lazy O-Pentazuru PGI
tMethyl ester MMR (a■U#): 3.6? (3M, #), 3.7-4.2 (2H,
m).

4, b & -4, f 1 (111,’br).

s, s　-s,t　(wo wing, thought).

Mass spectrum (go・v9m/・): 406.31
111.30! , 380.864,362.

(6z)-6-chloro-15-cyclobenzene 16
．． 17,11,141,20-pentanoyl PG.

Methyl ester NMR (J(DCLm): 3.67 (3M, gn, 3.7-4.2 (2H,
m).

4J-4, 15 (IH, br).

s, s-i, t(za, m).

Mass spectrum (zoev, m/e): 400j9
1,3112,380,364,362゜Example tOS SA Compound obtained in Example 10・(6!i3) 4■,
($z-@63) SN as an example @2
W] IIIK and the object (10'l), (6
-107) solution was obtained.

Example 11G Measurement of blood pressure lowering effect The effect of the glostanitalins of the present invention on blood pressure and heart rate in rats was determined by intravenous infusion under anesthesia.

That is, a 27-year-old Wistar strain was used, and the rats were given 9 rats.

we / Kg Ik' - Chloralose (a-ch
1OralQa@)looq/- was administered intraperitoneally and stabilized under anesthesia.

After the test compound is dissolved in a small amount of ethanol.

The mixture was diluted with 0.05 M) Lys buffer (pH·)K, and the final amount of ethanol was adjusted to less than sl, and the mixture was injected into the vein of a rat via a catheter inserted into the femoral vein.

Blood pressure was maintained constant using a pressure transducer through a catheter inserted into the common artery of the rat, and heart rate was measured from the blood pressure waveform during feeding.

Then, the effect of the test compound on blood pressure was determined by calculating the mean blood pressure by 2ofk'T relative to the mean arterial pressure before administration of the test compound.
Dose of test compound (p-1CD*s, μtl
k). The effect on heart rate aK was expressed as the dose of the test compound (H-ID+·, sf7%) that increased the heart rate by 1011 compared to the heart rate before administration.

As shown in table 1, Tsumugi is a foodie.

1 Sai Example 111 (1) Inhibitory effect on platelet aggregation Test compound O1tro platelet aggregation inhibiting effect was tested using rabbits. That is, weight 2. i~N,'AK4G L--trisodium citrate S from the ear vein of a Japanese native white male rabbit
Blood was collected at 1101iI11 for liquid IK, and 10
G Orpm IO minutes After S, the upper layer is PRP (platelet rich 11 and the portion is a circle. The lower layer is even more! @o.

rpm for 10 minutes, and then remove the upper layer, which is divided into two layers.
It was set aside as PP (platelet poor plasma). Platelet count is 6
Interpretation #II at ~7X10 exposures/sL K P P P. Add 5sL of adjusted PR22rhOsLK test sample, pre-incubate at 31°C for 2 minutes, and post-mortem.
Add P 1 osM (final) and record the change in m4& with an acribometer. The test compound was dissolved in ethanol Kl@IIIF/-.

When measuring its activity, phosphor iron-buffer moat (p
H? , 4) and used. Also, after diluting with buffer, O
The activity was measured after being left at ℃ for 4 hours.

The aggregation inhibition rate was determined using the following formula.

'To: Permeability of ('J acid buffer addition system) D: The test compound's permeability inhibition rate of the test compound addition system exceeds SO- C1.
Shown as a value. The results are shown in Table 2.

As is clear from Table 2 of the gz table, the platelet aggregation inhibitory activity of the prostacyclin of the present invention did not decrease even after 4 hours of incubation, supporting that it is a compound that is stabilized at once.

[) The ratio of antihypertensive activity and platelet aggregation inhibitory activity of Example 1 Oo and lotyop was calculated, and when compared with the ratio of PG, the results were as shown in Table #I3. From Table 3, it was found that the compound of the present invention (aSS) and (68-)
Compared to PGb, it has stronger antihypertensive activity and platelet aggregation inhibitory activity, and therefore, it can be seen that the action selectivity of J[ll activity is higher than that of PGIsK.

Example 112 Brostanitalins of the present invention were intra-intestinally administered to unanesthetized rats, and the effect on blood pressure was investigated.

That is, Wistar rats with a *ooto'is body weight were subjected to the experiment. These rats were fasted for 16 hours prior to the experiment. This rat was placed under ether anesthesia. A catheter was inserted into the vein of the eel, the eel was restrained in a Ballman cage, and the eel was kept for at least 1 hour after awakening.
The test compound was administered intraduolytically. After dissolving the test compound in a small amount of ethanol, it was diluted with .05 M Tris buffer solution, and finally the amount of ethanol was reduced to s% or less and administered intra-intra. Mean blood pressure was measured with a pressure transgenie via a catheter inserted into the femoral artery.

The results are shown in Table 4 and are a complete success.

Example 113 Book*@'s Glosta Italin's xtra vtv.

The anti-platelet aggregation effect was measured using rats. Wholesale tested hardware was dissolved in ethanol, then 0.0
hM) Diluted with Liss Mild II Solution (pHs, o). As a control, a 0.05 M) cis mild solution was used. These - 8 DJ9 pieces weighing approximately 5 oots) (14
(rats that have been fasted for hours) can be administered enterally at a dose of K t d /-.

After administration, 3.8-citric acid (3.8-citric acid) from the aorta after SO sorting.
Blood was collected at a ratio of 90 to +3um IK, @ 00
rpm l @Buntatsushin separated. PRP upper management (
As for platelet-rich plasma), the amount of blood collected is lower than that of the lower layer.
I ＠ ＠ rpm ＠ ＠ minutes Separate the heart and divide into two layers.

Take the obtained PPP snow S@voice t to Evet in the age dub meter and l? After incubating for 2 minutes at °C,
61M) Lithium salt (pHII, O) 1,2 SsM ADP2 sodium solution 25-2 dissolved in IC was added and the agglutination line was recorded for 3 minutes. Determine the maximum degree of platelet aggregation that occurs within that time, and calculate the platelet aggregation inhibition rate using the formula below.

To: Transmission of the control (0.05M) group (administration of only Lithium Ii solution) TD: The permeability results of the administration of the test drug are shown in Section 5IIK.

From Table 5, it can be seen that this @@0 compound (.88)ki exhibits a stronger platelet II collection inhibiting action than PGI sodium salt.

On the other hand, Table 4 shows that PGI sodium salt has a stronger antihypertensive effect (especially than the compound of the present invention (aSS)).
It can be seen that (kk).

From the above, it can be seen that the compound (6841) of the present invention has a low antihypertensive effect, but has a slightly stronger inhibitory effect on Koko M# collection, and is highly selective for one effect.

Practical IIA Example 114 Mass was used as an experiment am. Lewis Lang Cardino? (Lsvis lung carcinoma) (
4X l 6”0 @ 11 / l 00 st) was transferred to Max's foot pIL (l K. After transfer,
IIgl*Ryumei's compound (SaS) was administered intraperitoneally every day for 7 days from day 28 to day 11-1. Then, on the 12th day, the tail of the m-single was cut off, and after transplantation! On day 0, the rate of metastasis of lung JIc@ was kept constant. Results #i: The 6th mK was shown.

Table 6 Table 6 shows that the compound of the present invention suppresses the metastasis of the primary tumor to the lungs and reduces the weight of the primary tumor.

Example mouth S Next, IIS sex tab tablets were made, consisting of O.

Active ingredient 1 Nursing II
Z50■ Starch 8019 Talc
2. Magnesium stearate
S■366■ A mixture consisting of the active ingredient, milk m, starch, Merck and magnesium sunarate was compressed using a rotary tablet press to form a tablet, which was then mixed with ethanol in which hydroxyglobil methylcellulose 7-thaletate was dissolved. and sprayed in a coding pan to obtain enteric-coated tablets.

The compound (68 g) was typically used as the active ingredient.

Example ttS Production of injection The compound (aSS) was used as the active ingredient, and the compound 6
0 Osf was dissolved in ethanol 5WdK@, collected through a Pakdelia retention filter chamber, and the cocoons were put into 1 d11 ml of cocoons per ampoule, and the ampoules were sealed. The contents of the ampoule are diluted with, for example, Tris-HCl buffer for injection.

Implementation fee 117 One tablet consists of the following composition #! There were 17 left.

Active ingredient 1'1 Milk II 300II! P. Diagonal pyrrolidone 8o Polyvinylpyrrolidone 101a9 Magnesium stearate 5 & 9400 ■ The active ingredient, lactose and potato starch are combined, and this is evenly moistened with an ethanol solution to 205 polyvinyl pyrrolidone, passed through a 20 mesh sieve, and 45
'CK, dried, and passed through a 2o mesh sieve again. The granules thus obtained were mixed with magnesium suderate and compressed into tablets.

A compound (SSS) was typically used as the active ingredient.

*M example 18 A powder having the following composition was produced.

Active ingredient 2 lactose 1 ooq corn a-kosi f# 11 100 Nk droxyglobil cellulose 1 o 912 mg Active ingredient, lactose and corn a-kosi f# 14 combined,
Next, an aqueous solution of hydroxyglobil cellulose was added and mixed, and the mixture was dried to produce a powder.

Compound (686) was used as the active ingredient.

Real Ill 94 119 Nasal drops Natsume ffiney A nasal spray consisting of the following i[1 components] was produced.

Active ingredients 0.5 try antioxidant and 1. Tenojikum Bisuru 7 Eye) & 0.1511
6. A nasal spray was prepared by dissolving one active ingredient in a physiological saline solution containing O, S capsules and chlorobutanol as a preservative in an amount having the above composition (amount for single administration). A compound (SSS) was typically used as the active ingredient.

Continuation of page 1 0 shots clear by Toshio Tanaka 5-15-6 Tamadaira, Hino City 0 shots by Noriaki Okamura 1-31-1 Senyocho, Chofu City 0 shots clear by Kenzo Watanabe 3-5-18 Tamadaira, Hino City 0 shots Akira Seiji Kurozumi 1-2-28 Higashitogura, Kokubunji City 0 shots Akira Otsu 3-13-35 Inumon, Ome City 0 shots clear person Tatsuyuki Seichi 5-20-2 Tamadaira, Hino City

Claims (1)

[Scope of Claims] L: the following formula (Ml): halogenated PG represented by R@OR', and the following formula (
A halogenated Glostanitalin selected from the group consisting of halogenated PGIs represented by: 2. Claim II! selected from halogenated PG atoms in which R and Ra in the above formula (M) are water bulk atoms or fluorine atoms! The halogenated glostanitalin described in Item 1. 3. The halogenated brostanitalin according to claim S, which is selected from halogenated PGIs, wherein in the above formula (M), Ha and R1 are hydrogen atoms or fluorine atoms. 4. In the above formula (m), V and R1 are hydrogen atoms. The halogenated glostanniitalin according to claim 1, which is selected from halogenated pGI+l1llll, which is a chlorine atom, a bromine atom, or an iodine atom. 5. In the above formula (Muen), ip and R1 are hydrogen atoms. Halogenated Pσ which is a chlorine atom, bromine atom or iodine atom
The scope of patent claims that can be selected from the types i! l Daiichi Genki Soft's halogenated glostanitalin. 6. R1 is a hydrogen atom, an alkyl group of 01 to O+, or an equivalent cation of which the O salt is a pharmaceutically acceptable salt, any one of claims 1 to S The halogenated glostanitalin according to item 1. The halogenated glostanniitalin according to any one of claims 5 to 5, wherein 7°R4 is a hydrogen atom or a methyl group. Il, R' is n-be/tyl group, n-hemo syl group, 2
-Methyl-1-hexyl group, 2-methyl-2-henosyl group, and cyclopentyl group are cyclohexyl groups, 9. , R and Rg are single or different elementary atoms; Furanyl group, 1-ethoxyethyl group, 0] to] Kiss 4-
yl group and acetyl group are benzoyl groups.
1li! 8111 as any one of the terms 1iAIe to 5th term
llll of halogenated glostanitalin. In the Mu07 Joki style (Mujo), the carbon atom at the S position of the double bond between the S position and the 6th position is connected to the carbon atom at the 4th position, and the 6th position of the double bond The bond between the carbon atom and the oxygen atom is in a cis bond. 41 Houses - Wanted #l -
l-The first and third are the halogenated glostanitalins as described in item 5. ii, the bond between the ts position and the 14th position is a trans-triple bond or a triple bond;
I. Rogenated Glostanitalin according to any one of Item 0. 12. A halogenated PG compound represented by the following formula (M)-1, S1 and a halogenated PGI group represented by the following formula (Muzuka)-1, selected from the group consisting of halogenated PGIs represented by the following formula (M)-1, - halogenated prostacyclin. 13. In the above formula (mukai)-1, the carbon atom at the 5th position of the double bond between the 5th and 6th positions is bonded to the carbon atom at the 4th position, and the carbon at the 6th position of the double bond. 13. The halogenated prostacyclin according to claim 12, wherein the atom bonded to the oxygen atom is in a cis relationship. 14. The halogenated prostacyclin according to claim 12, wherein the bond between the 13th and 14th positions is a trans-double bond or a triple bond. is, PE represented by the following formula (Bl) RIIOfilm, S is represented by the following formula (c) x-Q
・・・・・・A halogenation reaction is carried out with the electrophilic halogenated excipient represented by (0) in inert organic 1141 in the presence of a basic compound according to 41. A method for producing a halogenated prostacyclin represented by the following formula (M)-1, which comprises subjecting it to an eel preservation reaction and a /l or salt production reaction. 1 g, electrophilic halogenating reagent is chlorine, bromine, iodine 9M-bromosuccinimide, N-chlorosuccinimide, M-519 tosuccinimide. N-bromo heptataric acid indo, M-chlorosuccinimide, diomusan dibucomide. Dichlorohydantoin, dibromodimethylhydantoin, trichloroincyanuric acid, -phthylhy+/20
16. The method for producing halogenated glostacycline according to claim 15, which is light, t-pur hypopromite, or viridinium hydrobromide perpromide. 17. 411fF in which the above halogenation reaction is carried out in the presence of a basic compound, Claim 16, and Company Section 111f
Method for producing f1- halogenated prostacytalin. ia, halogenated PGLs represented by the following formula (lees)-a are combined with an electrophilic halogenating reagent represented by the above formula (Q) in an inert organic solvent, if necessary in the presence of a basic compound. , followed by a halogenation reaction, and then, if necessary, an unbinding reaction and/or a salt formation reaction, the following formula (muso)-a
A method for producing halogenated PG material 1 represented by l. 39, halogenated PG represented by the above formula (M)-a
(b)) Treat the I+ group with a catalytic amount of a protic acid or an organic sulfone pyridine salt in an inert aprotic solvent, necessarily in the presence of sequential K or simultaneously with all the dehydrating agents. Alternatively, (b) treatment with a catalytic amount of protic acid X in a #l medium and then heating in an aprotic solvent; A method for producing a halogenated P1.1 compound represented by the following formula, which is patented by subjecting it to a deprotection reaction and a salt formation reaction. 2G, PG total represented by the following formula (Bl) is mixed with an electrophilic halogenating reagent represented by the above formula <a> in an inert organic medium,
A method for producing the following formula (M)-2, which is characterized by carrying out a halogenation reaction in the presence of a basic compound, and then subjecting it to a debinding reaction and/or a salt-forming reaction if necessary. 21. The electrophilic halogenating reagent is chlorine, bromine, iodine, N
-Promoco/S month 1 mido, N-chlorosuccinic acid ionic acid 1
M-bromo 7 tar acid iide, N-riao 7 tar saproimide, dichlorohydantoin, ) 17 chloroin cyanuric acid a1% parent is t-butyl hypochloride,
Particularly desired scope - A method for producing halogenated brostanitalin according to item 20. 22. Patent for carrying out the above halogenation reaction in the presence of a basic compound - Scope of Claim No. 20 and Company No.! The method for producing halogenated brostanitalin according to item 1. 23. A hepgenated PG compound represented by the following formula (MU)-1 is treated with an electrophilic halogenating reagent represented by the above formula (0) in an inert organic solvent, if necessary, to make it basic. In the presence of the compound, a halogenation reaction is carried out, followed by an uncoupling reaction from tlK and /l
The following formula (M +
) A method for producing IN, a halogenated PG compound represented by -at. Goose 4. Halogenated PG represented by the above formula (M5)-a
Jvs are treated with a catalytic amount of a protic acid or an organic sulfonic acid pyridine salt in a (-9 inert non-gutonic solvent, optionally sequentially or simultaneously in the presence of a dehydrating agent, or Alternatively, (b), the following formula % formula % is characterized by being treated with a catalytic amount of protic acid in a protic solvent and then heated. ) A manufacturing method for halogenated PG type 3 represented by 25, halogenated pG represented by the above formula (mu+)-a
I. or halogenated PG represented by the above formula (M1)-1
Ims are subjected to a fluorine substitution reaction with a fluorinating agent in an aprotic inert organic solvent, and then, if necessary, subjected to a debinding reaction and/or a salt formation reaction,
A method for producing a halogenated prostacyclin represented by the following formula (m)at. 26.7 Bulking agents are silver 77ide and cesium fluoride. Claim 25: The method for producing halogenated prostacyclins according to claim 25, wherein potassium fluoride, sodium fluoride, mercury fluoride, and borosulfide are detraptylammonium fluoride. 21. A fluorinating agent represented by the following formula (D) m@mo R41 is subjected to a fluorine substitution reaction in an aprotic inert m% medium, and then subjected to a deprotection reaction using IK. /l or subjected to a salt formation reaction, the above formula (M)-
Wrinkling method for halogenated prostacyclin represented by a + 28, the fluorinating agent is silver fluoride and cesium heptafluoride. 28. The method for producing halogenated prostacyclins according to claim 27, which is potassium fluoride, sodium heptadide, mercury fluoride, borosulfide, or tetrabutylammonium fluoride. 29, Hidokukikugu a stanakuri 7m expressed by the following formula (noun) is di(
01-CI) alkylamino-sy. bis(di(0+-Ql+) al hour ruakino] -5i
pt. Morpholino-S6 or '110FsOHIFCFtN (
The above formula (M)-a, which is characterized in that it is subjected to a fluorine substitution reaction with Of & b in an aprotic inert am solvent, and then subjected to an unbinding reaction and/or a salt formation reaction according to 41. A method for producing a rogenated prostacytalin represented by . SO, fluorinated PGI +ll represented by the following formula (AI)-am is treated with an electrophilic halogenation reagent represented by the above formula (0) in an inert organic solvent in the presence of a basic compound as necessary. The production of a halogenated PG compound represented by the following formula (80-4) is carried out by carrying out a halogenation reaction, and then subjecting it to a disassociation reaction and/or a salt-forming reaction. Method 31. Fluorinated PGI*ll [represented by the following formula (At)-as, and the above formula (0)
A halogenation reaction is carried out with an electrophilic halogenating reagent represented by 4I in an inert organic solvent in the presence of a basic compound, and then 1! A method for producing halogenated PGL@ represented by the following formula (at)-4, characterized by subjecting it to an IK disassociation reaction and/or a salt formation reaction. 77
A fluorine substitution reaction is carried out with a hydrogenating agent in an aprotic inert solvent, and then, if necessary, an unbinding reaction and/or
The first step is to subject it to a salt-forming reaction. The following formula (A
) - A method for producing fluorinated glostacyclines, which is honored with am. Ura, fluorinated P represented by the above formula (muden)-am
GI1 class is prepared (a) in an inert aprotic fII medium with a catalytic amount of a protic acid or an organic sulfone pyridine salt;
treatment with a catalytic amount of protic acid in a protic solvent, followed by heating, followed by a debinding reaction and /l, sequentially or temporarily in the presence of a dehydrating agent; 1. A method for producing a heptadated PE compound represented by the following formula (1 formula %), characterized in that it is subjected to a salt modification reaction or a salt modification reaction. 34, halogenated PG represented by the above formula (M+)-1
It contains as an active ingredient a halogenated prostanyclin from the group consisting of halogenated PG compound represented by I+rhyme and the above formula (mu,)-1, together with a carrier containing chestnut chemical Ktf. Pharmaceutical composition for controlling vascular system movement. The pharmaceutical composition according to claim 34 for is, vasodilation, hypotension or antithrombosis. 36. Anti-pulmonary artery sclerosis, anti-angina pectoris, pile myocardial infarction, anti-enterocardial shock, anti-pulmonary hypertension. Anti-stroke, anti-funcient isochemical attack (
transient engineering sabsmic attack
), the pharmaceutical composition according to claim 34 or 3s for anti-thrombocytopenic purpura, anti-profundus angiopathy or anti-cisternal vasculopathic disease. The pharmaceutical composition according to claim 34 1e-, which inhibits the metastasis of masturbation by 37%. Nishiki, organ transplantation, vascular surgery or extracorporeal circulation 11! The aphrodisiac composition according to claim 34, which is used for 3g, hydroxyglostacycline compound represented by the above formula (II).