JPS5927885A - Preparation of 5-halo-6-delta6-prostaglandins i1 - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for synthesizing drugs, various kinds of prostaglandins I2 using easily obtainable raw materials in high yield, by dehydrating a 5-halo-7-hydroxyprostaglandin I1. CONSTITUTION:A compound shown by the formula I [G is -CO2R<5> group (R<5> is 1-10C alkyl, phenyl, cycloalkyl, etc.), -CONR<6>R<7> group (R<6> and R<7> are 1-10C alkyl, etc.); R<1> and R<2> are tri(1-7C) hydrocarbon-silyl, 2-7C acryl, etc.; R<3> is 5-8C alkyl, etc.; R<4> is H, methyl, etc.; X is halogen; dotted line is alpha-configuration; thick line is beta-configuration] is dehydrated with a sulfonic acid halide shown by the formula II (R<8> is halogen-substituted 1-4C alkyl, etc.; Y is halogen) or a sulfonic acid anhydride shown by the formula III (R<9> and R<10> are halogen-substituted 1-4C alkyl, etc.) in the presence of a basic compound, to give the desired compound shown by the formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of 5-halo or monobutyl p-staglandins I. More specifically, the present invention uses a novel 5-halo-7-hydroxyp staglandin 11 class as a raw material compound that can be synthesized extremely efficiently, and by subjecting this compound to a dehydration reaction, it has excellent properties as a pharmaceutical product. and various other prostaglandin 12
5-halo scraps, which are also useful as intermediates for the synthesis of related compounds
The present invention relates to a method for efficiently producing prostaglandin I.

Prostaglandin 11 (hereinafter referred to as PGI) is a known compound represented by the following formula.

PGI2 is mainly released from the vascular endothelium, has the effect of inhibiting platelet aggregation, and also has a blood pressure lowering effect based on the effect of relaxing smooth muscle (Japanese Patent Application Laid-Open No. 13616-1982).
(see Publication No. 1), it is an important drug that is expected to be applied to pharmaceuticals (for example, G.R.Vain (J.R.)).

Vane et al.
clin)+Raven Press, N, Y,
1979: Journal Opmedicinal Chemistry (J, Med, Chem).

Vol 23. A6. June, 1980.59
(See pages 1 to 593).

However, PGI2 has an active half-life of only a few minutes in physiological pIl, and there are problems with its stability as a drug. The vinyl ether structure is easily hydrated,
It is believed that this is due to the fact that it is converted into 6-oxoprostaglandin, or that it is rapidly metabolized in vivo by 15-position dehydrogenase. On the other hand, regarding the pharmacological action of PCI□, it is considered to be inferior in action selectivity as a pharmaceutical, such as platelet aggregation inhibiting action and blood pressure lowering action being almost equivalent in medicinal terms. For this reason, a great deal of effort has been made both domestically and internationally to synthesize PCI2 types and compensate for the above-mentioned shortcomings of PCI2 (for example, Niss M. Activity Op Prostanoid (Ch
chemistry, biochemistry &
Pharmacological Activity
of Prostanoids), Perga
mon Pleas+Oxford, 1979
). In particular, the conventionally known PGIs that have stabilized the compound/-ru-r--5' are as follows: (1) 6,9-imino derivatives (G.L. Bundy et al.) , Tetrahedron Letters
, 1371 (197B)).

(216,9-thia derivative (GC Nicolaou (K
, C., N1colaou) et al., Journal of American Chemical Science (J.

Amer, CThem, Soc), 100.256
7 (1978): M Shibasaki (M, Shi
Tetrahedron Letters (Te
trahedron Letters), 559(1
978): +Y, Aral et al., Chem, Letters, 13
75 (1978)).

(3) 6.9-carba derivatives (K, C, N1eolaou et al., Chemical Communication (Chem, Commun), 1
067 (1978): G. Kojim
a) also Tetrahedron Letters (Tetrahe
Dron Letters).

3743 (197B): M. Shibasaki (M.

5hlbasaki) et al., Yubld, 433 (197
9): Y, Konishi et al., Chem, Letters,
1437 (1979): D.R. Morton (D.
, R, Morton) et al.

Journal Op Organic Chemistry −
(J, Org, Chem), 44. 2880(
(1979)).

(4) 5-oxo derivative (etch nishama (II).

NlN15hlya) et al., Tetrahedron Letters (
Tetrahedron Letters), 34
81 (1979)).

(5) 7-oxo derivative (European patent publication phase separation 31°42
(see 6).

(6) 5-cyano derivative (U.S. Pat. No. 4.219.47)
(See Specification No. 9).

(7) 5-7-enylthio derivatives (T-ol (T,
Tetr et al.
ahedron Letter 4), 2539 (
(1980)).

(816,9-aza-5-thia derivatives (W, Bartmann et al., Angew
, Chem+Int, Ed, Engl, 19.819
(1980)).

The present inventors previously proposed the following formula as one of the prostaglandins with excellent stability: [wherein, X represents a halogen atom]. ] (Japanese Patent Application No. 56-84463; Japanese Patent Application No. 57-329F11). Such 5-Hachinohe-perprostaglandin or its derivatives can be converted into various other prostaglandins and related compounds having excellent pharmacological actions, and therefore can be used as intermediates for the synthesis of useful compounds. is also extremely important.

And these 5-haloper prostaglandin I,
The derivatives are produced from prostaglandin 12 by the route shown in the following reaction formula (Japanese Patent Application No. 84463/1984; Japanese Patent Application No. 32981/1983).

Group (glostaglandin I2 class) In this production method, multiple steps are required to obtain prostaglandin class 12 used as a raw material compound, and it is not easily available. This is not an industrially satisfactory method for producing perprostaglandin X1.

Therefore, the present inventor conducted intensive research on a method for producing 5-halo-n-prostaglandin 11 using readily available raw material compounds, and found that 7-halo, which can be easily obtained from 4-hydroxycyclopentanones, A new compound, 5-halo-7-hydroxyprostaglandin, obtained by reacting hydroxyprostaglandin F1α with a fi-electronic halogenation reagent, is used as a raw material compound, and this compound is subjected to a dehydration reaction. By attaching 5-halo-prostaglandin 11, it is possible to efficiently obtain 5-halo-prostaglandin 11, and therefore, 5-halo-71! can be produced using readily available raw material compounds. -We have discovered that this is an industrially disadvantageous manufacturing method for Glostaglandin I1 class, and have arrived at the present invention.

That is, the present invention provides the following formula (CI) characterized in that 5-halo-7-hydro-p-xybrostaglandines represented by the following formula CI) are subjected to a dehydration reaction.
This is a method for producing 5-halo-prostaglandin 11 represented by I[).

The above formula (1) which is a raw material compound in the production method of the present invention
In the 5-norloaf-hydroxyprostaglandin I group represented by, G is -Co, R' or -〇〇N
R6R7, where R5 is a C1 to CIO alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted cycloalkyl group.

It is an N-substituted or unsubstituted phenyl (C, ~C2) alkyl group or a (C, ~C7) hydrocarbon-silyl group.

Examples of the C1-C100 alkyl group include methyl,
Ethyl, n-7'lopyl, 15O-propyl.

n-butyl, 5ee-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-
Mention may be made of straight chain or exobranched ones such as octyl, n-nonyl and n-decyl.

Examples of substituents for substituted or unsubstituted phenyl groups include halogen atoms and hydroxy groups.

A C2-C7 acyloxy group, a C1-C4 argyl group optionally substituted with a halogen atom, and a 01-C4 alkoxy group optionally substituted with a halogen atom.

A nitrile group, a carboxyl group, a (C+ to C6) flufucidicarbonyl group, etc. are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the C2-C, acyloxy group include acetoxy, propionyloxy, n-butyryloxy, 1BO-
Mention may be made of butyryloxy, , Cleryloxy, 180-valeryloxy, caproyloxy, enantyloxy or benzoyloxy.

Examples of the C1-C4 alkyl group optionally substituted with halogen include methyl, ethyl, n-propyl+ +so
Preferred examples include 7'lopyl, n-butyl, dichloromethyl, dichloromethyl, and trifluoromethyl. C optionally substituted with halogen
Examples of the 0-C4 alkoxy group include methoxy, ethoxy, n-propoxy, 180-propoxy, and n-butoxy.

Preferred examples include chloromethoxy, dichloromethoxy, trifluoromethoxy and the like. (C
Examples of the 1-C,) alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

7. Substituted or unsubstituted cycloalkyl groups include those substituted with the same substituents as above or unsubstituted,
saturated or unsaturated C6-C8, preferably C5-C0,
Particularly preferred are C6 groups such as cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.

Examples of the substituted or unsubstituted phenyl(C,-C,)alkyl group include benzyl, α-phenethyl, and β-phenethyl, in which the phenyl group is substituted with the same u1 substituent as mentioned above or unsubstituted.

)! Examples of the I(C, to C7) hydrocarbon silyl group include trimethylsilyl and triethylsilyl.

t-Butyldimethylsilyl group (C1-C4)
Preferred examples include alkylsilyl, t-butyldiphenylsilyl group, xyphenyl(01-C4)alkylsilyl group, tribenzylsilyl group, and dimethyl-(2,4,6-)so-t-butylphenoxy)silyl group. I can do it.

R' and R7 of -CONR6R7 are the same or different and are C1 to C7o alkyl groups, or R6 and R7, together with the nitrogen atom to which they are bonded, are 5- to 6-membered groups which may further contain a heteroatom. Represents a substituted or unsubstituted ring. Here, examples of the alkyl group of C1 to C1o include the same alkyl groups as mentioned above. Further, examples of the substituent in the above-mentioned substituted or unsubstituted ring include the same substituents as those mentioned above, and examples of the hetero atom include nitrogen, sulfur, or oxygen atoms. Examples of the above-mentioned ring include 1-pyridyl, thiazolyl, 1-piperidyl, morpholyl, piperazyl, and 5,6-cyhydrophenantridyl groups.

G is preferably 100, R'' (methoxycarbonyl), in which R11 is an 01-C1o alkyl group, particularly a methyl group.

R1 and R2 are the same or different, tri(c, -C
7) A hydrocarbon-silyl group, a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group, or a C9-C acyl group.

)! J(C, ~C7) hydrocarbon-silyl group, R
The same ones as those listed in 5 can be mentioned.

Examples of groups that form a 7-cetal bond with the oxygen atom of a hydroxyl group include methoxymethyl, 1-ethoxyethyl,
2-Methoxy-purpan-2-yl, 2-ethoxypropan-2-yl.

(2-methoxyethoxy)methyl, benzyloxymethyl, tetrahydropyran-2-yl.

Tetrahydrofuran-2-yl, 4-methoxytetrahydropyran-4-yl or 6,6-dimethyl-3-oxa-2-oxo-bicyclo[311,0]hexa-4-
The yl group can be mentioned. Among these, 1-ethoxyethyl, 2-methoxypropan-2-yl, (2-methoxyethoxy)methyl, tetrahydropyran-2-yl, 4-methoxytetrahydrobilan-4-yl or 6
．． 6-dimethyl-3-oxa-2-bicyclo(3,1,
0) Hex-4-yl group is preferred.

As the 02-C7 acyl group, for example, acety/L-.

Purpionyl, n-butyryl, 1ao-butyryl.

n-valeryl r igo-valeryl, caproyl.

Enantyl, benzoyl, etc. can be mentioned.

Among these, C7-C6 aliphatic acyl groups such as acetyl, n- or igo-butyryl, caproyl, or benzoyl are preferred.

R1 and R2 are t-butyldimethylsilyl group, tetrahydropyran-2-yl group, 4-methoxytetrahydrobilan-4-yl group, 6,6-cymethyl-3-oxa-2-oxo-bicyclo (3,1 ,0) hexa-4
-yl group is particularly preferred.

R8 is unsubstituted C! -C8 alkyl group, fijj optionally substituted phenyl group, phenoxy group, substituted C, -C5 alkyl group substituted with C1-C6 phenoxy group or C3-C6 cycloalkyl group.

or a substituted or unsubstituted cycloalkyl group.

The C6-C8 unsubstituted alkyl group may be linear or branched, such as n-pentyl, n-pentyl,
-hexyl, 2-methyl-2-hexyl, n-heptyl, n-octyl and the like.

The substituted C5-C, alkyl group may be linear or branched, such as methyl.

Ethyl, n-propyl, 1lIO-propyl,
n-butyl, 5ec-butyl, t-butyl, n-
Examples include pentyl. These substituted alkyl groups include phenyl group: phenoxy group; methoxy, ethoxy, n-propoxy + lso-buboxy, n
-C1-C, alkoxy groups such as -butoxy, 1so-butoxy, 1-butoxy, n-pentoxy, n-hexoxy; C such as cyclopentyl, cyclohexyl
Substituted with 6-C6 cycloalkyl group. These substituents may be further substituted with the substituents listed as substituents for the substituted phenyl group of KH2.

Examples of the substituted C8-C, alkyl group include fluorine atom, chlorine atom, methyl, and ethyl.

or F C substituted with a phenoxy group or a phenyl group which may be substituted with a fluoromethyl group, -
C2 alkyl group, or propoxymethyl, ethoxyethyl, fluoroxyethyl.

Butoxymethyl, methoxypropyl, 2-ethoxyl
, t-dimethylethyl, propoxydimethylethyl,
or cyclohexylmethyl, cyclohexylethyl, cyclohexyldimethylmethyl, 2-cyclohexyl-1
, 1-dimethylethyl and the like are preferred.

As the substituted or unsubstituted cycloalkyl group, the same ones listed for R' can be mentioned.

R3 is n-pentyl, 2-methyl-1-hexyl, 2,2-dimethyl-1-hexyl.

Cyclohexylmethyl, cyclopentyl or cycloalkyl groups are preferred.

lc'Lt Hydrogen UX atom, methyl group, ethynyl group (-〇kasumiOH) or protected ethynyl group. Preferable examples of the preserved ethynyl group include trimethylsilylethynyl and t-butyldimethylsilylethynyl groups.

Among these, a hydrogen atom or a methyl group, particularly a hydrogen atom, is preferred.

X is a halogen atom. Examples of the nitrogen atom include an iodine atom, an A atom, and a chlorine atom. Among these, a bromine atom or a chlorine atom is preferred, and an A atom is particularly preferred.

The configurations around the carbon atoms at the 5th, 6th, and 7th positions in the above formula (1) are R configuration, S configuration, or both coexist in arbitrary proportions.

The above formula [! Examples of the compounds of the above formula (1) are the following formulas (Ia), (Ib), (Ic), and (Id) depending on the arrangement around the carbon atoms at the 5th, 6th, and 7th positions.

(Ie), (If), (Ig), (Ih) (Ia)
(Ib) (tc) (Id) (Is)
(H) (■2)
Examples include compounds represented by (Ih).

The present invention encompasses the 15-form of these compounds, their enantiomers, ':l:, or mixtures of their isomers in arbitrary proportions.

Such 5-halo-7-hydroxyprostaglandins 11 represented by the above formula CI) can be converted into hydroxycyclobentenones by the method described in JP-A-55-153725, as shown by the following reaction formula. 7-
Hydroxyprostaglandin F2α is produced, and then electrophilic halogenation of the 7-hydroxyprostaglandin F2α with iodine, N-furomosuccinimide, t-butylhypopromite, t-butylhypochloride, etc. It is produced by reacting with a reagent.

OR” (7-hydroxyprostaglandin F2α) (5-
halo 7-hydroxy 7'l = staglandin l1a)
In the production method of the present invention, 5-halo-7-hydroxy prostaglandin 11 of the above formula CI) is subjected to a dehydration reaction to obtain 5-haloper prostaglandin 11.

Any method may be used for the dehydration reaction, and for example, the following method is preferred.

That is, 5-halo 7-hydro p-xyprostaglandin 11 of the above formula (1) is converted into the following formula (m) 1 R'-S -Y ... song in the presence of (1) a basic compound.・ (m)
Sulfonic acid halide represented by 1 or the following formula (
IV) React with sulfonic acid anhydride represented by V (first stage l)
v), (II) The dehydration reaction is preferably carried out by carrying out a two-step reaction, in which the mixture is then treated with a basic compound (step Ⅰ).

1 to the sulfonic acid halide represented by the above formula (m)
6, R8 is C optionally substituted with a halogen atom
0 to C2 furkyl group, f# substituted or unsubstituted pheninosyl group, or substituted or unsubstituted phenyl (C8 to C2
) is an alkyl group.

Examples of the C8-C4 alkyl group optionally substituted with a halogen atom include methyl and ethyl.

n-propyl + igo-propyl, n-butyl.

t-Butyl, chloromethyl, dichloromethyl.

Preferred examples include trifluoromethyl and nonafluorologutyl.

Substituents for substituted or unsubstituted phenyl groups include, for example, halogen atoms and hydroxy groups.

A C2-C7 acyloxy group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a C1-C4 alkoxy group optionally substituted with a halogen atom.

Nitro group, nitrile group, carboxyl group or (C8-C
0) Alkoxycarbonyl group and the like are preferred. The halogen atom is preferably fluorine, fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the C2-C7 acyloxy group include 7-cetoxy, propionyloxy, n-butyryloxy, and ls.

-butyryloxy, n-valeryloxy + ig.

- Valeryloxy, caproyloxy, enantyloxy or benzoyloxy may be mentioned. As the C3-C alkyl group which may be substituted with a halogen atom, the same substituents as mentioned above can be mentioned as preferred.

Preferred examples of the C3-c4 alkoxy group which may be substituted with a halogen atom include methoxy, ethoxy, n-propoxy, 18o-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, and trifluoromethoxy. Toshi” (can be mentioned. (C1~
Examples of the C4) alfkhiddicarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like.

Examples of the substituted or unsubstituted phenyl (C1-C2) alkyl group include benzyl, α-phenethyl, and β-phenethyl, in which the phenyl group is substituted with the same substituents as mentioned above, or unsubstituted.

Y is a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, with a chlorine atom or a bromine atom being preferred, and a chlorine atom being particularly preferred.

A specific compound of the sulfonic acid chloride represented by the above formula (m) is methanesulfonic acid chloride.

Ethanesulfonic acid bromide, n-butanesulfonic acid chloride, t-butanesulfonic acid chloride, trifluoromethanesulfonic acid chloride, nonafluorobutanesulfonic acid chloride, benzenesulfonic acid chloride, p-)luenesulfonic acid chloride 4-bromobenzenesulfonic acid chloride, pentafluorobenzenesulfonic acid chloride, 4-chloro-3-
These include nitrobenzenesulfonic acid chloride, 2,3゜4-trifluorobenzenesulfonic acid chloride, and 2-phenylethanesulfonic acid chloride, among which methanesulfonic acid chloride, trifluoromethanesulfonic acid Preferred are chloride, benzenesulfonic acid chloride, and p-)luenesulfonic acid chloride.

In the sulfonic acid anhydride of the above formula (rv), R9゜
``+i'' is the same or different and represents a C1-C4 alkyl group which may be substituted with a nitrogen atom, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl (01-C7) alkyl group.

Such R9. Specific examples of the RIO group include those similar to R'.

Specific compounds of the sulfonic anhydride of the above formula (IV) include methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfone E]12 anhydride, nonafluorobutanesulfonic anhydride, benzenesulfonic acid Anhydride, p-) Luenesulfonic anhydride, trifluoromethanesulfonic acid-benzenesulfonic acid mixed acid anhydride.

Trifluoromethanesulfone N12-p-) luenesulfonic acid mixed acid anhydride, trifluoromethanesulfonic acid-4-nitrobenzenesulfonic acid mixed acid anhydride, etc., among which methanesulfonic acid anhydride, trifluoromethanesulfonic acid anhydride p-)luenesulfonic anhydride is preferred.

The basic compound used in the reaction with the sulfonic acid loranide or sulfonic acid anhydride in the first step may be a single basic compound, or a group of basic compounds may be used. You can also use them in combination (・.

Basic compounds that can be used in step (2) include alkali metal carbonates such as potassium carbonate and sodium carbonate, nitrimethylamine, triethylamine, pyridine, 2.6-
Lutidine, 4-N,N-dimethylaminopyridine, 1,
5-diazabicyclo(4,3,0)non-5-ene, 1
．． Examples include organic bases such as 4-diazabicyclo[2,2,23 octane, and organic bases are preferred, especially triethylamine, pyridine, 2,6-lutidine, 4-N
, N-dimethylaminopyridine, and tetrabutyl ammonium fluoride are preferred.

The acid halide (ITI) or acid anhydride CIV) used in the first step of the dehydration reaction has the above formula CI)
The amount used is 0.9 to 50 times the mole, preferably 1 to 10 times the mole of 5-halo 7-hydroxyp staglandin (1) represented by the following formula.

The basic compound used in the first step of the dehydration reaction is used in an amount equal to or more, preferably 2 to ioo times, in mole relative to the 5-halo-7-hydroxyprostaglandin (2) represented by the above formula (I). As the solvent used at this time, the basic compound itself may be used as a solvent,
Alternatively, a solvent inert to the reaction, preferably halogenated hydrocarbons such as methylene chloride and carbon tetrachloride; ethyl ether and tetrahydrofuran.

Ethers such as dioxane can also be used.

The amount of solvent used is sufficient as long as it allows the reaction to proceed quickly, and is usually 1 to 1
000 times the capacity, preferably 5 to 500 times the capacity. The reaction temperature varies depending on the reagents and solvent used, but
-40°C to the reflux temperature of the solvent, preferably -20°C
The temperature range is 80°C to 80°C. The reaction time varies depending on the color property, but is preferably about 0.1 to 24 hours, more preferably 0.1 to 12 hours.

The progress of the reaction is monitored by methods such as thin layer chromatography, and the disappearance of the raw materials is considered to be the end.

Thus, a compound as shown in the following reaction formula is obtained by the reaction in the first step, and a dehydration reaction is carried out in the reaction in step 1I, in which the compound is further treated with a basic compound.

] After the completion of the reaction in the first stage, the reaction solution may be (a) used as it is in the reaction in the 1+ stage, or (b) washed, extracted, dried, and concentrated to obtain a reaction intermediate, and then used in the nth stage. May be used in step reactions.

The basic compound used in the nth step may be the same as that used in the first step, or other basic compounds such as tetraethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium tetrafluoroborate.

p--)tetraethylammonium luenesulfonate,
Examples include quaternary ammonium salts such as tetrabutylammonium succinate and tetraethylammonium acetate.
Among them, triethylamine, 2,6-lutidine, 4-N
, N-dimethylaminopyridine, and tetraphytylammonium fluoride are preferred.

In order to carry out the n-th reaction using such a basic compound, when the reaction solution after the first-step reaction is directly used in the n-th reaction (a), the reaction is carried out as follows.

That is, after the completion of the reaction in the first stage, if necessary, the basic compound used in the n-th stage is used as a raw material for 5-/% I:I-7-hydroxyprostaglandin I, etc. of the above formula CI). 100 times or less in mole or less, preferably 20 times or less in mole or less, and the reaction in the first stage is allowed to proceed at a temperature ranging from -20°C to the reflux temperature of the solvent. The reaction time varies depending on the color property, but is preferably about 0.1 to 24 hours, more preferably 0.1 to 12 hours.

The progress of the reaction is monitored by the method of thin layer chromatography, and the disappearance of the reaction intermediate is considered to be complete. After the reaction, 5-halo n-booster taglandin 11 represented by the above formula (II) is separated and purified by treating the reaction solution in a conventional manner. i.e. extraction, washing,
Dry.

It is separated and purified by a combination of methods such as concentration and chromatography.

After the first stage reaction is completed, the reaction solution is washed, extracted to dryness, dried,
After the reaction intermediate has been obtained through concentration, when the reaction in step (ii) is carried out (b), it is carried out as follows.

That is, 5-
It is used in an equimolar amount or more, preferably 1 to 20 times the molar amount, relative to H11ff-7-hydroxyprostaglandin. As the solvent used at this time, the basic compound itself may be used as a solvent, or a solvent inert to the reaction, preferably methylene chloride, tetracarbon
'417) Halogenated hydrocarbons; ethyl ether,
Ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; aprotic polar solvents such as N,N-dimethylpolamide, dimethyl sulfoxide, and hexamethylphosphoric triamide are used.

The amount of solvent used should be sufficient to allow the reaction to proceed quickly, and is usually 1 to 1,000 times the amount of the starting material compound.
A double volume cloth, preferably 5 to 500 times the volume, is used.

Reaction temperature 1 reaction time, 5- expressed by the above formula C11)
The separation and purification of Haloperbroscugrandin (1) can be carried out in the same manner as described in (A) above.

In addition, the dehydration reaction in the present invention is carried out in the presence of carbodiimides such as dicyclohexylcarbodiimide, or phosphoric acid halides such as postboryl chloride and phosphorus pentachloride; This can also be achieved by conventional dehydration reactions using sulfite halides such as phosphoric acid halides or thionyl chloride.

5 represented by the above formula (n) produced in this way
- Halomee prostaglandin ■, etc. can be exemplified by the arrangement around the carbon atom at the 5-position, as shown in the following formula (Ira)
, (■b] (na) Cl1b). The present invention includes the 15-forms of these compounds, their enantiomers, or mixtures of their isomers in arbitrary proportions.

Specific examples of 5-halo or monoprostaglandin 1 type 1 produced according to the present invention include the following.

(11,15-bis-t-butyldimethylsilyl ether of 115-7' lomoto-frostaglandine, methyl ester.

(2) 5-promo d -t 6,17,1 s, t
9,20-pentanol-15-cyclopentyl prostaglandin! , 11.15-bis-t of methyl ester
-butyldimethylsilyl ether.

(3) 5-Bromo〆1 (17S) -17,20-
Dimethyl prostaglandin I, methyl ester 11
．． 15-bis-t-butyldimethylsilyl ether.

(4) 5-Promote! 11.15-bis-t-butyldimethylsilyl ether of -15-methyl prostaglandin, methyl ester.

(5) 5-promoper 16.17, 18, 19.2
11.15-Bis-t-butyldimethylsilyl ether of 0-pentanol-15-cyclohexyl prostaglandin, methyl ester.

(6) 5-Plumoper prostaglandin I, methyl ester of 11,15-bis(tetrahydropyran-2
- ylether).

(11.1 of 5-bromo-(178)-17,20-dimethyl prostaglandin 1 methyl ester)
5-bis(tetrahydropyran-2-1' ether)
.

(8) 5-bromot! ! -16, 17, 1B, 19
．． 11.15-bis(tetrahydropyran-2-yl ether) of 20-pentanol-15-v clopentyl prostaglandin I, methyl ester.

(9) 5-bromo-16,17,1B, 19.20
- 11.15-bis(tetrahydropyran-2-yl ether) of pentanol-15-cyclohexyl prostaglandin I, methyl ester.

Thus, by the method of the present invention, a compound represented by the above formula (n), its 15-form, its enantiomer, or a mixture thereof in any proportion, 5-halo monoprostaglandin, can be obtained. It can be easily obtained from 5-halo-7-hydro-p-xybrostaglandin, which is a readily available raw material compound. The 5-haloper prostaglandins have physiological effects similar to prostaglandin I2, such as platelet aggregation inhibiting activity.

It is a useful compound that is expected to have smooth muscle relaxing effects, blood pressure lowering effects, etc., and can also serve as a useful intermediate that can lead to other useful prostaglandin I2 analogs.

The production method of the present invention provides such useful compounds more easily from readily available raw material compounds, and is therefore of great significance.

The present invention will be described below with reference to Examples, but the present invention is not limited to these examples.

Example 1 (1) 7-Hydroxyprostaglandin F2α methyl ester 11.15-bis-t-butyldimethylsilyl ether dissolved in 10 ml of methylene and 140 m of anhydrous potassium carbonate
(1 mmol), cooled to -50°C and soaked with N
-bromosuccinimide 47rs9 (260μm01)
Add 3 ml of methylene chloride solution of
Stir for a minute. After filtration and concentration, it was subjected to silica gel column chromatography (10 g of silica gel, IB solvent; benzene:ethyl acetate = 40:1) (20:1),
-7" lomo 7-hydroxybrostaglandine, methyl ester 1 1.1 2 for the carbon atoms at positions 5 and 6 of 5-bis-t-butyldimethylsilyl ether
A mixture of stereoisomers of the species was obtained in 123 cm (yield: 76 cm).

That is, the spectrum data of this product was as follows.

IR (liquid film); 3480, 1742, 125? ,8383-1HMR
(CD(43.δ); o ~ o.1 (m, 1 zH), 0.8 7 (
S, 9H).

0, 89 (s, 9H), 0.75 to 1.
1 (m, 3H).

1, 1-2.7 (m, 1 9H), 3.6 7
(!I, 3H).

3, 5 ~ 3.9 (m, IH), 3.8 ~ 4.4
(m, 4H) 14, 4-5.0 (m, IH),
5.4-5.7 (m, 2H).

Mass spectrum; (20evM/e); 6 3 5,
6a 3 (M+-C41(,)CI+) (5-promo 7-hydroxyprostaglandin!, methyl ester obtained in +1) 11. Mixture of stereogenic forms of 15-bis-t-butyldimethylsilyl ether 17■ (2
5 μmol) and 20 μmol of pyridine (250 μmol)
was dissolved in 1 ml of methylene chloride, and trifluorosulfonic anhydride 17F9 (60 μmol) was added.
Stirred at room temperature for 45 minutes. Aqueous sodium hydrogen carbonate solution was added, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. After P concentration, the obtained reaction intermediate is converted into N,N-
Dissolved in 1 ml of trimethylpolamide, added 20 my (200 μmol) of triethylamine and stirred at 50°C for 30 minutes.
Stir for hours. A saturated aqueous sodium chloride solution was added, extracted with hexane, dried over anhydrous potassium carbonate-anhydrous magnesium sulfate, filtered and concentrated, and subjected to silica gel column chromatography (2 g of Florzil, elution solvent: hexane:ethyl acetate-20:1). Promover prostaglandin ■, methyl ester 11.15-bis-t-butyldimethylsilyl ether 3.9II+9 (yield 24%
) was obtained. That is, the spectrum data of this product was as follows.

rR (liquid film); 1742.1256,838α-1 NMR (CD(J,, δ); o ~ o, 1 (m, 12H), 0.87 (8,9H).

o, s9 (It, 9H), 0.75-1.1
(m, 3H)+1.1~2.7 (m, s 8H)
, 3.69 (s, 3H).

3.78-4.15 (m, 2H), 4.3~
4.9 (m+ 2H) 15.02 (d, I
II), 5.4-5.7 (m, 2H) mass spectrum (20ev; M/e): 674.672 (M
”) Example 2 5-promo-7-hydroxyprostaglandin ■ obtained in Example 1 (1), methyl ester 11゜15-bis-t-butyldimethylsilyl ether 20 w19 (3
0μm01) and pyridine 25■ (316μmol)
was dissolved in 1 ml of methylene chloride, 2 oy + 9 (71 μmol) of trifluorosulfonic anhydride was added, and stirred at room temperature for 20 minutes.
1) was added and stirred at 50°C for 1 hour. Add saturated aqueous sodium chloride solution, extract with hexane, dry over anhydrous potassium carbonate-anhydrous magnesium sulfate, filter and concentrate, then silica gel column chromatography (3 g of Florisil, elution solvent: hexane: ethyl acetate: triethylamine-1o o
: 2 : 0.1) K to obtain 1.5 g (yield: 8%) of 5-promover prostaglandin methyl ester 11.15-bis-t-butyldimethylsilyl ether.

Example 3 (1) By the same halogenation reaction method as in Example 1 (1), 7-hydroxy-16,17,18,19,
20-Pentano-15-cyclopentyl prostaglandin F, alpha methyl ester 11.15-bis-t-butyldimethylsilyl ether 8oIIv to 5-bromo-7-hydropoxy-16,17,1B.

19.20-pentanol-15-cyclopentyl prostaglandin 11 thyl ester-11゜15-bis-t
-Mixture 31■ of stereoisomers regarding carbon atoms at the 5th and 6th positions of butyldimethylsilyl ether (yield 34%)
I got it. That is, the spectrum data of this product was as follows.

■R (CHCl, solution); 3450.1722,1260,837α-1NMR (
CDCl3. δ); o ~ o, 1 (m, 12H), 0.8'7 (!l
, 9H).

0.89 (s, qpI), 1.1-2.6 (m
, 2 on).

3.68 (s, 3H), 3.5-3.9 (m, IH).

3.8-4.4(m+4H), 4.4-s, o(m
, IH).

5.4-5.7 (m, 2H) Mass spectrum (20ev1M7/e); + 633, 631 (M -C41T.)CI+)
5-zolomo7-hydroxy-16 made with (+)
, 17,18,19,20-pentanol-15-cyclopentyl prostaglandin 11 methyl ester 11.
A mixture of stereoisomers of 15-bis-t-butyldimethylsilyl ether 25 w (36 μmol) and 30 my (a so μmol) of pyridine were dissolved in 1 ml of methylene chloride p-) toluenesulfonic acid chloride 2
1-(110 μmol) was added and stirred at room temperature for 3 hours.

Aqueous sodium hydrogen carbonate solution was added, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained reaction intermediate was dissolved in 1 portion of N,N-dimethylformamide, and 30 days (300 μmol) of triethylamine was added.
was added and stirred at 60°C for 2 hours. Add saturated aqueous sodium chloride solution, extract with pentane, and extract with anhydrous potassium carbonate.
After drying with anhydrous magnesium sulfate and concentrating P:A, silica gel column chromatography ()CRJ Jill 49.
Elution solvent: hexane: ethyl acetate: triethylamine 3
00:0.1), 5-bromod-16,17
, 18°19.20-pentanol-15-cyclopentyl prostaglandin! , methylnisder 11.15-
Bis-t-butyldimethylsilyl ether 3.2111
P (yield: 13) was obtained. That is, the spectrum data of this product was as follows.

IR (liquid film); 174B, 1255. s'locm-'NMR (CDC
l3. δ); 0-0.1 (m, 12H), 0.88 (s,
18H).

1, (1-3,2(m, 19H), 3.67(s, 3H
).

3.7-4.3 (m, 2H), 4.3-5.1
(m, 3H).

5.3-5.7 (m, 2H) Mass spectrum (20ev, M/e); Example 4 (1) 7-hydroxy-(17B) was produced by the same halogenation reaction method as in Example 1 (1). -17,20-dimethyl prostaglandin F2α methyl ester 11.
15-bis(tetrahydropyran-2-yl ether)
85II+9 to 5-promo 7-hydroxy-(17
S) -17,20-dimethyl prostaglandin 1
1 Methyl ester 11. Mixture of stereoisomers of 15-bis(tetrahydrobilan-2-yl ether) 42■ (
A yield of 43% was obtained. The spectral data of this product is as follows.

IRC liquid film); 3470, 1735. R35 1Niayt (
CD (J3.δ): o, s ~ 1.2 (m, e) I), 1.1 ~ 2. s
(m, 32H).

3.68 (8,3H), 3.2~4.5 (m,
9H).

4.5-4.85 (m, 3H'), 5.4-5;
8 (”m, 2H) mass spectrum (20eV +
'M/@ ): 636.634 (!11+) 1+) 5-promo 7-hydroxypoxy-(17S)-17,20-dimethyl prostaglandin 11 methyl ester 11.15-bis obtained by (1) Mixture of stereoisomers of (tetrahydrobilan-2-yl ether) 35■ (55 μmol) and 2,6-lutidine 59
M? (550 μmol) was dissolved in 1 ml of methylene chloride, and 29 μmol of mechunsulfonic acid chloride (253 μmol0
1) was added and stirred at room temperature for 3 hours.

Aqueous sodium hydrogen carbonate solution was added, extracted with methylene chloride, and dried over anhydrous magnesium sulfate.

After filtration and concentration, the obtained reaction intermediate was dissolved in 1 ml of tetrahydrofuran, and tetrabutylammonium fluoride Φ
Add trihydrate 80r9 (434 μmol), stir at room temperature for 40 minutes, add saturated aqueous sodium chloride solution,
Extract with ethyl ether and dry with anhydrous carbon dioxide and anhydrous magnesium sulfate.

After filtration and concentration, silica gel column chromatography (3 g of Florisil, elution solvent: hexane; ethyl acetate;
Triethylamine = 100:5; o, subjected to 1),
5-Bromo-d-(xys)-17,20-dimethyl prostaglandin 11 methyl ester 11.15-bis(tetrahydropyran-2-yl ether) 4.2% (
A yield of 12 cm) was obtained. That is, the spectrum data of this product was as follows.

IR (liquid film); -1 NMR of 1738.838 (CD (J3. δ); 0.8-1.2 (m, 6H), 1.1-2.8 (m, 3
'lH).

3.68 (II + 3 H) + 3-3~-
4-4 (m + 6H) +4; 4-5.1 (m
, 5JT), 5.4-5.7 s (m,
2H).

Mass spectrum (20ev + M/e) r61s
, 616 (M+).

Claims (1)

[Scope of Claims] 1. 5-halo barb represented by the following formula (r[) whose q4F characteristic is to subject 5-halo 7-hydrroxib p taglandin I, represented by the following formula (1), to a dehydration reaction A method for producing p-taglandin I. 2. The dehydration reaction is carried out using (I) a sulfonic acid halide represented by the following formula (]Tr) or a sulfonic acid halide represented by the following formula (l) in the presence of a basic compound.
(v) reacting with a sulfonic anhydride coated with 100 g of p-staglandin, and (n) then treating with a basic compound. Type 1 manufacturing method. 3. The 5-sulfonic acid halide according to claim 2, which is a sulfonic acid halide, methanesulfonic acid chloride, trifluoromethanesulfonic acid chloride, benzenesulfonic acid chloride, or p-toluenesulfonic acid chloride・Production method for Roper prostaglandin 11. 4. The sulfonic anhydride is methanesulfonic anhydride, triflic 10p methanesulfonic anhydride. or p-) luenesulfonic anhydride, wherein the 5-norlow according to claim 2 is one prostaglandin 1.
Type 1 manufacturing method. 5. The method for producing 5-halobarb p-staglandin (2) according to any one of claims 2 to 4, wherein the basic compound in CI) and (II) is an organic base. 6. Organic bases are triethylamine and pyridine. 2. The method for producing 5-no-roper prostaglandin 11 according to claim 5, which is 6-lutidine, 4-N,N-dimethylaminopyridine or tetrabutylammonium fluoride. 7. The method for producing the 5-halobarb μ-staglandin I according to any one of claims 1 to 6, wherein in the above formula CI), G is a methoxycarbonyl group. 8. The method for producing 5-haloper prostaglandin 11 according to any one of claims 1 to 7, wherein in the above formula (1), R4 is a hydrogen atom. 9. In the above formula CI), R3 is an n-pentyl group. 2-methyl-1-hexyl group, 2,2-dimethyl-1-
A method for producing 5-haloper prostaglandin 11 according to any one of claims 1 to 8, which is a hexyl, cyclopentyl, or cyclohexyl group. 10. In the above formula (, I), R1 and R11 are t-butyldimethylsilyl group, tetrahydrobilan-2-yl group, 6,6-dimethyl-3-oxa-2-oxo-bicyclo (3,1,0) A method for producing 5-halodo-prostaglandin 11 according to any one of claims 1 to 9, which is a hex-4-yl group or a 4-methoxytetrahydropyran-4-yl group. . 11. The 5-halo-prostaglandin according to any one of Items 1 to 10 of the scope of patent i1, wherein in the above formula (1), X is a bromine atom! Type 1 manufacturing method.