JPS63183574A - Oxygen-containing heterocyclic compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R<1> is H or lower alkyl; R<2> is carboxy(lower)alkyl or protected carboxy(lower)alkyl; R<3> is group of formula IV [R<4> is acyl, acylamino or ar(lower)alkoxy], formula V or formula VI [R<5> is acyloxy or heterocyclic (lower)alkoxy; X is -O- or -CH2-} or its salt. EXAMPLE:(2R,4R,5S)-5 [(Z)-6-carboxy-2-hexenyl ]-2-methyl-4-[4-(phenyl)thiosemi carbazonomethyl]1,3-dioxane. USE:A drug. A thromboxane A2 antagonist. Useful as a remedy for diseases caused by TXA2 such as thrombosis, asthma, etc. PREPARATION:A compound of formula I wherein R<3> is group of formula V can be produced by reacting a novel compound of formula II or its salt with an amine of formula III or its salt in a solvent in the presence of a small amount of an inorganic acid or an organic acid under cooling or heating.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel V-containing heterocyclic compounds and salts thereof.

More particularly, the present invention relates to novel oxygen-containing heterocyclic compounds and salts thereof, which are thromboxane A2 antagonists and are therefore useful as therapeutic agents for diseases caused by D-XA2, such as thrombosis and asthma.

The oxygen-containing heterocyclic compound of this invention can be represented by the following formula.

[In the formula, R1 is hydrogen or a lower alkyl group, R2 is a carboxy(lower) alkyl group or a protected carboxy(lower) alkyl group, R is -CH2NH-R, -CH丑N-R, or -CR2-R" (In the formula, R means an acyl group, an acylamino group, a heterocyclic amino group, a heterocyclic (lower) alkyl group, or an alkyl (lower) alkoxy group, and R5 means an acyloxy group or a heterocyclic (lower) alkoxy group). A group in which X represents 10- or -CH2-.

The salts of the target compound (I) are commonly used non-toxic salts, such as prucarium metal salts such as sodium salts and potassium salts, metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, e.g. Heavy equipment amine salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, such as acetate, maleate, tartrate, methanesulfonate, With organic acid salts such as benzene sulfonate and toluene sulfonate, arm-free salts such as hydrochloride, hydrobromide, sulfate, and phosphate, or with amino acids such as arginine, aspartic acid, and glutamine. Examples include salt.

According to this invention, the novel oxygen-containing heterocyclic compound (I) and its salt can be produced, for example, by the following production method.

Production method 2 Production method 4 + Y ↓ [In the formula, R1, R2, R3, R4 and X each have the same meaning as before, R2 is a protected carboxy (lower) alkyl group, R9
is carboxy (lower) alkyl group, R3 is alkyl (lower)
alkoxyiminomethyl group or heterocyclic (lower) alkoxymethyl group, 3, Rb is an alkoxymethyl group or acylaminomethyl group, R6 is a hydroxyiminomethyl group or hydroxymethyl group, R7 is an alkoxy(lower) alkyl group or a heterocyclic group ( (lower) alkyl group, R8 is a hydroxymethyl group or an aminomethyl group, and Y is an acid residue].

Raw material compounds (IF), (IV) and (VI) are new compounds, and can be produced, for example, by the following production examples and methods similar to them. (XW) CXV) (XIV) (XI[) (XI) (X) (■) or its salt (■) [■a or its salt [1 [a] or its salt production example B (XXI) (XIK ) or a salt thereof or a salt thereof or a salt thereof or a salt thereof (IVb) or a reactive derivative thereof or a salt thereof (■a) or a salt thereof C In the formula, R, R, R,, R , and X have the same meanings as above, R9 is a silylated hydroxymethyl group, R10 is an aryl group, R11 is a lower alkyl group, and 2 is an acid residue).

Compounds (Ia), (Ib), (Ic), (Id), (I
e), (If>, (VI) and (VIa) salts are:
These salts are the same as those exemplified in the description of suitable pharmaceutically acceptable salts of compound (I).

Compounds (It), (Ia), (πb8<rv>, (Na
), (IVb), (■), (IX), (X■), (X■
) and (X X I ) are the same as the salts with bases as exemplified in the explanation of compound (1).

The salts of compound (III) are the same as the salts with acids as exemplified in the explanation of compound (, I').

Preferred examples and explanations of the various definitions in the foregoing and following descriptions of this specification will be described in detail below.

"Lower shall mean 1 to 6 carbon atoms unless otherwise specified.

Suitable "lower alkyl groups" in ``1 lower alkyl group'', ``carboxy (lower) alkyl group'', ``protected carboxy (lower) alkyl group J, and 1 heterocyclic (lower) alkyl group j include meth 4. ethyl, propyl, -
Examples include isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

Examples of suitable 1-acyl groups in ``1-acyl group'', ``acylamino group'', ``acyloxy group'', ``acyloxymethyl group'' and ``acylaminomethyl group'' include phenylcarbamoyl, tolylcarbamoyl phthylcarbamoy, etc. Arylthiocarbamoyl groups such as phenylthiocarbamoyl, tolylthiocarbamoyl, xylylthiocarbamoyl, naphthylthiocarbamoyl, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, Lower alkoxycarbonyl groups such as tertiary butoxycarbonyl, pentyloxycarbonyl, alkylcarbamoyl groups such as phenyl(lower)alkylcarbamoyl such as benzylcarbamoyl, phenyl(lower) such as benzylglyoxyloyl, ) Al(lower) alkylglyoxyloyl groups such as alkylglyoxyloyl groups, heterocyclic carbonyl groups such as S-containing 5-membered heteromonocyclic carbonyl groups such as thenylcarbonyl, and the like.

Suitable monoaryl groups include phenyl, tolyl, xylyl, naphthyl, and the like.

Suitable "al(lower)alkoxy groups" for "1al(lower)alkoxy group J and 1al(lower)alkoxyiminomethyl group" include mono(or di- or tri)phenyl(s) such as benzylmethoxy, diphenylmethoxy, etc. (lower) alkoxy groups, etc.

Suitable protected carboxy groups in the "protected carboxy(lower) alkyl group" include lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl.

Suitable "heterocyclic amino groups" include, for example, N-containing 6-membered heteromonocyclic amino groups such as pyridylamino, and benzene-fused N-containing 6-membered heteromonocyclic amino groups such as phthalazinylamino.

Examples of "a preferred heterocyclic group in the heterocyclic (lower) alkyl group j, the heterocyclic (lower) alkoxy group, and the r heterocyclic (lower) alkoxymethyl group" include N-containing 6-membered groups such as pyridyl, etc. Examples include heteromonocyclic groups.

Suitable “lower alkoxy group” for “heterocyclic (lower) alkoxy group J and “heterocyclic (lower) alkoxymethyl group”
Examples include groups such as methoxy, ethoxy, and propoxy.

Suitable "acid residues" include, for example, halogens such as fluorine, chlorine, bromine, and iodine.

A "silylated hydroxymethyl group" is a hydroxymethyl group silylated with a conventional silylating agent such as a tri(lower)alkylhalosilane such as tertiary-butyldimethylchlorosilane, and a suitable " Examples of the "silylated hydroxymethyl group" include tri(lower)alkylsiloxymethyl groups such as tertiary-butyldimethylsiloxymethyl.

Preferred embodiments of the target compound (■) are as follows.

A preferred embodiment of R1 is hydrogen or a lower alkyl group; a preferred embodiment of R2 is a carboxy(lower)alkyl group or a protected carboxy(lower)alkyl group [more preferably a lower alkoxycarbonyl(lower)alkyl group]; A preferred embodiment is 10H2NH-R, -CH-N
-R or -CH2R [wherein R is an acyl group (more preferably an arylcarbamoyl group (most preferably a phenylcarbamoyl group)), an alk(lower)alkylcarbamoyl group (most preferably a phenyl(lower)alkylcarbamoyl group) group), Al (lower) alkylglyoxyloyl group (most preferably phenyl (lower) alkylglyoxyloyl group)], acylamino group (more preferably arylureido group (most preferably phenylureido group)), arylthioureido group group (most preferably a phenylthioureido group), a lower alkoxycarbonylamino group or a heterocyclic carbonylamino group (more preferably an S-containing 5-membered heteromonocyclic carbonylamino group (most preferably a te;nylcarbonylamino group) )), a heterocyclic amino group (preferably an N-containing 6-membered heteromonocyclic amino group (fi is also preferably a pyridylamino group) or a benzene-fused N-containing 6-membered heteromonocyclic amino group (most preferably phthalazinyl) amino group)), a heterocyclic (lower) alkyl group (preferably an N-containing 6-membered heteromonocyclic (lower) alkyl group (most preferably a pyridyl (lower) alkyl group)
), or an ar(lower) alkoxy group (more preferably a mono(or di- or tri)phenyl(lower) alkoxy group (most preferably a diphenyl(lower) alkoxy group)); R5 is an acyloxy group (more preferably an arylcarbamoyl group); oxy group (most preferably phenylcarbamoyloxy group) or heterocyclic (lower) alkoxy group (more preferably N-containing 6-membered heteromonocyclic (lower) alkoxy group (most preferably pyridyl (lower) alkoxy group)
A preferred embodiment of X is 10- or -c)I2-
It is.

The manufacturing method and manufacturing examples will be described in detail below.

Production method 1 Target compound (Ia) or a salt thereof can be produced by reacting compound (I[) or a salt thereof with compound (II) or a salt thereof.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide, and the like.

Preferably, the reaction is carried out in the presence of a small amount of an inorganic or organic acid such as hydrochloric acid, acetic acid, trifluoroacetic acid, etc.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or heating.

Production method 2 The target compound (4c) or a salt thereof can be produced by subjecting compound (Ib) or a salt thereof to an elimination reaction of the carboxy protecting group.

Examples of elimination reactions in this production method include hydrolysis and the like.

The reaction is usually carried out in a solvent that does not adversely affect the reaction, such as water, methanol, ethanol, propatool, and the like.

The reaction is carried out with an alkali metal such as sodium, an alkaline earth metal such as calcium, an alkali metal hydride such as sodium hydride, calcium hydride or an alkaline earth metal hydride such as sodium hydroxide, potassium hydroxide, Alkali metal hydroxides or alkaline earth metal hydroxides such as calcium hydroxide, e.g. alkali metal or alkaline earth metal hypoacids or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, e.g. sodium ethoxide , alkali metal alkoxides or alkaline earth metal alkoxides such as lithium methoxide, magnesium methoxide, trialkylamines such as triethylamine, pyridine, e.g. 1,5-diazabicyclo[3,4,0cononene-5°1.5 It is preferable to carry out the reaction in the presence of an inorganic base or an organic base such as a bicyclodiaza compound such as -diazabicyclo[5,4,0oundecene-5.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or under heating.

Production method 3 The target compound (Id) or a salt thereof can be produced by reducing the compound <F) or a salt thereof.

Reduction is usually carried out using a reducing agent such as an alkali metal borohydride, such as sodium borohydride, an alkali metal cyanoborohydride, such as sodium cyanoborohydride, and the like.

This reduction is usually carried out in a solvent that does not adversely affect the reaction, such as methanol, ethanol, acetic acid, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, and the like.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or under heating.

Production method 4 Object (Ie) or a salt thereof is compound (IV) or -
't5- can be produced by reacting its salt with compound (V).

The reaction is usually carried out in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dioxane, and the like.

This reaction is preferably carried out in the presence of an inorganic base or an organic base such as the bases exemplified in the explanation of Production Method 2 above.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or under heating.

Production method 5 The target compound (, If) or its salt is
) or a salt thereof with an acylating agent.

Yes as an acylating agent! Ikm, i.e. R120H
(in the formula, R12 means an acyl group) or a reactive derivative thereof.

Suitable reactive derivatives of organic acids include, for example, acid halides such as acid chlorides and acid bromides, acid azides, acid anhydrides,
Examples include activated amides, activated esters, aryl isocyanates such as phenyl isocyanate, alkyl isocyanates such as phenyl(lower) alkyl isocyanate, and the like.

When using a free acid as an acylating agent, N, N'
It is preferred to carry out the acylation reaction in the presence of a conventional condensing agent such as -dicyclohexylcarbodiimide, etc.

The reaction is preferably carried out in the presence of an inorganic or organic base as exemplified in the explanation of Production Method 2.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as methanol, ethanol, propatool, tetrahydrofuran, chloroform, and the like.

The reaction temperature is not particularly limited, and the reaction is carried out in a range of cooling to heating.

Production Example A-1 Compound (XV) can be produced by reacting compound (XVI) with a silylating agent.

In the starting compound (XVI), (2R,4S,5R)-5-
hydroxy-4-hydroxymethyl-2-methyl-1,
3-Dioxane (2,4-D-ethylidene-D-erythritol) and its production method were published in the Journal
American Chemical Society (Journa)
of the American Chemica
lSociety) Volume 82, Page 2302, (196
0), and other compounds (XVI) can be produced in the same manner.

Examples of the silylating agent include conventional silylating agents such as trialkylhalosilanes.

The reaction is usually carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide.

11Natsujin 21 Compound (XIV) can be produced by oxidizing compound (X V ).

The oxidation is carried out in a conventional manner using a conventional oxidizing agent such as dimethyl sulfoxide in a solvent which does not adversely affect the reaction, such as benzene, under cooling or heating.

Production Example A-3 Compound (Xlr) is compound (XIV) compound (x■)
It can be produced by reacting with

The reaction is usually carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as tetrahydrofuran.

Production Example A-4 Compound (XI) can be produced by subjecting compound (XI) to catalytic reduction.

Catalytic reduction is carried out in a conventional manner in a solvent such as ethanol that does not adversely affect the reaction at a temperature around room temperature.

(Production Example A-5) Compound (X) can be produced by reducing compound (XI).

The reduction is usually carried out in a conventional manner using a reducing agent such as alkyl aluminum hydride in a solvent that does not adversely affect the reaction, such as toluene, at room temperature or under cooling.

Production Example A-6 Compound (■) or a salt thereof is prepared by converting compound (X) into compound (
IX) or a salt thereof.

The reaction is usually carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as dimethyl sulfoxide.

Production Example A-7 Compound (■) can be produced by subjecting compound (■) or a salt thereof to a reaction for introducing a carboxy protecting group.

The reaction is usually carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide.

Production Example A-8 Compound (IVa) or a salt thereof can be produced by subjecting compound (■) or a salt thereof, or compound (■) to a silyl group elimination reaction.

This reaction is carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as tetrahydrofuran.

Production Example A-9 Compound (I[a) or a salt thereof can be produced by oxidizing compound (IVa) or a salt thereof.

Oxidation is carried out using conventional oxidizing agents capable of converting hydroxymethyl groups into formyl groups, such as chromium trioxide.

The reaction is usually carried out in a solvent that does not adversely affect the reaction, such as dichloromethane, under cooling or heating.

Production Example B-1 Compound (XIX) or its salt, Compound (X
> can be produced by reacting with compound (XX).

The reaction is usually carried out in a conventional manner under cooling in a solvent that does not adversely affect the reaction, such as tetrahydrofuran.

Production Example B-2 Compound (X■) can be produced by reacting compound (XIX) or a salt thereof with compound (X■).

The reaction is usually carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as dimethyl sulfoxide.

Production Example B-3 Compound (I[b) or a salt thereof can be produced by subjecting compound (X■) or a salt thereof to an elimination reaction of the carbonyl protecting group.

The reaction is usually carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as methanol.

Production Example C Compound Bvb) or a salt thereof can be produced by reacting compound (1) or a salt thereof with hydroxylamine or a salt thereof.

The reaction is usually carried out in a conventional manner under cooling or heating in a solvent that does not adversely affect the reaction, such as water or methanol.

Production Example D-1 Compound (X X n ) or a salt thereof is compound (IV
It can be produced by reacting a) or a reactive derivative thereof or a salt thereof with an alkali metal phthalimide salt.

The reaction is usually carried out in a conventional manner in a solvent such as pyridine that does not adversely affect the reaction, under cooling or under heat.

Production Example D~2 Compound (■8) or its salt is compound (X
) or a salt thereof can be produced by subjecting it to an amine-protecting group elimination reaction.

This reaction is usually carried out in a conventional manner using a commonly used amino-protecting group removing agent such as hydrazine, in a solvent that does not adversely affect the reaction, such as ethanol, under cooling or heating.

The target compounds of the above production methods and production examples can be purified according to conventional methods and converted into desired salts.

The target compound (1,) of this reaction and its pharmaceutically acceptable salts are thromboxane A2 (TXA2) antagonists and are therefore useful as therapeutic agents for diseases caused by TxA2, such as thrombosis and asthma. .

In order to demonstrate its effect, the results of a 2°3 biological test of the target compound (4) are shown below.

9,11-azo PGH2 and 9,11-methanoepoxy PGH2 (U 466
L 9 ) has pharmacological characteristics as a TxA2 mimetic and is widely used for evaluating TXA2 antagonism of test compounds [e.g.
and experimental terrabeautics (r
heJournal of Pharmacology
and Experimental Therapy
utics), Vol. 234, pp. 435-441.

Effect of the test compound on 9,11-azo PGH2-induced rabbit platelet aggregation in the elephant duct (a) Test method 3.8% turn lithium oxide aqueous solution from the carotid artery of a rabbit 0
．． Blood was collected in a plastic container containing 1 volume.

Platelet rich plasma (PRP) was prepared by centrifugation at 150g' for 15 minutes. Platelet aggregation was measured using a platelet aggregometer (NKK
It was measured by turbidity method using hematotracer 1). P
25 portions of the test compound solution were added to RP2251All, and then stirred at 37° C. and 11,000 rpm for 2 minutes. Five units of 9.11-azo PGH2 (final concentration 1.0 μM) were added to this solution as an aggregation inducing agent. 50% agglomeration inhibition concentration engineering C5
o was measured graphically.

(b) Test results Test 2 9,11-methanoepoxy PGH in vitro
2 Effect on induced blood/JX plate aggregation (a) Test method Body 11 Hartley male guinea pigs weighing approximately 300 g were used after overnight fasting. Test compounds were administered orally to the animals one hour before blood collection from the abdominal artery. PRP was prepared as described above and PRP250S was
Platelet aggregation was induced by adding 5 doses of M2 (046619, 0.5 μM).

(b) Test results The target compound (1) or a pharmaceutically acceptable salt thereof is usually prepared in capsules, microcapsules, tablets, granules, powders, troches, syrups, aerosols, inhalants, solutions, injections, suspensions, such as emulsions, suppositories, ointments, etc.
, m can be administered to mammals, including humans, in the form of pharmaceutical formulations.

The pharmaceutical composition of the present invention may contain excipients such as sucrose, starch, annit, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc., such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin. , gum arabic, polyethylene glycol, sucrose, starch, etc., such as starch, carboxymethylcellulose,
Disintegrants such as carboxymethylcellulose salts, hydroxypropyl starch, glycol-starch sodium, sodium bicarbonate, calcium phosphate, calcium citrate, lubricants such as magnesium stearate, talc, sodium lauryl sulfate, such as citric acid, menthol, glycine , fragrances such as orange powder, preservatives such as sodium benzoate, sodium bisulfite, methylvaladin, propylparaban, etc.
Stabilizers such as citric acid, sodium citrate, acetic acid, suspending agents, dispersants such as methylcellulose, polyvinylpyrrolidone, aluminum stearate, aqueous diluents such as water, e.g. cocoa butter, polyethylene glyfur, white It can contain various organic or inorganic carrier materials commonly used in pharmaceutical applications, such as base waxes such as petrolatum.

The dosage of the active ingredient will vary depending on various factors such as the weight and/or age of the patient and/or the type of disease, as well as the type of administration route. Generally, the effective dosage may be selected from the range of 1 to 50 mg/day for oral administration, and 0.1 to 5 mg/day for intramuscular or intravenous injection.

The daily dose may be administered to the patient in divided doses at intervals of 6 to 12 hours per day. A preferred single dose of this active ingredient is, for example, about 1 to 50 m per tablet or capsule.
g, 0.1 to 5 mg per vial or ambuli.

The present invention will be explained below with reference to Examples.

(1000b) Example 1 (1N(2R,4S,5R)-5-hydroxy-4-hydroxymethyl-2-methyl-1,3-dioxane
g), $tertiary butyldimethylchlorosilane (14.5g
) and imidazole (13,1 g).

A warm mixture of N-dimethylformamide ([omQ) was stirred at room temperature for 2 hours, and the mixture was diluted with ethyl acetate (500 mA).
Dilute with The solution is washed sequentially with water, dilute hydrochloric acid, saturated aqueous sodium hydrogen oxide solution, and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (2R,4S,
5R)-4-tert-butyldimethylsiloxymethyl-5
-Hydroxy-2-methyl-1,3-dioxane (24
, 2g) as a colorless oil.

IHNMR (CDCl2) & ppm: 0.10
(3H,s), 0.12(3)! , s), 0.91
(9H,s), 1.32 (3H,d.

J=5Hz), 3.3-3.6 (3H,m>, 3
．． 7-3.8 (2H.

m), 3.94 (IH, dd, J: 4.9Hz),
4.13 (IH, dd, J=5.9Hz), 4.7
0 (LH, q, J = 5Hz) (green onion light) (2R, 43, 5R) -4-Tertiary butyldimethylsiloxymethyl-5-hydroxy-2-methyl-1,3-dioxane (4,2g ) in benzene (30+uQ) and dimethyl sulfoxide (5,7 mQ) mixture solution,
Pyridine (1,301119), trifluoroacetic acid (0
, szmQ) and N,N'-dicyclohexylcarbodiimide (90 g) in a water bath with cooling, and the mixture is stirred at room temperature for 3 hours. The solution is diluted with ethyl acetate (50 mQ). and water (30m11
) and stir for 30 minutes. After filtering off insoluble urea, the organic layer is separated and washed sequentially with water and brine. The solution is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to give a crude oil. Transfer the oil to a silica gel column (
5(Ig) (eluted with n-hexane:ethyl acetate-10=1) to give (2R,45)-4-tert-butyldimethylsiloxymethyl-2-methyl-1,3-dioxane-5 -one (3.22 g) is obtained as a pale yellow oil.

'HNMR (CDCl2) & ppm: 0.07
(31(,s), 0.09(3H,s), 0.89
(9H,s), 1.47 (3H,d.

J=5.5Hz), 3.98 (2H, d, J-3,
5Hz>, 4.3-4.5 (3)1. m), 5.
11 (IH, q, J = 5.5Hz) (2R, 4S) -
4-tert-butyldimethylsiloxymethyl-2-methyl-1,3-dioxan-5-one (2,50 g) and carboethoxymethylenetriphenylphosphorane (4,
A warm mixture of OOg) in tetrahydrofuran (z5mQ) is stirred at room temperature for 24 hours, and the solvent is distilled off under reduced pressure. The residue was chromatographed using a silica gel column (50 g), and a mixture of n-hexane and ethyl acetate (1
(0:1) and (2R,4R)-4-tert-butyldimethylsiloxymethyl-rubonylmethylene-2-methyl-1,3-dioxane (
2.09 g) as an oil.

1) I NMR (CDCl2) δppm: 0.0
8 (6H, 2s), 0.90 (9H, s), 1.
38 (3H.t.J=7.5Hz), 1.47 (L
H. d. J=5.0Hz>, 3.83 (IH.dd
．． J=9.

11) 1z), 3.87 (IH.dd.J=9.
11Hz), 4.17 (IH, q.J-7.5Hz)
, 4.30 (LH.m), 4.56 (IH.dd
．． J=17. 2Hz>, 4.93 (IH.q.

J=5Hz), 5.44 (1)1. d. J=17H
z), 5.89 (IH.m> (2R.4R)-4-tert-butyldimethylsiloxymethyl-5-ethoxycarbonylmethylene-2-methyl-
1.3-dioxane (17.0g) in ethanol (1
7 omrb,) solution in a hydrogen atmosphere under 3 atm.
% palladium-carbon and shake for 1.5 hours at room temperature. After filtering off the catalyst, the solvent was distilled off under reduced pressure, and the residue was subjected to chromatography using a silica gel column (500 g), eluting with a mixture of n-hexane and ethyl acetate (20:1), (2R.

4R. 5S)-4-tert-butyldimethylsiloxymethyl-5-ethoxycarbonylmethyl-methyl-1.3-
Dioxane (9.52 g) is obtained as a pale yellow oil.

IH NMR (CDCl2) δppm: 0.07
(6H, 2s), 0.89 (9H.s), 1.2
6 (3H.t.J=7Hz), 1.31 (3H.

dJ=5Hz), 2.06 (IH, m), 2.4
3 (IH.m).

2, 71 (IH, dd, J=10.16Hz),
3.52 (IH.

ddJ-7. 11Hz), 3.68 (IH.dd
．． J=7.

11Hz>, 3.83 (LH.dt.J=2.1
1Hz), 3.89 (IH.dt, J=3.7Hz
), 4.06 (IH, d.

J=12Hz), 4.14 (2H,q.J=7Hz
), 4.72 (IH. q. J=5Hz) (1,000 ga) <5) (2R,4R,5S)-4-tert-butyldimethylsiloxymethyl-5-ethoxycarbonylmethyl-2-methyl- 1,3-dioxane (9,30 g) toluene (9
The solution is cooled in a dry ice-acetone solution and a 1.5 M diisobutyl aluminum hydride solution in toluene (26.4 ml) is added dropwise to this solution. The mixture is stirred at the same temperature for 1 hour. After stopping the reaction, the mixture was washed with a saturated aqueous ammonium chloride solution, and the solution was added with ethyl acetate (3o
Add a mixture of omQ) and water (3QQmEl).

Insoluble matter is filtered off. The filtrate is extracted with ethyl acetate, and the organic layer is washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was transferred to a silica gel column (250 g
) and eluted with a mixture of n-hexane and ethyl acetate (10:1) to obtain (2R
,4R,53)-4-tert-butyldimethylsiloxymethyl-5-formylmethyl-2-methyl-1,3-dioxane (6,61 g) is obtained as a colorless oil.

IHNMR (CDCl2) & pI) m' 0.08
(6H02s), o, 5s (9H, s), 1.31
(3H, d, J=5.5Hz>, 2.19(IH,
m>, 2.63 (IH, dd, J=5.17Hz)
, 2.88 (IH, dd, J=9.17Hz>, 3
．． 50 (IH, dd, J=10°11Hz), 3.
68 (LH, dd, J=7.11Hz), 3.8-
4.1 (3H, m), 4.74 <LH, q, J=
A suspension of sodium hydride (3,49 g, 60% in oil) in dimethyl sulfoxide (7 lma) is heated to 75° C. for 1 hour and the solution is cooled to room temperature. To a solution was added (4-carboxybutyl)triphenylphosphonium bromide (32.2 g) in dimethyl sulfoxide (100 ml).
). After stirring for 15 minutes at room temperature, the mixture was dissolved in dimethyl sulfoxide (10 mQ) (2R94R,5S).
-4-Tertiary butyldimethylsiloxymethyl-5-formylmethyl-2-methyl-1,3-dioxane (6,3
g) is added and the solution is stirred at room temperature for 1.5 hours. Aqueous ammonium chloride solution (1 oomu) is added to the reaction mixture and the mixture is adjusted to pH 4 with oxalic acid. The mixture is extracted with ethyl acetate and the organic layer is washed successively with water and brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was chromatographed using a silica gel column (150 g), eluting with a mixture of n-hexane and ethyl acetate (10:1 to 1:1) to give (2R ,4R,
5S)-4-tert-butyldimethylsiloxymethyl-5
-[(Z)-6-carboxy-2-hexenylco2-
Methyl-1,3-dioxane (5.50 g) is obtained as a colorless oil.

'HNMR (CDCl2) δppm: 0.07 (
6H, 2s), 0.89 (9H, s), 1.31
(3H, dJ=5)1z), 1.50 (IH.

m>, 1.6-1.8 <2H, m), 2.0-2.
2 (3H, m).

2.3-2.8 (3H, +n), 3.5-3.8
(3H, m), 3.89 (IH, m), 4.02
(IH, d, J=11Hz), 4.73 (IH, q,
J=5Hz>, 5.3-5.6 (2H, m) (7
〉 (2R,4R,53)-4-tert-butyldimethylsiloxymethyl-5-[(Z)-6-carpoxy-2-hexenyl-2-methyl-1,3-dioxane (4,75
Potassium carbonate (1,76 g) and methyl iodide (
1,6zmQ) is added and the mixture is stirred at room temperature for 5 hours. Pour the solution into water and extract the aqueous solution with ether. The organic layer is washed sequentially with water and brine and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure, and the residue was purified using a silica gel column (75
chromatography using n-hexane and ethyl acetate (20:1) to give (2
R,4R,5S)-4-tert-butyldimethylsiloxymethyl-5-[(Z)-,6-medoxycarbonyl-2
-hexenyl-2-methyl-1,3-dioxane (4
, 17 g) as an oil.

'HNMR (CDC13) Sppm: 0.07 (
6H, 2s), 0.96 (9H, s), 1.31
(3H, d, J=5.0.Hz), 1.48(1)1
．． m>, 1.6-1.8 (2H, m), 2.0-
2.2 (3H.

m), 2.3-2.6 (3H, m), 3.5-3
．． 7 (3H, m).

3.68 (3H, s), 3.89 (IH, m),
4.00 (IH.

d, J=11Hz>, 4.72 (IH, q, J=5
Hz), 5.3-5.6 (2H,m) (Team Ii) 0O- (2R,4R,5S)-4-tert-butyldimethylsiloxymethyl-5-[(Z)-6-medoxy Carbonyl-1,3-dioxane (4.OOg) and tetra-n-
A warm mixture of butylammonium fluoride (15 mmol) in tetrahydrofuran ('4011111) is stirred at room temperature for 3 hours and the solvent is removed under reduced pressure. The residue was subjected to chromatography using a silica gel column (80 g), and a mixture of n-hexane and ethyl acetate (20:
15) and (2R.4R.5S)-4-hydroxymethyl-5-[(Z)-6-medoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (
2.88 g) as a colorless oil.

'H NMR (CDC1g)I)I)m' 1.3
5 (3H.d.J=5.0Hz>.

1, 43 (LH, m), 1.6-1.8 (2H,
m), 1.9-2.2 (3H.m>, 2.3-2.
6 (3H.m), 3.68 (31(,s).

3, 7-3.9 (31, m>, 3.93 (IH.
m>, 4,00 (IH.dd, J=2.12.5H
z), 4.76 (IH, q.

J = 5.0Hz), 5.3-5.6 (2H.m) Pyridine (1,'64mQ) dichloromethane (45m
m) Add chromium trioxide (1', 07g) to the solution at 10°
C. and the solution is stirred at room temperature for 1 hour. The solution was cooled in a water bath and dissolved in dichloromethane (3 mQ) (2R).

4R,5S)-4-1=Droxymethyl-5-[(Z)
-6-Medoxycarponyl-2-hexenyl-2-methyl-1,3-dioxane (500 mg) is added.

After stirring P1 for 2 hours at room temperature, the solution is diluted with water (LOOmQ ) and passed through a silica gel column. The solvent of the eluate was distilled off under reduced pressure, and the residue was transferred to a silica gel column (20 g).
chromatography using n-hexane and ethyl acetate (1:1) to give (2R,4
R,58)-4-formyl-5-[(Z)-6-medoxycarbonyl-2-hexenyl-2-methyl-1.3
-Dioxane (336 mg) is obtained as a colorless oil.

'HNMR (CDCl2) δppm: 1.43 (
31 (,d, J=5.5Hz).

1.5-1.8 (3H, m>, 1.91 (11, m
), 2.0-2.2 (2H, m>, 2.3-2.4
(2H, m), 2.55 (1)1. m).

3.69 (38,s), 3.78 (IH,m),
4.03 <IH.

dd, J=2. 11Hz), 4.27 (IH,
dJ=2Hz).

4.80 (IH, q, J=5.5Hz), 5.3-
5.6 (2H, m).

9.62 (IH,5) (2R,4R,5S)-4-formyl-5-[(Z)-
6-Medoxycarbonyl-2-hexenyl-2-methyl-1,3-dioxane (62 mg) and 4-phenyl-
3-thiosemicarbazide (46 mg) in ethanol (
2mQ) To medium-temperature Q, add acetic acid (1 drop) and stir the solution at room temperature for 4 hours. The mixture was dissolved in chloroform (15 mm)
-C dilute IRL, the solution is washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (2R,4R
.

55)-5-[(Z)-6-1t + Shika & Bonirou 2-
hexenyl]-2-methyl-4-[4-(phenyl)thiosemicarbazonomethyl]-1゜3-dioxane (11
0+ng) as an oil.

'HNMR (CDCl2) δppm: 1.38 (
3H, d, J = 5Hz).

1.5-1.8 (3M, m), 2.0-2.2 (
3H, m), 2.2-2.4 (2H, m'), 2
．． 53 (IH, m), 3.69 (3) 1°s),
3.85 (IH, m), 4.05' (IH, m
), 4.53 (LH, dd, J=3.4.5Hz),
4.82 (LH, m>.

5.3-5.6 (2H, m), 7.2-7.5 (
4H, m), 7.62 (3H, m), 9. Q4 (
1)1. s), 9.73 (IH,5)(11> (2R,4R,55)-5-[(Z)-6-medoxycarbonyl-4-[4-(phenyl)thiosemicarbazonomethyl]
-1,3-dioxane (11 (1 mg)) in methanol (
A mixture solution of 2mi) and IN sodium hydroxide (1ml) was stirred at room temperature for 2 hours, and the mixture was adjusted to pH with IN hydrochloric acid.
Adjust to 7. The solvent was distilled off under reduced pressure, and the residue was dissolved in a mixture of chloroform and methanol (3:1, 10 ml). The solution is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to give a crude oil. The oil was purified by preparative thin layer chromatography (ILC) to give (2R.4R.5S
)-5-[(Z)-6-carboxy-2-hexenyl-2-methyl-4-[4-(phenyl)thiosemicarbazinomethyl]-1,3-dioxane (65 mg) is obtained as an oil.

'HNMR (CDCl2) δppm: 1.42 (
3H, dJ=5)1z).

3.88 (IH, dd, J=11.5.2Hz>,'
4.10 (IH.

d, J=11.5Hz), 4.56 (IH, dd,
J=2.3゜5.2Hz), 4.83 (IH, qJ
=5Hz), 5.55 (2)! .

m), 7.2-7.7 (6H, m), 9.07
(LH,s).

10.8 (LH,br 5) (2R,4R,5s)-5-['(z)-s-carboxy-2-hexenyl-2-methyl-4-[4-(phenyl)thiosemicarbazinomethyl ]-1,3-dioxane (1,39 g) in methanol (1 omQ) and IN aqueous sodium hydroxide solution (3,4 button) was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. Dip the residue in water (
soma), and the solution was dissolved in ``Diaion HP-2''.
0, (trademark, sold by Mitsubishi Chemical Industries, Ltd.) (”200mQ
) column. Wash the column with water (soomu),
The target compound was mixed with water and methanol (1:1.1j2
). The solution was concentrated under reduced pressure and the residue was lyophilized to give (2R, 4R.

5S)-5=[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-[4-(phenyl)thiosemicarbazinomethyl]-1,3-dioxane sodium salt (1, 77 g) as a pale yellow powder.

IHNMR (D20) δppm F 1.39 (3H
, d, J=5.5Hz>.

1.5-1.7 (3H, m), 1.9-2.1 (
3H, m), 2.1-2.3 (4H, m>, 2.
37 (IH, m), 4.05 (18°s), 4
．． 98 (IH, q, J=5.5Hz>, 4.8-
5.1 (2H, m), 7.3-7.5 (6H, m>
63-Example 2 (2R,4R,5S)-4-formyl-5-[(Z)-
A warm mixture of 8-methoxycarbonyl-2-hexenyl coke-methyl-1,3-dioxane (300 mg), 4-phenyl semicarbazide (227 mg) and a few drops of acetic acid in methanol (5 ml) was stirred at room temperature for 3 hours.
Dilute the mixture with chloroform (30 mQ). The solution is washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column (15 g).
chromatography using n-hexane and ethyl acetate (3:1) to give (2R,4
R.

s 5)-s-[(z)-s-methoxycarbonyl-phenylsemicarbazinomethyl)-1,3-dioxane (
403 mg) as a pale yellow oil.

'H NMR (CDCl2) δppm: 1.40
(3H, d., C5.5Hz).

1, 6-1.8 (3H.m), 2.0-2.2 (
3H. m), 2.2-2, 4 (28, m>, 2.

55 (IH.m), 3.69 (3H.

s), 3.85 (II, m), 4.04 (LH
, m>, 4.57 (IH, dd, J=3. 4.5H
z), 4.85 (IH, m).

5, 3-5.6 (2H.m>, 7.09 (1) 1
, t. J=7Hz).

7, 18 (IH.d.J=5Hz>, 7.35 (
2H; m), 7.50 (3H, m), 7.95 (
IH. s), 8.53 <1)1. s) 衷鳳迩1 (2R,4R,5S)-5-[(Z)-6-Mehoxycarbonyl-2-hexenyl]-2-methyl-4-(4-
A mixture solution of phenylsemicarbazinomethyl)-1,3-dioxane (403 mg) in methanol (9 mQ) and IN aqueous sodium hydroxide solution (51) was added at room temperature for 4 hours.
Stir for an hour and adjust the mixture to pH 7 with IN hydrochloric acid. The solvent was distilled off under reduced pressure, and the 'A residue was dissolved in a mixture of chloroform and methanol (3:1.30 mfl). The solution is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to give a crude oil. The crude product was passed through a silica gel column (15
g) chromatography using n-hexane 1. Elution with a mixture of ethyl acetate and acetic acid (2,5nia 5:,1) yielded (2R,4R,5S)-5-[(Z)
-6-carboxy-2-hexenyl-2-methyl-4
-(4-Phenylsemicarbazidomethyl)-1,3-dioxane (203 mg) is obtained as a pale yellow oil.

'HNMR (CDCl2) δppm: 1.39 (
3H, d, J・5.5Hz>.

1.5-1.8 (3H, m), 2.0-2.2 (
2H, m), 2.3-2.6 (3H, m), 3.
87 (IH, dd, J=2.13Hz>.

4.0! j(LH, d, J=13Hz>, 4.55
(IH, dd, J=2゜5)1z), 4.83 (L
H, q, J = 5.5Hz), , 5.4-5.6 (2H
, m), 7.10 (IH, t, J=7.5Hz),
7.2-7.4 (4H, m>, 7.50 (2H,
m), 8.05 (IH, s).

9.40 (1B, 5) (2) Example 1 The following compound is obtained in the same manner as in (12).

(2R,4R,53)-5-[(Z)-6-levoxy-2-hexenyl]-2-methyl-4-(4-phenylsemicarbazidomethyl]-1,3-dioxane sodium salt.

IHNMR D20) δ ppm: L41 (3
H, d, J = 5.5Hz).

1.5-1.7 (3H, m), 1.8-2.4 (
8H, m>, 4.02 (IH, s), 4.95 (
IH, q, J=5.5Hz), 5.3-5.6 (2
H, m>, 7.21 (1)1. m), 7.4-7
．． 5(5H,m>(2R,4R,5S)-5-[(Z)-6-1+Lupoxy-2-hexenyl]-2-methyl-4-(4-phenylsemicarbazino)methyl-1, 3-dioxane (48
mg) in ethanol (21d) are added sodium cyanoborohydride (15 mg) and acetic acid (1 drop) and the mixture is stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, the residue is extracted with chloroform at pH 3, and the organic layers are combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was purified by preparative thin layer chromatography (ffLc) using ethyl acetate as eluent to obtain (2R,4R,5S)-5-[(Z)-6-carpoxy 2-hexenyl]-2-methyl-4-(4-phenylsemicarbazidomethyl)-1,3-dioxane (2
2 mg).

'HNMR (CDCl2) δppm: 1.32 (
3H, d, J = 5Hz).

1.6-1.9 (2H, m), 2.0-2.2 (
4H, m), 2.36 (2H, t, J=7Hz),
2.4-2.6 (IH, m'), 2.85 (LH,
dd, J = 2.6.12.8Hz), 3゜05 (I
H, dd.

J=9.7.12.8Hz), 3.72 (IH, m
>, 4,01 (LH, m), 4.70 (IH, q
, J=5Hz), 5.4-5.6(2H,m>, 7
．． 04 (IH, t, J=7.3Hz), 7.30(
2H,m,), 7.45 (2)1. d, J=7.5
Hz>, 8.28 (IH, s) (1,000 times) Example 5 The following compound was obtained in the same manner as in Example 2.

(2R,4R,5S)-4-tert-butoxycarbonylhydrazinomethyl-5-[(Z)-6-medoxycarbonyl-2-hexenyl]'-2-mef-1,3-dioxane.

IHNMR (CDCl2) δppm: 1.35 (
3H, d, J-5Hz).

1.50 (9H, s), 1.6-1.8 (3H,
m), 2.0-2.2 (2H, m>, 2.2-2.
4 (2H, m), 2.50 (LH,'m).

3.68 (3H, s), 3.78 (IH, d, J
=11.5Hz>.

3.98 (IH, d, J=11.5Hz>, 4.5
8 (LH, dd.

J=2.5Hz), 4.77 (IH, q, J=5H
z>, 5.3-5.6 (2)1. m), 7.23
(1)1. m>, 8.01 <11. s) fire "u"
The following compound was obtained in the same manner as in Example 3.

(2R,4R,53)-4-tert-butoxycarbonylhydrazinomethyl-5-[(Z)'-6-carpoxy-2-hexenyl]-2-methyl-1°3-dioxane.

IHNMR (CDCl2) Eppm: 12-1.5
(LH, m), 1.35 (3H, d, J=5H2)
, 1.50 (9)1. s>, 1.6-1.8
(31, m>, 2.0-2.2 (2H, m>,
2.35 (2H, d.

J=6.51(z), 2.46 (IH,m>,
3.77 (IH, m>.

4.04 (IH, d, J=11Hz>, 4.57
(IH, m).

4.80 (LH, m), 5.3-5.5 (2H
, m), 7.21 (IH, m), 7.26 (
LH, s) Backside ■l The following compound is obtained in the same manner as in Example 2.

(2R,4R,5S)-5-[(Z)-6-medoxycarbonyl-2-hexenyl-2-methyl-4-(1-
Phthalazinylhydrazotumethyl)-1,3-dioxane.

'HNMR (CDCl2) δppm: 1.33 (
3)1. d, J=5.5Hz>.

1.6-1.8 (3H, m), 2.0-2.2 (
2H, m), 2.43 (214, t, J=8Hz>,
2.67 (LH, m>, 3.67 (IH.

m), 3.85 (IH, d, J=12Hz), 4.
05 (LH, d.

J=12Hz>, 4.68 (LH, dd, J=3.4
Hz), 4.87 (IH, q, J=5.5H2),
5.3-5.6 (2)1. m>, 7.51 (IH,
m), 7.15-7.7 ('2H, m), 7.8
8 (IH, m).

7.36 (IH, m), 10.48 (1B
, Broad) Example Name The following compound was obtained in the same manner as in Example 3.

(2R,4R,5S)-5-[('Z)-6-carpoxy-2-hexenyl-2-methyl-4-(1-phthalazinylhydrazotumethyl)-1,3-dioxane.

IHNMR (CDCl2) δppm: 1.45 (
3)1. d, J=5.5Hz>.

1.6-1.9 (3H, m)', 2.0-2.2(
3H,m>, 2.3-2.6 (3H,m), 3.
90 (IH, dd, J=2.11Hz).

4.18 (IH, d; J: 1'1Hz), 4.70
(1)1. dd, J=3゜4Hz>, 4.88 (
IH', q, J=5.5Hz), 5.4-5.7 (2
1 (, m), 7.56 (IH, m>, 7.'6"
-7:8 (2H, m).

7. 90 (IH, m), 7.98 (IH, m>
, 8.41 (IH', m) (g 1,000 bales ¥3) (2R,,4,R,5S)-4-formyl-5-[(Z
)-6-Medoxycarbonyl-2-hexenyl]-2-
Methyl-1,3-dioxane (326 mg), hydroxylamine hydrochloride (374 mg) and sodium bicarbonate (374 mg) in methanol (6!n11)
and water (3 mQ) and stirred at room temperature for 3 hours. Chloroform and saline are added to this solution, and the organic layer is separated. Magnesium sulfate for organic layer? The mixture was dried with a vacuum cleaner and the solvent was distilled off under reduced pressure. The residue was transferred to a silica gel column (1
5 g) and eluted with a mixture of n-hexane and ethyl acetate (5:1). From the first fraction, (2R,4R,5,3)-(Z)=4-1 droxyiminomethyl-5-[(Z:)-6-medoxycarponyl-1,3-dioxane (ioomg) obtain.

IH NMR (CDCl2)εppm: 1.35
<IH, d, J=5Hz).

1, 6-1.8 (3H, m), 1.9-2.2 (
4H, m), 2, 34 (2H.d, J=7.5Hz)
, 2.57 (IH.m>, 3.69 (31,s)
,, 3.81 (LH.d.C11.5Hz>, 3
．． 98 (IH, dJ=11.5Hz), 4.79 (
IH. q, J = 5Hz).

4,98 (1B, dd.J=3.5, 4.5H
z), 5.4-5, 6 (2H.m), 6.78
(d, J = 3.5Hz>, 8.00 (IH.s) from the second half (2R.4R.5S)-(E)-4-hydroxyiminomethyl-5-E(Z)-6-med Oxycarponyl-2-hexenyl]-2-methyl-1,3-dioxane (1.42 mg) is obtained.

'H NMR (CDCl2)εppm: 1.37
(3H.d.J=5Hz).

1, 58 (IH, m), 1.6-1.8 (2H.
m), 2.0-2.2 (2H.m), 2.27
(IH, m), 2.85 (2H.t.

J=7.5Hz), 2.55 (IH, m),
3.69 (3H.s).

3, 80 (LH.d, J=11.5Hz>, 4
．． 03 (IH.d.

J=11.5Hz), 4.55 (LH, dd.J
=2. 4.5Hz).

4, 80 (IH, q.J=5Hz), 5.3-5
．． 6 (2H, m>.

7, 43 (LH.d.J4.5Hz), 7.8
3 (LH, s)
hexenyl]-2-methyl-1.

N. of 3-dioxane (100 mg). Sodium hydride (14
mg, 60% in oil) at 5°C. After stirring at the same temperature for 30 minutes, diphenylmethyl bromide (86.6m
g) is added and the mixture is stirred for 2 hours in a water bath. The solution is diluted with ethyl acetate, washed successively with water and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the crude residue was dissolved in a mixture of n-hexane and ethyl acetate (
4:, 1) was purified by prepared ILC as an eluent to obtain (2R,4R,5S)-(E)-4-diphenylmethoxyiminomethyl-5-[(Z)-6-medoxycarboxylate. Ni-2-hexenyl-2-methyl-1
, 3-dioxane (130 mg) is obtained.

lHNMR (CDC13) εppm: 1.34 (
3H. d. J=5Hz).

1,49 (1)1,m), 1.6-1.8 (3H
．． m), 2, O-2.2 (3H, m>, 2.32
(2H.t, J=7.5Hz), 2.55 - (I
H. 'm>, 3. '68 ('3)1,s)'. 3
．． 70 (IH.d.

J=11.5Hz), 3. '96 (IH, d.J=
11.5Hz).

4, 49 (IH, dd. J = 2. 5.5 Hz),
4.74 (circulation, q.

J=5Hz), 5.2-5.5 (2H, m), 6
．． 23 (IH.s).

7, 2-7.4 (111, m>, 7.59 (L
H, d, J = 5.5 Hz > order m (Mtt) The following compound is obtained in the same manner as in Example 3.

(2R.4R.5S)-5-[(Z)-6-carboxy-2-hexenyl-4-diphenylmethoxyiminomethyl-2-methyl-1.3-dioxane.

')l NMR (CDC13)εppm: 1.3
4 (3H, d, J=5Hz).

1,50 (LH.m), 1.6-1.8 (3H.m)
m>, 2.0-2.2 (3H, m>, 2.85
(2H.t.J=7.5Hz), 2.59 (IH.m
>,, 3.77 (IH.m), 3.96 (1.
H. d.

J=11.5Hz), 4.50 (dd.J=2.5
, 5.5Hz).

4,74 (IH,m), 5.00 (IH.dd,
J=2.5.

4,5Hz), 5.2-5.6 (2)1. m>,
6.22 <LH,s>.

5, 78 (IH, dJ=4.5Hz), 7.2-7
．． 4 (LH, m).

7,56 (IH.d.J=5.5Hz>(more than 1,000 b) Example 12 (2R,4R,5S)-5-[(Z)-6-1 Toxycarbonyl-2-hexenylco2- Methyl-4-(1-
Phthalazinylhydrazotumethyl)-1,3-dioxane (450 mg) in methanol (4 mQ) and acetic acid (2+
Sodium cyanoborohydride (125 mg) is added to the mixture solution with nQ) and the mixture is stirred at room temperature for 2 hours. The solution is adjusted to pH 7 with saturated aqueous sodium bicarbonate solution and the mixture is diluted with chloroform. The solution is washed sequentially with water and brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give (2R,4R,5S)-
5-[(Z)-6-Medoxycarbonyl-2-hexenylcoke-methyl-4-(1-phthalazinylhydrazinomethyl)-1,3-dioxane is obtained as a residue. This residue is dissolved in a mixture of methanol (5111Q) and aqueous sodium hydroxide solution (2 ml). After stirring overnight at room temperature, the mixture is neutralized with IN hydrochloric acid and the solution is evaporated to dryness under reduced pressure. The residue was purified by preparative TLC using a mixture of chloroform and methanol (10:1) as eluent to give (2R14R,5S)-5-[(Z)-6-carboxy-2-hexenyl-2-methyl. -4-(1-phthalazinylhydrazinomethyl)-1,3-dioxane (
96.3 mg> is obtained as a pale yellow oil.

IHNMR (CDC13) δppm: 1.44 (
1)1. d, J=5Hz).

1.5-1.9 (3H, m), 1.9-2.2
(3H, m), 2.3-2.6 (3)1. m),
3.88 (IH, dJ=12.5Hz).

4.15 (IH, d, J=12.5Hz>, 4.
70 (IH, m>.

4.87 (IH, q, J=5Hz>, 5..4-
5.7 (2H, m).

7.57 (LH, m), 7.6=7.8 (2H
, m), 7.9-8.1 (2H, m), 8.4
1 (IH, m), 9.60 (IH, s) Example 13 8O- (2R,4R,5S)-4-formyl-5-[(Z)-
6-Medoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (200 mg) and 2-aminomethylpyridine (0,1511Q) in methanol (4
To a mixture in mQ''? and acetic acid (1 mQ) is added sodium cyanoborohydride (100 mQ) and the solution is stirred at room temperature overnight. The mixture is neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract is washed with brine and dried over magnesium sulfate.The solvent is distilled off under reduced pressure, and the residue is passed through a silica gel column (Log
) and eluted with a mixture of chloroform and methanol (30:j) to give (2R
,4R,5S)-5-[(:j)-6-medoxycarponyl-4-(2-pyridylmethylaminomethyl)-1.

3-dioxane (165 mg) is obtained.

'H NMR (CDCl2) δppm: 1.33
(3H.d, J=5Hz>.

1,40 (1)1. m), 1.6-1.8 (2H
．． m), 1.9-2, 0 (2H.m), 2.0-
2.2 (3) 1, m), 2.32 (2) 1. d, J
=7.5Hz), 2.48 (1M, m>, 2
．． 63 (IHJd, J = 3.5. 12.5) 1z>,
2.90 (IH, dd.

J=3.5. 12.5Hz>, 3.66 (3H
,s), 3.70(IH,m), 3.95(
2)1. m), 4.01 (IH, m).

4.74 (LH, q, J=5Hz), 5.3-5.
6 (2)1. m＞.

7.07 (LH, dd, J=5.7.5Hz>,
7.32 (IH, d.

J=7.5Hz), 7.66 (LH, dt,,C
1, 5, 10Hz).

8.56 (IH, d, J: 514z) Example 14 The following compound is obtained in the same manner as in Example 3.

(2R,4R,5S)-5-[(Z)-6-carpoxy-2-hexenyl-2-methyl-4-(2-pyridylmethylaminemethyl)-1,3-dioxane.

IHNMR (CDC13) Sppm: 1.27 (
1)1. m), 1.30 (IH, dJ45) 1z>,
1.45 (IH, m), 1.5-1.8 (2H,
m), 2.05 (LH, m), 2.2-2.4
(4H, m).

2.8-3.0 (2H, m), 3.72 (IH,
dd, J=1.5゜11.5Hz>, 3.9-4.2
(4H, m>, 4.73 (IH, q.

J=5)+z>', 5.3-5.6 (2H, m),
5.94 (IH.

Broad>, 7.2-7.4 (2H, m),
7.72 (IH, dt.

J-1,5,10Hz>, 8.65 (IH, d,
J=5Hz) Example 15 (2R,4R,53)-4-hydroxymethyl-5-[
N.I. of (Z)-6-medoxycarponyl-xenyl-2-methyl-1,3-dioxane (272 mg). To a solution in N-dimethylformamide (10 mm) are added sodium hydride (80+ng, 60% in oil) and 2-picolyl chloride hydrochloride (110 mg) and the mixture is stirred at room temperature overnight. The mixture is quenched with saturated aqueous ammonium chloride solution and the solution is extracted with ethyl acetate. The organic layer is washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative TLc using ethyl acetate as eluent to give (2R',4R.5S)-5
-[(Z)-6-Medoxycarbonyl-2-hexenyl]-2-methyl-4-(2-pyridylmethoxymethyl)-1,'s-dioxane (201 mg) is obtained as a pale yellow oil.

'H NMR (CDCl2) Sppm: 1.35
(3H.d., C5.”5Hz).

1, 47 (IH, m), 1.6-1.8 (3H.
m>, 1.9-2.2 (3H, m>, 2.2-2.
4 (28, m), 2.50 (1)1. m＞.

3, 57' (IH, dd, J=5.10Hz),
'3.67 <3H, s).

3,74 (LH,m>, 4.00 (IH,d,J
= 12Hz).

4, 13 (LH.m>, 4.70 <2H.ABq
．． J=13Hz).

4, 78 (IH, qJ=5.5Hz>, 5.3-5
．． 6 (2H, m>.

7, 19 (1)1. ddJ=5. 7Hz), 7.
45 (IH, d.

J=8Hz), 7.71 (IH.dt.J=1.5
．． 8) 1z).

8, 55 (LM,'d.J=5Hz) Example 16 The following compound is obtained in the same manner as in Example 3.

(2R.4R,ss)-s-[(z)-s-carfoxy2-hexenyl]-2-methyl-4-(2-pyridylmethoxymethyl)-1,3-dioxane.

IH NMR (CDC1a) & ppm: 1.3
3 (3H.d.J=5Hz).

1, 49 (IH.m), 1.6-1.9 (3H.
m), 2.0-2.3 (4H.m), 2.38
(2H.t.J=7Hz), 3.6-3.8 (21
(, m), 4.0-4,1 (2H.m), 4
, 70 (2H.

ABq, J=13Hz), 4.77 (IH.q.J
=5Hz>, 5.4-5, 6 (2H, m), 7
．． 33 (IH.dd.J=5.7Hz).

7, 48 (IH, d, J=8) 1z), 7.80
(IH.dt.

J=1.5. 8) 1z>, 8.69 (1) 1',
d. J=5Hz) Example 17 (2R,4R,5S)-4-hydroxymethyl-5-[
Phenyl isocyanate (Q, 1 mQ) was added to a solution of (Z)-6-medoxycarbonyl-2-1xenyl-2-methyl-1,3-dioxane (108 mg) in pyridine (0.5 mQ), and the mixture was Stir for 30 minutes at room temperature. Add water (t, mg) and extract with ether, and the organic layers are combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was purified using prepared rLc (eluent; hexane:ether = 1 = 1), (2R, 4R, 5S
)-5-[(Z)-6-medoxycarponyl-2-methyl-4-phenylcarbamoyloxymethyl-
1,3-dioxane (140 mg) is obtained.

'H NMR (CDCl2) δppm: 1.36
(3H, d, J=5Hz>.

1, 4, -1.8 (3H.m), 2.0-2.3
(3H.m), 2.33 (2H.t, J=7Hz),
2.4-2.6 (IH.m), 3.67 (3H,
s), 3.72 (IH, m), 3.95-4.2
5 (41(.

m), 4.75 (LH.q.J:5Hz>, 5.
3-5.6 (2H.

m), 6.94 (IH, br s), 7
．． 07 (IH, m).

7, 3-7.5 (4H, m> Example 18 (2R.4R.5S)-5-[(Z)-6-Medoxycarbonyl-2-hexenylcoke-methyl-4-phenylcarbamoyloxymethyl- 3-dioxane (140
IN sodium hydroxide aqueous solution (1 mu) is added to a methanol (2 mQ) solution of Mg), and the mixture is stirred at room temperature for 90 minutes. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was neutralized with acetic acid and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. The crude product was prepared by evaporating the solution to dryness and purified by TLC (eluent; ether: dicyclomethane≠1=1) to give (2R,4R,5S)-5-
[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-phenylcarbamoyloxymethyl.

IH. NMR (, CD(:13)δppm:
1.35 (3H.d, J=5Hz>.

1, 4-1.13 (3H.m>, 2.-0-2.3
(3H, +n), 2.38, (2H, t.J=7H
z>, 2.4-2.6 (IH.m), 3.73 (
LH. m), 4.0-4.4 (4H.m), 4.
75 (18, q.

J=5Hz), 5.3-5.6 (2H.m),
6.88 (IH.

br s), 7.0-7.15 (11(, m), 7
．． 3-7.5 (4H, m) East 111su〇 (2R, 4R.5S)-4-hydroxymethyl-5-[
To a solution of (Z)-6-medoxycarbonyl-2-hexenylcok-methyl-1,3-dioxane (456 mg) in pyridine (2 ma) was added p-toluenesulfonyl chloride (
'640 mg) is added and the mixture is stirred at room temperature for 2 hours. Water (1 omQ) was added to the mixture, extracted with ethyl acetate, and the organic layer was returned to aqueous sodium hydrogen oxide solution (5 ml
) and brine (5 ml) and dry the crude product solution over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was dissolved in dimethyl sulfoxide (z mu.).
Potassium butylimide (550 mg) is added in solution and the mixture is stirred at 100° C. for 6 hours. The reaction mixture is cooled, added to water and extracted with ether. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by preparative ILC to give (2R,4
R,5S)-5-[(Z)-6-medoxycarbonyl-2-hexenyl-2-methyl-4-phthalimidomethyl-1,3-dioxane (400 mg) is obtained.

IHNMR (CDCl2) Sppm: 1.28 (
3H, dJ=5Hz).

1.3-1.9 (4H, m), 2.0-2.5 (
5H, m), 2.63 (IH, m), 3.69 (
3H,s), 3.6-3.8 (2H,m).

4.00 (2H, m), 4.18 (IH, m>,
4.63 (LH.

q, J=51:z>, 5.3-5.6 (2H, m)
, 7.7-7.9(4H,m) (2R,4R,5S)-5-[(Z')-6-medoxycarponyl-4-phthalimidomethyl-1,3-dioxane (5
4mg) o>xTanol (2 mQ) solution hydrazine-hydrate (0.00711111
) and the mixture is stirred at room temperature overnight. The solvent was distilled off under reduced pressure and a crude product was prepared by ILC (eluent; chloroform: methanol: concentrated ammonia water = 85: 15:
(2R.4R.5S)-4-aminomethyl-5-[(Z)-6-medoxycarponylucenyl]-2-methyl-1.3-dioxane (13 mg
).

'H NMR (CDCl2)Sppn+: 1.3
3 (3H.d, J=5Hz).

1, 69 (2H.m), 1.9-2.2 (3H.m)
m>, 2.32 (2H.t, J=7.6Hz), 2
．． 3-2.6 (2H.m), 2,71 (LH,'m
>, 2.94 (LH.dd, J=9.13Hz)
, 3.68 (38,s), 3.65-3.85 (
2H. m), 3.98 (IH.

d, J=11.2Hz>, 4.73 (LH.q, J
=5Hz>, 5.3-5,6 (2H.m) (2R.4R.5 s)-4-aminomethyl-5-[(
Z)-6-Medoxycarbonyl-2-hexenyl coke-methyl-1,3-dioxane (13 mg) in pyridine ('O.'3+all) was added benzyl isocyanate (0. ozmQ) and the mixture was stirred at room temperature. 6
Stir for 0 minutes. Water (0.1 mL) was added and the solvent was distilled off under reduced pressure to give (2R,4R.5S)-4-(3-benzylureidomethyl)-5-[(Z)-6-medoxycarboxylate. Ni-2-hexenyl]-2-methyl-1.3-
Dioxane is obtained as a residue. The residue was dissolved in methanol (1.
5111 fl), add IN aqueous sodium hydroxide solution (0.311111 fl), and stir at room temperature for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was
Neutralize with hydrochloric acid and extract with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. Evaporate the solution to dryness,
The crude product was purified by preparative ILC (eluent; ethyl acetate) (2R.

4R,5S)-4-(3-benzylureidomethyl)-
5-[(Z)-6-carboxy-2-hexenyl]-2
-Methyl-1,3-dioxane (20 mg) is obtained.

IH NMR (CIjC13) Sppm: 1.2
2 (3H.d.J=5Hz).

1, 68 (2H.m>, 1.9-2.3 (3H.m)
m), 2.32 (2H.t.J=6.5Hz), 3
．． 18 (IH.m), 3.38 (18,m), 3
．． 6-4.1 (3H, m>, 4.2-4.4 (2
1.

m), 4.63 (IH.q.J=5Hz), 5.
3-5.7 (3H.

m), 7,1-7,4 (5H.m) Example 20 IJIJ (2R,4R,5S)-4-aminomethyl-5-[(Z
)-6-Medoxycarbonyl-2-hexenyl]-2-
To a solution of methyl-1,3-dioxane (35 mg) in ethyl acetate (2,amQ) were added N,N'-dicyclohexylcarbodiimide (33,6 mg) and benzylglyoxyl rjl (27 mg), and the mixture was incubated at room temperature overnight. Stir. The reaction mixture was filtered and the filtrate's solvent was distilled off under reduced pressure to give (2R, 4R.

5s)-4-benzylglyoxyroylaminomethyl-
5-[(Z)-a-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane is obtained as a residue. Dissolve the residue in methanol (1.5m+1) and add 1.
Add 5N aqueous sodium hydroxide solution (0, smu) and stir at room temperature for 2 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was neutralized with IN hydrochloric acid and extracted with ethyl acetate.

The organic layers are combined and dried over anhydrous sodium sulfate. The solution was evaporated to dryness and the crude product was prepared by TLC (chloroform:
Purification with ethyl acetate (1:1) yielded (2R,4R.

5S) 4-benzylglyoxyroylaminomethyl-5
-[(Z)-6-carboxy-2-hexenylco2-
Methyl-1,3-dioxane (12 mg) is obtained.

'HNMR (CDCl2) δppm: 1.30 (
3H, d, J = 5Hz).

1.5-1.8 (2H, m), 2. (1-2
, 2 (2H, m), 2.36 (2H, t, J=7
Hz>, 2.47 (IH, m>, 3.21 (L
H.

m), 3.5-4.0 (48, m), 4.22
(2H, s).

4.67 (IH, q, J=5Hz), 5.3-5.
6 (2H, m).

7.1-7.4 (5H, m) Example 21 (1,000 bodies b) (2R,4R,5S) -4-formyl-5-[(Z
)-6-Medoxycarbonyl-2-hexenyl-2-
Add tenohydrazine (27 mg) to a solution of methyl-1,3-dioxane (47 mg) in ethanol (1 liter),
The mixture is stirred at room temperature for 1 hour, then sodium cyanoborohydride (20 mg) and acetic acid (0,z5mc) are added and the mixture is stirred for 1 hour. Next, an aqueous sodium hydrogen solution is added and extracted with chloroform, and the organic layers are combined and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to obtain (2R,4R,5S)-5-[(Z)-6-me! -xycarbonyl-2-hexenyl-2-methyl-
4-(N'-thenoyl and drazino)methyl-1゜3-
The dioxane residue was dissolved in methanol (2 mA) and I
Add N aqueous sodium hydroxide solution (0.4 m+1) and stir at room temperature for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was neutralized with IN hydrochloric acid and extracted with chloroform. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was subjected to preparative TLC (eluent;
(2R,4R,5S)-5-
[(Z)-6-carboxy-2-hexenyl-2-methyl-4-(N'-thenoylhydrazino)methyl-
1,3-dioxane (55 mg) is obtained.

'HNMR (CDCl2) δppm: 1.34 (
3H, d, J=5)1z).

1.5-1.9 (2H, m>, 4.0-2.5 (
4H, m), 2.36 (2H, t, J=7Hz>,
8.03 (IH, dd, J=3.8°12.5)1z
), 3゜18 (IH, dd, J=8.1.12.5
Hz).

3.74 (2H, m), 4.04 (3H, m>,
4.75 (IH.

q, J=5Hz), 5.3-5.6 (2H, m),
7.10 (IH.

Example 22 (1) From diisopropylamine (0,351d'I and n-butyllithium (1,7mi, 1.5M solution in hexane) To a solution of lithium diisopropylamide (2.40 mmol) in tetrahydrofuran (5 volumes) prepared by a conventional method, 4-oxotetrahydrobilane (220 mg) in tetrahydrofuran (211111) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Stir.This solution was added with (Z>-7-promo 5) in tetrahydrofuran (2ml).
- Add methyl heptanoate (500 mg) at -78°C. After stirring for 5 hours at room temperature, the mixture is quenched with saturated aqueous ammonium chloride solution and the solution is extracted with ethyl acetate. The organic layer is washed sequentially with water and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to chromatography using a silica gel column (10 g), and a mixture of n-hexane and ethyl acetate (4:1) was added.
Elution with 3-[(Z:)-6-methoxycarbonyl-2-hexenyl]-4-year-old xotetrahydrobilane (100 mg) was obtained as a colorless oil.

IHNMR (CDCl2) δppm: 1.6-1.
8 (2H, m), 2.0-2.2 <2H, m>,
2.34 (2H, t, J: 8Hz>, 2.4-2
．． 7 (4H, m), 3.42 (IH, dd, J=
9.11Hz).

3.77 (11, dt, J=4.11Hz), 3.
98 <IH, m).

4.1-4.3 (2H, m>, 5.25-5.35
(2H, m>(methoxymethyl)triphenylphosphonium chloride (s, t7g) in dimethyl sulfoxide (2
0111Q) solution, add sodium hydride (370 mg
, 60% in oil) and dimethyl sulfoxide (zsmQ) is added at room temperature. After stirring for 30 minutes at room temperature, the mixture was diluted with 3-[(Z)-6-medoxycarbonyl-2 in dimethyl sulfoxide (2).
-hexenyl-4-oxotetrahydropyran (74
0 mg) is added and the solution is stirred for a further 4 hours at room temperature. The reaction mixture was mixed with water (1oomQ) and ethyl acetate (10
The organic layer was separated, washed sequentially with water and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified using a silica gel column (3
0 g) and eluted with a mixture of n-hexane and ethyl acetate (4:'i) to give 3
-[:(Z)-6-Medoxycarbonyl-2-hexenyl]-4-methoxymethylenetetrahydropyran (27
9 mg) as a colorless oil.

'HNMR (CDCl2) δ ppm: 1.6
-1.8 (3H, m), 1.9-2.2 (
3)1. m), 2.2-2.4 (4H, m),
3.2-3.7 (3H, m>, 3.55 (3H
,s), 3.67 (3)(,s).

3.7-3.9 (2H, m), 5.3-5.5
(2)1. m>, 5.84 (IH, 5) 3-[(Z)-6-medoxycarbonyl-2-hexenyl-4-methoxymethylenetetrahydropyran in methanol (10 mfl) and 50% trifluoroacetic acid aqueous solution (10 mm). The mixture solution was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and 4-formyl-□3-[(
z')-6-Medoxycarponyl-2-hexenyl]tetrahydrobilane is obtained as a residue. The residue is dissolved in methanol (10ml).

4-phenyl semicarbazide (200 mg) in solution
and sodium cyanoborohydride (100 mg) are added and the mixture is stirred at room temperature for 2 hours. The mixture was diluted with chloroform (50 m m ) and the solution was washed sequentially with saturated aqueous sodium hydrogen oxide solution and brine.
□Ru. The solution is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue was chromatographed on a silica gel column (10 g), eluting with a mixture of n-hexane and ethyl acetate (3:1). 3-[(Z)
-6-Medoxycarponyl-2-hexenyl]-4-(
4-Phenylsemicarbazidomethyl)tetrahydrobilane (266 mg) is obtained as a pale yellow oil.

'H NMR (CDCl2) δppm: 1.4-
1.7 (58, m), L9-2, 2 (4)1. m
>, 2.2-2.4 (3H.m), 2.7-3.
0 (2H, m>, 3.3-3.5 (2H, m),
3.69 (3H, s).

3, 7-4.1 (2H, m), 5.2-5.5 (
2H. m), 5.97 (1M, s), 7.04 (
IH, t. J=7Hz), 7.28 (3H.

m), 7.34 (IH.s), 7.45 (2H.
．． m>, 8.10 (LH, s) (4) The following compound is obtained in the same manner as in Example 3.

3-[(Z)-6-carboxy-2-hexenyl]-4
-(4-phenylsemicarbazidomethyl)tetrahydrobilane.

IH NMR (CDCl2) δppm: 1.5-
1.8 (4H.m) 2.0-2, 2 (4H.m)
, 2.36 (2H.t.J=7Hz), 2.80
(LH,m), 2.96 (LH.m>, 3.09
(IH.m).

3, 3-3.6 (2H, m), 3.77 (IH.
m>, 3.9-4.0 (2H.m>, 5.4-5
．． 6 (2H, m), 7.05 (IH.t.

, J=8Hz>, 7,2-7.4 (3H.m>,
7.33 (114).

7, 4-7. , 5 (2H,m>, 8.15 (I
H. s) Block] d1 senior ~ (2R.4R,5S)-4-aminomethyl-5-[(Z
)-6-carboxy-2-hexenyl]=2-methyl-
1.3-dioxane (50n+g) in pyridine (0.
51111) solution, phenyl isocyanate (
0. 111111) and stirred at room temperature for 1 hour. Add water (1 ml) to this mixture and stir for 2 hours. The reaction mixture is diluted with ethyl acetate and the organic layer is washed with IN hydrochloric acid. The solvent of the organic layer was evaporated under reduced pressure and the crude residue was purified by preparative ILC (2R, 4R.

5S)-5-['(Z)-6-carboxy-2-hexenyl]-2-methyl-4-(3-phenylureidomethyl)-1,3-dioxane (27 mg) is obtained.

'HNMR (CDCl2) Sppm: 1.32 (
3H, d, J = 5Hz).

1.45 (IH, m), 1.5-1.8 (2H,
m), 2.0-2.4 (4H, m), 2.37 (
2H, t, J=6.5Hz), 3.2-3.5<2H
, m), 3.68 (IH, dd, J=11.3
．． 2Hz>.

3.94 (IH, m), 4.03 (IH, d, J
= 11.3Hz).

4.71 (IH, q, J=5Hz), 5.4-5.
6 (2H, m).

5.74 (1)1. br t, J=6Hz), 7.
02 (LH, m).

7.1-7.4 (4H, m), 7.55 <IH,
br s) Example 24 The following compound is obtained in the same manner as in Example 3.

(2R,4R,5S)-5-[(Z)-6-carpoquin-2-hexenyl]-2-methyl-4-(2-pyridylhydrazotumethyl)-1,3-dioxane.

'HNMR (CDC1a) Sppm: 1.41 (
3H, d, J = 5Hz>.

1.53 (LH, l11), 1.6-1.9
(2H, m), 2.0-2.2 (2H, m>,
2.35-2.55 (4H, m), 3.85 (
18°dd, J=11.3. 2.5Hz), 4.
08 (IH, d.

J=11.3Hz), 4.55 (IH, dd, J
=5. 3Hz>.

4.83 (11,q, J=5Hz>, 5.4-5
．． 6 (2)1. m).

6.76 (1B, br t, J=6Hz), 7
．． 25 (1)1. d.

Claims (1)

[Scope of Claims] 1) Formula: ▲Mathematical formula, chemical formula, table, etc.▼(I) [In the formula, R^1 is hydrogen or a lower alkyl group, R^2 is a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, R^3 is -CH_2NH-R^4, -CH=N-R^4
or -CH_2-R^5 {wherein R^4 is an acyl group, acylamino group, heterocyclic amino group, heterocyclic (lower) alkyl group, or Al (lower)
an alkoxy group, R^5 means an acyloxy group or a heterocyclic (lower) alkoxy group, X means -O- or -CH_2-, or a salt thereof. 2) Formula (a): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R^1 is hydrogen or a lower alkyl group, R^2 is a carboxy (lower) alkyl group or a protected carboxy ( A compound represented by the formula: H_2N-R^4 [wherein R^4 is an acyl group, an acylamino group, a heterocycle Amino group, heterocyclic (lower) alkyl group or Al (lower)
meaning an alkoxy group] or a salt thereof, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I a) (In the formula, R^1, R^2, R^4 and (b) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I b) [In the formula, R^1 and X each have the same meaning as before. has the same meaning as R^3 is -CH_2NH-R^4, -CH=N-R^4
, or -CH_2-R^5 {wherein R^4 has the same meaning as before, and R^5 means an acyloxy group or a heterocyclic (lower) alkoxy group}, R^2_a is a group represented by means a protected carboxy (lower) alkyl group] or a salt thereof is subjected to an elimination reaction of the carboxy protecting group to form the formula: ▲mathematical formula, chemical formula,
There are tables, etc. ▼ (I c) [In the formula, R^1, R^3 and X each have the same meaning as before, and R^2_b means a carboxy (lower) alkyl group] or (c) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I a) (In the formula, R^1, R^2, R^4 and X each have the same meaning as before). By reducing the indicated compound or its salt, the formula: ▲Mathematical formula, chemical formula, table, etc.▼(I d) (In the formula, R^1, R^2, R^4 and X each have the same meaning as before. ); (d) Formula: ▲Mathematical formula, chemical formula, table, etc. ▼(IV) (In the formula, R^1, R^2 and X each have the same meaning as before. and R^6 means a hydroxyiminomethyl group or a hydroxymethyl group) or a salt thereof,
Formula: R^7Y(V) [In the formula, R^7 is an Al (lower) alkyl group or a heterocyclic (lower) alkyl group, Y means an acid residue] by reacting with a compound represented by the formula : ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Ie) [In the formula, R^1, R^2 and X each have the same meaning as before, and R^3_a is an alkoxyiminomethyl group or heterocyclic (lower) alkoxymethyl group] or a salt thereof; or (e) Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (VI) (In the formula, R^1, R^2 and There are chemical formulas, tables, etc. ▼ (I f) (In the formula, R^1, R^2 and X each have the same meaning as before, and R^3_b means an acyloxymethyl group or an acylaminomethyl group). A formula characterized by obtaining the compound shown or its salt: ▲Mathematical formula, chemical formula, table, etc.▼(I) (wherein R^1, R^2, R^3 and X are respectively the preceding and (same meaning) or a method for producing a salt thereof. 3) As an active ingredient, the formula: ▲Mathematical formula, chemical formula, table, etc.▼(I) [In the formula, R^1 is hydrogen or a lower alkyl group, R^2 is a carboxy (lower) alkyl group or a protected carboxy (Lower) alkyl group, R^3 is -CH_2-NH-R^4, -CH=N-R^
4 or -CH_2-R^5 {wherein R^4 is an acyl group, acylamino group, heterocyclic amino group, heterocyclic (lower) alkyl group, or Al (lower)
An alkoxy group, R^5 means an acyloxy group or a heterocyclic (lower) alkoxy group}, X means -O- or -CH_2-], or a thrombophilic compound containing a salt thereof. Xane A_2 antagonist.