JPH11279184A - Enol phosphate derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having lipophilicity effective as a prodrug of prostaglandin(PG) E1 by converting the 9-position of PGE1 to enol phosphate group, and COOH group at the 1-position to an ester. SOLUTION: This new compound is the one of formula I [Q is CH2 CH2 or CH=CH; R<1> is OR<6> -substituted alkyl (R<6> is H or a protective group of OH); R<2> is a 1-8C alkyl; R<3> and R<4> are each R<2> , or together form an alkylene; R<5> is R<6> ], e.g. diphenyl (3R,4R)-2-(6-methoxycarbonylhexyl)-3-[(1E)-4-methyl-4- triethylsiloxy-1-octenyl]-4-t-butyldimethylsiloxy-1-cyclopentenyl} phosphate. The compound of formula I is obtained, for example, by carrying out 1,4-addition of an organic metal reagent of formula III (M is a monovalent metal or the like) to a cyclopentenone derivative of formula II to provide a metal enolate, and reacting the obtained metal enolate with an organic phosphorus reagent of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel enol phosphate derivative and a method for producing the same.

[0002]

2. Description of the Related Art In 1960, prostaglandins (hereinafter referred to as PG) were classified into PGE ₁ , PGE ₂ and PGE.
_3, PGF ₁ alpha, from six structures PGF ₂ alpha and PGF ₃ alpha is determined, after another discovery of PG analogs are compounds analogous, also has been demonstrated also physiological effects. The physiological effects of PG and PG analogs (hereinafter collectively referred to as PGs) include a platelet aggregation inhibitory effect,
It has been found to have vasodilatory hypotensive action, gastric acid secretion inhibitory action, smooth muscle contraction action, cytoprotection action, diuretic action, etc., and further utilizing this physiological activity, myocardial infarction, angina, arteriosclerosis, hypertension Disease, duodenal ulcer, secretion induction,
It has also been found to be useful as a therapeutic or prophylactic agent for abortion and the like. The literature predicts that the role of these PG drugs will increase in the future.

By the way, PGs are typical local hormones, and are a kind of so-called autakoids, which are produced locally and act locally as needed, and are therefore less effective when administered systemically as conventional drugs. On the other hand, systemic side effects may appear strongly. Therefore, it has been proposed that a drug prepared from PGs requires a drug release system (drug delivery system) that takes into account the properties and chemical properties of an autakoid. As a drug release system, a drug using lipid microspheres (hereinafter referred to as LM) as a carrier of PGs and encapsulating PGs in LM is under study. The drug is actually considered to be emulsified fine particles of lipid containing PGs, and is also called a fat emulsion. Fat emulsion -PG in the following,
It refers to an emulsion of lipids containing PGs.

[0004] Conventionally, a target therapeutic agent comprising fat emulsion -PGE ₁ encapsulating PGE ₁ in LM having a diameter of 2μm has high stability in vivo, stronger than PGE ₁ alone vasodilating action and platelet aggregation inhibitory action (Sim, AK et al., Arzneim-Forsch / Drug Res., 1
206-1209, 1986.).

However, when administered fat emulsion -PGE ₁ in vivo, there is a disadvantage that PGE ₁ is released. Therefore, studies to suppress the release amount were studied using fat emulsion-PGE ₁ esters (Igarashi et al., Inflammation, 8, 24).
3-246, 1988). Specifically, first, PGE ₁
After confirming that there is no activity of the esters and that the PGE ₁ ester exerts its activity by cleavage of the ester bond by the esterase in the living body, the fat emulsion is obtained.
The stability of PGE ₁ in blood was examined. As the PGE ₁ ester in the study, a methyl ester, an ethyl ester, a butyl ester, or an octyl ester was used. The activity of PGE ₁ esters was determined based on the effect of inhibiting platelet aggregation. In addition, the stability in blood was measured by measuring the amount of PGE ₁ released when incubated in an isotonic salt. And as a result,
The effectiveness and stability of each PGE ₁ ester as a fat emulsion have been confirmed.

[0006]

The fat emulsion-P
In order to enhance the sustained release of GE ₁ esters, it is necessary to finely disperse the fat emulsion in a dispersion medium. At that time, PG
E ₁ esters, lipids oils and fats, and other materials were dissolved by heating, but homogenized it in water at a high temperature of about 80-90 ° C., PG in such high temperature
There was a problem that rapid decomposition of E ₁ esters occurred. In addition, PGE ₁ esters have a problem that the storage stability is low, so that rapid decomposition occurs in a commercial distribution channel.

[0007] Therefore, it has been desired to develop a PGE ₁ analog which can be stably formulated even at a high temperature and has excellent storage stability in a distribution channel, and the carbonyl group at the 9-position is converted to an enol ester. A PGE ₁ enol ester has been reported (Japanese Patent No. 2602964).

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide a PGE.
Has an effective fat-soluble as _a prodrug, and is to develop the enol phosphate type prodrug PGE ₁ derivative having a persistence of superior efficacy.

The present inventors have a sustained release and stability,
Natural PGE with proper fat solubility and efficient in vivo
The structure of a compound that can be converted to ₁ and exhibit excellent activity was examined. As a result, the 9-position of PGE ₁ and enol esters, which than is converted is hydrolyzed to a carboxyl group by esterases, the 9-position of PGE ₁ and enol phosphate, the better it is converted into a carboxyl group, efficiency It was considered that this was advantageous from the viewpoint of sustainability and that the 9-position of PGE ₁ was an enol phosphate group. Furthermore, PG is advantageous in terms of fat solubility.
In order to convert the carboxyl group at the 1-position of PGE ₁ into an ester in order to obtain an E ₁ derivative, the present invention has been achieved.

That is, the present invention provides an enol phosphate derivative represented by the following formula 1.

However, the symbols in the formula 1 have the following meanings. Q: -CH ₂ CH ₂ - or -CH = CH-. R ¹ : an alkyl group substituted by —OR ⁶ (where R ⁶ is
Shows a protecting group for a hydrogen atom or a hydroxyl group. ). R ² : an alkyl group having 1 to 8 carbon atoms. R ³ and R ⁴ may be the same or different and each represent an alkyl group having 1 to 8 carbon atoms. Also, R ³ and R ⁴
May together form an alkylene group, and a catechol derivative residue represented by the following formula 2 (wherein R in formula 2)
⁷ represents a halogen atom or an alkyl group having 1 to 4 carbon atoms. ) May be formed. R ⁵ : a protecting group for a hydrogen atom or a hydroxyl group.

[0012]

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The present invention also provides a cyclopentenone derivative represented by the following formula (3) with an 1,4 addition reaction of an organometallic reactant represented by the following formula (4) to form a metal enolate. A method for producing an enol phosphate derivative represented by the following formula 1 characterized by reacting with an organophosphorus reactant represented by the following formula 5:

Where Q, R ¹ , R ² , R ³ , R
⁴ and R ⁵ each have the same meaning as described above, and M has the following meaning. M: represents a monovalent metal atom or -M ¹ -X (provided that M
¹ represents a divalent metal atom, and X represents a halogen atom. ).

[0015]

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[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The enol phosphate derivative (formula 1) of the present invention is a novel compound. Q in the formula 1 is -CH ₂ CH ₂ - shows a or -CH = CH-. Q is-
When CH = CH-, the stereochemistry may be E or Z.

[0017] R ¹ in formula 1 is an alkyl group -OR ⁶ is substituted, the portion excluding the -OR ⁶ of the alkyl group may be straight-chain structure or a branched structure. −OR ⁶
The carbon number of R ¹ except for is preferably 4 to 9. R ¹ is such that at least one hydrogen atom of the alkyl group having 4 to 9 carbon atoms is —OR.
^When it is a group substituted by ⁶ , the alkyl group having 4 to 9 carbon atoms includes n-pentyl, 2,2-dimethylpropyl, n-hexyl, 3-methylheptyl, and n-pentyl.
An octyl group, an n-nonyl group and the like are preferable, and an n-hexyl group and a 3-methylheptyl group are particularly preferable.

[0018] R ⁶ in -OR ⁶ represents a hydrogen atom or a protecting group of a hydroxyl group. Greene protecting groups include Greene
Et al. (Protective Groups in Organic Synthesis, J
ohnWiley & Sons, 1981), and a protecting group for a hydroxyl group is mentioned, and preferred specific examples thereof include the groups shown in the following examples. There is no particular limitation on the substitution position of R ¹ in -OR ^6, preferably substituted at the 1-position carbon atom of R ^1.

When R ⁶ is a hydroxyl group, specific examples of R ¹ include 1-hydroxyhexyl group and 1-hydroxy-
2-methylheptyl group, 2-hydroxy-2-methylhexyl group, 1-hydroxy-2-methyl-4-hexynyl group, 1-hydroxy-2-methyl-4-heptinyl group, 1-hydroxy-2-methyl- 4-octynyl group and the like.

When R ⁶ is a protecting group for a hydroxyl group,
Examples of ^1, 1-t-butyl-dimethylsiloxy-hexyl group, 1-t-butyl-dimethylsiloxy-2-methylheptyl group, 2-t-butyl-dimethylsiloxy -2
-Methylhexyl group, 1-tert-butyldimethylsiloxy-2-methyl-4-hexynyl group, 1-tert-butyldimethylsiloxy-2-methylheptynyl group, 1-tert-butyldimethylsiloxy-2-methyl-4-octynyl Group,
1-trimethylsiloxyhexyl group, 1-trimethylsiloxy-2-methylheptyl group, 2-trimethylsiloxy-2-methylhexyl group, 1-trimethylsiloxy-
2-methyl-4-hexynyl group, 1-trimethylsiloxy-2-methyl-4-heptynyl group, 1-trimethylsiloxy-2-methyl-4-octynyl group, 1-triethylsiloxyhexyl group, 1-triethylsiloxy-2 −
Methylheptyl group, 2-triethylsiloxy-2-methylhexyl group, 1-triethylsiloxy-2-methyl-
4-hexynyl group, 1-triethylsiloxy-2-methyl-4-heptynyl group, 1-triethylsiloxy-2-
Methyl-4-octynyl group, 1-acetoxyhexyl group, 1-acetoxy-2-methylheptyl group, 2-acetoxy-2-methylhexyl group, 1-acetoxy-2-
Methyl-4-hexynyl group, 1-acetoxy-2-methyl-4-heptynyl group, 1-acetoxy-2-methyl-
4-octynyl group and the like.

When an asymmetric carbon atom is present in R ¹ , the stereochemistry of the asymmetric carbon atom may be R or S, and both R and S may be present. Specific examples of R ¹ in the case where there is an asymmetric carbon atom in R ¹ is
(S) -1-hydroxyhexyl group, (S) -1-hydroxy-2-methylheptyl group, (S) -1-hydroxy-2-methyl-4-heptynyl group, 2-hydroxy-
And a 2-methylhexyl group.

R ² is an alkyl group having 1 to 8 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, and the alkyl group may have a straight-chain structure or a branched structure. Specific examples of R ² include a methyl group, an ethyl group, an n-propyl group,
iso-propyl group, n-butyl group, iso-butyl group, t-butyl group, n-pentyl group, n-hexyl group,
Examples thereof include an n-heptyl group and an n-octyl group.

R ³ and R ⁴ may be the same or different and each is an alkyl group having 1 to 8 carbon atoms, and the alkyl group may have a straight-chain structure or a branched structure. . Specific examples of R ³ and R ⁴ include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, n-hexyl Group, n-heptyl group, n-octyl group and the like. R ³ and R ⁴ may together form an alkylene group. The alkylene group may have a linear structure or a branched structure. The alkylene group preferably has 1 to 6 carbon atoms. Specific examples of the alkylene group include an ethylene group, a propylene group, and a 2,3-dimethyltriethylene group.

Further, R ³ and R ⁴ may form a catechol derivative residue represented by the formula (2). Here, R ^{7 in} Formula 2 represents a halogen atom or an alkyl group having 1 to 4 carbon atoms. When R ⁷ is a halogen atom, a fluorine atom or a chlorine atom is preferable, and R ⁷ has 1 to 4 carbon atoms.
When the alkylene group is a methyl group or an ethyl group, The bonding position of R ⁷ may be at the ortho position or the meta position.

Specific examples of the catechol derivative residue represented by Formula 2 include a 3-fluoro-1,2-phenylene group,
4-fluoro-1,2-phenylene group, 3-chloro-
1,2-phenylene group, 4-chloro-1,2-phenylene group, 3-methyl-1,2-phenylene group, 4-methyl-1,2-phenylene group, 3-ethyl-1,2-phenylene group , 4-ethyl-1,2-phenylene group and the like.

R ⁵ is a protecting group for a hydrogen atom or a hydroxyl group. For specific examples of hydroxyl protecting groups, see Greene et al.
(Protective Groups in Organic Synthesis, John Wile
y & Sons, 1981) include protecting groups described, specific examples thereof include the same groups as R ^6. further,
When R ⁵ is a protecting group for a hydroxyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a triethylsilyl group, an acetyl group, a benzoyl group, and a tetrahydropyranyl group are preferred.

The enol phosphate derivative (formula 1) of the present invention is a PG derivative. The enol phosphate derivative (Formula 1) has 11, 1 in the carbon number of the PG skeleton.
The carbon atoms at positions 2 and 15 are asymmetric carbon atoms, and there are various stereoisomers. In the present invention, any of these stereoisomers or a mixture of the stereoisomers may be used. .

Specific examples of the enol phosphate derivative (formula 1) of the present invention include the following compounds. Diphenyl {(3R, 4R) -2- (6-methoxycarbonylhexyl) -3-[(1E) -4-methyl-4-
Triethylsiloxy-1-octenyl] -4-t-butyldimethylsiloxy-1-cyclopentenyl {phosphate, diethyl} (3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S )-
3- (t-butyldimethylsiloxy) -5-methyl-1
-Nonenyl] -4-t-butyldimethylsiloxy-1-
Cyclopentenyl {phosphate, diisopropyl} (3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S) -3- (t-butyldimethylsiloxy) -5-methyl-1- Nonenyl]-
4-tert-butyldimethylsiloxy-1-cyclopentenyl {phosphate, diphenyl} (3R, 4R) -2-
(6-Butoxycarbonylhexyl) -3-[(1E,
3S, 5S) -3- (t-butyldimethylsiloxy)-
5-methyl-1-nonenyl] -4-tert-butyldimethylsiloxy-1-cyclopentenyl} phosphate,

Diphenyl {(3R, 4R) -2- (6-
Methoxycarbonylhexyl) -3-[(1E) -4-
Methyl-4-hydroxy-1-octenyl] -4-hydroxy-1-cyclopentenyl {phosphate diethyl} (3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S)- 3-Hydroxy-5-methyl-1-nonenyl] -4-t-hydroxy-1-cyclopentenyl {phosphate, diisopropyl} (3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S) -3-Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-1-cyclopentenyl {phosphate, diphenyl} (3R, 4R) -2- (6-butoxycarbonylhexyl) -3- [ (1E, 3S, 5S) -3-Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-1-
Cyclopentenyl phosphate.

The enol phosphate derivative (formula 1) of the present invention can be synthesized by combining known methods. That is, the procedures and conditions of a method in a known literature described as a method for producing a similar compound can be employed. Examples of the known documents include the following. Sih. Et al,
J. Am. Chem. Soc., 110, 3588, (1998) .Sato, F. et al., Chem.
Lett., P.2095-2098, (1992) .Sato, F.etal., Tetrahedron
Lett., 30, 4379-4382, (1989) .Sato, F. et al., Tetrahedr.
on Lett., 34,6427-6430 (1993), Knochel, P., J.Org.Che
m., 53, 2392-2394 (1988); Yoshida, Z. et al., Angew.
Int. Ed. Engl., 28, 353-353 (1989).

Specifically, the cyclopentanone derivative (Formula 3) is subjected to a 1,4-addition reaction with an organometallic reactant (Formula 4) to form a metal enolate, and then the metal enolate is treated with an organic phosphorus reactant (Formula 3). It can be synthesized by reacting with 5).

Q, R ² and R ⁵ in the cyclopentanone derivative (formula 3) have the same meaning as in formula 1. Specific examples of the cyclopentanone derivative (Formula 3) include the following examples.

4R-t-butyldimethylsiloxy-2-
(6-methoxycarbonylhexyl) -2-cyclopenten-1-one, 4R-t-butyldimethylsiloxy-
2- (6-ethoxycarbonylhexyl) -2-cyclopenten-1-one, 4R-t-butyldimethylsiloxy-2- (6-butoxycarbonylhexyl) -2-cyclopenten-1-one, 4S-t-butyldimethyl Siloxy-2- (6-butoxycarbonylhexyl) -2
-Cyclopenten-l-one.

M in the organometallic reagent (formula 4) represents a monovalent metal atom or -M ¹ -X. Examples of the monovalent metal atom include a monovalent copper atom, a monovalent lithium atom, and a monovalent zinc atom. When M is -M ¹ -X, M ¹ (a divalent metal atom) includes divalent copper atom. An atom is preferable, and as X (halogen atom), a chlorine atom, a bromine atom or an iodine atom is preferable. As M in the organometallic reagent (formula 4), a monovalent copper atom is preferable.

The compound in which M in the organometallic reagent (formula 4) is a monovalent copper atom is obtained by using, as a raw material, a corresponding compound in which the M portion in the organometallic reagent (formula 4) is an iodine atom. Lithium (for example, t-butyllithium or the like) is reacted to replace the iodine atom with Li, and then reacted with a trialkylphosphine-copper (I) complex (for example, tributylphosphine-copper iodide). Can be synthesized.

Specific examples of the organometallic reagent (formula 4) include the following compounds. (1E) -1-copperized-4-triethylsiloxy-4-methyloctene, (1E, 3S, 5S) -1-copperized-3-
(T-butyldimethylsiloxy) -5-methyl-1-nonene, (1E, 3S, 5R) -1-copperized-3- (t-butyldimethylsiloxy) -5-methyl-1-nonene,
(1E, 3R, 5S) -1-copperized-3- (t-butyldimethylsiloxy) -5-methyl-1-nonene.

In the present invention, a metal enolate is produced by subjecting a cyclopentanone derivative (formula 3) to an 1,4-addition reaction with an organometallic reactant (formula 4). The metal enolate may be isolated or used in the next reaction without isolation.

The amount of the organometallic reagent (formula 4) is preferably 0.5 to 5 times the molar amount of the cyclopentanone derivative (formula 3). The reaction temperature of the 1,4-addition reaction is preferably -78 to 20C, and the reaction time is preferably 0.5 to 10 hours.

Further, in the present invention, by reacting a metal enolate with an organic phosphorus reactant (formula 5),
This is referred to as an enol phosphate derivative (formula 1).

R ³ and R ^{4 in the} organophosphorus reagent (formula 5) have the same meaning as in formula 1. Specific examples of the organic phosphorus reactant (Formula 5) include the following compounds.
Diphenylchlorophosphate [ClP (O) (OC ₆
H _{5) 2],} diethyl chlorophosphate, diisopropyl chlorophosphate.

The amount of the organophosphorus reactant (formula 5) is preferably 0.5 to 5 times the amount of the cyclopentanone derivative (formula 3). The reaction temperature between the metal enolate and the organophosphorus reactant (formula 5) is preferably -30C to + 40C, and the reaction time is preferably 0.5 to 5 hours.

When a protecting group for a hydroxyl group is present in the enol phosphate derivative (formula 1) produced by the production method of the present invention, the protecting group may be converted to a hydroxyl group by performing a deprotection reaction, if necessary. The method and conditions of the deprotection reaction may employ known methods and conditions of the deprotection reaction, for example,
Book written by Prot Greene et al. (Protective Groups in Orga
nic Synthesis, John Wiley & Sons, (1981)).

The enol phosphate derivative (formula 1) of the present invention has an effective lipid solubility as a prodrug of PGE ₁ and has excellent persistence of drug efficacy. The medicinal properties of the enol phosphate derivative (formula 1) include platelet aggregation inhibitory action, vasodilatory hypotensive action, gastric acid secretion inhibitory action, smooth muscle contraction action, cytoprotection action, diuretic action and the like. Therefore, the enol phosphate derivative (formula 1) of the present invention is useful as a therapeutic or preventive agent for myocardial infarction, angina, arteriosclerosis, hypertension, duodenal ulcer, secretion induction, and abortion, etc., utilizing the above-mentioned medicinal effects. is there.

[0044]

EXAMPLES Examples of the present invention will be specifically described below, but the present invention is not limited to these examples.

Example 1 Diphenyl {(3R, 4R) -2- (6-methoxycarbonylhexyl) -3-[(1E) -4-methyl-4-
Synthesis Example of Triethylsiloxy-1-octenyl] -4-t-butyldimethylsiloxy-1-cyclopentenyl diphosphate (1E) -1-iodo-4-triethylsiloxy-4-
A solution of methyl octene (0.46 g, 1.2 mmol) in ether (5 ml) was cooled to −78 ° C., and tert-butyl lithium (1.43 M pentane solution 1.68) was added under a nitrogen stream.
ml, 2.4 mmol) was added dropwise. After stirring at the same temperature for 2 hours, tributylphosphine-copper (I) complex (0.41 g, 1.1 mmol) and tributylphosphine (0.27 ml, 1.09 mmol) in ether (4
ml) solution was added dropwise.

After stirring at -78 ° C for 50 minutes, 4R-t
-Butyldimethylsiloxy-2- (6-methoxycarbonylhexyl) -2-cyclopenten-1-one (0.
A solution of 36 g (1.0 mmol) in ether (16 ml) was added dropwise. 20 minutes at -78 ° C, -30 to -20
After stirring for 50 minutes while maintaining the temperature at 0 ° C, diphenylchlorophosphate (0.26 ml, 1.0 mmol) was added to -20.
C., and the mixture was stirred for 2 hours while maintaining the temperature at 0 ° C. to room temperature.
After pouring into a saturated aqueous solution of ammonium sulfate (100 ml) and separating from the organic layer, the aqueous layer was extracted with ether (50 ml), and the combined organic layers were dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (hexane: ethyl acetate = 10:
Purification in 1) gave the title compound (0.60 g).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 0.0 (s, 6H),
0.58 (q, J = 7.5Hz, 4H), 0.85 (s, 9H), 0.92 (t, J = 7.5Hz, 3H),
0.98 (t, J = 7.5Hz, 3H), 1.1-1.7 (m, 18H), 2.1-2.3 (m, 3H), 2.
7-3.0 (m, 2H), 3.65 (s, 3H), 4.0-4.1 (m, 1H), 5.13 (dd, J = 8.
4,15.0Hz, 1H), 5.53 (dd, J = 9.3,15.0Hz, 1H), 7.2-7.4 (m, 10
H).

[0048]

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Example 2 Diphenyl {(3R, 4R) -2- (6-methoxycarbonylhexyl) -3-[(1E) -4-methyl-4-]
Hydroxy-1-octenyl] -4-hydroxy-1-
Synthesis example of cyclopentenyl diphosphate Adduct obtained in Example 1 (0.60 g, 0.7 mmol)
Was dissolved in acetonitrile (20 ml), and 46%
An aqueous solution of hydrofluoric acid (2 ml) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was treated with a 20% aqueous potassium carbonate solution (50 m
1) and chloroform (40 ml), and the mixture was poured into a mixed solution. The organic layer was extracted, dried and filtered with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: acetone = 8: 1 to 3: 1) to obtain the title compound (0.22 g).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 0.86 (t, J = 7.5
Hz, 3H), 1.12 (s, 3H), 1.1-1.8 (m, 18H), 2.1-2.3 (m, 3H), 2.5
5 (dm, J = 14.1Hz, 1H), 2.9-3.1 (m, 2H), 3.63 (s, 3H), 4.0-4.1
(m, 1H), 5.26 (dd, J = 8.4,15.0Hz, 1H), 5.60 (dd, J = 7.5,15.0
Hz, 1H), 7.2-7.4 (m, 10H).

[0051]

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Example 3 Diethyl {(3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S) -3-
Synthesis Example of (t-butyldimethylsiloxy) -5-methyl-1-nonenyl] -4-t-butyldimethylsiloxy-1-cyclopentenyl diphosphate Example 1 (1E) -1-iodo-4-triethylsiloxy- Instead of 4-methyloctene, (1E, 3S, 5
Using S) -1-iodo-3- (t-butyldimethylsiloxy) -5-methyl-1-nonene (0.48 g),
Instead of 4R-tert-butyldimethylsiloxy-2- (6-methoxycarbonylhexyl) -2-cyclopenten-1-one, 4R-tert-butyldimethylsiloxy-2
The same reaction was carried out using-(6-butoxycarbonylhexyl) -2-cyclopenten-1-one (0.40 g) and using diethylchlorophosphate (0.18 g) instead of diphenylchlorophosphate to give the title compound 0.60 g was obtained.

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 0.1 (s, 3H), 0.
20 (s, 6H), 0.25 (s, 3H), 0.85 (s, 9H), 0.87 (s, 9H), 0.8-1.0
(m, 15H), 1.2-1.5 (m, 17H), 1.5-1.7 (m, 4H), 2.28 (dd, J = 8.4
-9.3Hz, 2H), 2.45 (dm, J = 16.9Hz, 1H), 2.8-3.0 (m, 2H), 4.0-
4.2 (m, 9H), 5.31 (dd, 8.4,15.0Hz, 1H), 5.48 (dd, J = 6.6,15.
0Hz, 1H).

[0054]

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Example 4 Diethyl {(3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S) -3-hydroxy-5-methyl-1-nonenyl] -4 Synthesis Example of -t-hydroxy-1-cyclopentenyl diphosphate (0.60 g, 0.74 mmol) obtained in Example 3
1) was dissolved in acetonitrile (7.4 ml), a 46% aqueous hydrofluoric acid solution (2 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 0.5 hour. The reaction solution was poured into a mixture of a 20% aqueous potassium carbonate solution (50 ml) and chloroform (40 ml), and the organic layer was extracted, dried and filtered over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride: acetone = 3: 2-
2: 3) to give the title compound (0.39 g).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): δ 0.8-1.0 (m,
6H), 1.0-1.5 (m, 17H), 1.5-1.7 (m, 4H), 2.26 (d, J = 8.4Hz, 1
H), 2.32 (d, J = 9.3Hz, 1H), 2.55 (dm, J = 15.0Hz, 1H), 2.9-3.1
(m, 2H), 4.0-4.2 (m, 8H), 5.42 (dd, J = 8.4,15.0Hz, 1H), 5.56
(dd, J = 6.6,15.0Hz, 1H).

[0057]

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Example 5 Diisopropyl {(3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S)-
3- (t-butyldimethylsiloxy) -5-methyl-1
-Nonenyl] -4-t-butyldimethylsiloxy-1-
Example of synthesis of cyclopentenyl diphosphate Instead of (1E) -1-iodo-4-triethylsiloxy-4-methyloctene in Example 1, (1E, 3S, 5
Using S) -1-iodo-3- (t-butyldimethylsiloxy) -5-methyl-1-nonene (0.89 g),
Instead of 4R-tert-butyldimethylsiloxy-2- (6-methoxycarbonylhexyl) -2-cyclopenten-1-one, 4R-tert-butyldimethylsiloxy-2
Using-(6-butoxycarbonylhexyl) -2-cyclopenten-1-one (0.79 g), the same reaction was carried out using diisopropylchlorophosphate (0.42 g) instead of diphenylchlorophosphate,
1.22 g of the title compound was obtained.

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 0.05-0.07 (m,
12H), 0.8-1.0 (m, 24H), 1.2-1.8 (m, 23H), 2.2-2.5 (m, 2H),
2.48 (dm, J = 15.0Hz, 1H), 2.9-3.0 (m, 2H), 4.0-4.2 (m, 4H),
4.6-4.8 (m, 2H), 5.30 (dd, J = 15.0,9.0Hz, 1H), 5.50 (dd, J =
(8.4, 15.0Hz, 1H).

[0060]

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Example 6 Diisopropyl {(3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S)-
Synthesis Example of 3-Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-1-cyclopentenyl diphosphate The compound obtained in Example 5 (1.22 g, 1.47 mmol) was dissolved in acetonitrile (15 ml). At 0 ° C., a 46% aqueous solution of hydrofluoric acid (3 ml) was added, and the mixture was stirred at the same temperature for 0.5 hour. The reaction solution was treated with a 20% aqueous potassium carbonate solution (50%).
ml) and chloroform (40 ml), and the organic layer was extracted, dried and filtered over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: acetone = 3: 2 to 1: 1) to obtain the title compound (0.68 g).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 0.88 (t, J = 7.5
Hz, 3H), 0.95 (t, J = 7.5Hz, 3H), 1.36 (d, J = 5.6Hz, 6H), 1.2-
1.5 (m, 21H), 1.5-1.8 (m, 4H), 2.28 (dd, J = 9.0,9.2Hz, 2H),
2.54 (dm, J = 15.0Hz, 1H), 2.9-3.1 (m, 1H), 4.08 (t, J = 7.5Hz,
2H), 4.0-4.2 (m, 2H), 4.6-4.7 (m, 2H), 5.41 (dd, J = 15.0,9.3
Hz, 1H), 5.57 (dd, J = 15.0,8.4Hz, 1H).

[0063]

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Example 7 Diphenyl {(3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S) -3-
Synthesis Example of (t-butyldimethylsiloxy) -5-methyl-1-nonenyl] -4-t-butyldimethylsiloxy-1-cyclopentenyl diphosphate Example 1 (1E) -1-iodo-4-triethylsiloxy- Instead of 4-methyloctene, (1E, 3S, 5
Using S) -1-iodo-3- (t-butyldimethylsiloxy) -5-methyl-1-nonene (0.48 g),
Instead of 4R-tert-butyldimethylsiloxy-2- (6-methoxycarbonylhexyl) -2-cyclopenten-1-one, 4R-tert-butyldimethylsiloxy-2
The same reaction was carried out using-(6-butoxycarbonylhexyl) -2-cyclopenten-1-one (0.40 g) to obtain 0.77 g of the title compound.

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 0.0
−0.1 (m, 12H), 0.8-1.0 (m, 27
H), 1.0-1.7 (m, 21H), 2.1-2.
4 (m, 4H), 2.25 (dm, J = 15.0 Hz,
1H), 2.9-3.0 (m, 2H), 4.0-4.2.
(M, 4H), 5.25 (dd, J = 15.0, 9.0
Hz, 1H), 5.48 (dd, J = 15.0, 8.3)
Hz, 1H), 7.2-7.4 (m, 10H).

[0066]

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Example 8 Diphenyl {(3R, 4R) -2- (6-butoxycarbonylhexyl) -3-[(1E, 3S, 5S) -3-
Example of Synthesis of [Hydroxy-5-methyl-1-nonenyl] -4-hydroxy-1-cyclopentenyl} phosphate The compound obtained in Example 7 (0.77 g, 0.86 mmol) was dissolved in acetonitrile (8.6 ml). 46% at 0 ° C
An aqueous solution of hydrofluoric acid (2.5 ml) was added, and
Stirred for 0 minutes. The reaction solution was poured into a mixture of a 20% aqueous potassium carbonate solution (50 ml) and chloroform (40 ml), and the organic layer was extracted, dried and filtered over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride: acetone = 3.5:
Purify in 1) to give the title compound (0.49 g).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 0.8
5-1.0 (m, 9H), 1.1-1.8 (m, 25
H), 2.24 (dd, J = 9.0, 9.2 Hz, 2
H), 2.58 (dm, J = 15.0 Hz, 1H),
2.9-3.1 (m, 2H), 4.05 (t, J = 7.
5 Hz, 2H), 4.0-4.2 (m, 2H), 5.4
1 (dd, J = 15.0, 9.3 Hz, 1H), 5.5
6 (dd, J = 15.0, 8.4 Hz, 1H), 7.2
-7.4 (m, 1H).

[0069]

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[0070]

According to the structure of the enol phosphate derivative (formula 1) of the present invention, the carboxylic acid portion at the 1-position of prostaglandin is converted into an ester group, and the carbonyl portion at the 9-position is converted into an enol phosphate. It has both chemical stability and fat solubility. Therefore, the enol phosphate derivative (formula 1) has an effective lipophilicity as a prodrug of PGE ₁ , and has excellent persistence of drug efficacy.
It is an E ₁ derivative. According to the production method of the present invention,
An enol phosphate derivative (formula 1) is obtained efficiently.

Claims (2)

[Claims] 1. An enol phosphate derivative represented by the following formula 1. However, the symbols in Formula 1 have the following meanings. Q: -CH ₂ CH ₂ - or -CH = CH-. R ¹ : an alkyl group substituted by —OR ⁶ (where R ⁶ is
Shows a protecting group for a hydrogen atom or a hydroxyl group. ). R ² : an alkyl group having 1 to 8 carbon atoms. R ³ and R ⁴ may be the same or different and each represent an alkyl group having 1 to 8 carbon atoms. Also, R ³ and R
⁴ may together form an alkylene group, and a catechol derivative residue represented by the following formula 2 (where R ⁷ in the formula 2 represents a halogen atom or an alkyl group having 1 to 4 carbon atoms) .) May be formed. R ⁵ : a protecting group for a hydrogen atom or a hydroxyl group. Embedded image 2. A cyclopentenone derivative represented by the following formula (3) is subjected to 1,4 addition reaction with an organometallic reactant represented by the following formula (4) to form a metal enolate. A method for producing an enol phosphate derivative represented by the following formula 1, characterized by reacting with an organic phosphorus reactant represented by the following formula: However, the symbols in the formula have the following meanings. Q: -CH ₂ CH ₂ - or -CH = CH-. R ¹ : an alkyl group substituted by —OR ⁶ (where R ⁶ represents a hydrogen atom or a hydroxyl-protecting group). R ² : an alkyl group having 1 to 8 carbon atoms. R ³ and R ⁴ may be the same or different and each represent an alkyl group having 1 to 8 carbon atoms. Also, R ³ and R
⁴ may together form an alkylene group, and a catechol derivative residue represented by the following formula 2 (where R ⁷ in the formula 2 represents a halogen atom or an alkyl group having 1 to 4 carbon atoms) .) May be formed. R ⁵ : a protecting group for a hydrogen atom or a hydroxyl group. M: represents a monovalent metal atom or -M ¹ -X (provided that M
¹ represents a divalent metal atom, and X represents a halogen atom. ). Embedded image