JPS6133029B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula: The present invention relates to a method for producing optically active 5β-halo-2β-hydroxymethyl-cyclopentane-3α-hydroxy-1α-acetic acid (1′→3)δ-lactone, [wherein X represents a chlorine atom or a bromine atom]. The above compounds are useful intermediates in the synthesis of natural or enantioprostaglandins. As is well known, Corey's bicyclic lactone, namely 2β-hydroxymethylcyclopentane-3α·5α-dihydroxy-1α-acetic acid (1′→5)γ-lactone [EJCorey et al. “Journal of the American・Chemical Society “(J.Am.
Chem.Soc.) Volume 92, Page 397, 1970] and its enantiomers are widely used in the synthesis of natural prostaglandins and synthetic prostaglandin analogs, and their enantiomers for further synthetic development. The high stability indicates that it is highly favorable for the discovery of new synthetic methods to produce these compounds at low cost. In recent years, JSBindra and others have published “J. Am. Chem. Soc.,” Vol. 95, No. 7522.
(1973) and R. Pecl and JK Sutherland, “Journal of the Chemical Society,
Comiunications” (J.Chem.Soc.Chem.
Commun.) Volume 151 (1974), bicyclic [2.
2.1] From hepto-2,5-diene (formula A)
We present a new method to generate a bicyclic intermediate (formula B) in which Rc represents acyl: This method is completely innovative compared to the already known Corey method. That is, there are fewer chemical steps, different types and costs of reagents, and different reaction conditions. However, the above method is not suitable for the basic intermediate 5β-halo-2β-hydroxymethyl-cyclopentane-3α-hydroxy-1α-acetic acid (1′→3)δ-lactone (from which the above authors obtain the compound of formula B). It has significant manufacturing drawbacks. The method for producing 5β-halo-2β-hydroxymethyl-cyclopentane-3α-hydroxy-1α-acetic acid (1′ → 3)δ-lactone described in the above document uses paraformaldehyde, formic acid, and nor-bornadiene (A). The Prins reaction of gives the tricyclic diformate (C), which is then converted into a tricyclic keto acid.
After oxidation to (D) and resolution with L-(-)-α-methyl-berzylamine, chloric acid was added with boiling aqueous hydrochloric acid.
(E), which was sequentially oxidized to δ-lactone (F) by Bayer-Villiger reaction, and then reduced to 1
alcohol (I), namely 5β-halo-2β-hydroxymethyl-cyclopentane-3α-hydroxy-1α-acetic acid (1′→3)δ-lactone. In this case, the acid (F) is prepared by successive treatment with ethyl chlorocarbonate and triethylamine.
The mixed anhydride (G) obtained from
Reduce with _NaBH4 or _ZnBH4 in tetrahydrofuran: Treatment of (D) with HBr/acetic acid in a similar reaction system yields the corresponding bromine derivative of (E), which upon subsequent treatment of the reaction system contains bromine instead of chlorine.
bring about (I). This synthetic system has advantages over other known methods, primarily due to the ready availability of the starting materials and the low cost of the reagents used. However, according to experiments, especially when carried out on a large scale, approximately 75
% of cyclopropyl ketone (D) never yields the same yield, and the extremely expensive base used in the resolution, L-
(-)-α-Methylbenzamine is a synthetic product and therefore this material also has to be resolved during the synthesis process. Attempts to resolve chloric acid (E) and similar bromine derivatives showed that the method did not work. This is because (E) has the remarkable property of regenerating cyclopropyl ketone (D) when treated with a base. The instability of the halogen in the presence of a base to form the corresponding cyclopropyl derivative, which is characteristic of all intermediates (E) to (I), is another negative factor in this synthetic system. Furthermore, (E) is obtained by Bayer-Villiger oxidation with peracid.
When changing to (F), significant damage is caused by δ-lactonic acid.
To obtain (F), the reaction requires at least 1 mole of peracid per mole of (E). That is, in the final step of purification it is necessary to remove the compound consisting of at least one equivalent of acid resulting from the peracid. Although this process can be facilitated by using m-chloro-perbenzoic acid, which is very expensive, the process creates problems regarding the cost of the product to be dissolved. Finally, the reduction of the carboxylic acid (F) to give the corresponding primary alcohol (I) gives good yields but requires a difficult purification of the compound from the anhydride or the starting acid and Purification cannot be achieved chemically, since δ-lactone-
The alcohol has the property of hydrolytically decomposing upon treatment with a base, or because of the unreacted δ-lactone-halo-carboxylic acid, it can be converted into a cyclopropane derivative by the base, reducing the overall yield of the process. This is because it reduces the By the way, it does not have the above-mentioned disadvantages and has significant advantages over the above-mentioned methods, namely: (1) The yield in each step is practically quantitative;
Average about 90-95%, only in worst case about 78-80%
It is. In all steps, unreacted starting materials can be easily recovered, and the yield reaches 100%. (2) The reaction time is very short, usually not exceeding 2 hours, but about 15 to 30 minutes. (3) The final product can be recovered and purified without any difficulty. In particular, crystalline compounds or easily crystallizable compounds are obtained, and no undesirable by-products are produced due to the particular reaction conditions used. A new method for producing the compound of formula () has been found. These features of the new method, which is the object of the present invention, allow its use in large-scale production. The new method consists of the following steps: (a) Formula (): [In the formula, X represents a chlorine atom or a bromine atom, and Y represents a carboxy group] is acetalized to obtain the formula (): [In the formula, X and Y represent the above, and Z is a group:

[Formula] represents R and which may be the same or different
Each of R' represents a _C1 - _C6 alkyl group, or R and R' together represent the group: -( _CH2 ) _o- (n is 2, 3 or 4) or the group:

[Formula] (m ₁ is 1, 2 or 3, m ₂ is 0, 1, 2 or 3, and X represents the above)]
(b) optically resolve the racemic compound of formula to obtain an optically active compound; (c) reduce the obtained optically active compound of formula () to obtain formula (): (d) The optically active compound of the formula () is deacetalized to form the optically active compound of the formula (): (e) The optically active compound of the formula () is oxidized by the Bayer-Villiger method to form the compound of the formula (). All of the above compounds having formulas () to () are optically active compounds, and the compounds are nat-
It may be a derivative (i.e., useful in the production of natural prostaglandins) or an ent-derivative (i.e., useful in the production of enantioprostaglandins, i.e., 8,12-diiso-prostaglandins). . Z in the compounds of formulas () and () is preferably a group of the following formula: The acetalization reaction of the compound of formula () is carried out by a conventional method of organic chemistry. For example, a compound of formula () with a mono- or di-hydroxy alcohol;
The reaction can be carried out in the presence of catalytic amounts of an acid and an organic solvent such as benzene. The acid may be a Lewis acid or an organic acid such as p-toluenesulfonic acid, or an inorganic acid such as an inorganic hydrohalic acid such as HCl, but may also be an ion exchange resin in acid form such as a styryl-sulfonic acid resin. The solvent used in the reaction is preferably an inert solvent, such as benzene as described above, and one that removes water produced as an azeotrope. The acetalization reaction is carried out by reacting the compound of formula () with a mono- or di-hydroxy alcohol and also with an orthoester of a lower aliphatic alcohol, such as methyl or ethyl orthoformate, and distilling off the resulting lower aliphatic alcohol. It can be carried out as follows. In this case the reaction is preferably carried out in the presence of a catalytic amount of an acid, for example one of the acids mentioned above. Furthermore, an acetalization reaction can be used to convert a compound of formula () to a mono- or di-hydroxy alcohol or to a compound of formula:

A dialkyl acetal of a ketone of the formula: (in which R ₁ , R ₂ , R ₃ and R ₄ each represent a C ₁ -C ₆ alkyl group, which may be the same or different) and an acid, such as one of the above acids. It can also be carried out by reacting in the presence of a catalytic amount of the species and distilling off the resulting lower aliphatic alcohol. In reactions using orthoesters of lower aliphatic alcohols or dialkyl acetals of ketones, respectively with the above formula, these compounds act as solvents, but also other solvents, such as aromatic carbons such as benzene and toluene, or linear It is also possible to add ethers such as ethyl ether or isopropyl ether, or cyclic ethers such as tetrahydrofuran or dioxane. If the acetalization is carried out with mono-hydroxy alcohols, at least 2 moles of alcohol should be used per mole of compound of formula (), but if carried out with di-hydroxy alcohols, such as ethylene glycol, formula()
At least 1 mole of alcohol per mole of compound is sufficient. The acetalization reaction is advantageously carried out at temperatures from room temperature to the boiling temperature of the solvent used, and the reaction time varies from about 15 to 30 minutes to about 2 hours. As mentioned above, catalytic amounts of acid are used, for example about 0.05 to 0.5 mol, preferably 0.05 to 0.1 mol, of acid per mole of compound of formula (). Further, the reduction of the compound of formula () is carried out in a conventional manner. For example, a compound of formula () with an alkyl chlorocarbonate such as ethyl chlorocarbonate,
When reducing the mixed anhydride obtained by treatment in the presence of a base such as triethylamine or sodium bicarbonate, the reaction involves converting a hydride such as sodium borohydride, _LiAlH4 or tetrabutylammonium borohydride into a halogenated solvent such as CH It is carried out in ₂ Cl ₂ and CHCl ₃ or in ethereal solvents such as tetrahydrofuran or in alcoholic solvents such as ethanol. Reduction may also be carried out with the acid, for example by treatment with LiAlH ₄ in an inert ethereal solvent such as tetrahydrofuran or dimethoxyethane, or with borane in an inert ethereal solvent such as tetrahydrofuran or dimethoxyethane. can. The compound of formula () can be used either separately or directly in the subsequent deacetalization reaction. Particularly if the solvent used in the reduction reaction is also suitable for the deacetalization reaction, for example if the solvent is a water-miscible solvent, such as tetrahydrofuran and dimethoxyethane, it is possible to separate the compound of formula (). Not necessary. The deacetalization reaction is carried out in an acidic medium, i.e. organic acids such as acetic acid, oxalic acid, p-toluenesulfonic acid, benzenesulfonic acid, or inorganic acids such as hydrochloric acid or sulfuric acid, or ion conversion resins in the acid form such as styryl-sulfonic acid resins. , and aqueous organic solvents such as ketones such as acetone, lower aliphatic alcohols such as ethanol and methanol, or water-miscible solvents such as tetrahydrofuran and dimethoxyethane. Temperatures can range from room temperature to reflux temperature and reaction times vary from about 15 minutes to about 2 hours. The acetalization or reduction or deacetalization is carried out in an acidic medium, thereby avoiding the formation of undesirable cyclopropane derivatives. The oxidation reaction according to the Bayer-Billiger process comprises, under the conditions customary for reactions of this type, a peracid, preferably monoperphthalic acid, in an organic solvent such as ethyl acetate, per mole of peracid, an inorganic base, For example, at least 1 sodium or potassium bicarbonate
Performed in the presence of equivalent amounts. By using mono-perphthalic acid,
The following advantages arise. That is, at the end of the oxidation reaction, the phthalic acid formed is insoluble in the organic solvent used in the oxidation reaction, such as ethyl acetate, and by adding a base, such as sodium or potassium bicarbonate, to the reaction mixture, all phthalic acid is precipitated as an insoluble alkali phthalate. do. In fact, during the oxidation reaction,
The formation of undesired cyclopropane derivatives is prevented even if a base, such as an alkali bicarbonate, is used, in which case the alkali bicarbonate is insoluble in the solvent used, such as ethyl acetate, which is actually anhydrous. By adding alkali bicarbonate to the reaction mixture, any acid resulting from the reduction of the peracid as well as any unreacted peracid precipitates as an insoluble alkali salt. By treating the organic phase containing the final product with a buffer, for example 20% NaH ₂ PO ₄ , a completely base-free solution is obtained, thus avoiding the formation of undesired cyclopropane derivatives. Furthermore, when the compound of formula () in which Y is a carboxy group is in racemic form, it can be resolved into its optical antipodes at low cost and in high yield (approximately 70-80%) by treatment with ephedrin. and thus a pure optically active salt with ephedrin of a compound of formula () in which Y is a carboxy group is obtained, from which the pure optical antipode can be obtained in a conventional manner. When using 1-ephedrin, the optical enantiomer useful in the production of natural prostaglandins is 1-ephedrin.
When d-ephedrin is used, the enantio-optical enantiomer useful for the preparation of ent-prostaglandins is obtained in the form of a salt with d-ephedrin. The treatment of salting a compound of formula () where Y is a carboxy group with efuedrin (1-ehuedrin or d-ehuedrin) is carried out by treating a compound of formula () where Y is a carboxy group in an organic solvent such as benzene, acetone, or acetonitrile. This is advantageously carried out by treating a solution or suspension of the compound with a solution of ephedrin (1-ephedrin or d-ephedrin) in an organic solvent such as benzene, acetone, acetonitrile, thereby reducing the optical properties of ephedrin. Pure salt crystals are obtained directly. Pure optically active compounds of formula (), where Y is a carboxy group, can be prepared from ehuedrin salts by, for example, acidifying an aqueous solution of the salt to a pH of about 3-4 or by making an aqueous solution of the salt stronger than ehuedrin. Y is prepared by removing the ephedrin by making alkaline with a base such as sodium or potassium hydroxide, then extracting with an organic solvent such as benzene, ethyl acetate or ethyl ether, and then acidifying the remaining aqueous solution. It can be obtained by producing a pure optically active compound of formula () which is a carboxy group. The compound is precipitated or extracted with an organic solvent such as ethyl acetate, chloroform or benzene, in the latter case a pure optically active compound of formula () in which Y is a carboxy group is obtained by evaporating the organic phase to dryness. : Next, the present invention will be explained in detail based on Examples, but the present invention is not limited thereto. Example 1 dl-syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1] in benzene 1.7
- A suspension of 169.3 g of heptane-3-one, 57 g of ethylene glycol and p-toluenesulfonic acid.
Add 1.7g. The mixture was refluxed for 2 hours and 30 minutes,
The water produced during the reaction (approximately 17 ml) is removed by azeotropic distillation in a Marcusson apparatus. The reaction is stopped by adding pyridine (1.2 ml) and the mixture is cooled to room temperature. The crystalline precipitate (188.74 g) is filtered off. The benzene phase is washed with a saturated solution of ammonium sulphate, evaporated to dryness and the residue is crystallized from CH ₂ Cl ₂ /acetone, yielding a further 17.51 g of product, melting point 160-162°C. Therefore dl-syn-6-exo-chlor-7-
Carboxy-bicyclo[2.2.1]heptane-
The total yield of 3-one-3,3-ethylene dioxide is 206.25 g (99% yield). Example 2 dl-syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one
A mixture of 110 g, ethylene glycol (70 ml) and triethyl orthoformate (195 ml) was heated at 90°C.
The mixture is heated for 1 hour at 120 DEG C. and for 2 hours at 120 DEG C. in the presence of p-toluenesulfonic acid (2.15 g), and the resulting ethanol is distilled off. The reaction is quenched by adding anhydrous pyridine (1.8 ml) and the mixture is cooled to 0-5°C. After filtering off the crystalline product that precipitates, the melting point is 162~
dl-syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptane-3- at 165℃
This yields 110.2 g of 1-3,3-ethylene dioxide. The filtrate is diluted with benzene, washed with water and evaporated to dryness in vacuo. Crystallization of the residue from CH ₂ Cl ₂ /acetone gives
A further 14.1 g of product with a melting point of 160 DEG-162 DEG C. are obtained. Therefore, the total yield is 91.66%. Example 3 Tetrahydrofuran (432
A solution of 1.5 mol of borane in (-)-syn in anhydrous tetrahydrofuran cooled to 0-2 °C
-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-
Add to a stirred solution of ethylene dioxide (115.94 g). The mixture is allowed to warm to room temperature and then stirred for 3 hours. Excess reagents are removed with 2N NaOH aqueous solution (580
ml) and the tetrahydrofuran is distilled off in vacuo. The remaining aqueous phase is extracted repeatedly with dichloromethane. The organic extracts were combined, washed to neutrality, dried and evaporated to dryness to yield (-)syn-6-exo-chloro-7-hydroxymethyl-, mp 68-70°C (from isopropyl ether). Bicyclo[2.2.1]heptane-3-one-3.3-ethylene dioxide 106
g (yield 97.3%) is produced. [α] _D = −3.8° (MeOH), [α] _D = −12.5° (CHCl ₃ ). If the alkaline aqueous phase is acidified, no appreciable amount of starting material is obtained. Example 4 18.5 g of (-)syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-ethylene dioxide in 120 ml of dichloromethane cooled to 0°C. The solution was sequentially: (1) a solution of 12.1 ml of triethylamine in 10 ml of dichloromethane over a period of 10 minutes; (2) a solution of 30 ml of triethylamine over a period of 10 minutes;
Add a solution of 8.3 ml of ethyl chlorocarbonate in ml. Mixed anhydride formation is complete within 20 minutes from the time the last reagent is added. The mixed anhydride solution was then added over 20 minutes (5 ml/dose in the first 10 minutes).
min, then 15 ml/min), 13 g of sodium borohydride in 90 ml of ethanol cooled to about -5°C to 0°C.
Add to the suspension. The mixture was heated to 0 for 2 hours and 30 minutes.
Stir at °C, then add 20 ml of water to remove excess
The NaBH ₄ is destroyed and the reaction mixture is evaporated to dryness.
Add 80ml of 2N NaOH and heat at 60-65°C for 30 minutes. Extract with 300 ml of methylene chloride (3 x 100 ml),
The extract was washed with water until neutral and evaporated to dryness, yielding (-)syn-6-exo-chloro-7-hydroxymethyl-bicyclo[2.2.1]heptan-3-one-3. 3-ethylene dioxide
15.64g is produced. [α] _D = −3.7° (MeOH),
[α] _D = -12.4° (CHCl ₃ ) (melting point 67-68°C, from isopropyl ether). Acidification and extraction of the alkaline aqueous phase yields the starting material: (-)syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptane-3
0.7 g of -one-3,3-ethylene dioxide is produced. The overall yield of the method is 93%. Example 5 Solution of (-)syn-6-exo-chloro-7-hydroxymethyl-bicyclo[2.2.1]heptane-3-one-3.3-ethylene dioxide (103 g) in acetone (0.4) at reflux temperature
Treat with 4N aqueous sulfuric acid (0.2) for 2 hours. Most of the solvent is evaporated in vacuo and (NH ₄ ) ₂ SO ₄ (40
After addition of g), the aqueous phase is extracted with methylene chloride. Combine the organic extracts, wash until neutral,
Drying over sodium sulfate and evaporation to dryness yielded crude (-)syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one [81.89 g, [α] _D = +36°(MeOH)] is generated. Crystallization of this from ethyl ether-isopropyl ether gives 76 g of pure compound with a melting point of 77-79°C. [α] _D = +39.2° (MeOH):
[α] _D = +37.4° (CHCl ₃ ). Example 6 A solution of 0.95 molar borane in tetrahydrofuran (0.15) of (-)syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1] in tetrahydrofuran (350 ml) cooled to 0-5°C.
Heptane-3-one-3,3-ethylene dioxide (0.374 mol) is added to a stirred solution of 87.18 g. In this case, the initial addition must be carried out gradually. This is because the gas evaporates. Stirring is continued for 4 hours at room temperature, then water (87 ml) and 4N aqueous H ₂ SO ₄ (180 ml) are added to destroy excess reagent. The mixture is refluxed for 2 hours, most of the tetrahydrofuran is evaporated in vacuo and the aqueous phase is extracted with dichloromethane. The combined organic extracts are washed with a 20% solution of ammonium sulfate until neutral, dried over sodium sulfate and evaporated to dryness, yielding 65.6 g of crude product. Pure (+)syn-6-exo-chloro-7-hydroxymethyl-bicyclo[2.2.1]heptane-3 with a melting point of 79-81°C after crystallization from isopropyl ether
61.5 g of -on is obtained. [α] _D = +37.5° (chloroform, C = 1%) (theoretical amount 65.2 g, yield
94.5%) Example 7 A solution of monoperphthalic acid (120.5 g) in ethyl ether (0.74) was mixed with (+)syn-6 in anhydrous dichloromethane (1.09) with vigorous stirring.
-exo-chloro-7-hydroxymethyl-bicyclo[2.2.1]heptan-3-one 72.42g
is added to a suspension of anhydrous NaHCO ₃ (to 36.5 g) in a solution of NaHCO 3 and the temperature of the reaction mixture is kept at about 20° C. by external cooling. After 5 hours, another 36.8 g of anhydrous NaHCO ₃ are added and stirring is continued for a further 2 hours. The precipitate is filtered and washed with dichloromethane (50 ml) and anhydrous ethyl acetate (50 ml). Combine the filtrates, add ₃ x 20 ml of 10% NaCO3 and -
Wash with 3 x 40 ml of a 10% solution of basic phosphate;
After drying over Na ₂ SO ₄ and evaporation to dryness, the crude δ−
78 g of lactone are obtained. Yield 96.5%. When crystallized from methylene chloride, melting point 127-129
pure (-)5β-chloro-2β-hydroxymethyl-cyclopentane-3α-hydroxy-
65 g of 1α-acetic acid (1′→3)δ-lactone are produced. [α] _D = -63° (CHCl ₃ ), when the mother liquor is concentrated, the melting point is further 124-127°C, [α] _D = -62°C
5.23 g of (CHCl ₃ ) product are obtained. Example 8 dl-syn-6-exo-bromo-7-carboxy-bicyclo[2.2.1]heptan-3-one (23.3 g, melting point 179-181°C), anhydrous benzene (0.25
), anhydrous ethylene glycol (6.3 ml) and p-
A mixture of toluenesulfonic acid (180 mg) is heated at reflux temperature with azeotropic removal of the water formed during the reaction. After 2 hours and 30 minutes the reaction is stopped by adding 0.4 ml of pyridine. dl−syn when cooled
-6-Exo-bromo-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-
Ethylene dioxide (25.48g, melting point 154-155
℃) crystallizes and is collected by filtration. Example 9 dl-syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one
189g (1 mol), anhydrous ethylene glycol (63
ml) and anhydrous benzene (2.5) is heated at reflux temperature in the presence of 1.72 g of p-toluenesulfonic acid and the water (18 ml) formed during the reaction is removed. At this point (approximately 1 hour), anhydrous benzene (2
A solution of 1-ephedrin (167 g) in ) is added to the reaction mixture, which is cooled to 25-30°C and crystallized. When the crystalline product is filtered out, nat-syn-6
151 g of -exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-ethylenedioxy-1-ephedrin salt are obtained. Melting point 170-172℃, [α] _D = -33.05゜,
[α] _D = -97° (MeOH, C = 1%). Example 10 dl-syn-6-exo-chloro-7-carboxy-bicyclo[2.
2.1] A solution of heptane-3-one-3,3-ethylene dioxide (100 g) is treated with 1-ephedrine (70.8 g). After 4 hours, the crystal precipitate was filtered and nat-syn-6-exo-chlor-
7-Carboxy-bicyclo[2.2.1]heptan-3-one-3.3-ethylene dioxide-1
- 62.3 g of efuedrin salt are obtained. Melting point 173~
174°C, [α] _D = -33.5°, [α] ₃₆₅ = -97.8° (MeOH; C = 1%). 39.7 g of this salt is dissolved in 50 ml of water and treated with 4.2 g of sodium hydroxide. The solution is extracted with benzene to remove ephedrin. 1N organic extract
Wash with 3 x 5 ml of NaOH and 3 x 5 ml of water. The aqueous phases are then combined, acidified to PH4 and extracted with ethyl acetate. When the solvent was evaporated (-)syn-6-
22.1 g of exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-ethylene dioxide is obtained, melting point 128~
129.2℃. [α] _D = −10.2°, [α] ₃₆₅ = −19.6° (MeOH, C = %). 2.33 g of this compound was deketalized by treatment with aqueous 4N sulfuric acid (4 ml) and acetone (20 ml) for 1 hour at reflux temperature and, when worked up in a conventional manner, produced pure (+)syn-6-exo-chloro. -7
17.5 g of -carboxy-bicyclo[2.2.1]heptan-3-one are obtained. Melting point 157-158℃,
[α] _D = +14°, [α] ₃₆₅ = +200° (MeOH). Example 11 dl-syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-ethylene dioxide in 400 ml of benzene.
A solution of 23.3 g and 16.5 g of d-ephedrin at 20°C.
Cool to When the crystal precipitate is filtered, the enanthate
syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.
3-ethylene dioxide-d-ephedrine salt
14.72g is produced. Melting point 171-172℃, [α] _D = +
33.2° (MeOH, C=1%). Example 12 dl-syn-6 in anhydrous acetonitrile (5)
A solution of 100 g of -exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-ethylene dioxide was treated with d-ephedrine (70.8 g) and crystallized after 3 hours. Filtration of the precipitate gives 69.8 g of a salt with an optical rotation of +32.8° (MeOH). Acetonitrile (1.75
After recrystallizing the compound from
59.4 g of 3,3-ethylene dioxide-d-ephedrin salt are obtained. Melting point 174-174.5℃, [α] _D
= +34.1°, [α] ₃₆₅ = +100.75° (MeOH). 4 g of this compound is dissolved in water, 0.44 g of sodium hydroxide is added, and the mixture is extracted with ethyl ether to remove d-ephedrin. The ether extracts are washed with 2 x 3 ml of 1N NaOH and the combined aqueous phases, acidified to PH 4.8, are extracted with ethyl acetate. These organic extracts were dried and evaporated to yield enanth-syn-6-exo-chloro-7-carboxy-bicyclo[2.2.1]heptan-3-one-3.3-ethylene dioxide 2.21 g occurs. Melting point 124-126℃. [α] _D = +11° (MeOH). After deketalization, enanth-syn-6-exo-chloro-7-carboxy-bicyclo[2.
2.1] 1.71 g of heptane-3-one is obtained.
Melting point 156-157°C, [α] _D = -14.5° (MeOH).

Claims (1)

[Claims] 1 Formula (): In order to obtain an optically active compound of [wherein X represents a chlorine atom or a bromine atom], (a) formula (): [In the formula, X represents a chlorine atom or a bromine atom, and Y represents a carboxy group] is acetalized to obtain the formula (): [In the formula, X and Y represent the above, Z represents a group: [Formula], and R and
Each of R' represents a C ₁ -C ₆ alkyl group, or R and R' together represent the group: -(CH ₂ ) _o - (n is 2, 3 or 4) or the group: [ Formula】 (m ₁ is 1, 2 or 3, m ₂ is 0, 1, 2 or 3, and X represents the above)
(b) optically resolve the racemic compound of formula to obtain its optically active compound; (c) reduce the optically active compound of formula () to obtain formula (): (d) The optically active compound of the formula () is deacetalized to form the optically active compound of the formula (): (e) oxidizing the optically active compound of formula () by the Bayer-Villiger method to produce a compound of formula ();
Optically active 5β-halo-2β characterized by
-Hydroxymethyl-cyclopentane-3α-
Method for producing hydroxy-1α-acetic acid (1′→3)δ-lactone. 2 formula: [In the formula, X represents a chlorine atom or a bromine atom, Z represents a group: [Formula], and each of R and R', which may be the same or different, represents a C ₁ to C ₆ alkyl group, or R and R′ together represent the group: −(CH ₂ ) _o
- (n is 2, 3 or 4) or a group: [Formula] (m ₁ is 1, 2 or 3, m ₂ is 0, 1, 2 or 3, and X represents the above) ) represents a racemic compound represented by ehuedrin, which is then optically resolved by salt formation with ehuedrin and then obtaining the pure optical enantiomer from the ehuedrin salt in a conventional manner.
The method described in section. 3. The method according to claim 2, which uses l-ephedrin. 4. The method according to claim 2, which uses d-ephedrin.