JP3025706B2 - Optically active bicyclo (2.2.1) heptane-2,3-dicarboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an optically active bicyclo [2.2.1] heptane-2,3-dicarboxylic acid derivative useful as a synthetic intermediate for pharmaceuticals or industrial products, and more particularly to the following general formula:

[0002]

Embedded image Wherein R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl group;

[0003]

Embedded image Wherein G and L each independently represent an oxygen atom or a sulfur atom, R ² represents a lower alkyl group or a lower alkoxycarbonyl group, and R ³ and R ⁴
Each independently represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a lower alkoxycarbonyl group, a lower alkoxyalkyl group or a substituted or unsubstituted aryloxyalkyl group, With respect to the compound represented by

Heretofore, as an optically active compound having a bicyclo [2.2.1] heptane skeleton, for example, JP-A-49-49
JP-A-132069 and JP-A-52-10268 each disclose the following formula:

[0005]

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In the formula, R ^a and R ^b represent a hydrogen atom or a lower alkyl group, or together with a nitrogen atom to which they are bonded, represent a substituent of the following formula:

[0007]

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Wherein R ^c represents a lower alkyl group;
Is an integer of 2 to 4;

The above publication describes that the compound of the above formula exhibits excellent antiarrhythmic activity, and in particular, the degree of its pharmacological activity differs between optical isomers.

[0010] However, the method disclosed in the above publication as a method for producing these optically active compounds is that the final target compound obtained as a racemate is converted into a salt with a chiral organic acid, and then this salt is prepared. Is isolated as a salt of each optical isomer. Such a method is not only complicated in operation, but further reduces the yield of a valuable final target compound obtained through several steps, and is never satisfactory as a method for synthesizing an optically active compound. Absent.

The present inventors have made intensive studies to establish a simple and high-yield production method of an optically active compound of a compound having a bicyclo [2.2.1] heptane skeleton, which is expected as a useful pharmaceutical product. I have piled up. And, this time, the novel compounds represented by the formulas (Ia) and (Ib) are extremely useful as intermediates for synthesizing optically active forms of bicyclo [2.2.1] heptane derivatives. They have found and completed the present invention.

That is, the formulas (Ia) and (Ia)
The compound of -b) is a racemic bicyclo [2.2.1]
It is very easily obtained from heptane-2,3-diendo-dicarboxylic acid-6-endo-hydroxy-γ-lactone derivatives. Further, the compounds of formulas (Ia) and (Ib) are both highly reactive, and easily react with amines, alcohols, thiols, water, etc., and are optically active compounds having various substituents. give. Therefore, the formula (I) of the present invention
When the compounds represented by -a) and (Ib) are used as synthesis intermediates, various optically active compounds having a bicyclo [2.2.1] heptane skeleton can be optically selectively synthesized with high yield. Can be.

As used herein, the term "lower" means that the group or compound to which this term is attached has 1 to 7 carbon atoms,
It preferably means 1 to 4.

The "lower alkyl group" may be either linear or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. , N-pentyl, isopentyl, n-hexyl, isohexyl group and the like.

A "lower alkoxy group" is a lower alkyloxy group in which the lower alkyl moiety has the above-mentioned meaning,
Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy groups and the like.

The "lower alkylsulfonyl group" is a lower alkylsulfonyl group in which the lower alkyl moiety has the above-mentioned meaning, and examples thereof include a methylsulfonyl group and an ethylsulfonyl group.

The "lower alkoxycarbonyl group" is a carbonyl group having a lower alkoxy group having the above meaning as a substituent, and examples thereof include methoxycarbonyl, ethoxycarbonyl and n-propoxycarbonyl.

The "lower alkoxyalkyl group" is a lower alkyl group having a lower alkoxy group having the above meaning as a substituent, and examples thereof include methoxymethyl and methoxyethyl groups.

A “substituted or unsubstituted aryl group” is
It may be monocyclic or polycyclic, and may have one or more substituents on the ring, for example, a lower alkyl group or a lower alkoxy group. Examples of such substituted or unsubstituted aryl groups include phenyl, tolyl, methoxyphenyl, xylyl, α-naphthyl, β-naphthyl and the like.

"Substituted or unsubstituted aralkyl group"
Is an alkyl group in which the alkyl moiety and the aryl moiety are each substituted with a substituted or unsubstituted aryl group having the above-mentioned meaning, and specific examples thereof include benzyl, trityl, p-methoxybenzyl, phenethyl, and α-methylbenzyl. Phenylpropyl, naphthylmethyl group and the like.

The "substituted or unsubstituted aryloxyalkyl group" is an alkyl group in which an alkyl portion and an aryl portion are each substituted by a substituted or unsubstituted aryloxy group having the above-mentioned meanings, for example, phenoxymethyl, methoxy A phenyloxymethyl group and the like are exemplified.

The "halogen atom" includes chlorine, bromine, iodine and fluorine atoms.

The above formula (Ia) provided by the present invention
And the compounds of formulas (Ib) are each optically active, and the compound of formula (Ia) and the compound of formula (Ib) are in a diastereomeric relationship to each other.

Representative examples of the compounds of the formulas (Ia) and (Ib) are as shown in Table 1 below.

[0025]

[Table 1]

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Table 4]

[0029]

[Table 5]

The compounds represented by formulas (Ia) and (Ib) of the present invention can be produced, for example, according to the method shown in the following reaction formula A.

[0031]

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Where R ² , R ³ , R ⁴ , E, G and L
Is as defined above.

Hereinafter, the above method will be described in more detail.

In the above reaction, the racemic compound represented by the formula (III) is converted into an inert solvent such as ethers such as diethyl ether and tetrahydrofuran; hydrocarbons such as benzene, toluene, xylene and cyclohexane; dichloromethane and chloroform. Halogenated hydrocarbons such as N, N-dimethylformamide, acetonitrile and the like, preferably in dichloromethane or tetrahydrofuran, in the presence of a base and a carboxylic acid activating reagent;
General formula

[0035]

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In the formula, R ² , R ³ , R ⁴ , L and G are as defined above, and can be obtained by reacting with any of the optically active heterocyclic compounds represented by

The base which can be used in this reaction includes, for example, alkali metals such as lithium, sodium and potassium; alkaline earth metals such as calcium; alkali metal hydrides such as sodium hydride; alkalis such as calcium hydride Earth metal hydrides; alkali metal hydroxides such as sodium hydride and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrocarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate And so on.

Further, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal carbonates such as sodium acetate and the like; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate Salts; tri (lower) alkylamines such as trimethylamine, triethylamine, N, N-diisopropyl-N-ethylamine; and pyridine, picoline, lutidine, N, N
Pyridine compounds such as N, N-di (lower) alkylaminopyridine such as N-dimethylpyridine; quinoline; N-lower alkylmorpholine such as N-methylmorpholine;
Organic or inorganic bases such as N-di (lower) alkylbenzylamine and the like can be mentioned, preferably
Triethylamine or N, N-dimethylaminopyridine can be used.

These bases can be used in an amount of usually 0.01 to 1.0 equivalent, preferably 0.05 to 0.2 equivalent, per mol of the racemic compound represented by the formula (III).

Examples of the carboxylic acid activating reagent include a carboxylic acid chlorinating agent such as thionyl chloride phosphoryl chloride, phosphorus pentachloride and oxalyl chloride; and a halogenating agent such as ethyl chlorocarbonate, isobutyl chlorocarbonate and methyl chlorocarbonate. Alkyl carbonate compound; dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, or the like can be used. These activating reagents can be used usually within a range of 1.0 to 2.0 equivalents, preferably 1.2 to 1.8 equivalents, per mol of the racemic compound represented by the formula (III).

The compound of the formula (IV) or (V) used in this reaction includes, for example, (4S) or (4R)
4-methyl-1,3-thiazolidine-2-thione, (4
S) or (4R) 4-ethyl-1,3-thiazolidine-
2-thione, (4S) or (4R) 4-isopropyl-
1,3-thiazolidine-2-thione, (4S) or (4
R) 4-methoxycarbonyl-1,3-thiazolidine-
2-thione, (4S) or (4R) (5S) -4-methyl-5-phenyl-1,3-thiazolidine-2-thione, (5R) -4-methyl-5-phenyl-1,3-thiazolidine (4S) or (4R) 1,
A 3-thiazolidine-2-thione derivative can be exemplified.

Further, (4S) or (4R) 4-ethyl-
1,3-oxazolidine-2-thione, (4S) or (4R) 4-isopropyl-1,3-oxazolidine-
2-thione, (4S) or (4R) 4-methoxycarbonyl-1,3-oxazolidine-2-thione, (4S)
Or (4R) -4-isopropyl-5-phenyl-1,
3-oxazolidine-2-thione, (5S) or (5
(4S) or (4R) 1, such as R) -4-isopropyl-5-phenyl-1,3-oxazolidine-2-thione;
A 3-oxazolidine-2-thione derivative can be exemplified.

Further, (4S) or (4R) 4-ethyl-1,3-oxazolidin-2-one, (4S) or (4R) 4-isopropyl-1,3-oxazolidin-
2-one, (4S) or (4R) 4-methoxycarbonyl-1,3-oxazolidin-2-one, (4S) or (4R) -4-methyl-5-ethyl-1,3-oxazolidin-2- Examples of (4S) or (4R) 1,3-oxazolidin-2-one derivatives such as on, (5S) or (5R) -4-methyl-5-ethyl-1,3-oxazolidine-2-one and the like. be able to.

These optically active heterocyclic compounds, for example, (4S) or (4R) 1,3-thiazolidine-2-
Thione derivatives and 1,3-oxazolidine-2-thione derivatives are described by Yoshimitsu Nagao et al. [J. Org. Chem. , 51 ,
2393, 1986], JP-A-59-14479.
No. 4, JP-A-59-144795 and the like. Also,
(4S) or (4R) 1,3-oxazolidin-2-one derivatives can be obtained from Evans et al. [Aldrichmica
Acta 15 , 23, 1982].

The amount of the compound of formula (IV) or (V) used in the reaction is not strictly limited, but is generally 0.7 to 0.7 mol per mol of the compound of formula (III).
1.5 mol, preferably 0.8 to 1.2 mol can be used.

The reaction temperature varies depending on the compound of the formula (IV) or (V), the kind of the carboxylic acid activating reagent to be used, and the like, but is usually in the range of about -40 ° C to about 100 ° C. And the reaction is carried out at that temperature for about 5 minutes to about 24 hours.
It can be done in time.

The compound of the formula (III) used as a starting material in the above reaction is a racemic compound, and is reacted with the optically active heterocyclic compound of the formula (IV) or (V) by the above method. Yields a mixture of the two diastereomers of formulas (Ia) and (Ib). The mixture of diastereomers can be easily separated and purified into respective diastereomers by usual separation and purification means, for example, chromatography, recrystallization and the like.

Formula (Ia) obtained by the above method
The optically active compounds represented by (Ib) and (Ib) are highly reactive, and readily react with, for example, primary or secondary amine compounds, alcohol compounds, thiol compounds, etc. to derive amide compounds, esters, and thioesters. can do. Therefore, the compounds of the formulas (Ia) and (Ib) have optically active bicyclo [2.
2.1] Useful as an intermediate for producing heptane derivatives.

Among the racemic compounds of the formula (III) used as starting materials in the above reaction, those in which the substituent R ¹ is a hydrogen atom or a lower alkyl group are compounds known per se, Those in which ¹ is a phenyl group can be easily produced by reacting phenylmaleic anhydride with cyclopentadiene according to the method described in, for example, JP-A-2-28153.

The formulas (Ia) and (I) of the present invention
When the optically active compound represented by -b) is used, a general formula having excellent antiarrhythmic activity

[0051]

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Wherein R ¹ is a hydrogen atom, a lower alkyl group or a phenyl group; R ⁵ is a hydrogen atom or

[0053]

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Wherein R ¹⁰ , R
¹¹ , R ¹² , R ¹³ and R ¹⁴ each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group or a hydroxy group; R ⁶ represents a lower alkyl group; R ⁷ , R ⁸ and R ⁹ is a hydrogen atom, a halogen atom,
A lower alkoxy group, a lower alkylsulfonyl group, an amino group, a mono- or di- (lower alkyl) amino group, a nitro group or a hydroxy group; a methylene group or a carbonyl group represented by Y ¹ , Y ² , Y ³ and Y ⁴ ; Represents; m is 0
N is an integer of 2 to 4;

A novel bicyclo [2.2.1] represented by
An optically active form of a heptane derivative can be easily produced.

[0056]

EXAMPLES Hereinafter, the present invention will be described in more detail by reference examples and examples, but the scope of the present invention is not limited by these descriptions.

In the following description, abbreviations have the following meanings, respectively.

WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

Embodiment 1

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Racemic compound (1) 3.64 g, 1,3-
2.38 g of thiazolidine-2-thione (2), WSC
5.8 g and 240 mg of dimethylaminopyridine are dissolved in 100 ml of dichloromethane and the solution is stirred at room temperature for 1 hour. The reaction solution was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give the racemic compound (3) as yellow crystals.
68 g (quantitative yield) were obtained.

¹ H-NMR (CDCl ₃ ) δ;
1.80 (3H, m), 2.30 (1H, dd, J = 1
5.0, 2.8 Hz), 2.75 to 2.83 (1H,
m) 3.06-3.19 (2H, m), 3.28-
3.32 (1H, m), 3.43 to 3.54 (1H,
m), 4.35-4.46 (1H, m), 4.58-
4.66 (1H, m), 4.82 to 4.87 (1H,
m) 4.94-4.98 (1H, m).

Reference Example 1

Embedded image

283 mg of the racemic compound (3) obtained in Example 1 was dissolved in 2 ml of tetrahydrofuran, and N- (3,4-dimethoxyphenethyl) was added to this solution.
A solution of 252 mg of -N-methyl-propylenediamine (4) in 2 ml of tetrahydrofuran is added, and the mixture is stirred at room temperature for 1 hour. After the completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel chromatography to give 300 mg of the racemic compound (5) as a pale yellow oily substance (yield 7).
2%).

H ¹ -NMR (CDCl ₃ ) δ: 1.08 to
1.18 (1H, m), 1.64 to 1.84 (4H,
m), 1.95 to 2.08 (1H, m), 2.27 (3
H, s), 2.44 to 2.73 (7H, m), 2.89
~ 2.99 (1H, m), 3.01 to 3.05 (1H,
m), 3.15 to 3.23 (1H, m), 3.48 to
3.54 (2H, m), 3.85 (3H, s), 4.3
4-4.43 (1H, m), 6.70-6.80 (3
H, m).

Reference Example 2

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125 mg of indole-3-carboxylic acid chloride (6) are dissolved in 1 ml of dichloromethane and the solution is cooled to 0 ° C. To this solution is added dropwise a solution of 250 mg of the racemic compound (5) obtained in Reference Example 1 in 1 ml of dichloromethane, and the mixture is stirred at room temperature for 3 hours. The reaction solution is washed with saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography,
269 of the racemic compound (7) as a slightly yellow amorphous powder
mg (80% yield).

IR (CHCl ₃ ): 1695 cm ^-1 H ¹ -NMR (CDCl ₃ ) δ; 1.20 to 1.30 (1
H, m), 1.53-1.85 (4H, m), 2.05
(3H, s), 2.23 to 2.58 (5H, m), 2.
61 to 2.64 (2H, m), 2.80 to 2.90 (1
H, m), 3.15-3.30 (4H, m), 3.40
-3.49 (1H, m), 3.85 (3H, s), 3.
88 (3H, s), 5.10 to 5.20 (1H, m),
6.67 to 6.80 (3H, m), 7.21 to 7.34
(3H, m), 7.95 (1H, s), 8.10-8.
14 (1H, m), 9.22 (1H, brs).

Embodiment 2

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(A) 3.64 g of racemic compound (1), 4
2.9 g of (S) -4-ethyl-1,3-thiazolidine-2-thione (8), 5.8 g of WSC and 240 mg of dimethylaminopyridine are dissolved in 100 ml of dichloromethane, and the solution is stirred at room temperature for 1 hour. The reaction solution was washed successively with water and saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 6.18 g of a mixture of diastereomers (9) as a yellow solid (yield determination). Target) I got it.

(B) The mixture of diastereomers (9) obtained in the above (a) was subjected to silica gel chromatography (silica gel 220 g, elution solvent: n-hexane-ethyl acetate (75:25)), Each diastereomer (9a) and (9b) was isolated.

Under the above conditions, the diastereomer (9a) eluted first was 2.99 g (yield 49) as yellow crystals.
%), And 2.69 g (44% yield) of a diastereomer (9b) eluted later as yellow crystals.

¹ H-NMR (CDCl ₃ , δ ppm): diastereomer (9a) ; 1.00 (t, 3H, J =
7.42 Hz), 1.58 to 1.82 (m, 3H),
1.84 to 2.00 (m, 2H), 2.88 (dd, 1
H, J = 2.8, 14.7 Hz), 2.71 to 2.80
(M, 1H), 2.89 (d, J = 11.0 Hz),
3.05 (dd, 1H, J = 5.0, 10.7 Hz),
3.26 to 3.30 (m, 1H), 3.70 (dd, 1
H, J = 7.0, 11.0 Hz), 4.81 to 4.86
(M, 1H), 4.90-4.97 (m, 2H).

Diastereomer (9b) ; 0.99
(T, 3H, J = 7.4 Hz), 1.60 to 1.75
(M, 3H), 1.81 to 1.95 (m, 2H), 2.
47 (dd, 1H, J = 2.6, 14.5 Hz);
62 to 2.70 (m, 1H), 2.96 (dd, 1H,
J = 1.3, 11.0 Hz), 3.15 (dd, 1H,
J = 5.10, 4 Hz), 3.27 to 3.30 (m, 1
H) 3.51 (dd, 1H, J = 7.8, 11.0H)
z) 4.83-4.92 (m, 2H), 5.07-
5.15 (m, 1H).

Example 3 According to the method described in Example 1 above, a mixture of diastereomers shown below was obtained, and each diastereomer was separated and purified by silica gel chromatography.

In addition, among the following diastereomers,
(10a), (11a), (12a), and (13a)
Is the one previously eluted by column chromatography (elution solvent; n-hexane-ethyl acetate),
b), (11b), (12b), and (13b) showed the later eluted.

Mixture (10)

Diastereomer (10a) ; yield: 46
% ¹ H-NMR (CDCl ₃ , δ ppm); 0.98 (t,
3H, J = 7.6 Hz), 1.26 (s, 3H), 1.
50 to 1.75 (m, 3H), 1.76 to 2.05
(M, 2H), 2.26 (dd, 1H, J = 3.2, 1
4.4 Hz), 2.86 to 2.88 (m, 2H), 2.
95 (d, 1H, J = 11.2 Hz), 3.63 (d
d, 1H, J = 6.4, 11.2 Hz), 4.58 (d
d, 1H, J = 1.7, 1.5 Hz), 4.82 (d
d, 1H, J = 5.4, 8.1 Hz), 4.99-5.
06 (m, 1H).

Diastereomer (10b) ; yield: 42
% ¹ H-NMR (CDCl ₃ , δ ppm); 0.99 (t,
3H, J = 7.4 Hz), 1.28 (s, 3H), 1.
58-1.71 (m, 3H), 1.77-1.97
(M, 3H), 2.78 (brs, 1H), 2.86-
2.88 (m, 1H), 2.97 (dd, 1H, J =
2.0, 11.4 Hz), 3.49 (dd, 1H, J =
7.6, 11.4 Hz), 4.79 (dd, 1H, J =
5.1, 8.1 Hz), 5.03 (dd, 1H, J =
1.7, 3.0 Hz), 5.05-5.14 (m, 1
H).

Compound (11)

Diastereomer (11a) ; yield: 47
_{^{% 1 H-NMR (CDCl 3}} , δppm); 1.55~1.
80 (m, 3H), 2.16 (dd, 1H, J = 2.
6,4.9 Hz), 2.77 (brs, 1H), 2.9
9 (dd, 1H, J = 5.2, 10.7 Hz), 2.2
2-3.37 (m, 2H), 3.69-3.78 (m, 2H)
1H), 3.75 (s, 3H), 4.77 (dd, 1
H, J = 4.8, 8.1 Hz), 4.85 to 4.95
(M, 1H), 5.43 (d, 1H, J = 12.0H
z).

Diastereomer (11b) ; yield: 45
_{^{% 1 H-NMR (CDCl 3}} , δppm); 1.66~1.
75 (m, 3H), 2.55 (dd, 1H, J = 2.
7,14.5 Hz), 2.76 (brs, 1H), 3.
05 (dd, 1H, J = 4.8, 10.4 Hz);
29 to 3.33 (m, 1H), 3.43 (dd, 1H,
J = 2.8, 11.6 Hz), 3.65 (dd, 1H,
J = 8.3, 11.6 Hz), 3.83 (s, 3H),
4.82 to 4.90 (m, 2H), 5.59 (dd, 1
H, J = 2.6, 8.2 Hz).

Compound (12)

Diastereomer (12a) ; yield: 35
% ¹ H-NMR (CDCl ₃ , δ ppm); 0.91 (t,
3M, J = 7.5 Hz), 1.27 (s, 3H), 1.
63-1.91 (m, 5H), 2.02 (dd, 1H,
J = 3.3, 14.6 Hz), 4.30 (dd, 1H,
J = 2.5, 9.1 Hz), 4.47 (t, 1M, J =
9.1 Hz), 4.70 to 4.84 (m, 2H);
94 (dd, 1H, J = 1.3, 3.0 Hz).

Diastereomer (12b) ; yield: 30
% ¹ H-NMR (CDCl ₃ , δ ppm); 0.92 (t,
3M, J = 7.6 Hz), 1.29 (s, 3H), 1.
60-1.79 (m, 4H), 1.84-1.93
(M, 1H), 2.06 (dd, 1H, J = 2.7, 1
4.5 Hz), 2.76 (brs, 1H), 3.05
(Dd, 1H, J = 3.3, 14.5 Hz), 2.80
~ 2.89 (m, 1H), 2.90 ~ 2.95 (m, 1
H), 4.27 (dd, 1H, J = 4.0, 8.9H)
z), 4.49 (t, 1H, J = 8.9 Hz), 4.6
7 to 4.76 (m, 1H), 4.81 (dd, 1H, J
= 5.1, 8.1 Hz), 5.08 (dd, 1H, J =
1.7, 3.0 Hz).

Compound (13)

Diastereomer (13a) ; Yield: 47
% ¹ H-NMR (CDCl ₃ , δ ppm); 0.97 (d,
3M, J = 6.6 Hz), 1.61-1.82 (m, 3
H), 2.35 (dd, 1H, J = 3.2 Hz, 14.3).
4 Hz), 2.81 (brs, 1H), 3.24-3.
35 (m, 2H), 4.78 to 4.90 (m, 2H),
4.96 to 5.01 (m, 1H), 5.89 (dd, 1
H, J = 6.6 Hz), 7.32 to 7.45 (m, 5
H).

Diastereomer (13b) ; yield: 40
% ¹ H-NMR (CDCl ₃ , δ ppm); 0.92 (d,
3M, J = 6.6 Hz), 1.64 to 1.77 (m, 3
H), 2.48 (dd, 1H, J = 2.7, 14.2H)
z), 2.74 (brs, 1H), 3.31-3.35
(M, 2H), 4.83 to 4.90 (m, 1H), 5.
01 to 5.10 (m, 2H), 5.75 (d, 1H, J
= 7.2 Hz), 7.32 to 7.43 (m, 5H).

[0088]

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According to the method described in Example 1 (a), the racemic compound (1) is reacted with the optically active thiazolidine derivative represented by the formula (14) to obtain a mixture of diastereomers (15). Was obtained as a yellow solid (yield 70
%).

¹ H-NMR (CDCl ₃ , δ ppm);
0.98 to 1.07 (m, 6H), 1.45 to 2.10.
(M, 5H), 2.93-3.03 (m, 2H), 3.
42 to 3.65 (m, 2H), 4.90 to 5.0 (m, 2H)
1H), 4.90-5.0 (m, 1H), 5.30-
5.40 (m, 1H), 5.76 to 5.78 (m, 1
H), 7.27-7.43 (m, 5H).

Continuation of the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 413/06 C07D 417/06 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl group; Wherein G and L each independently represent an oxygen atom or a sulfur atom, R ² represents a lower alkyl group or a lower alkoxylcarbonyl group, R ³ and R ⁴ each independently represent a hydrogen atom, A compound represented by the formula: lower alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, lower alkoxycarbonyl group, lower alkoxyalkyl group, or substituted or unsubstituted aryloxyalkyl group.