JP2789365B2 - Dicarboxylic acid monoester and production method thereof - Google Patents

Description

The present invention is useful for asymmetric synthesis of various compounds derived from natural products, and more specifically, dicarboxylic acids useful for the synthesis of optically active prostaglandins and the like. The present invention relates to monoesters and a method for producing the same.

Prior art Diels-Alder reaction and enzymatic hydrolysis of diester moieties are known methods for obtaining optically active dicarboxylic acid monoesters. However, it has been very difficult to obtain a pure compound easily, in large quantities and at low cost by using a special reagent.

Problems to be Solved by the Invention Obtaining a compound having high optical purity by asymmetric synthesis has an important meaning not only for the synthesis of natural organic compounds but also for the synthesis of various compounds including drugs in a broad sense.

The present invention is an intensive study of an asymmetric synthesis method capable of further increasing the optical purity by allowing the reaction to proceed stereoselectively and removing very few by-products generated in the reaction process very easily. It should be noted that the present invention also intends that the above reaction can be carried out easily with an inexpensive reagent.

Means to solve the problem The present inventors have made intensive studies in view of the above points,
It has been found that a dicarboxylic acid monoester having a desired configuration can be selectively obtained by reacting an (R)-or (S) -arylacetic acid derivative with an acid anhydride having σ symmetry, and completed the present invention. did. Although details will be described later, in this reaction, by-products generated during the reaction can be easily removed by recrystallization. The asymmetric synthesis method provided by the present invention provides various σ
It is applicable to acid anhydrides having symmetry, and the resulting dicarboxylic monoesters are useful for the synthesis of various prostaglandins, amino sugars, nucleotides, terpenes, alkaloids, steroids, and other useful compounds derived from natural products. It is extremely important as a body.

The present invention provides such important intermediates of the general formula: Wherein R ¹ is (1) alkyl, alkoxy, halogen,
Alkyl optionally substituted with amino, amino derivative or nitro, (2) alkyl, alkoxy, halogen, amino, alkenyl optionally substituted with amino derivative or nitro, (3) alkyl, alkoxy, halogen, amino, An amino derivative or an aryl optionally substituted with nitro or (4) an alkyl, alkoxy, halogen, amino, amino derivative or an aralkyl optionally substituted with nitro, -X- is -O
-, - S -, - ( CH 2) m-, (Wherein, m represents an integer of 0 to 4, R ² represents hydrogen, methyl or ethyl, R ³ represents hydrogen, methyl, benzyloxycarbonyl or formyl) Y represents (CH ₂ ) n, (In the formula, n represents an integer of 0 to 3, R ² has the same meaning as described above, and R ⁴ represents hydrogen, methyl or ethyl.) Z represents hydrogen, lower alkyl or phenyl (provided that m is And n are simultaneously 0, then (1S, 2R, 3S, 4R) −
7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid 2-methyl ester, (1S, 2R, 3S, 4R) -bicyclo [2.2.1] heptene-2,3-dicarboxylic acid 2-methyl ester And optically active dicarboxylic monoesters represented by (1R, 2S, 3R, 4S) -bicyclo [2.2.1] heptene-2,3-dicarboxylic acid 2-methyl ester
III and, furthermore, a general formula for obtaining this: (Wherein, X, Y and Z have the same meanings as described above). (Wherein M ¹ is hydrogen or a metal atom, R ⁵ is hydrogen, (2) alkyl optionally substituted with alkyl, alkoxy, halogen, amino, amino derivative or nitro or (3) alkyl, alkoxy, halogen, An amino, an amino derivative or an aralkyl optionally substituted with nitro, Ar represents an alkyl, an alkoxy, a halogen, an amino, an amino derivative or an aryl optionally substituted with nitro; Reaction of the S) -arylacetic acid derivative with the general formula: (Wherein, R ⁵ , X, Y, Z and Ar have the same meanings as described above), and then the ester II is subjected to an esterification reaction to introduce R ^1. , An arylacetic acid derivative residue is removed or the ester II is represented by the general formula: R ¹ OM ² IV (where R ¹ is (1) alkyl, alkoxy, halogen,
Alkyl optionally substituted with amino, amino derivative or nitro, (2) alkyl, alkoxy, halogen, alkenyl optionally substituted with amino, amino derivative or nitro, (3) menthyl, (4) alkyl, alkoxy Aryl optionally substituted with halogen, amino, amino derivative or nitro or (5)
Alkyl, alkoxy, halogen, amino, amino derivative or aralkyl optionally substituted with nitro, and M ² represents an alkali metal atom or an alkaline earth metal atom). Characteristic general formula: (Wherein R ¹ , X, Y and Z have the same meanings as described above), which provides an asymmetric synthesis method for obtaining an optically active dicarboxylic acid monoester III represented by the following formula: As a body, the general formula: (Wherein, R ⁵ , X, Y, Z and Ar have the same meanings as described above)
II is also offered as high purity.

In a preferred embodiment, the general formula: Wherein R ¹ is (1) alkyl, alkoxy, halogen,
Alkyl optionally substituted with amino, hydroxyamino, alkylamino or nitro, (2) alkyl,
Alkenyl optionally substituted with alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro, (3) aryl optionally substituted with alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro or ( 4) alkyl,
Aralkyl which may be substituted with alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro], and optically active dicarboxylic acid monoesters represented by the following formulas and enantiomers thereof.

In another embodiment, the general formula: [Wherein, X is -O -, - S -, - (CH 2) m- or (Wherein, m represents an integer of 0 to 4, R ² represents hydrogen, methyl or ethyl) Y represents (CH ₂ ) n or (In the formula, n represents an integer of 0 to 3, and R ² has the same meaning as described above.) Z represents hydrogen, lower alkyl or phenyl (except when m and n are simultaneously 0)] The acid anhydride I represented by the general formula: (Wherein, M ¹ is hydrogen or a metal atom, R ⁵ is (1) hydrogen,
(2) alkyl optionally substituted with alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro; or (3) alkyl substituted with alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro. Good aralkyl,
Ar represents alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or aryl optionally substituted with nitro), and reacting an (R)-or (S) -arylacetic acid derivative represented by the general formula : (Wherein, R ⁵ , X, Y, Z and Ar have the same meanings as described above), and then the ester II is subjected to an esterification reaction to introduce R ^1. , An arylacetic acid derivative residue is removed or the ester II is represented by the general formula: R ¹ OM ² IV (where R ¹ is (1) alkyl, alkoxy, halogen,
Alkyl optionally substituted with amino, hydroxyamino, alkylamino or nitro, (2) alkyl,
Alkenyl optionally substituted with alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro, (3) menthyl, (4) alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro; Aryl or aralkyl optionally substituted with (5) alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro, and M ² represents an alkali metal atom or an alkaline earth metal atom. A compound of the general formula: (Wherein R ¹ , X, Y and Z have the same meanings as described above), and an asymmetric synthesis method for obtaining an optically active dicarboxylic acid monoester III represented by the following formula:

Further, as another embodiment, as a synthetic intermediate via the above reaction step, a compound represented by the general formula: (Wherein, R ⁵ , X, Y, Z and Ar have the same meanings as described above)
II.

Hereinafter, the present invention will be described in more detail by showing a reaction process diagram.

Method for producing trans dicarboxylic acid monoester (In the formula, R ¹ , R ⁵ , X, Y, Z, Ar and M ¹ have the same meanings as described above.) First Step To the σ-symmetric prochiral cyclic anhydride represented by the compound I, The target compound II-D can be obtained by reacting the (R) -arylacetic acid derivative in a solvent.

The reaction is completed when the reaction is carried out at about -100 to about 50C, more preferably at about -78 to about 0C for about several ten minutes to several hours.

Examples of the solvent include tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, n-hexane, DMSO, toluene, HMPA and the like.

At this time, depending on the aryl acetic acid derivative used, the desired product II
-D, and the free carboxylic acid type is II-D
(A) The ester type is represented by II-D (e). Compound II-D (a) can be easily crystallized and isolated, and the impurities can be separated, so that it can be subjected to the next reaction. Compound II-D (e) can be subjected to a deprotection reaction to give compound II-D (a), if desired, and then subjected to the next reaction.

As the deprotection reaction, a reaction performed under neutral to acidic conditions is recommended. That is, it is necessary to perform deprotection while maintaining the ester bond between the arylacetic acid residue and the carbonyl bonded to the ring, but this is not suitable under alkaline conditions because the ester bond is broken. Usually, a reductive deprotection reaction is carried out under neutral conditions using palladium-carbon. However, when the compound has a functional group which is easily reduced or when X and Y have a double bond, they may be hydrogenated to form a single bond. If you want to deprotect while keeping the functional group or double bond,
Deprotection may be performed under acidic conditions using a reagent such as trifluoroacetic acid, aluminum chloride, hydrochloric acid, or zinc-acetic acid. The desired protecting group can be cleaved by subjecting it to a thermal decomposition reaction using LiI, LiCl, NaCl, or the like.

Second step The target compound III-D is obtained by transesterifying compound II-D with a compound represented by the general formula: R ¹ OM ² IV (wherein R ¹ or M ² has the same meaning as described above) and stereochemistry. It can be obtained by subjecting it to a selective isomerization reaction.

Examples of the compound IV represented by the above general formula include alkoxides of alkali metals or alkaline earth metals, aryl oxides, alkenyl oxides, menthyl oxides, aralkyl oxides and the like.

As the alkali metal or alkaline earth metal alkoxide, sodium methoxide, lithium methoxide,
Magnesium ethoxide and the like.

As the alkali metal or alkaline earth metal aryl oxide, sodium phenoxide, lithium phenoxide, magnesium phenoxide, sodium-α-
Naphthoxide, lithium-β-naphthoxide and the like can be mentioned.

Examples of the alkali metal or alkaline earth metal alkenyl oxide include sodium allyl oxide, lithium allyl oxide, and magnesium allyl oxide.

Examples of the alkali metal menthyl oxide include sodium menthyl oxide and lithium menthyl oxide.

Examples of the alkali metal aralkyl oxide include sodium benzyl oxide and lithium benzyl oxide.

As the solvent, methanol, ethanol, allyl alcohol, phenol, or the like is used, and if necessary, menthyl alcohol, pyridine, tetrahydrofuran, or the like may be added.

The reaction temperature is from about -30C to about 150C, more preferably,
The reaction is performed at about 0 ° C. to about 80 ° C., and the reaction is completed in about 1 to about 10 hours.

In the first step, a small amount of a by-product is represented by the following general formula: (Wherein R ⁵ , X, Y, Z and Ar have the same meanings as described above), which, if necessary, can be subjected to a deprotection reaction. Dicarboxylic acid II'-D
(A) (where R ⁵ is hydrogen)
100% of by-product II'-D can be removed, and pure product II-
D can be used in the next second step. II-D and II '
-D can be separated and purified using chromatography.

Further, II-D and II'-D in the first step can be subjected to the next reaction as a mixture without separation.

(In the formula, R ¹ , R ⁵ , X, Y, Z, Ar and M ¹ have the same meanings as described above.) First Step The compound (S) -aryl acetic acid derivative is prepared by the method described above (R The target compound II-L is obtained by reacting in the same manner as in the first step of the) -arylacetic acid derivative. The obtained target product II-L depends on the aryl acetic acid derivative used.
Two types are available, and the free carboxylic acid type is represented by II-L (a) and the ester type is represented by II-L (e). Compound
II-L (a) crystallizes and can be easily isolated.

Second step The compound II-L obtained in the first step is converted to the D
By reacting in the same manner as in the second step of the
I-L is obtained.

In the first step, a small amount of by-products represented by the following general formula: (Wherein R ⁵ , X, Y, Z, and Ar have the same meanings as described above), which is represented by the following formula:
It can be separated in the same manner as when the D-form arylacetic acid derivative is used, and the mixture can be subjected to the next reaction as it is. Similarly, the ester can be separated and purified by chromatography.

The by-products II′-D and II′-L are subjected to the reaction in the second step, whereby the by-products II′-D are converted to the target product III-L and the by-products II′-L. Is the target III-D
Can also be obtained.

Production of cis-dicarboxylic acid monoester [Production of compound III-D-2] Compound II obtained in the same manner as in the first step of Method A and Method B for production of trans-dicarboxylic acid monoester
(Compounds II-D, II'-D, II-L or II'-L).

(Wherein R ¹ , X, Y and Z have the same meanings as described above, and R ⁵ ′
Represents an optionally substituted alkyl, an optionally substituted alkenyl, a menthyl, an optionally substituted aryl or an optionally substituted aralkyl. ) The first step In this step a free carboxylic acid of the compound II-D or II'-L esterified, is a step of introducing the R ^1.

The esterification reaction is carried out while maintaining the ester bond between the arylacetic acid derivative and the ring-bonded carbonyl and the configuration at the 2-position. Diazoalkanes having a desired R ¹ -forming group (eg, diazomethane, diazoethane, diphenyldiazomethane, phenyldiazomethane, etc.), alcohols (methanol, ethanol, propanol, isopropanol, tert-butanol, benzyl alcohol, phenethyl alcohol, naphthylmethyl alcohol, menthol) , Phenol, nitrophenol, methylphenol, chlorophenol, methoxyphenol, aminophenol, etc.) according to a conventional method.

In order to accelerate the reaction, an acid such as formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid and the like may be used.

Step 2 In this step, the ester bond between the arylacetic acid derivative and the ring-bonded carbonyl is cleaved to give a cis-type compound II of the present invention.
This is a step of obtaining ID-2.

Since it is necessary to carry out the deesterification reaction while maintaining the configuration, it is usually preferable to carry out the reduction under neutral conditions with palladium-carbon.

(Wherein R ¹ , R ⁵ ′, X, Y and Z have the same meanings as described above.) Using compound II-L or II′-D, compound III-
Compound III-L-2 can be obtained by reacting D-2 in the same manner as in the above first and second steps.

The aryl acetic acid derivative monoester of the compound of the present invention represented by the general formula II includes II-D and II 'as described above.
It contains four stereoisomers, -D, II-L and II'-L.

The dicarboxylic acid monoester of the compound of the present invention represented by the general formula III has 4 asymmetric carbon atoms, and has a total of 8 stereoisomers and optical isomers. The present invention includes all such isomers. Specifically, a compound having a configuration represented by the following general formula (Wherein R ¹ , X, Y and Z have the same meanings as described above) and their enantiomers.

General formula: The enantiomer of an optically active dicarboxylic acid monoester represented by the following general formula: Is a compound having the following configuration:

 The terms used in the above definition will be described.

As alkyl, methyl, ethyl, isopropyl,
n-propyl, n-butyl, isobutyl, t-butyl,
Examples include sec-butyl, pentyl, neopentyl and the like.

As alkenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-
Methyl-3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, prenyl and the like.

Aryl includes phenyl, α- or β-naphthyl and the like.

Aralkyl includes benzyl, phenethyl, naphthylmethyl and the like.

Examples of the metal atom mainly include an alkali metal atom and an alkaline earth metal atom.Examples of the alkali metal atom include lithium, sodium, and potassium, and examples of the alkaline earth metal atom include magnesium and calcium. Zinc is also used.

As the bicyclo ring, a norbornane type (bicyclo [2.
2.1] heptane, bicyclo [2.2.1] hept-5-ene, etc.) or 7-oxabicyclo [2.2.1] heptane,
7-oxabicyclo [2.2.1] hept-5-ene, 7-
Azabicyclo [2.2.1] heptane, 7-azabicyclo [2.2.1] heptane-5-ene, 7-thiabicyclo [2.
2.1] Heptane, 7-thiabicyclo [2.2.1] heptane-
5-ene and the like.

The acid anhydride to be used is applicable to bicyclic or tricyclic cyclic anhydrides having σ symmetry.

Examples of the substituent which may be present on the alkyl, alkenyl, aryl and aralkyl include the above-mentioned alkyl and alkoxy, halogen, amino, amino derivative and nitro.

Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy and the like.

Halogen includes fluorine, chlorine, bromine and iodine.

Examples of the amino derivative include hydroxyamino and alkylamino.

EXAMPLES Hereinafter, the present invention will be described in more detail by way of Examples and Reference Examples, but they do not limit the present invention in any way.

Abbreviations used in Tables, Examples and Reference Examples are described below.

Me: methyl CH ₂ Ph: benzyl Et; ethyl CHPh ₂ : benzhydryl Bu: butyl Ph: phenyl THF: tetrahydrofuran DMF: dimethylformamide HMPA: hexamethylphosphoramide D-Mande: D-mandelic acid and its ester L-Mande: L -Mandelic acid and its ester PCC: pyridinium chlorochromate PMB: p-methoxybenzyl Example 1 (1S, 2R, 3S, 4R) -bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic acid 2- Preparation of (benzyl D-mandelate) ester II-1-D (e1) Under a nitrogen atmosphere, D-mandelic acid benzyl ester (5.
33g, 22.0mmol) was dissolved in THF (50ml), cooled to -78 ° C, and n-BuLi (1.6M hexane solution 13.13ml, 21.0mmo)
l) is added dropwise and stirred for 15 minutes. Bicyclo [2.
2.1] A solution of hepta-5-ene-2-endo, 3-endo-dicarboxylic anhydride I-1 (3.32 g, 20.0 mmol) in THF (20 ml) is added. After stirring at -78 ° C for 1 hour, 2N hydrochloric acid is added, and the mixture is extracted with ethyl acetate. After washing with water and brine and concentrating, the target product II-1-D (e1) and by-product II'-1 were obtained.
-D (e1) is obtained (II-1-D (e1) + II'-1-)
D (e1) = 9.33 g). Compound II-1-D (e1) is purified by silica gel calama chromatography (toluene = ethyl acetate).

IR (liquid film): 3600-2400,1748,1710,1498,1456,1342,125
7,1208,1165,1084,1072,912,732,696 ¹ H-NMR (CDCl ₃ -TMS) δ ppm: 1.33 (ABq, Apart, J = 8.9
Hz; 1H), 1.48 (ABq, Bpart, J = 8.9 Hz, 1H), 3.16 (br.s, 1
H), 3.21 (br.s, 1H), 3.30 (dABq, Apart, J = 3.2,10.2H
z, 1H), 3.47 (dABq, Bpart, J = 3.4Hz, 10.2Hz, 1H), 5.13
(S, 2H), 5.97 (s, 1H), 6.11 (dABq, Apart, J = 2.9H, 5.9
Hz, 1H), 6.28 (dABq, Bpart, J = 2.8,5.9Hz, 1H), 7.13 ~
7.52 (m, 10H) Example 2-7 The target compound II-D (e), II-D (a) or II was reacted in the same manner as in Example 1 as shown in the following reaction formula.
-Obtain L (e).

 Table 1 shows the reaction conditions.

(Wherein, R ⁵ , X, Y and Z have the same meanings as described above.) In Table 1, the target product II-2 obtained in Example 5 was used.
The mixture of -D (e1) and by-product II'-2-D (e1) is
Purification by toluene-ethyl acetate after silica gel column chromatography yields only the target compound II-2-D (e1) (75 g, isolated yield: 78.6%). Elemental analysis (C ₁₈ H ₂₀ O _6. 0.2 H ₂ O) calculated value (%): C, 64.35: H, 6.13 Found (%): C, 64,37; H, 6.49 1 H-NMR (CDCl 3 -TMS) δ ppm: 1.37~2.00 (M, 6H), 2.6
2 (br.S, 2H), 3.06 (dABq, Apart, J = 3.0,12.0Hz, 1H),
3.22 (dABq, Bpart, J = 3.0,12.0Hz, 1H), 3.74 (s, 3H),
6.01 (s, 1H), 7.33 to 7.55 (m, 5H) ▲ [α] ²⁴ _D ▼ = -70.2 ± 0.6 ゜ (CHCl ₃ , C = 1.965%) The same applies to other compounds. D
(E1), II-1-D (e2), II-1-D (e3), II-2
-D (a1) and II-2-l (e1) were isolated.

Example 8 (IR, 2R, 3S, 4S) -bicyclo [2.2.1] heptane-2,3-
Dicarboxylic acid 2-D-mandelic acid) -ester II-2
-Manufacture of D (a1) Crude product II-1-D in 10% palladium on carbon (0.4 g)
(E1) Methanol solution (30 ml) of (4.06 g, 10.0 mmol)
, And stirred at room temperature under a hydrogen atmosphere at room temperature for 1.5 hours.
The catalyst is filtered off and concentrated. Ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution are added to the reaction mixture, and the aqueous layer is separated. The organic layer is washed again with water, and the first aqueous layers are combined and washed with ethyl acetate. After adding 2N hydrochloric acid, extracting with ethyl acetate, washing with saturated saline, and concentrating, the crude product II-2 was obtained.
-D (a1) is obtained [3.14 g, yield from acid anhydride: 99
%, II-2-D (a1): II'-2-D (a1) = 86: 14 (HP
LC)).

The target compound II- was recrystallized from ethyl acetate.
2-D (a1) is isolated (2.05 g, yield: 64%).

After concentration of the mother liquor, recrystallization from methylene chloride gives II'-2-D (a1) as a by-product.

II-2-D (a1) Melting point: 164 to 166 ° C Elemental analysis (as C ₁₇ H ₁₈ O ₆ ) Calculated value (%): C, 64.13; H, 5.71 Actual value (%): C, 63.83; H, 5.73 ¹ H-NMR (CDCl ₃ , TMS) δ ppm: 1.46 (br.s, 4H), 1.57-
1.75 (m, 1H), 1.84 to 2.08 (m, 1H), 2.40 to 2.62 (m, 2
H), 3.02 (dABq, Apart, J = 3.6,11.6Hz, 1H), 3.29 (dAB
q, Bpart, J = 4.4,11.6Hz, 1H), 5.86 (s, 1H), 7.33-7.65
(M, 5H) ▲ [α] ²⁵ _D ▼ = -117.1 ± 0.8 ゜ (MeOH, C = 1.934%) II'-2-D (a1) Melting point: 157-158 ° C. Elemental analysis (C ₁₇ H ₁₈ O ₆ ) calculated value (%): C, 64.13; H, 5.71 Found (%): C, 64.02; H, 5.57 1 H-NMR (CDCl 3, TMS) δ ppm: 1.30~1.66 (m, 4H), 1.69
~ 1.87 (m, 1H), 1.96 ~ 2.13 (m, 1H), 2.60 (br.s, 2H),
3.04 (dABq, Apart, J = 2.8,12.1Hz, 1H), 3.13 (dABq, Bpa
rt, J = 3.8,12.1Hz, 1H), 5.84 (s, 1H), 7.33-7.58 (m, 5
H) ▲ [α] ²⁵ _D ▼ = -81.8 ± 0.6 ゜ (MeOH, C = 2,005%) Example 9 Compound II-1-D (e1) obtained in Example 2 was subjected to the same reaction as in Example 8. To the following dicarboxylic acid II-2-D
(A1) is obtained.

Example 10 Compound II-1-D (e3) obtained in Examples 4 and 5
And II-2-D (e1) is reacted with LiI in DMSO to give the dicarboxylic acid II-2-D (a1).

Example 11 The compound II-2-L (e1) obtained in Example 7 was subjected to the same reaction as in Example 8 to give the following dicarboxylic acid II-2-L.
(A1) is obtained.

Melting point: 162-164 ° C ▲ [α] ^23.5 _D ▼ = -113.2 ± 1.5 ゜ (MeOH, C = 1.0075
%) Example 12 (1S, 2R, 3S, 4R) -Bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic acid 2- (D-mandelic acid) ester II-1-D (a1) Manufacturing of A solution of the crude product compound II-1-D (e2) (43 g) in methylene chloride (60 ml) was cooled to 0 ° C. and anisole (18 ml)
And trifluoroacetic acid (50 ml) are added and stirred for 1 hour. After concentrating the reaction solution, ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution are added. The aqueous layer is separated, washed with ethyl acetate, and made acidic with 2N hydrochloric acid. Extract with ethyl acetate, wash with brine, concentrate and dry to give crude product
II-1-D (a1) is obtained [II-1-D (a1): II '
-1-D (a1) = 74: 26 (by HPLC)]. The target compound II-1-D (a1) was obtained by recrystallization from ethyl acetate.
Only (13.37 g, 47% yield).

Mp: 169-171 ° C. Elemental analysis (C ₁₇ H ₁₈ as O ₆₎ Calculated (%): C, 64.55; H, 5.10 Found (%): C, 64.46; H, 5.12 IR (CHCl 3): 3500 −2400,1734,1438,1375,1342,1256,11
68,1146,1072 ¹ H-NMR (CDCl ₃ , TMS) δ ppm: 1.36 (ABq, Apart, J = 7.2H
z; 1H), 1.51 (ABq, Bpart, J = 7.2 Hz, 1H), 3.15 (br.s.2
H), 3.43 (dABq, Apart, J = 2.9,10.4Hz, 1H), 3.53 (dABq, Apart, J = 2.9,10.4Hz, 1H)
q, Bpart, J = 3.1,10.4Hz, 1H), 5.86 (s, 2H), 6.14-6.33
(M, 2H), 7.32 to 7.62 (m, 5H) ▲ [α] ²⁴ _D ▼ = -159.5 ± 1.0 ゜ (MeOH, C = 1.993%) Example 13 Reaction was carried out in the same manner as in Examples 1 and 8. To obtain the desired product II-2-D (a1).

Bicyclo [2.2.1] heptane-2-endo, 3-endo-dicarboxylic anhydride 1-2 (1.66 g, 10.0 mmol), D
-Intermediate II using benzyl mandelic acid (2.66 g, 11.0 mmol) and n-BuLi (6.40 ml, 10.2 mmol)
The 2-D (e2) is not purified, and the hydrogenolysis reaction is continued to obtain 2.64 g of crude target product II-2-D (a1). [Yield: 83% / II-2-D (a1): II'-2-D (a1) = 80: 2
0] The target product II-2-D (a
1) 1.47g is obtained. (Isolation yield: 46%) Intermediate II-2-D (e2) can be purified by silica gel column chromatography. ¹ NMR (CDCl ₃ -TMS) δ ppm: 1.32 to 1.97 (m, 6H), 2.55 (b
rs, 1H), 2.60 (br.s, 1H), 2.98 (dABq, Apart, J = 3.7,1
1.6Hz, 1H), 3.18 (dABq, Bpart, J = 3.9,11.6Hz, 1H), 5.1
4 (s, 2H), 6.03 (s, 1H), 7.15 to 7.52 (m, 10H) Examples 14 to 16 The reaction was carried out in the same manner as in Example 13, and the target product II-2-
D (a1) is obtained. Table 2 shows the reaction conditions.

Example 17 (1R, 2S, 3S, 4S) -Bicyclo [2.2.1] heptane-2,3-
Production of dicarboxylic acid 2-methyl ester III-2-D-1 Under a nitrogen atmosphere, compound II-2-D (a1) (5.51 g, 17.
3 mmol), THF (40 ml), methanol (50 ml) and sodium methylate (2M / methanol, 22.0 ml, 44.0 mmol) are added, and the mixture is refluxed for 4 hours. After adding 2N hydrochloric acid and extracting with ethyl acetate, the mixture is washed with water and saturated saline and concentrated. Methylene chloride was added to the obtained mixture, and the mixture was washed three times with water and then concentrated to obtain 3.22 g of the target product III-2-D-1 (yield: 94
%).

Mp: 59-60 ° C. Elemental analysis (C ₁₀ H ₁₄ as O ₄₎ Calculated (%): C, 60.58; H, 7.13 Found (%): C, 60.66; H, 7.08 1 H-NMR (CDCl 3 , TMS) δ ppm: 1.20 to 1.74 (m, 6H), 2.59
(Br.s, 1H), 2.69 (br.s, 1H), 2.79 (d, J = 5.4Hz, 1H),
3.27 (dd, J = 3.8, 5.4 Hz, 1H), 3.69 (s, 3H) ▲ [α] ²⁵ _D ▼ = + 38.4 ± 0.4 ゜ (MeOH, C = 2.002%) Example 18 (1S, 2R, 3R, 4R) -Bicyclo [2.2.1] heptane-2,3-
Production of dicarboxylic acid 2-methyl ester III-2-L-1 The reaction is carried out in the same manner as in Example 17, and the starting material is the enantiomer II-2-L (a1) of the compound of Example 17. Compound II-2-L (a1) (15.27 g, 48.0 mmol) was reacted with methanol (55 ml), THF (60 ml), and sodium methylate (2 M / methanol, 60 ml, 120 mmol) to give the desired compound. 7.46 g of III-2-L-1 is obtained. (Yield: 78%) Melting point: 59-60 ° C ▲ [α] ²⁵ _D ▼ = -38.3 ゜ ± 0.4 ゜ (MeOH, C = 2.013
%) Example 19 (1S, 2S, 3S, 4R) -Bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic acid 2-methyl ester III-1-D
Production of -1 The reaction was carried out in the same manner as in Example 17, and the compound II-1-
D (a1) (15g, 47.4ml) and methanol (50ml), THF
(100 ml), sodium methylate (2M / methanol, 7
1.1 ml, 142 mmol) to give the desired product III
7.96 g of -1-D-1 is obtained (yield: 93.2%).

Mp: 78-79 ° C. Elemental analysis (C ₁₀ as H ₁₄ O ₄₎ Calculated (%): C, 61.21; H, 6.17 Found (%): C, 60.89; H, 6.13 IR (CHCl 3): 3400 −2400,1729,1708,1438,1422,1335,13
11,1271,1245,1190,1175,1162,1114,1022 ¹ H-NMR (CDCl ₃ , TMS) δ ppm: 1.48 (ABq, AAprt, J = 8.0H
z, 1H), 1.63 (ABq, Bpart, J = 8.0Hz, 1H), 2.66 (dd, J =
1.6,4.6Hz, 1H), 3.14 (br.s, 1H), 3.30 (br.s, 1H), 3.4
3 (dd, J = 3.6,4.6Hz, 1H) 3.73 (s, 3H), 6.14 (dABq, Apa
rt, J = 2.9,5.5Hz, 1H), 6.29 (dABq, Bpart, J = 3.1,5.5H
z, 1H) ▲ [α] ²⁴ _D ▼ = + 138.1 ± 0.9 ゜ (MeOH, C = 2.005%) Example 20 (1R, 2R, 3S, 4S) -bicyclo [2.2.1] heptane-2,3 −
Dicarboxylic acid 2- (D-mandelic acid) ester II-2
-Manufacture of D (a1) Sodium hydride (60%, 0.447g, 11.1
mmol) is washed with hexane and then THF (10 ml) is added. To this suspension is added a solution of D-mandelic acid benzyl ester (2.69 g, 11.1 mmol) in THF (30 ml) at room temperature, and the mixture is stirred for 30 minutes. The reaction solution was cooled to -78 ° C, and bicyclo [2.2.
1] Hepta-5-ene-2-endo, 3-endo-dicarboxylic anhydride I-1 (1.64 g, 10.0 mmol) in THF (10
ml). After completion of the dropwise addition, stirring is continued and the reaction temperature is reduced to 0 ° C
I'll give you After post-treatment in a conventional manner, the product was subjected to a deprotection reaction in the same manner as in Example 8 to obtain a crude product II-2-D (a1) 2.04
g (yield: 64%) are obtained.

(II-2-D (a1): II'-2-D (a1) = 59: 41) Example 21 (1R, 2R, 3R, 4S) -bicyclo [2.2.1] hept-5-ene-2 , 3-Dicarboxylic acid 2-methyl ester III-1-L
Production of -1 The same reaction was carried out using L-mandelic acid paramethoxybenzyl ester in place of D-mandelic acid benzyl ester of Example 1 to obtain a crude product having compound II-1-L (e4) as a main product. This is subjected to the next reaction without isolation.

The above crude product (30.6 g, 70 mmol) was added to acetonitrile 160
Then, 35.9 ml of concentrated hydrochloric acid (70 mmol × 6) is added, and the mixture is stirred at room temperature for 16 hours. The pH is adjusted to 4 with a 4NNaOH aqueous solution, and the aqueous solution is made alkaline by adding an aqueous NaHCO ₃ solution under ice-cooling, and washed with ethyl acetate. The organic layer is further extracted with water, the aqueous solutions are combined, adjusted to pH 2 with concentrated hydrochloric acid, and then extracted with ethyl acetate. After washing with water, it is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crystalline residue. This crude product (II-1-
L (a1): II′-1-L (a1) = 85: 15 mixture (by HPLC)) was recrystallized from ethyl acetate to give compound II-1-L
(A1) 11.12 g (50.2% yield) is obtained. Mp 168-170 ° C.

IR, ¹ H-NHR (CDCl ₃ ) is consistent with II-1-D (a1).

[Α] _D = + 160.5 ± 1.0 ° (MeOH, 23 ° C., c = 2.002%) Compound II-1-L (a1) (601 m 2) was obtained in the same manner as in Example 17.
g), Compound 345-1-L-1 (345 mg, yield 92.7%)
Get. 78-79 ° C. IR and NMR are those of compound III-1-D-
Matches 1.

[Α] _D = -140.8 ± 0.9 ° (MeOH, 23 ° C, c = 2.018%) mp. Example 22 (1R, 2S, 3R, 4S) -7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid 2-D-mandelic acid ester I
Production of I-3-D (a1) From 10.5 g (62 mmol) of compound I-3, compounds II-3-D (a1) and I were prepared in the same manner as in Examples 1 and 8.
A mixture of I'-3-D (a1) is obtained. (II-3-D (a
1): II'-3-D (a1) = 73: 27 (HPLC)) From this mixture, compound II-3-D (a1), 7.1 g (35.8% yield) and II'-3-D (a1 ) And 1.5 g (7.6% yield) are each isolated by recrystallization.

Compound II-3-D (a1) mp.

Elemental analysis (as C ₁₆ H ₁₆ O ₇₎ Calculated (%): C, 59.99; H, 5.04; Found (%):. C, 59.85 ; H, 5.04 1 HNMR (CD 3 OD-TMS) δ ppm : 1.55 to 1.88 (m, 4H), 3.13
(ABq, A-part, J = 9.6 Hz, 1H), 3.19 (ABq, B-part,
J = 9.6Hz, 1H), 4.83 ~ 4.90 (m, 2H), 5.85 (s, 1H), 7.3
5 to 7.65 (m, 5H). IR (Nujol) νmax: 3480-2200,1733,1712,1659,1229,12
20,1185,1011,969,936,766,735,696 cm ^-1 . [Α] _D- 111.9 ± 1.5 ° (MeOH, 23 ° C., C = 1.113%) Compound II′-3-D (a1) mp.

Elemental analysis (as C ₁₆ H ₁₆ O ₇ · 0.5 H ₂ O) Calculated value (%): C, 58.35; H, 5.21; Actual value (%): C, 58.33; H, 5.48. ¹ HNMR (CD ₃ OD) −TMS) δ ppm: 1.55 to 1.90 (m, 4H), 3.12
(ABq, A-part, J = 9.6 Hz, 1H), 3.22 (ABq, B-part,
J = 9.6Hz, 1H), 4.75-4.90 (m, 2H), 5.74 (s, 1H), 7.3
5 to 7.65 (m, 5H). IR (Nujol) νmax: 3680-2200,1733,1710 (sh), 1230,1
177; 1044,994,925,819,724 cm ^-1 . [Α] _D- 92.0 ± 1.3 ゜ (MeOH, 23 ° C., C = 1.014%). Example 23 (1R, 2R, 3R, 4S) -7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid 2-methyl ester III-3-
Production of D-1 According to Example 17, compound III-3-D-T1, 190 mg (yield: 50.0) from compound II-3-D (a1), 610 mg (1.9 mmol)
%).

. Mp 134-135 ° C. Elemental analysis (C ₉ H ₁₂ O as ₅₎ Calculated (%): C, 54.00; H, 6.05; Found (%): C, 53.98; H, 5.97 1 HNMR (CDCl 3 - TMS) δ ppm: 1.45 to 1.95 (m, 4H), 3.14
(D, J = 5.1Hz, 1H), 3.50t-d, J = 5.5,1.5Hz, 1H), 3.74
(S, 3H), 4.84 (t, J = 5.0Hz, 1H), 4.92 (d, J = 5.0Hz, 1
H). IR (Nujol) νmax: 3400-2480,1736,1725,1255,1215,12
01,1184,1173,921,816cm ^-1 . [Α] _D + 73.3 ± 0.6 ± (MeOH, 24 ° C, C = 2.009)
%). Example 24 (1S, 2S, 3S, 4R) -7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid 2-methyl ester III-3-
Production of L-1 Enantiomer of compound III-3-D-1 III-3-L
-1 is a by-product of the cleavage reaction, compound II'-3-D (a1)
It is manufactured according to the above method. (Yield 27.5%).

Mp 133-134 ° C. Elemental analysis (C ₉ H ₁₂ as O ₅₎ Calculated (%):. C, 54.00 ; H, 6.05; Found (%); C, 54.03; H, 6.06 1 HNMR and IR of the compound Consistent with III-3-D-1.

[Α] _D -73.5 ± 0.6% (MeOH, 23 ° C, C = 2.013%). Example 25 (1S, 2R, 3S, 4R) -7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid 2-methyl ester III-3-
Production of D-2 Compound II-3-D (a1), 4.5 g (14.05 mmol) was treated with a diazomethane ether solution in a conventional manner to give compound II-D.
4.77 g (97.5% yield) of 3-D (e5) are obtained.

Dimethyl ester II-3-D (e5) mp 131-132 ° C. Elemental analysis (C ₁₈ as H ₂₀ O ₇₎ Calculated (%): C, 62.05; H, 5.80: Found (%): C, 61.87: ^{. H, 5.78 1 HNMR (CDCl} 3 -TMS) δppm: 1.45~1.70 (m, 2H), 1.77~
1.93 (m, 2H), 2.99 (ABq, A-part, J = 9.6 Hz, 1H), 3.15
(ABq, B-part, J = 9.6Hz, 1H), 3.53 (s, 3H), 3.70 (s, 3
H), 4.85 to 4.93 (m, 1H), 4.95 to 5.03 (m, 1H), 5.93 (s,
1H), 7.34 to 7.55 (m, 5H). IR (Nujol) νmax: 1742,1732,1198,1143,1055,1009,93
6,725,695cm ^-1 . [Α] _D -103.2 ± 1.4 ゜ (CHCl ₃ , 23.5 ° C, C = 1.09
%). Dimethyl ester II-3-D (e5), 4.18 g (12 mmo
l) was dissolved in 30 ml of ethyl acetate, 400 mg of 10% Pd-C was added, and the mixture was stirred for 1 hour in hydrogen gas. Then, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether, and cis half ester III-3-D-2, 2.02 g (yield: 84.2%)
Get.

. Mp 104 to 106 ° C. Elemental analysis (C ₉ H ₁₂ O as ₅₎ Calculated (%): C, 54.00; H, 6.05; Found (%): C, 53.83; H, 6.04 1 HNMR (CDCl 3 - TMS) δ ppm: 1.45-1.60 (m, 2H), 1.73-
1.93 (m, 2H), 3.01 (ABq, B-part, J = 9.6Hz, 1H), 3.66
(S, 3H), 4.87 to 5.03 (m, 2H), 6.56 (br.s, 1H). IR (Nujol) νmax: 3400-2480,1736,1731,1228,1198,10
69,1010,996,924,900,821cm ^-1 . [Α] _D -4.9 ± 0.2 ゜ (MeOH, 23.5 ° C, C = 2.010%). [Α] ₃₆₅ −7.9 ± 0.2 ゜ (MeOH, 23.5 ° C, C = 2.010
%). This is the compound I reported by R. Bloch et al.
II-3-D-2 and [α] _D value are almost the same. [Tetrah
edron Letters, Vol. 26, No. 34, pp. 4087-4090, 1985 ([α] _D −3.9 ° (MeOH, 20 ° C., C = 2%), melting point 104
° C)] Example 26 (1R, 2S, 3R, 4S) -7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid 2-methyl ester III-3-
Production of L-2 By-product II'-3-D (a1) of the cleavage reaction, 720 mg (7.2
5 mmol) and the compound II-3-D (a1) was used to prepare II-3-
According to the method for obtaining D (e5), compound II'-3-D (e
5), 678 mg (86.6% yield) are obtained.

Dimethyl ester II'-3-D (e5) mp 115-116 ° C. Elemental analysis (as C ₁₈ H ₂₀ O ₇₎ Calculated (%): C, 62.05; H, 5.80; Found (%): C, 61.85 ^{; H, 5.74 1 HNMR (CDCl} 3 -TMS) δppm:. 1.45~1.70 (m, 2H), 1.74~
1.95 (m, 2H), 2.97 (ABq, A-part, J = 9.6 Hz, 1H), 3.17
(ABq, B-part, J = 9.6Hz, 1H), 3.36 (s, 3H), 3.71 (s, 3
H), 4.84 ~ 4.95 (m, 2H), 5.00 ~ 5.10 (m, 1H), 5.89 (s,
1H), 7.33 to 7.50 (m, 5H). IR (Nujol) νmax: 1753,1737,1725,1220,1190,1164,114
5,1056,1028,1004,817,735,693 cm ^-1 . [Α] _D −84.7 ± 1.2% (CHCl ₃ , 23 ° C., C = 1.008%). Dimethyl ester II'-3-D (e5), 523 mg (1.5 mm
ol) from compound II-3-D (e5) to compound III-
Cis half ester II by the method for producing 3-D-2
271 mg (yield: 90.3%) of I-3-L-2 are obtained.

Mp 103 to 105 ° C. Elemental analysis _{(C 9 H 12 O 5 ·} 0.1H as ₂ O) Calculated (%): C, 53.51; H, 6.10; Found (%):. C, 53.67 ; H, 5.90 1 HNMR and IR are completely consistent with compound III-3-D-2.

[Α] _D + 4.4 ± 0.2% (MeOH, 24 ° C., C = 2.006%). [Α] ₃₆₅ + 7.0 ± 0.2% (MeOH, 24 ° C., C = 2.006%). Example 27 (1R, 2R, 3S, 4S) -2- (methyl-D-mandeloxycarbonyl) -3-methoxycarbonylbicyclo [2.2.
1] Production of heptane II-2-D (e5) Compound II-2-D (a1) (22.72 g, 71.3 mmol) and p-toluenesulfonic acid monohydrate (2.73 g, 14.3 mmol)
Is refluxed in methanol (375 ml) for 24 hours. After concentration, 5
The mixture is separated with a 20% sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with water, dried and concentrated to give crude product II-2
26.06 g of -D (e5) are obtained. When recrystallized from ether / petroleum ether, the target compound II-2-D (e5) was obtained as the first crystal: 1
8.59 g (53.7 mmol), second crystal: 0.62 g (1.8 mmol), third
Crystals: 0.53 g (1.5 mmol) are obtained. (Total isolated yield / yield 1
9.74g, 79.9%).

Melting point: 61.5-63.5 ° C.

Elemental analysis (as C ₁₉ H ₂₂ O ₆ ): Calculated value (%): C 65.88: H 6.40; Actual value (%): C 65.72, H 6.42. IR (KBr) νmax: 3700-3160, 2970, 2885, 1758,1745,173
0,1457,1365,1345,1198,1165,1122,1082,1060,1055,104
_{^{. 2,1022,748,698cm -1 1 HNMR (CDCl 3}} -TMS) δppm: 1.20~2.00 (m, 6H), 2.50~
2.65 (brm, 2H), 2.96 (dABq, A-part, J = 3.8,11.8Hz),
3.21 (dABq, B-part, J = 4.3,11.8Hz), 3.54 (s, 3H), 3.
70 (m, 3H), 5.94 (s, 1H), 7.30 to 7.52 (m, 5H). [Α] _D -77.8 ± 1.2 ゜ (CHCl ₃ , 23.5 ° C, C = 1.00
%). Example 28 (1S, 2S, 3R, 4R) -Bicyclo [2.2.1] heptane-2,3-
Production of dicarboxylic acid 2-methyl ester III-2-D-2 Compound II-2-D (e) was added to 10% palladium carbon (1.77 g).
5) A solution of (17.79 g, 51.4 mmol) in ethyl acetate (200 ml) is added, the mixture is stirred at room temperature under a hydrogen atmosphere at room temperature for 50 minutes, and the catalyst is removed by filtration and concentrated. Toluene, 5
% Aqueous sodium bicarbonate solution and separate the aqueous layer. Wash the organic layer again with water, wash each with toluene,
Match. After adding 2N hydrochloric acid, extracting with ethyl acetate, washing with water, drying and concentration, the target product III-2-D-2 (10.2
g: quantitative).

Elemental analysis (as C ₁₀ H ₁₄ O _4): Calculated (%): C 60.59, H 7.12; Found (%):. C 60.42, H 7.05 IR (KBr) νmax: 3400~2400,2960,2880, 1735,1707,143
_{^{. 5,1356,1295,1288,1132,1122,1082,1058cm -1 1 HNMR (CDCl 3}} -TMS) δppm: 1.35~1.53 (m, 4H), 1.65~
1.88 (m, 2H), 2.48 to 2.64 (brm, 2H), 2.96 (dABq, A-pa
rt, J = 3.4,11.7Hz, 1H), 3.03 (dABq, B-part, J = 4.4,1
1.7Hz, 1H), 3.64 (s, 3H). [Α] _D + 17.1 ± 0.3 ゜ (MeOH, 23.0 ° C., C = 2.059
%). Example 29 (1S, 2S, 3R, 4R) -2- (methyl-L-mandeloxycarbonyl) -3-methoxycarbonylbicyclo [2.2.
1] Production of heptane II-2-L (e5) By subjecting it to the same reaction as in Example 27, compound II-2-L
(E5) is obtained. (Yield: 87.5%) Melting point: 61.5-62.5 ° C.

[Α] _D + 76.3 ± 1.2% (CHCl ₃ , 24 ° C., 1.005%). Example 30 (1R, 2R, 3S, 4S) -Bicyclo [2.2.1] heptane-2,3-
Production of dicarboxylic acid 2-methyl ester III-2-L-2 The reaction was carried out in the same manner as in Example 28.
L-2 is obtained. (Yield: quantitative) [α] _D -17.4 ± 0.3 ゜ (MeOH, C = 2.052%, 24 ° C.). Reference Example 1 Method for producing aryl acetic acid derivative (1) D-mandelic acid benzyl ester D-mandelic acid (85.1 g, 559 mmol), benzyl alcohol (65 ml, 628 mmol) and p-toluenesulfonic acid
(1.01 g, 5.35 mmol) was refluxed in benzene (700 ml) for 6.5 hours, washed with water and concentrated. Recrystallization from ether gave 123.5 g of the desired product D-2.

Yield: 91% mp: from 103.5 to 105 ° C. Elemental analysis (as C ₁₅ H ₁₄ O ₃₎ Calculated (%): C, 74.36; H, 5.82 Found (%): C, 74.53; H, 5.90 1 H _{-NMR (CDCl 3 -TMS) δppm:} 3.44 (d, J = 5.6Hz, 1H),
5.14 (ABq, Apart, J = 12.3Hz, 1H), 5.22 (d, J = 5.6Hz, 1
H), 5.24 (ABq, Bpart, J = 12.3 Hz, 1H) 7.15 to 7.50 (m, 10
H) ▲ [α] ²⁴ _D ▼ = -55.7 ± 1.0 ゜ (CHCl ₃ , C = 1.003%) (2) D-mandelic acid 4-methoxybenzyl ester D-mandelic acid (15.3 g, 100 mmol), 4-methoxybenzyl alcohol (15.2 g, 110 mmol) and p-toluenesulfonic acid (0.197 g, 1.01 mmol) were added to benzene (300 m
l) After immersion in medium for 7 hours, the reaction solution is washed four times with water and concentrated.
The obtained crude product was subjected to silica gel column chromatography, purified with toluene-ethyl acetate, and purified with ether-ethyl acetate.
Recrystallization from petroleum ether gives 6.58 g of the desired product D-3.

Yield: 24% mp: from 70.5 to 73.5 ° C. Elemental analysis (as C ₁₆ H ₁₆ O ₄₎ Calculated (%): C, 70.58; H, 5.92 Found (%): C, 70.55; H, 6.00 1 H _{-NMR (CDCl 3 -TMS) δppm:} 3.80 (s, 3H), 5.05 (ABq,
Apart, J = 11.8Hz, 1H), 5.19 (s, 1H), 5.19 (ABq, Bpart,
J = 11.8Hz, 1H), 6.84 (d, J = 8.7Hz, 2H), 7.17 (d, J = 8.
7 Hz, 2H), 7.30 to 7.45 (m, 5H) ▲ [α] ²⁴ _D ▼ = -36.0 ± 0.8 ゜ (CHCl ₃ , C = 1.017%) (3) D-mandelic acid-4-nitrobenzyl ester D-mandelic acid (15.2 g, 100 mmol) in DMF (300 ml),
Add 4-nitrobenzyl bromide (21.6 g, 100 mmol) and triethylamine (14.0 ml, 100 mmol) and stir at room temperature for 8 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with dilute hydrochloric acid and water, and then recrystallized from ether-petroleum ether to obtain 1.96 g of the desired product D-4.

Yield: 68% mp: 143 to 145 ° C. Elemental analysis (C ₁₅ H ₁₃ NO as ₅₎ Calculated (%): C, 62.72; , 4.56; N, 4.88 Found (%): C, 62.76; , 4.61 ; N, 4.99 ¹ H-NMR (CDCl ₃ -TMS) δ ppm: 3.26 to 3.52 (br.s, 1H),
5.25 (ABq, Apart, J = 13.5Hz, 1H), 5.28 (s, 1H), 5.32
(ABq, Bpart, J = 13.5Hz, 1H), 7.27 (d, J = 8.4Hz, 2H),
7.34 to 7.48 (br.s, 5H), 8.14 (d, J = 8.4 Hz, 2H) ▲ [α] ²⁴ _D ▼ = -40.0 ± 0.8 (CHCl ₃ , C = 0.995%) (4) D-Mandel Acid benzhydryl ester D-mandelic acid (25.0 g, 164 mmol) ethyl acetate (200 m
Dissolve in l) and add diphenyldiazomethane (38.9 g, 164 mmol) with stirring at room temperature. After confirming the completion of the reaction by TLC, concentrate. By recrystallizing from ether-petroleum ether, 47.7 g of the target product D-5 was obtained.

Yield: 91% Melting point: 91-91.5 ° C Elemental analysis (as C ₂₁ H ₁₈ O ₃ ) Calculated value (%): C, 79.22 ;, 5.71 Actual value (%): C, 79.44 ;, 5.67 ¹ H-NMR (CDCl ₃ −TMS) δppm: 3.47 (d, J = 5.3Hz, 1H),
5.28 (d, J = 5.3Hz, 1H), 6.87S (s, 1H), 6.87 ~ 7.46 (m,
15H) ▲ [α] ²⁴ _D ▼ = -57.4 ± 1.0 ゜ (CHCl ₃ , C = 1.023%) (5) L-mandelic acid benzhydryl ester The reaction was carried out in the same manner as in Reference Example 1- (4). Using L-mandelic acid (30.4 g, 200 mmol), ethyl acetate (200 ml) and diphenyldiazomethane (38,9 g, 200 mmol), 54.7 of the target product L-2 was obtained. g (172 mmol) are obtained.

Yield: 86% Melting point: 91.5 to 92.0 ° C ▲ [α] ²⁴ _D ▼ = + 55.7 ± 0.9 ゜ (CHCl ₃ , C = 1.013%) Reference Example 2 An example of the use of compound (III) provided by the present invention Is described below.

Under a nitrogen atmosphere, compound III-2-D-1 (2.80 g, 14.1 g)
(24 ml) in acetone was cooled to 0 ° C. and triethylamine (2.54 ml, 18.3 mmol) and ethyl chlorocarbonate (1.75 ml, 18.3 mmol) were added. Immediately after a white precipitate is formed, stirring is continued for 15 minutes in this state, and an aqueous solution (8 ml) of sodium azide (2.75 g, 42.3 mmol) is added. After stirring for 30 minutes under ice cooling, 2N hydrochloric acid is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and brine, and then concentrated. To remove ethyl acetate completely, add benzene and concentrate once more.

Dissolve the obtained oil in benzene (20 ml),
To perform thermal rearrangement. At the end of the nitrogen evolution, triethylamine (2.54 ml, 18.3 mmol) and benzyl alcohol (1.75 ml, 16.9 mmol) are added and refluxed for 1.5 hours. After completion of the reaction, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate.
After washing with water and brine, concentrate. The crude product is purified by silica gel column chromatography and recrystallization to obtain Compound 1 (3.03 g, yield: 71%).

Mp: 61-62 ° C. Elemental analysis (as C ₁₇ H ₂₁ NO ₄₎ Calculated (%): C, 67.30; H, 6.69; N, 4.62 Found (%): C, 67.46; H, 7.04; N, _{^{4.73 1 N-NMR (CDCl 3}} -TMS) δppm: 1.22~1.86 (m, 6H), 1.92
(Dd, J = 2.0,5.0Hz, 1H), 2.50 (br.s, 2H), 3.70 (br.s,
3H), 4.23 (br.s, 1H), 4.90 (br.s, 1H), 5.09 (br.s, 2
H), 7.22 ~ 7.45 (m, 5H) ▲ [α] ²⁵ _D ▼ = + 40.1 ± 0.4 ゜ (CHCl ₃ , C = 2.006%) Compound 1 (1.42 g) was added to 10% palladium-carbon (0.130 g).
g, 4.67 mmol) in methanol (13 ml),
Hydrogenolysis is performed by stirring at room temperature for 30 minutes in a hydrogen atmosphere. After the reaction, the catalyst is removed by filtration and concentrated.

Under a nitrogen atmosphere, the crude product obtained was treated with methylene chloride (10
ml) and cool to 0 ° C. Triethylamine (1.94ml, 14.0mmo) and benzenesulfonyl chloride (0.66m
l, 5.17 mmol) and stir for 30 minutes. 2N Hydrochloric acid is added, extracted with ethyl acetate, washed with water and brine, and concentrated. Purification by silica gel column chromatography gives the desired product 2. (1.17 g, yield: 81%) Melting point: 129 to 130 ° C Elemental analysis (as C ₁₅ H ₁₉ O ₄ ) Calculated value (%): C, 58.22; H, 6.20; N, 4.52; S, 10, 36 Obtained value (%): C, 58.11; H, 6.07 ;, 4.53; S, 10.09 ▲ [α] ²⁵ _D ▼ = -0.4 ± 0.4 ゜ (CHCl ₃ , C = 0.992%) ▲ [α] ²⁵ ₃₆₅ ▼ = −36.2 ± 0.8 ゜ (CHCl ₃ , C = 0.92
%) Under a nitrogen atmosphere, a solution of compound 2 (1.12 g, 3.62 mmol) in THF (15 ml) was added at room temperature to lithium aluminum hydride (0.41 g).
2 g, 10.9 mmol) are added. After stirring for 30 minutes, ethyl acetate and water are added to the reaction solution in this order, and excess lithium aluminum hydride is crushed. Extraction with ethyl acetate three times and concentration give the desired product 3 (1.00 g, 98.2%).

Mp: 121-122 ° C. Elemental analysis (C ₁₄ H ₁₉ NO ₃ as S) Calculated (%): C, 59.75; H, 6.82; N, 4.98; S, 11,39 Found (%): C, 59.83 ; H, 6.91;, 5.02; S, 11.33 ▲ [α] ²⁶ _D ▼ = + 6.8 ± 0.5 ゜ (CHCl ₃ , C = 1.000%) Under a nitrogen atmosphere, PCC (18.4 g, 85.4 mmol) and molecular sieve (4A powder, 25.1 g) are added to a methylene chloride solution (600 ml) of compound 3 (8.01 g, 28.5 mmol), and the mixture is stirred at room temperature. After confirming the completion of the reaction by TLC, inorganic substances are removed by silica gel column chromatography, and the mixture is concentrated to obtain an intermediate product 4. Since compound 4 is not very stable, it proceeds to the next operation without further purification.

Under a nitrogen atmosphere, a methoxymethyltriphenylphosphonium chloride (31.20 g, 91.0 mmol) THF solution (160 ml) was
Cool to 78 ° C. and add n-butyllithium (1.6 M in hexane, 56.0 ml, 84.0 mmol). After completion of the dropwise addition, the mixture is changed from a dry ice-acetone bath to an ice bath, and stirred at 0 ° C. for 25 minutes. The reaction solution is cooled again to -78 ° C in a dry ice-acetone bath, and a THF solution (80 ml) of the intermediate product 4 (7.27 g) obtained above is added. After dropping, remove the ice bath and stir for 35 minutes. After adding ice water and extracting with ethyl acetate, the organic layer is washed with water and brine, and then concentrated. Intermediate product 5 is obtained by silica gel column chromatography, but this compound is not very stable, so that the next operation is carried out without further purification.

Under nitrogen atmosphere, 90% formic acid (5.0m
l) and stir at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the mixture is neutralized with sodium hydrogen carbonate and a 5% aqueous sodium hydrogen carbonate solution. After adding water, the mixture is extracted with ethyl acetate, washed with water and brine, and concentrated.
Purification by silica gel column chromatography gives the desired product 6 (3.30 g, yield from compound 3: 40%).

Compound 6 Melting point: 100-103 ° C Elemental analysis (as C ₁₅ H ₁₉ NO ₃ S) Calculated value (%): C, 61.40; H, 6.54; N, 4.77; S, 10, 93 Actual value (%): C , 61.39; H, 6.51;, 4.90; S, 11.02 ▲ [α] ^25.5 _D ▼ = + 36.5 ± 0.8 ゜ (CHCl ₃ , C = 0.994
%) Under a nitrogen atmosphere, 4-carboxybutyltriphenylphosphonium bromide (14.8 g, 33.3 mmol) was added to THF (80 m
l) to the suspension to which potassium t-butyrate (7.55 g,
67.3 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was cooled to -20 ° C and the T of compound 6 (3.25 g, 11.1 mmol) was added.
Slowly add HF solution (20 ml). After stirring at -20 ° C for about one and a half hours, remove the ice bath and stir for another hour. The reaction mixture is added with 2N hydrochloric acid, extracted with ethyl acetate, washed with water and brine, and concentrated. Toluene and a 1N sodium hydroxide solution are added to the obtained crude product, and the aqueous layer is separated. The organic layer is washed again with water, combined with the aqueous layer, and then added with 2N hydrochloric acid. After extraction with ethyl acetate, the extract is washed with water and brine, dried over sodium sulfate and concentrated. Purification by silica gel column chromatography affords the desired product 7 (3.29 g, 79% yield).

Melting point: 62 ° C Elemental analysis (as C ₂₀ H ₂₇ NO ₄ S) Calculated value (%): C, 63.63; H, 7.21; N, 3.71; S, 8, 49 Actual value (%): C, 63.56; H , 7.21 ;, 3.83; S, 8.43 ▲ [α] ²² _D ▼ = + 5.3 ± 0.5 ₃ (CHCl ₃ , C = 1.003%) ▲ [α] ²⁴ _D ▼ = +27.1 ± 0.7, (MeOH ₃ , C = 1.015%) Reference Example 3 Under a nitrogen atmosphere, compound III-2-L-2 (5.00 g, 25.2
(25 ml) in acetone was cooled to 0 ° C. and triethylamine (3.90 ml, 28.0 mmol) and ethyl chlorocarbonate (2.65 ml, 27.7 mmol) were added. Immediately after a white precipitate is formed, stirring is continued for 30 minutes in this state, and an aqueous solution (6 ml) of sodium azide (1.72 g, 26.5 mmol) is added. After stirring for 45 minutes under ice-cooling, 2N hydrochloric acid is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with a 5% sodium hydrogen carbonate solution, water and brine, dried and concentrated. To remove ethyl acetate completely, add benzene and concentrate once more.

After dissolving the obtained oil in benzene (25 ml),
Heat and perform thermal rearrangement. At the end of the nitrogen evolution, benzyl alcohol (2.74 ml, 26.5 mmol) triethylamine (3.90 ml, 28.0 mmol) is added and stirred for 75 minutes.
After completion of the reaction, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate.
After washing with sodium hydrogen carbonate solution, water and brine, drying and concentration. The crude product is subjected to silica gel column chromatography and is formed with toluene-ethyl acetate to obtain the desired product 8 (3.99 g, 13.2 mmol). (Yield: 52.1%).

Elemental analysis (as C ₁₇ H ₂₁ NO ₄ ) Calculated value (%): C, 67.31; H, 6.98; N, 4.62; Actual value (%): C, 67.12; H, 6.96; N, 4.63 IR (CHCl ₃ ) Νmax: 3400,2950,2880,1718,1505,1453,143
8,1358,1325,1316,1163,1152,1080,1062,1035,1028c
^{. m -1 1 N-NMR (} CDCl 3 -TMS) δppm: 1.32~1.70 (m, 6H), 2.49
(Br.s, 2H), 2.93 (dd, J = 4.3Hz, J = 11.1Hz, 1H), 3.63
(S, 3H), 3.97 to 4.18 (m, 1H), 5.08 (s, 2H), 6.65 to 6.8
3 (br.m, 1H), 7.28 to 7.44 (m, 5H) [α] _D = + 6.1 ± 0.5 ゜ (CHCl ₃ , C = 1.010%, 23.5
℃) [α] ₃₆₅ = + 28.5 ± 0.7 ゜ (CHCl ₃ , C = 1.010%, 23.5
℃) Compound 8 (3.87 g) was added to 10% palladium-carbon (0.602 g).
g, 12.8 mmol) in methanol solution (15 ml),
Hydrogenolysis is performed by stirring at room temperature for 100 minutes in a hydrogen atmosphere. After the reaction, the catalyst is removed by filtration and concentrated.

Under a nitrogen atmosphere, the crude product obtained was treated with methylene chloride (10
ml) and cool to 0 ° C. Triethylamine (3.60 ml, 25.8 mmol) and phenylsulfonyl chloride (1.66
ml, 13.0 mmol) and stir for 30 minutes. After adding 2N hydrochloric acid, the mixture is extracted with ethyl acetate, washed with a 5% sodium hydrogen carbonate solution, water and brine, dried and concentrated. Purification by silica gel column chromatography and recrystallization affords the desired product 9 (3.20 g, 10.3 mmol). (Yield 81.
0%) Melting point: 112.5-113.5 ° C. Elemental analysis (as C ₁₅ H ₁₉ NO ₄ S) Calculated value (%): C, 58.23; H, 6.19; N, 4.53; S, 10, 36 Actual value (%): C, 58.33; H, 6.19 ;, 4.45; S, 10.08. IR (CHCl ₃ ) νmax: 3335,3270,2965,2880,1705,1445,143
5,1368,1352,1330,1202,1165,1092,905,758,732,725,69
^{. 0,667,586,552cm -1 1 N-NMR (} CDCl 3 -TMS) δppm: 1.22~1.76 (m, 6H), 2.30
(Br.s, 2H), 2.43 (br; s, 1H), 2.64 (dd, J = 4.8Hz, J = 1
0.6Hz, 1H), 3.51 (s, 3H), 3.66-3.82 (m, 1H), 6.74
(D, J = 8.8Hz, 1H), 7.42 ~ 7.51 (m, 3H), 7.77 ~ 7.90
(M, 2H). [Α] _D = -42.1 ± 0.8 ゜ (CHCl ₃ , C = 1.002%, 24 ° C.) Lithium aluminum hydride (1.54
g) in THF (30 ml) was added to Compound 9 (3.00 g, 9.70 mmol).
l) THF solution (30 ml) is added. After stirring for 2 hours, ethyl acetate and water are sequentially added to the reaction solution to decompose excess lithium aluminum hydride. After extraction with ethyl acetate three times, drying and concentration, purification by silica gel chromatography gives the target product 10 (2.70 g). (Yield: 99.0%) Melting point: 97.5-99.5 ° C. Elemental analysis (as C ₁₄ H ₁₉ NO ₃ S) Calculated value (%): C, 59.76; H, 6.81; N, 4.98; S, 11, 39; Actual value (%): C, 59.68; H, 6.77; , 4.92; S, 11.14. IR (KBr) νmax: 3640-3360, 3260, 2960, 2890, 1482, 146
3,1448,1340,1310,1165,1155,1092,1046,955,755,718,6
^{. 88,595,575,549cm -1 1 H-NMR (} CDCl 3 -TMS) δppm: 1.16~2.27 (m, 10H), 3.4
0 ~ 3,56 (m, 1H), 3.62 (dABq, Apart, J = 5.0,11.0Hz, 1
H) .3.81 (dABq, Bpart, J = 9.0,11.0Hz, 1H), 5.51-5.78
(Br.m, 1H), 7.46 ~ 7.70 (m, 3H), 7.85 ~ 8.00 (m, 2
H). [Α] _D = + 35.1 ± 0.8 ゜ (CHCl ₃ , C = 1.005%, 24.0
° C) The racemate of compound 10 is a chiral column (ULTRONES-OV
(+) Form and (-) form can be separated by HPLC using M).

Under a nitrogen atmosphere, a solution of PCC (0.700 g, 3.25 mmol) and molecular sieve (4A powder, 0.703 g) in methylene chloride (15
A solution of compound 10 (0.304 g, 1.08 mmol) in methylene chloride (5 ml) is added to the mixture under ice-cooling. After stirring at 0 ° C for 45 minutes, 30
Stir at 45 ° C. for a further 45 minutes. After confirming the completion of the reaction by TLC, inorganic substances are removed using silica gel, and the mixture is concentrated to obtain a mixture of compound 11a and compound 11b.
(0.301 g, quantitative) Compound 11a: Compound 11b = 9: 1. Compound 1
1a is unstable and changes gradually to compound 11b during the isolation procedure. ¹ H-NMR (CDCl ₃ -TMS) δ ppm: 2.58 to 2.66 (br.m, 1H),
2.74 to 2.88 (m, 1H), 3.64 to 3,78 (d, J = 7.5 Hz, 1H), 9.4
9 (s, 1H). (Only the signal characteristic of compound 11a is described) Under a nitrogen atmosphere, a mixture of compound 11a and compound 11b (0.55
Sodium methylate (0.2N / methanol, 1.0ml, 0.200mmol) in methanol solution (3.0ml) of 1g, 1.97mmol)
Add. After stirring at room temperature for 60 minutes, TLC confirms the completion of the reaction. The reaction solution is concentrated once, separated with 2N hydrochloric acid and ethyl acetate, washed with water, dried and concentrated to give the desired product.
11b (0.537 g) is obtained. (Yield: 97.5%) Melting point: 100-103 ° C Elemental analysis (as C ₁₄ H ₁₇ NO ₃ S) Calculated value (%): C, 60.19: H, 6.13; N, 5.01; S, 11.48; %): C, 60.08; H, 6.09; N, 5.11; S, 11.41. IR (KBr) νmax: 3250,2960,2940,1712,1462,1448,1338,
1325,1158,1145,1128,1090,1080,753,720,682,655,590,
^{. 542cm -1 1 H-NMR (} CDCl 3 -TMS) δppm: 1.05~1.85 (m, 6H), 2.18
~ 2.31 (m, 2H), 2.45 (d, J = 3.6Hz, 1H), 3.81 ~ 3.94
(M, 1H), 4.90 ~ 5.05 (br.m, 1H), 7.40 ~ 7.67 (m, 3H),
7.76 to 7.97 (m, 2H), 9.55 (s, 1H). [Α] _D = 47.6 ± 0.9 ° (CHCl ₃ , C = 1.09%, 24.0 ° C.) Since compound 11b is identical to compound 4 (an intermediate produced in Reference Example 2 (4)), the following Reference Example 2 ( Compound 7 can be obtained by reacting according to 4) and (5).

Compound 7 has a greater effect as a thromboxane A ₂ receptor antagonists, burns, trauma, acute pancreatitis, cardiac dysfunction, blood loss, sepsis, due endotoxin shock, after blood reperfusion coronary or fire extinguisher system artery such as Shock, various inflammation, myocardial infarction, cerebral infarction, pulmonary embolism, renal failure, angina pectoris, thrombosis, peripheral vascular obstructive circulatory insufficiency, heart failure, etc. Prevention and treatment of vasospasm, cancer metastasis, etc., prevention of thrombus generation during extracorporeal circulation such as organ transplantation or hemodialysis, cardiopulmonary bypass, etc. It can be used for prevention and treatment of allergic diseases.

────────────────────────────────────────────────── (4) Continuation of the front page (56) References JP-A-54-19960 (JP, A) JP-A-2-250852 (JP, A) JP-A-2-180862 (JP, A) Med. Chem. , 14 [2] (1971), 175. Bull. Soc. Chim. Berg g. , 93 [11] (1984), 999-1003 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 69/753 C07C 67/08 C07D 521/00 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) a general formula: Wherein R ¹ is (1) alkyl, alkoxy, halogen,
Alkyl optionally substituted with amino, hydroxyamino, alkylamino or nitro, (2) alkyl,
Alkenyl optionally substituted with alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro, (3) aryl optionally substituted with alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro or ( 4) alkyl,
And aralkyl optionally substituted with alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro.] And an optically active dicarboxylic acid monoester represented by the formula: 2. The general formula: [Wherein, X is -O -, - S -, - (CH 2) m- or (Wherein, m represents an integer of 0 to 4, R ² represents hydrogen, methyl or ethyl) Y represents (CH ₂ ) n or (In the formula, n represents an integer of 0 to 3, and R ² has the same meaning as described above.) Z represents hydrogen, lower alkyl or phenyl (except when m and n are simultaneously 0)] The acid anhydride I represented by the general formula: (Wherein, M ¹ is hydrogen or a metal atom, R ⁵ is (1) hydrogen,
(2) alkyl optionally substituted with alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro; or (3) alkyl substituted with alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro. Good aralkyl,
Ar represents alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or aryl optionally substituted with nitro), and reacting an (R)-or (S) -arylacetic acid derivative represented by the general formula : (Wherein, R ⁵ , X, Y, Z and Ar have the same meanings as described above), and then the ester II is subjected to an esterification reaction to introduce R ^1. , An arylacetic acid derivative residue is removed or the ester II is represented by the general formula: R ¹ OM ² IV (where R ¹ is (1) alkyl, alkoxy, halogen,
Alkyl optionally substituted with amino, hydroxyamino, alkylamino or nitro, (2) alkyl,
Alkenyl optionally substituted with alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro, (3) menthyl, (4) alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro; Aryl or aralkyl optionally substituted with (5) alkyl, alkoxy, halogen, amino, hydroxyamino, alkylamino or nitro, and M ² represents an alkali metal atom or an alkaline earth metal atom. A compound of the general formula: (Wherein, R ¹ , X, Y and Z have the same meanings as described above). 3. The general formula: (Wherein, R ⁵ , X, Y, Z and Ar have the same meanings as described above)
II.