JPH06256336A - New compound, its production and production of acetogenin compound - Google Patents

Abstract

PURPOSE:To obtain a new compound producible in high yield with relatively short steps from an easily available inexpensive reagent and useful as a production intermediate for an acetogenin compound having antitumor activity such as muricatacin. CONSTITUTION:The compound of formula I (A is vinylene, ethylene or epoxyethylene; B is OH, halogen or alkoxycarbonylmethyl; (n) is 9-14), e.g. (Z)-2-pentadecen-1-ol. The compound of formula IV which is one of the compound of formula I wherein A is ethynylene and B is OH can be produced by reacting a halogen compound of formula II with 2-propylen-l-ol of formula III. An acetogenin compound of formula IX is produced in high yield by reducing the compound of formula IV, epoxidizing the double bond of the obtained compound of formula V, halogenating the resultant compound of formula VI to obtain a compound of formula VII, reacting with an alkyl acetate and finally cyclizing the obtained epoxy ester compound of formula VIII (R<1> is alkyl).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound and a method for producing the same, and more particularly to a compound useful in producing an acetogenin compound and a method for producing the same. Furthermore, the present invention relates to a method for producing an acetogenin compound using the compound.

[0002]

PRIOR ART The following formula IV-1

[0003]

[Chemical 10]

Mulicatacin represented by the general formula
ur sop ”or“ guana ”
Annona , a tropical fruit called "bana"
is a kind of acetogenin compound having an antitumor activity, isolated from M.

[0005]

[Chemical 11]

A (-)-(4R, 5R) body represented by
Formula IV-1b

[0007]

[Chemical 12]

It exists as a mixture with the (+)-(4S, 5S) form shown by (the former is slightly excessive) [M. J. R
ieser, J .; F. Kozlowski, K .; V. W
ood, and J.D. L. McLaughlin, Te
trahedron Lett. , 32 , 1137-1
140 (1991)].

Further, this muricatacin is a solamin represented by the formula V-1, which exhibits a wide range of physiological activities such as antitumor, insecticidal and antimalarial [J. K. Rup
precht, Y. -H. Hui, and J. L. M
cLaughlin, J .; Nat. Prod. , 53 ,
237-278 (1990)], Formula V-2

[0010]

[Chemical 13]

The reticulacin represented by
latacin) [S. H. Myint, D.M. Cort
es, A.A. Laurens, R.A. Hocquemill
er, M.E. Leboeuf, A .; Cave, J .; Cot
te, and A. -M. Quero, Phytoch
chemistry , 30 , 3335-3338 (199)
1)]] and other acetogenin compounds (annonan
ceos acetogenins) [J. M. Saa
d, Y. -H. Hui, J .; K. Rupprecht,
J. E. Anderson, J. et al. F. Kozlowsk
i, G. -X. Zhao, K .; V. Wood, and
J. L. McLaughlin, Tetrahedro
n , 47 , 2751-2756 (1991)].

Conventionally, the production of mulicatacin has been carried out by the following method.

1) Diel of cyclooctyne and furan
Starting from an s-Alder adduct and undergoing optical resolution along the way to obtain compounds of formula IV-1a and formula IV-1b in multiple steps [G. Scholz and W. Tochter
mann, Tetrahedron Lett. , 3
2 , 5535-5538 (1991), W.W. Tocht
ermann, G.M. Scholz, G .; Bunte,
C. Wolff, E. -M. Peters, K .; Pet
ers, and H.M. G. von Schnerin
g, Liebigs Ann. Chem. , 1992 ,
1069-1080].

2) Method for obtaining a compound of formula IV-1b by stereoselective reduction of ketolactone derived from L-glutamic acid [B. Figadere, JC. Harmang
e, A. Laurens and A. Cave, Te
trahedron Lett. , 32 , 7539-7
542 (1991)].

3) D-glucose in multiple stages according to formula IV-1a
[S. -K. Kang, H .; -S.
Cho, H .; -S. Sim, and B.M. -K. Ki
m, J.M. Carbohydr. Chem. , 11 , 80
7-812 (1992)].

4) Method for leading optically active oxystannanes obtained by asymmetric reduction of acylstannanes with (R)-and (S) -BINAL-H to compounds of formula IV-1a and formula IV-1b [J. A. Marshall and
G. S. Welmaker, Synlett , 199
2 , 537-538].

5) Formula IV-1a directly from the γ, δ-unsaturated ester using the asymmetric oxidation reagents AD-mix-β and AD-mix-α derived from quinine and quinidine.
And methods of obtaining compounds of formula IV-1b [Z. -M. Wa
ng, X. -L. Zhang, K .; B. Sharple
ss, S.S. C. Sinha, A .; Sinha-Bagc
hi, and E. Keinan, Tetrahedr
on Lett. , 33 , 6407-6410 (199
2)]].

[0018]

However, the above-mentioned conventional methods have drawbacks such as an extremely multi-step reaction, and expensive oxidizing and reducing reagents which are not suitable for mass production.

Therefore, an object of the present invention is to provide a novel compound capable of producing an acetogenin compound such as muricatacin in a relatively short step and a high yield using a reagent which is easily available and inexpensive, and a method for producing the same. And a method for producing an acetogenin compound using the compound.

[0020]

Means for Solving the Problems As a result of earnestly advancing research under such circumstances, the present inventors have shown the following formula I

[0021]

[Chemical 14]

(Wherein A represents a vinylene group, an ethynylene group or an epoxyethylene group, B represents a hydroxyl group, a halogen atom or an alkoxycarbonylmethyl group, and n represents an integer of 9 to 14). But the following formula
IV

[0023]

[Chemical 15]

The present invention has been completed by finding that it is useful for producing an acetogenin compound represented by the formula (wherein n has the same meaning as described above).

That is, the compound according to the present invention is a compound represented by the above formula I, and the compound according to the present invention is produced by carrying out any of the following steps (1) to (3).

Formula II

[0027]

[Chemical 16]

(Wherein n represents an integer of 9 to 14 and X represents a halogen atom),
Formula III

[0029]

[Chemical 17]

A step of reacting with 2-propyn-1-ol represented by

Formula I-1

[0032]

[Chemical 18]

A step of reducing the alkynyl alcohol compound represented by the formula (wherein n has the same meaning as defined above).

Formula I-2

[0035]

[Chemical 19]

A step of epoxidizing the double bond of the alkenyl alcohol compound represented by the formula (n has the same meaning as defined above).

Formula I-3

[0038]

[Chemical 20]

A step of halogenating the epoxy alcohol compound represented by the formula (n has the same meaning as described above).

Formula I-4

[0041]

[Chemical 21]

A step of reacting a halogenated epoxy compound represented by the formula (wherein n and X have the same meanings as described above) with an acetic acid alkyl ester.

The method for producing the acetogenin compound represented by the above formula IV according to the present invention is

[0044]

[Chemical formula 22]

(In the formula, R ¹ represents an alkyl group, and n is 9
Represents an integer of -14. ) The epoxy ester compound represented by (4) is cyclized.

In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine. Also,
The number of carbon atoms of the alkoxy moiety in the "alkoxycarbonylmethyl group" is preferably 1 to 10, more preferably 1 to 7, and may be linear, branched or cyclic.
For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, t
-Butoxy group, pentyloxy group, cyclohexyloxy group and the like can be mentioned.

The production method of the compound of formula I will be described below.

[Method 1] Of the compounds of formula I, the alkynyl alcohol compound of formula I-1 (in formula I,
A represents an ethynylene group and B represents a hydroxyl group. ) Manufacturing method

[0049]

[Chemical formula 23]

(In the formula, n and X have the same meanings as described above.) The compound of the formula I-1 is the halogen compound of the formula II and the compound of the formula III.
Of 2-propyn-1-ol. 2-propyn-1-ol of formula III has the formula
It is desirable to convert the acetylide anion with a base before reacting with the halogen compound of II.

To form the acetylide anion, the formula is
2.0 to 2.5 equivalents of base are reacted with the compound of III. In this reaction, it is preferable to dissolve 2-propyn-1-ol of the formula III in advance in a solvent and gradually add dropwise to a solvent containing a base. In advance 2-propyne-
As a solvent for dissolving 1-ol, benzene,
Toluene, xylene, tetrahydrofuran, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dioxane, dimethyl sulfoxide, or a mixed solvent thereof may be mentioned, but any other solvent may be used as long as it does not affect the reaction.

Suitable bases include amides with alkali metals such as lithium and sodium, n-butyllithium, ethylmagnesium bromide and the like. Also,
As a solvent containing a base, liquid ammonia,
Examples thereof include dimethyl sulfoxide, diethyl ether and tetrahydrofuran.

The reaction of the halogen compound of formula II with 2-propyn-1-ol of formula III is usually carried out by adding 1.0 to 2.0 equivalents of the compound of formula III to the compound of formula II. , -70 ° C to -40 ° C, preferably -50 ° C to -40
It is carried out by stirring at 0 ° C. for 2 hours to 3 hours.
The halogen compound of formula II is preferably dissolved in a solvent similar to the above and gradually added dropwise to the solution in which 2-propyn-1-ol of formula III is dissolved. Then, a post-treatment is carried out according to a conventional method to obtain the compound of the formula I-1.

[Method 2] Of the intermediates of formula I, the alkenyl alcohol compound represented by formula I-2 (in formula I,
A represents a vinylene group and B represents a hydroxyl group. ) Manufacturing method

[0055]

[Chemical formula 24]

(In the formula, n has the same meaning as described above.) The compound of the formula I-2 is produced by reducing the alkynyl alcohol compound of the formula I-1.

In this step, it is desirable to adopt the catalytic hydrogenation method. Suitable catalysts used in the catalytic hydrogenation process include platinum catalysts (eg platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, etc.), palladium catalysts (eg palladium sponges,
Palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalyst (eg, reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (eg, reduced cobalt, Raney) Cobalt etc.), iron catalysts (eg reduced iron, Raney iron etc.), copper catalysts (eg reduced copper, Raney copper etc.) and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, pyridine, ethyl acetate, N, N-dimethylformamide, dichloromethane or a mixture thereof. And stirring for 30 minutes to 1 hour.

The reaction temperature for this reaction is not critical. The reaction is usually performed under cooling to heating. Then, a post-treatment is carried out according to a conventional method to obtain the compound of the formula I-2.

[Method 3] Of the compounds of formula I, the epoxy alcohol compound of formula I-3 (in formula I, A
Represents an epoxyethylene group, and B represents a hydroxyl group. ) Manufacturing method

[0061]

[Chemical 25]

(In the formula, n has the same meaning as described above.) In the compound of the formula I-3, the double bond of the alkenyl alcohol compound of the formula I-2 is replaced with hydrogen peroxide or perbenzoic acid, m
Produced by epoxidation with an organic peroxide such as chloroperbenzoic acid, monoperoxyphthalic acid, peracetic acid, t-butyl hydroperoxide.

Asymmetric epoxidation is carried out by the so-called Sharpl
It is carried out by ess oxidation and is carried out in the presence of a catalyst such as a metal oxide complex such as molybdenum, vanadium or titanium. During this reaction, the epoxide can be stereospecifically obtained by epoxidation in the presence of L-(+)-dimethyl tartrate, L-(+)-diethyl tartrate, or the like. That is, the formula I-3a

[0064]

[Chemical formula 26]

About 80% of the (2S, 3R) body represented by
e. e. The above can be obtained, and the formula I-3b

[0066]

[Chemical 27]

It is a by-product compound represented by (2R, 3
S) body is about 20% e. e. It can be suppressed to the following.
For example, tartaric acid ester, which is an asymmetric source, is easily available and a catalytic amount may be used, so that the production cost can be suppressed and industrial mass production is possible.

The epoxidation reaction is usually carried out by adding 1.5 to 2.0 equivalents of an organic peroxide such as t-butylhydroperoxide or cumene hydroperoxide to the compound of the formula I-2. 80 ° C to 25 ° C, preferably -20
It is carried out by stirring at 20 ° C. to −10 ° C. for 20 minutes to 1 hour and then leaving it for 5 days to 1 week. The catalyst and the L-(+)-tartaric acid ester may be added in the usual catalyst amounts.

Examples of the solvent include toluene, xylene, methylene chloride, isooctane, dioxane, dimethyl sulfoxide, and a mixed solvent thereof, but any other solvent may be used as long as it does not affect the reaction.

After completion of the reaction, the compound of the formula I-3 is obtained by post-treatment according to a conventional method.

[Method 4] Of the compounds of formula I, the halogenated epoxy compound of formula I-4 (in formula I, A
Represents an epoxyethylene group, and B represents a halogen atom. ) Manufacturing method

[0072]

[Chemical 28]

(In the formula, R ² represents a reactive group, and n and X have the same meanings as described above.) The compound of the formula I-4 is preferably the compound of the formula I-3 and tosyl chloride, A compound of formula I-6 is obtained by reacting with a sulfonic acid chloride such as mesyl chloride.
After isolation of the compound of 6 or without isolation, by reacting with a halide such as an alkali metal halide,
It is produced by performing halogenation.

The reaction of the compound of formula I-3 with sulfonic acid chloride is carried out in the presence of a base such as trimethylamine, 4-dimethylaminopyridine, pyridine and the like.
1.0 to 1.5 equivalents of base and 1.0 to 1.5 equivalents of sulfonic acid chloride are added to the compound of
It is carried out by stirring at 0 ° C to 20 ° C, preferably 15 ° C to 20 ° C for 5 hours to 6 hours.

Examples of the solvent include benzene, toluene, xylene, carbon tetrachloride, methylene chloride, tetrahydrofuran, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dimethylformamide, chloroform, acetonitrile, ethyl acetate, dioxane, dimethyl sulfoxide, or a compound thereof. A mixed solvent may be used, but any other solvent may be used as long as it does not affect the reaction.

Through the steps described above, a compound of formula I-6 is obtained, and the halide is reacted with or without isolation of the resulting compound of formula I-6.

This reaction is carried out at 10 ° C. to 30 ° C., preferably 20 ° C. to 25 ° C., by adding 5.0 to 10.0 equivalents of a halide to the initially used compound of the formula I-3. , Stirring for 1 to 2 days. After completion of the reaction, post-treatment is carried out according to a conventional method to give a compound of formula I-4
The compound of

[Method 5] A method for producing an epoxy ester compound represented by Formula I-5 (wherein A represents an epoxyethylene group and B represents an alkoxycarbonylmethyl group) among the compounds of Formula I.

[0079]

[Chemical 29]

(In the formula, R ¹ , n and X have the same meanings as described above.) The compound of the formula I-5 was prepared by reacting n in the presence of a base such as isopropylcyclohexylamine and hexamethyldisilazane.
-It is produced by reacting an organolithium compound such as butyllithium with an acetic acid alkyl ester to give a lithium enolate, and then reacting with a compound of the formula I-4.

The number of carbon atoms of the "alkyl group" in the alkyl acetate is preferably 1 to 10, more preferably 1 to 7, and may be linear, branched or cyclic.
For example, methyl, ethyl, n-propyl, isopropyl,
Examples thereof include n-butyl, isobutyl, s-butyl, t-butyl, pentyl, n-hexyl and cyclohexyl.

The reaction of the above-mentioned organolithium compound with acetic acid alkyl ester is carried out in the following manner:
0-1.5 equivalents of organolithium compound and 1.0-
Add 1.5 equivalents of acetic acid alkyl ester to -80
1 ° C. to −40 ° C., preferably −80 ° C. to −60 ° C.
It is carried out by stirring for ~ 2 hours.

As the solvent, an inert (dry) solvent such as benzene, toluene, xylene, methylene chloride, tetrahydrofuran, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dioxane, dimethyl sulfoxide, HMPA (hexamethylphosphoramide), Alternatively, a mixed solvent thereof may be used, but any other solvent may be used as long as it does not affect the reaction.

Subsequently, the compound of the formula I-4 is added to the reaction solution, the temperature of the reaction solution is raised to about room temperature, and post-treatment is carried out according to a conventional method to obtain the compound of the formula I-5.

The steps shown in the above method 1 to method 5 are steps for producing the compound of formula I, and the method for producing the acetogenin compound of formula IV will be described below.

Among the compounds of the formula I, an epoxy ester compound represented by the formula I-5 (in the formula I, A represents epoxyethylene and B represents alkoxycarbonylmethyl), camphorsulfonic acid and p-toluene sulfone are used. Cyclization with an acid, such as an acid, forms the γ-lactone.

This cyclization reaction is carried out by adding 0.5 to 1.0 equivalent of acid to the compound of the formula I-5, and then from 0 ° C to 20 ° C.
It is carried out by stirring at 0 ° C, preferably 0 ° C to 5 ° C for 10 to 20 hours.

Examples of the solvent include benzene, toluene, xylene, carbon tetrachloride, methylene chloride, tetrahydrofuran, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dimethylformamide, chloroform, acetonitrile, ethyl acetate, dioxane, dimethyl sulfoxide, and the like. Alternatively, a mixed solvent thereof may be used, but any other solvent may be used as long as it does not affect the reaction.

After the completion of the reaction, the acetogenin compound of the formula IV is obtained by subjecting it to a post-treatment according to a conventional method.

In this reaction, among the epoxy ester compounds of formula I-5, especially those of formula I-5a

[0091]

[Chemical 30]

By using the (2S, 3R) form represented by:

[0093]

[Chemical 31]

Approximately 80% of the (4R, 5R) form represented by
e. e. The above can be obtained.

Although the acetogenin compound of the formula IV obtained by the above steps has antitumor activity in itself, the solamin (formula V-1),
It can be directed to other acetogenin compounds such as reticulatacin (formula V-2).

[0096]

EXAMPLES Examples and experimental examples will be given to explain the present invention in more detail, but the present invention is not limited thereto.

1) 2-Pentadecyn-1-ol (formula I
-1A) production

[0098]

[Chemical 32]

28 mg (0.45 mol) of 2-propyn-1-ol (formula III) was added to a lithium amide solution prepared by reacting liquid ammonia (450 ml) with metallic lithium (7.0 g, 1.01 mol). Of diethyl ether (50 ml) is added dropwise over 30 minutes. After stirring for 2 hours, n-dodecyl bromide (74.8 g, 0.3 m
ol) in diethyl ether (50 ml) was added over 1 hour.

After stirring for 1 hour, DMSO (dimethylsulfoxide) (85 ml) was added and the ammonia was evaporated. 300m each of diethyl ether and water
l was added and the layers were separated, and the aqueous layer was extracted 3 times with diethyl ether. The diethyl ether layer was washed with water, dried and concentrated, and the resulting crude product was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3: 1).
2-Pentadecyn-1-ol (Formula I-1A) was obtained (47.1 g, 71%).

Mp: 41-42.5 ° C. IR (KBr) ν _max cm ⁻¹ : 3340,3200,2
950, 2930, 2850, 2290, 2230, 1
470, 1130, 1020, 720 ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t,
J = 6.6 Hz), 1.26-1.47 (20H,
m), 1.54 (1H, br, OH), 2.20 (2
H, tt, J = 7.1, 2.2 Hz), 4.25 (2
H, t, J = 2.2 Hz) High resolution EIMS: measured value 224.2134, theoretical value 224.2140 (C ₁₅ H ₂₈ O)

2) Preparation of (Z) -2-pentadecen-1-ol (formula I-2A)

[0103]

[Chemical 33]

2-Pentadecyn-1-ol (Formula I-1
A) (2.95 g, 14.5 mmol) was dissolved in methanol (25 ml), and 5% Pd-CaCO ₃ (50 m) was added.
Using g) as a catalyst, catalytic hydrogenation was carried out. After completion of the reaction, the oily substance obtained by filtration and concentration was purified by silica gel column chromatography and eluted with hexane-ethyl acetate (3: 1) to give (Z) -2-pentadecen-1-ol (formula I -2A) (2.71 g, 91%) was obtained.

IR (film) ν _max cm ^-1 : 333
0,3020,2960,2930,2850,165
_{^{5,1465,1375,1020,720 1 H-NMR (CDCl 3}} ) δ: 0.88 (3H, t,
J = 6.7 Hz), 1.20 (1H, br, OH),
1.26-1.47 (20H, m), 2.08 (2H,
m), 4.20 (2H, m), 5.57 (2H, m) High resolution EIMS: measured value 226.2289, theoretical value 226.2297 (C ₁₅ H ₃₀ O).

3) Preparation of (2S, 3R) -2,3-epoxypentadecanol (formula I-3A)

[0107]

[Chemical 34]

Powdered molecular sieve 4A (1.95)
g) was added to methylene chloride (100 ml) and cooled to 0 ° C. L-(+)-Diethyl tartrate (0.99 g, 4.8 mmol) and tetraisopropoxytitanium (0.82 g, 2.87 mmol) were added to this reaction solution, and after cooling to -20 ° C, t-butyl was added. Hydroperoxide (3M in toluene, 37.6 ml, 113 mmo
1) was added and stirred for 20 minutes.

(Z) -2-pentadecene-
1-ol (formula I-2A) (13.0 g, 57.5 mm
ol) is added and the mixture is stirred for 30 minutes and then left at -12 ° C for 1 week. After completion of the reaction, water was added and the layers were separated, and the aqueous layer was extracted with methylene chloride. The organic layer was washed with water, dried and concentrated, and the residue was recrystallized from hexane to give (2S, 3
R) -2,3-epoxypentadecanol (formula I-3
A) (10.55 g, 76%) was obtained.

Mp: 66 to 67 ° C. Enantiomeric excess: 84% e. e. [ ¹ H-NM of MTPA (methoxytrifluoromethylphenylacetic acid) ester
R analysis] [α] ²⁴ _D : −4.2 ° (c = 2.2, CHCl ₃ ) IR (KBr) ν _max cm ⁻¹ : 3400, 3300, 2
950, 2920, 2850, 1470, 1035, 9
00,875,850,715 ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3 H, t,
J = 6.6 Hz), 1.26-1.58 (22H,
m), 1.74 (1H, br, OH), 3.04 (1
H, ddd, J = 6.6, 5.6, 4.4 Hz), 3.
15 (1H, ddd, J = 6.8, 4.4, 4.2H
z), 3.68 (1H, dd, J = 12.2, 4.2H
z), 3.84 (1H, dd, J = 12.2, 6.8H
z) High resolution EIMS: measured value 242.2247, theoretical value 242.2246 (C ₁₅ H ₃₀ O ₂ ).

4) (2S, 3R) -1-iodo-2,3
-Preparation of epoxy pentadecane (formula I-4A)

[0112]

[Chemical 35]

(2S, 3R) -2,3-epoxypentadecanol (formula I-3A) (4.84 g, 20 mmo)
l), trimethylamine (2.43 g, 24 mmol)
Tosyl chloride (4.57 g, 24 mmol) was added to a solution of 4-dimethylaminopyridine (10 mg) and methylene chloride (200 ml) under ice cooling. After stirring under ice-cooling for 1 hour and further at room temperature for 5 hours, the reaction solution was diluted with methylene chloride, washed with water, dried and concentrated to obtain crude tosylate (formula I-6A).

[0114]

[Chemical 36]

This crude tosylate (formula I-6A) was dissolved in acetone (200 ml) without isolation and sodium iodide (30 g, 200 mmol) was added. After reacting for 2 days at room temperature, the reaction solution was filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (20: 1) to give (2S, 3R)-.
1-iodo-2,3-epoxypentadecane (formula I-4
A) (6.84 g, 97%) was obtained.

[Α] ²⁶ _D : + 41 ° (c = 1.39, CHCl ₃ ) IR (film) ν _max cm ⁻¹ : 2920, 2850,
1470, 1420, 1265, 1180, 1145,
1115, 1020, 955, 850, 835, 82
_{^{0,720,610 1 H-NMR (CDCl 3}} ) δ: 0.88 (3H, t,
J = 6.7 Hz), 1.26-1.58 (22H,
m), 2.95-3.11 (2H, m), 3.26-
3.37 (2H, m) High resolution EIMS: measured value 352.1257, theoretical value 352.1263 (C ₁₅ H ₂₉ OI)

5) Preparation of t-butyl (4S, 5R) -4,5-epoxyheptadecanoate (Formula I-5A)

[0118]

[Chemical 37]

Isopropylcyclohexylamine (3.
39 g, 24 mmol) of tetrahydrofuran (TH
F) (50 ml) solution at −78 ° C. with n-butyllithium (1.56 M in hexane, 15.4 ml, 24 mm
ol) was added and stirred for 1 hour. Acetic acid t was added to this reaction solution.
-Butyl (2.79 g, 24 mmol) in THF (5 m
l) The solution was added and stirred for another hour.

Then, (2S, 3R) -1-iodo-
2,3-Epoxy pentadecane (Formula I-4A) (7.0
4 g, 20 mmol) HMPA (5.2 ml, 30 m
mol) solution was added, the reaction solution was warmed to room temperature, poured into a saturated ammonium chloride solution, and extracted with diethyl ether. The diethyl ether layer was washed with water, dried and concentrated, and the crude ester obtained was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (5: 1) to obtain (4S, 5R) -4,5-epoxyhepta. T-Butyl decanoate (Formula I-5A) (5.53 g, 81%)
was gotten.

[Α] ²⁴ _D : -2.8 ° (c = 1.33, CHCl ₃ ) IR (film) ν _max cm ⁻¹ : 2975, 2950,
2920, 2850, 1730, 1465, 1455,
1390, 1360, 1255, 1150, 850 ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t,
J = 6.7 Hz), 1.26 (20H, br), 1.4
5 (9H, s), 1.50 (2H, m), 1.69-
1.88 (2H, m), 2.40 (2H, m), 2.9
4 (2H, m) high resolution EIMS: measured value 340.2964, theoretical value 340.2977 (C ₂₁ H ₄₀ O ₃ ).

6) (4R, 5S) -5-Hydroxyheptadecane-4-olid [(-)-mulicatacin] (formula IV
-1a) production

T-Butyl (4S, 5R) -4,5-epoxyheptadecanoate (formula I-5A) (128 mg, 0.
38 mmol) in methylene chloride (5 ml) at 0 ° C.
At camphor sulfonic acid (44.1mg, 0.19m
(mol) was added and stirred at that temperature for 15 hours. The residue was recrystallized from hexane-diethyl ether to give (−)-mulicatacin (formula IV-1a) (75 mg,
70%) was obtained. The enantiomer excess rate at this time is MTP.
By ¹ H-NMR analysis of the A ester, 84% e. e.
I found out.

When this compound was recrystallized twice more, 100% e. e. (-)-Muricatacin (Formula IV-
1a) was obtained.

Mp: 73 ° C. [reference value 72 ° C., G. Sc
holz and W. Tochtermann, Te
trahedron Lett. , 32 , 5535 (1
991)]]

[Α] ²⁴ _D : -23.5 ° (c = 1.0
0, CHCl ₃ ) [reference value [α] ²⁴ _D : −22.9 °
(C = 1.1, CHCl ₃ ), G.I. Scholz an
d W. Tochtermann, Tetrahedr
on Lett. , 32 , 5535 (1991)].

IR (KBr) ν _max cm ^-1 : 3400,
2950, 2920, 2850, 1750, 1470,
1375, 1360, 1220, 1190, 1100,
1020, 980, 900, 830, 720

¹ H-NMR (CDCl ₃ ) δ: 0.88
(3H, t, J = 6.7Hz), 1.26-1.53
(22H, m), 1.84 (1H, br, OH), 2.
12 (1H, ddt, J _{3a, 4} = 7.3 Hz, J _{3a, 3b} =
12.7 Hz), 2.24 (1H, ddt, J _{3b, 4} =
7.3 Hz), 2.54 (1H, dt, J _{2a, 3a} = J
_{2a, 3 b = 10.0Hz, J} 2a, 2b = 17.8Hz),
2.63 (1H, dt, J _{2b, 3 a} = 10.0 Hz, J
_{2b, 3b} = 5.4Hz), 3.57 (1H, m), 4.4
1 (1H, dt, J _3,4 = 7.3 Hz, J _4,5 = 4.6
Hz)

¹³ C-NMR (CDCl ₃ ) δ: 14.
0, 22.6, 24.0, 25.4, 28.6, 29.
2, 29.4, 29.5, 31.8, 32.9, 73.
4,82.9,177.4

Elemental analysis: Found C, 71.76%;
H, 11.27%, theoretical value C, 71.78%; H, 1
1.34% (C ₁₇ H ₃₂ O ₃ )

As is apparent from the above examples, since the Sharpless oxidation is adopted as the asymmetric introduction method, L-(+)-tartaric acid ester which is easily available can be used as the asymmetric source. Also, the amount used may be a catalytic amount. Furthermore, muricatacin, which is an acetogenin compound, can be obtained stereospecifically in a relatively short step. Therefore, the manufacturing cost can be reduced,
Since it can be mass-produced, it is useful for industrial production.

[0132]

INDUSTRIAL APPLICABILITY The compound of formula I according to the present invention is useful as a synthetic intermediate in the production of the acetogenin compound of formula IV. Further, the method for producing the compound of formula I according to the present invention can obtain the compound of formula I in high yield. Furthermore, in the method for producing an acetogenin compound according to the present invention, the acetogenin compound of formula IV can be obtained in high yield and stereospecifically using the compound of formula I.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 33/042 8930-4H 69/533 9279-4H 69/606 9279-4H C07D 303/08 303 / 14 303/40 // A61K 31/365 ADU 7431-4C

Claims (4)

[Claims] 1. Formula I (In the formula, A represents a vinylene group, an ethynylene group or an epoxyethylene group, B represents a hydroxyl group, a halogen atom or an alkoxycarbonylmethyl group, and n represents an integer of 9 to 14.). 2. The compound according to claim 1, wherein n is 11. 3. The method for producing a compound according to claim 1, wherein any one of the following steps (1) to (3) is performed. Formula II (In the formula, n represents an integer of 9 to 14, and X represents a halogen atom.), And a halogen compound represented by the formula III: And a step of reacting with 2-propyn-1-ol. Formula I-1 (In the formula, n has the same meaning as described above.) A step of reducing the alkynyl alcohol compound. Formula I-2 (In the formula, n has the same meaning as described above.) A step of epoxidizing the double bond of the alkenyl alcohol compound. Formula I-3 (In the formula, n has the same meaning as described above.) A step of halogenating the epoxy alcohol compound. Formula I-4 (In the formula, n and X have the same meanings as described above.) A step of reacting a halogenated epoxy compound with an acetic acid alkyl ester. 4. Formula I-5: (Wherein R ¹ represents an alkyl group, and n represents an integer of 9 to 14), and the epoxy ester compound represented by the formula IV is cyclized. (In the formula, n has the same meaning as described above.) A method for producing an acetogenin compound.