CZ20011147A3 - Selective lactonization process - Google Patents

Abstract

The present invention relates to a process for lactonization of a compound of the general formula of formula (1), wherein the reaction can be largely inhibited, dimer. The solution goes further a process for the preparation of a compound of formula (2) includes lactonization of a compound of formula (1) to such conditions that the solubility of said compound of formula (1) and / or solubility of said compound of formula (2) is not greater than 0.5% by weight percent to give said compound of formula (2) which does not contain more than 0.3 mole percent dimer.

Description

Method of selective lactonization

Technical field

The present invention relates to a process for preparing a lactone of formula (2), wherein the free acid of formula (1) is the starting compound.

BACKGROUND OF THE INVENTION

Many drugs with antihyperlipemic effects are currently commercially used, and highly functional drugs that are capable of reducing cholesterol biosynthesis by inhibiting HMG-CoA reductase include compounds of formula (4) or (5).

· '·.

tr ·· «· ·· 99 99 99 9

Í4)

HIM"

CO ^ \ ^ 0H

R * where

Z * is hydrogen, alkyl of 1 to 5 carbon atoms, or alkyl of 1 to 5 carbon atoms substituted with one substituent selected from the group consisting of phenyl, dimethylamino and acetylamino;

R * is a group of formula (6)

where

R ¹ is methyl or hydroxyl;

R ² is hydrogen or methyl;

a, b, c and d are optionally double bonds, especially b and d are double bonds, or all bonds a, b, c and d are single.

· '«

• · ? · • ·. • · · • · • · 0 • 0 · 0 0 · « • 0 0 • e · • 0 0 · • · 0 e · · · • 0. ·· ·· • 0 • 00

Many of these natural substances and their semisynthetic analogs are commercially available in the form of lactones, and therefore it is very important to use high efficiency technologies in high yields in the lactonization of free acids or salts.

To date, the lactonization of said compounds is carried out by heating said starting compound in an organic solvent in which it is sufficiently soluble, such as toluene, ethyl acetate and isopropyl acetate, under reflux or substantially reflux conditions (see European Patent Application Publication No. EP 0033536 A2). ). Lactonization is catalyzed by acids, the necessary acidity of the reaction mixture being ensured either by the carboxyl group present in the starting compound itself or by the addition of a strong acid, thereby ensuring that the lactonization occurs at a relatively low temperature.

Lactonization generally is an equilibrium reaction, and it is therefore necessary to shift the reaction equilibrium towards the lactone by suitable means to obtain the lactonization product in high yield. Generally, the lactonization reaction can basically be carried out in a manner in which azeotropic distillation and / or a stream of nitrogen is used to remove reaction by-products from the reaction system (e.g., water and ammonia).

It is also known that the necessary shift of equilibrium in the lactonization reaction is achieved in another way.

In this case, the equilibrium between the lactone and the starting free acid is shifted towards the lactone by carrying out the reaction and maturation at low temperature in a mixture of acetic acid.

9 «4» 9 · 9 9 9 9 9 9 9

9.9 9-9 9 9 9 and then water is added to the mixture to precipitate the lactone product from the reaction mixture (see Japanese Patent Application No. JP H09-188672 A1).

Commonly used methods of lactonization have several disadvantages. Thus, for example, when the starting free acid serves as an acid catalyst itself, the reaction time is prolonged as the starting compound is gradually consumed, resulting in an increased amount of by-products formed and a decrease in the reaction rate. Because the lactone formed is exposed to the remaining free acid for a long time under these reaction conditions, the hydroxyl group of the lactone at the 3-position undergoes an esterification reaction with this free acid, so that a larger amount of the dimer of formula 3 is formed. is almost impossible t

by recrystallization (see Japanese Patent Application No. JP H09-188672 A1), the purity and yield of the main reaction product is reduced.

9 9 9 9 * 9

The method of minimizing formation of the above dimer may comprise performing said lactonization reaction under high dilution conditions. However, it is clear that in this case the productivity of the whole process will be low.

In the case of the above reaction in a mixture of acetic acid and trifluoroacetic acid according to Japanese Patent Application No. JP H09-188672 A1, the amount of said dimer resulting from this reaction is reportedly reduced to not more than 0.2 percent. However, this process is not suitable for use in practice, since this reaction, which is carried out at low temperature, requires a long reaction time, water is repeatedly added to the reaction mixture to shift the equilibrium, and then it is necessary to regenerate the solvents.

SUMMARY OF THE INVENTION

In the development of the present invention, considerable efforts have been made to overcome the above drawbacks, and based on the theory that lactonization is an auto-condensation reaction, it has been found that carrying out the lactonization reaction in a medium in which the free acid of formula (1) and / or The resulting lactone of formula (2) is substantially insoluble / it is possible to dramatically inhibit the reaction between the lactone of formula (2) and the free acid of formula (1) to form the above-mentioned dimer, thereby enabling the development of a completely new lactonization technology.

Thus, the present invention relates to a process for the preparation of a compound of the above formula (2) by lactonizing a compound of the above formula (1), which comprises carrying out an embodiment of the formula (1).

-C.

The lactonization reaction under conditions such that the solubility of the compound of formula (1) and / or the solubility of the compound of formula (2) is not more than 0.5% by weight, thereby forming a compound of formula (2) more than 0.3 mole percent of the dimer of formula (3) above.

The present invention is described in more detail in the following paragraphs.

In the above general formulas (1). (2) and (3), the symbols have the following meanings:

R is an alkyl group containing from 1 to 10 carbon atoms;

R ¹ is methyl, CH ² OH, CH ² OCOR ² , CO ² R ³ , CONR ⁴ (R ⁵ ), hydroxyl, CH ² OR ² or CH 2 NR ⁴ (R ⁵ );

Z is hydrogen, ammonium (NH ₄ ^+). a cation or a metal cation;

R ² is an alkyl group containing from 1 to 5 carbon atoms;

R ³ is a hydrogen atom or an alkyl group containing from 1 to 5 carbon atoms;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and alkyl groups containing from 1 to 5 carbon atoms; a * ^: 9 9 9 99 99 99 99 99 99 99 99 99 99 99 99 99

9999 9 9 99 ·· ·· ··· a and b are both double bonds at the same time, or one of the bonds a or b is single, or both bonds a and b are simple.

In a preferred embodiment of the present invention, the individual symbols in the above general formulas have the following meanings:

R is preferably a sec-butyl group or a 1,1-dimethylpropyl group;

R ¹ is preferably methyl, or hydroxyl, particularly preferably methyl;

Z is preferably hydrogen or ammonium (NH ₄ ⁺⁾ cation, particularly preferably a hydrogen atom;

a and b are preferably both double bonds at the same time.

In a particularly preferred embodiment of the invention, it is

R ^{1 is} methyl or hydroxyl; and

Z is hydrogen, or ammonium (NH ₄ ⁺⁾ cation.

In another preferred embodiment of the present invention is

R sec is butyl or 1,1-dimethylpropyl;

R ¹ is methyl or hydroxyl; a and b are both double bonds.

«· ·· ·· ···· ·«? In another particularly preferred embodiment of the present invention, R is a butyl group or 1-carboxylic acid group. 1,1-dimethylpropyl

R ¹ is methyl;

Z is hydrogen; and and a‘b are both double bonds.

Said free acid of formula (1), which is used as a starting material according to the present invention, can be obtained as a product of cultivation by the techniques described, inter alia, in published international applications WO 94/10328 and WO 98/50572. The general formula (1) used as the starting material according to the present invention may generally be a free acid of formula (1) and / or a partially cyclized mixture composed of the free acid of formula (1) and the lactone of formula (2) can be obtained by suitable means, for example by extraction, from the culture medium. Suitable compositions include a process comprising alkaline extraction and isolation from a cell-free extract described in WO 94/10328, and a method of isolation using free acids wherein the cell-free alkaline extract is further purified by adsorption on a resin as described in WO 98/50572. It is also possible to use a solution prepared by replacing the medium used in the lactonization reaction with solvents from the extract.

to this to this to this to it to <<· · ···

The lactonization reaction of the present invention is carried out under conditions where the solubility of the above compound of formula (1) and / or the solubility of the above compound of formula (2) does not exceed 0.5 weight percent. Thus, the conditions of the lactonization reaction of the present invention are controlled such that the solubility of the compound of formula (1) itself, or the solubility of the compound of formula (2) itself, or both the solubility of the compound of formula (1) and the solubility of the compound of formula (2) 0.5 weight percent or less. To ensure such a solubility value, it is necessary to select not only a suitable reaction medium, but also to carefully select the correct reaction temperature, reaction pressure and acidity of the reaction mixture. Solubility in this context is understood to mean the amount of the substance in percent by weight, based on the total weight of the reaction mixture.

The reaction medium for the lactonization reaction of the present invention may be any medium in which the solubility of the free acid of formula (1) and / or the solubility of the lactone of formula (2) does not exceed 0.5 weight percent under lactonization conditions. is preferably stable under lactonization conditions. Such a medium is selected from the group consisting of saturated hydrocarbons having from 5 to 16 carbon atoms, the composition of which may be represented by the formula C _n H 2 _n +2 or C _n H 2 _n . In the lactonization reaction of the present invention, it is possible to use either one or more such media. Preferred saturated hydrocarbon media include pentane,

2-methylpentane, 2,2-dimethylpentane, hexane, isohexane, n-heptane, octane, isooctane, methylcyclopentane, ethylcyclopentane, c · · · Propylcyclopentane, methylcyclohexane, ethylcyclohexane, propylcyclohexane and mixtures thereof.

While maintaining the stability condition for the lactonization conditions, it is possible according to the present invention can also be one or more unsaturated hydrocarbon médií- containing 5-16 carbon atoms, whose composition is možné'vyjádřit general formula _CnH2n or C _n H _2n-2r being it is also possible according to the invention to use mixtures of one or more of said saturated hydrocarbon media with one or more of said unsaturated hydrocarbon media. If, under the conditions of the lactonization reaction, both the condition that the solubility of the free acid of formula (1) and / or the solubility of the lactone of formula (2) is not greater than 0.5% by weight and the condition of medium stability, and a mixture of one or more of these aqueous media with one or more of said hydrocarbon media.

In a preferred embodiment of the present invention is a medium for the lactonization reaction mixture of water and at least one substance selected from the group consisting of saturated hydrocarbon media containing 5 to 16 carbon atoms of the general formula _{CnH2n + 2} or _CnH2n and unsaturated hydrocarbon of 5 to média'obsahující 16 carbon atoms of the formula _CnH2n or _CnH2n - _2nd

In another preferred embodiment of the present invention, water is used as the lactonizing medium.

Usually, the amount of said medium is in the range of about 80 weight percent to about 80 weight percent

«9 • 9 • 9 • 9 * · 9 fc • 9 '9 fc 9 'fc 9 • • 9 • 9 · 9 9 · 9 ' 9 • 9 9 9 9 . · ♦ · 9 9 • · · 99 · '· 9 · • 9 9 9

% by weight based on the total weight of the free acid of formula (1) and the medium.

Said reaction is effected in the presence of an acid; for example, when expressing acidity by pH, the reaction of the present invention generally proceeds under acidic conditions where the pH does not exceed 5. The group of acids whose use is necessary to adjust the acidity of the mixture to not exceed pH 5 includes, inter alia, formic acid. acid, phosphoric acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, ^perchloric: p-toluenesulfonic acid and methanesulfonic acid. These acids may be used alone or several may be used in the form of a suitably formed mixture. For practical reasons, the reaction of the present invention is carried out by adjusting the pH of the reaction mixture not exceeding 5 by means of a mineral acid which is relatively inexpensive, but it is also permissible to add several acids to the reaction mixture. For example, it is permissible to lower the pH to a certain value with a mineral acid and subsequently to add an organic acid to the reaction mixture. As the lactonization progresses, the reaction rate decreases, but it has been shown that the necessary support of the ongoing reaction can be achieved if the acid is additionally added to the reaction mixture during the reaction.

The lactonization reaction according to the invention may be carried out at a temperature as low as, for example, 5 ° C, but in terms of productivity said reaction preferably proceeds at a temperature not lower than 20 ° C, taking into account the stability of the medium and the starting compound. the reaction is preferably carried out in a temperature range of 40 ° C to 80 ° C.

ΦΦ φ φ φ φ · · · · · · · · · »» »· · • • • · · · · φ φ φ φ φ φ · Φ φ φφφ

If water is produced as a by-product in the reaction, it is convenient to use a mixture of water and a hydrocarbon medium as the reaction medium and carry out lactonization while azeotropically distilling off the water. In this case, the removal of water is preferably associated with the simultaneous addition of said hydrocarbon medium.

The lactonization reaction of the present invention may be conducted at atmospheric pressure, but may optionally be conducted at reduced pressure in the range of about 4 kilopascals to 80 kilopascals (from about 30 millimeters Hg to

600 millimeters Hg) at which the medium reflux occurs at a relatively low temperature.

The time required to carry out the lactonization of the present invention is usually about 1 hour to 30 hours.

Isolation of the resulting lactone of general formula (2) is generally very easy. Thus, since the present lactone of formula (2) has very low solubility in a given reaction medium, it is possible to isolate the lactone from the reaction mixture by simply separating the solid from the liquid either during or after the reaction, or cooling the reaction mixture and then separating the solid from the liquid.

If desired, it is of course possible to increase the purity of the product obtained by purification, for example by recrystallization.

Thus, by the process of the present invention, it is possible to obtain a lactone of formula (2) which does not contain more than 0.3 mole percent of the by-product which is the dimer of formula (3). In a preferred embodiment of the present invention

9 9 <9 9 9 99 9 9 9 9 9 9 • 9 9 '9 9 9 9 9 9 • • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 · 9 99 9 9

According to the invention, it is possible to obtain a lactone of formula (2) which contains 0.2 mole percent or less of the by-product which is the dimer of formula (3).

DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided to illustrate the invention in more detail without limiting its scope in any way. In the following examples, the free acid and / or lactone content was determined by high performance liquid chromatography (HPLC) under the following conditions (referred to as analytical conditions A).

Analytical conditions

Device: Shimadzu Corporation LC-10A

Column ·: Nacalai Tesque ODS column, Cosmosil

5C18-AR-30O

Eluent: acetonitrile containing 0.1 percent phosphoric acid / water (48:52 parts by volume)

Flow rate: 2.0 mL / min

Detection: UV detector at 238 nanometers

Temperature: 45 ° C

The content of the dimer formed as a byproduct of lactonization was determined by high performance liquid chromatography (HPLC) under the following conditions (referred to as analytical conditions B).

Φ · '' • φφ

ΦΦΦ

Φ Φ φ φ φ

ΦΦΦ Φ Φ

Analytical conditions

Equipment

Column

Eluent

Flow

Detection

Temperature

Shimadzu Corporation LC-10A Nacalai Tesque ODS column, Cosmosil

5C18-AR-300 acetonitrile containing 0.1 percent phosphoric acid / water (80:20 by volume)

1.0 ml / min

UV detector at 238 nanometers 45 ° C

Example 1

6 (R) - [2- [8 (S) - (2-Methylbutyryloxy) -2 (S), 6 (R) -dimethyl], 2,6,7,8,8a (R) -hexahydronaphthyl-1 (S) )] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (ie, a compound of formula (1) wherein R is sec-butyl, R ¹ is methyl) , a and b are double bonds, and Z is hydrogen) milliliters of an aqueous solution of 7-1.2, 6.7, 8.8a (R) hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2-methylbutyryloxy) -1 (S) naphthyl-3 (R), 5 (R) -dihydroxyheptanoic acid (starting heptanoic acid concentration 4.0% by weight) was adjusted by adding sulfuric acid to a pH of 3 and With continuous stirring, the solution was heated to 70 ° C. After. A suspension sample was taken from the reaction for 5 hours and analyzed by high performance liquid chromatography (HPLC) to confirm that the lactonization was at least 70 percent. Heating of the reaction mixture was terminated 6 hours after the start of the reaction, and after cooling to room temperature, the mixture was vacuum suctioned. 9 · · · ·

A slurry solid was isolated by filtration, dried under vacuum at 50 ° C and analyzed by High Performance Liquid Chromatography (HPLC). confirmed that the desired lactone was produced in 78 percent yield. The lactone obtained was found to contain 0.11 mole percent of the dimer formed as a by-product in the reaction. Coincidentally, the solubility of both the starting heptanoic acid and the lactone formed was not greater than 0.05 weight percent.

Example 2

6 (R) - [2- [8 (S) - (2,2-Dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl], 2,6,7,8,8a (R) -hexahydronaphthyl-1 (S)] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (i.e., a compound of formula (1) wherein R is

1,1-dimethylpropyl, R ¹ is methyl, a and b are double bonds and Z is hydrogen)

100 ml of an aqueous solution of 7-1,2,6,7,8,8a (R) hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2,2-dimethylbutyryloxy) 1 (S) ) -naphthyl-3 (R), 5 (R) -dihydroxyheptanoic acid (starting heptanoic acid concentration was 3.6% by weight) was adjusted by adding sulfuric acid to a pH of 3 and heated to 70 with continuous stirring After a 5 hour reaction, a slurry sample was taken from the mixture and analyzed by high performance liquid chromatography (HPLC) to confirm that the lactonization was at least 70 percent. The heating of the reaction mixture was stopped 6 hours after the start of the reaction, and after cooling to room temperature, a slurry solid was isolated from the mixture by suction filtration, dried in vacuo at 50 ° C and analyzed by high-efficiency. · To toto toto to to to to toto toto toto toto toto toto toto toto toto · to to to to to to to to to toto toto toto to By liquid chromatography (HPLC) to confirm that the desired lactone was formed in a yield of 76 percent. The lactone obtained was found to contain 0.13 mole percent of the dimer formed as a by-product in the reaction. Coincidentally, the solubility of both the starting heptaic acid and the lactone formed was not greater than 0.05 weight percent.

Example 3

6 (R) - [2- [8 (S) - (2-Methylbutyryloxy) -2 (S), 6 (R) -dimethyl], 2,6,7,8,8a (R) -hexahydronaphthyl-1 (S) 1] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (ie, a compound of formula (1) wherein R is sec-butyl, R ¹ is methyl) , a and b are double bonds and Z is hydrogen) milliliters of an aqueous solution of 7-1,2,6, 7,8,8a (R) hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2-methylbutyryloxy) -1 (S) naphthyl-3 (R), 5 (R) -dihydroxyheptanoic acid (concentration of starting heptanoic acid was 4.0% by weight) was adjusted by adding sulfuric acid to a pH of 3, followed by 80 ml of n-heptane was added to the solution. This mixture was refluxed in a flask equipped with a Dean-Stark trap and heated to an internal temperature of the mixture under reduced pressure (approximately 29.3 kilopascal (i.e. approximately

220 mm Hg) was 60 ° C. During the reaction, water trapped in the receiver was removed from the mixture while the corresponding amount of n-heptane was added to the mixture. Refluxing under reduced pressure was continued until the water substantially stopped azeotropically distilling, and after a further 4 hours maturation, a slurry sample was taken from the mixture and analyzed by high performance liquid chromatography (HPLC) to

99 '99' 9 9 ···· '9 9' 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9

9 9 99 9 .999 8

9 9 9999 99 confirmed that lactonization was over 90 percent.

Therefore, the heating was stopped and the reaction mixture was cooled to room temperature. The suspension was collected by suction filtration and dried under vacuum at 50 ° C and analyzed by high performance liquid chromatography (HPLC) to confirm that _: required. the lactone was produced in 95 percent yield. The lactone obtained was found to contain 0.11 mole percent of the dimer formed as a by-product in the reaction. Coincidentally, the solubility of the starting heptanoic acid and the resulting lactone was not greater than 0.05 weight percent, or 0.08 weight percent throughout the reaction.

percent.

Ř

Example 4 ...

(R) - [ ₂₇ [8 (S)] - (2,2-Dimethyl-butyryloxy) -2 (S), 6 (R) -dimethyl-1,2,6,7,8,8a (R) -hexahydronaphthyl -1 (S)] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyrrole-2-one (ie. A compound of formula (1)) wherein R is

1,1-dimethylpropyl group; R ¹ is methyl, a and b are double bonds, and Z 'is hydrogen je-)

100 ml of an aqueous solution of 7-1,2,6,7,8,8a (R) hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2,2-dimethylbutyryloxy) 1 ( S) -naphthyl-3 (R), 5 (R) -dihydroxyheptanoic acid (the concentration of starting heptanoic acid was 3.6% by weight) was adjusted by adding sulfuric acid to a pH of 3 followed by addition of 80 ml of the solution. -heptane. This mixture was refluxed in a flask equipped with a Dean-Stark trap and heated to maintain the internal temperature of the mixture under reduced pressure (approximately 13.3 kilopascal (i.e.

Approximately 100 millimeters Hg)) was 40 ° C. Water was removed azeotropically in the same manner until the water had substantially stopped distilling. After a further 4 hours of maturation, a slurry sample was taken from the mixture and analyzed by high performance liquid chromatography (HPLC) to confirm that the lactonization was more than 90 percent complete. Therefore, the heating was 'terminated' and the reaction mixture was cooled to room temperature. A slurry solid was isolated from the mixture by suction filtration and dried under vacuum at 50 ° C and analyzed by high performance liquid chromatography (HPLC) to confirm that the desired lactone was produced in 94 percent yield. The lactone obtained was found to contain 0.26 mole percent of the dimer formed as a by-product in the reaction. Coincidentally, the solubility of the starting heptanoic acid and the resulting lactone was not greater than 0.07 weight percent and 0.21 weight percent, respectively, throughout the reaction.

Example 5

The lactonization reaction was run with the same starting material and under the same conditions as in Example 3 except that before the end of the azeotropic distillation of water, 10 mole percent, based on the amount of starting material, of a 10 percent aqueous sulfuric acid solution was added. promoting lactonization. The additional addition of the above acid solution during the on-going reaction promoted the lactonization to such an extent that the ripening time following the azeotropic distillation was reduced by 1 hour and, moreover, the yield of lactonization was increased. After .3 hours of maturation, · · · · · · · · · · · · · · · · · · · · · · · · ·

reflux was complete and the reaction mixture was cooled to room temperature. The solid was isolated by vacuum filtration and dried under vacuum at 50 ° C and analyzed by high performance liquid chromatography (HPLC) to confirm that the desired lactone was produced in 97 percent yield. The lactone obtained was found to contain 0.12 mole percent of the dimer formed as a by-product in the reaction. Throughout the reaction time, the solubility of the starting heptanoic acid and the resulting lactone was not more than 0.05 weight percent and 0.08 weight percent, respectively. Example 6

The lactonization reaction was carried out with the same starting material and under the same conditions as in Example 3, immediately after the azeotropic distillation of water, 10 mol% based on the amount of the starting material trifluoroacetic acid was added to promote the lactonization. As in Example 5, additional addition of the above acid enough to promote lactonization such that the yield of lactonization was increased. The reaction mixture was worked up in the same manner as in Example 5 and the resulting product was analyzed by high pressure efficient chromatography (HPLC). This analysis showed that the desired lactone was produced in 97 percent yield. Further, it was found that the lactone obtained contained 0.12 mole percent of the dimer formed as a by-product in the reaction. During the entire reaction time, the solubility of the starting heptanoic acid and the resulting lactone was not more than 0.06 weight percent and 0.08 weight percent, respectively.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · A

Example 7

The lactonization reaction was run with the same starting material and under the same conditions as in Example 3 except that hexane was used instead of n-heptane. After the reaction was carried out under the same conditions as in Example 3 (but in this case, the pressure was reduced to 73.3 kilopascal to 17.8 kilopascal (i.e.

550 mm Hg to 600 mm Hg were confirmed by high pressure efficient chromatography (HPLC) analysis to provide the desired lactone in 95 percent yield. Further, it was found that the lactone obtained contained 0.09 mole percent of the dimer formed as a by-product in the reaction. During the entire reaction time, the solubility of the starting heptanoic acid and the resulting lactone was not more than 0.05 weight percent and 0.06 weight percent, respectively.

Example 8.

The lactonization reaction was run with the same starting material and the same conditions as in Example 3 except that octane was used instead of n-heptane. After the reaction was carried out under the same conditions as in Example 3 (but in this case, the pressure was reduced to 9.3 kilopascal to 12 kilopascal (i.e.

millimeters (Hg to 90 millimeters (Hg)) was confirmed by HPLC analysis to give the desired lactone in a94 percent yield. Further, it was found that the lactone obtained contained 0.10 mole percent of the dimer formed in the reaction as a by-product. During the entire reaction time, the solubility of the starting heptanoic acid and the resulting lactone was not more than 0.05 weight percent and 0.08 weight percent, respectively.

• · · ·

• · · · · ·

Example 9

The lactonization reaction was run with the same starting material and the same conditions as in Example 3 except that methylcyclohexane was used instead of n-heptane and the reaction temperature was changed to 70 ° C. After the reaction was carried out under the same conditions as in Example 3, HPLC analysis showed that the desired lactone was produced in 97 percent yield. Furthermore, it was found that the lactone obtained contained 0.21 mole percent of the dimer formed as a by-product in the reaction. Throughout the reaction time, the solubility of the starting heptanoic acid and the resulting lactone was not more than 0.05 percent by weight, respectively.

0.11% by weight.

Example 10

The lactonization reaction was run with the same starting material and under the same conditions as in Example 3 except that the pH of the mixture was adjusted to 2 with sulfuric acid before the start of the reaction.

After the reaction was carried out under the same conditions as in Example 3, HPLC analysis showed that the desired lactone was produced in 95 percent yield. Further, it was found that the lactone obtained contained 0.12 mole percent of the dimer formed as a by-product in the reaction. During the entire reaction time, the solubility of the starting heptanoic acid and the resulting lactone was no more than

0.05 weight percent and 0.08 weight percent, respectively.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Φφ ·

EXAMPLE 11 The lactonization reaction was carried out with the same starting material a. Under the same conditions as in Example 1 except that before starting the reaction the pH of the mixture was adjusted to 5 with sulfuric acid, the reaction temperature was changed to 80 ° C and lactonization was continued for 30 hours. hours. After the reaction was carried out under the same conditions as in Example 1, HPLC analysis showed that the desired lactone was formed in a yield of 81 percent. Further, it was found that the lactone obtained contained 0.27 mole percent of the dimer formed as a by-product in the reaction. During the entire reaction time, the solubility of the starting heptanoic acid and the resulting lactone was not more than 0.08% by weight and

0.10 weight percent.

Comparative Example 1

The lactonization reaction was carried out with the same starting material and under the same conditions as in Example 3 except that toluene was used instead of n-heptane. After the reaction was carried out under the same conditions as in Example 3, HPLC analysis showed that the desired lactone was produced in 40% yield. However, after counting the amount of lactone that contained the filtrate, the total lactone yield was 98 percent. However, it was further found that the lactone obtained contained 0.63 mole percent of the dimer formed as a by-product in the reaction. In a particular solubility test of the resulting lactone under reaction conditions, which was carried out by high performance liquid analysis

4-9, 4-4 «· 4-4 44 4 9 4 9

93. 4 9 4 4 45

44 4 '4 4 4 4 • 4 9 4 4 4 9 4 4.9

4 4 4 4 9 4 4 4 • 9.4 4 · 4 4-4 chromatography, it was found that this solubility was not less than 2 percent.

According to the present invention, the free acid of formula (1) is lactonized by reaction in a medium in which the solubility of said free acid of formula (1) and / or the solubility of the resulting lactone of formula (2) is not more than 0.5% by weight. The amount of dimer of formula (3) which cannot be separated from the mixture dramatically by conventional purification processes, such as recrystallization, is formed which is formed in a side reaction of said free acid of formula (1) and lactone. of formula (2). Thus, the present invention relates to a very efficient process for preparing lactones of formula (2). 7 fltóvésrlS

TV • 9 9 ~ 9 «9 9 · 9 '9

999 98 9 9 9

999 9 9 99 ·

9 9 9 9 9.9 9.9 9 «. 9-9 «999

Claims (10)

PATENT CLAIMS A process for the preparation of a compound of the general formula - (2) wherein R 6 is an alkyl group containing from 1 to 10 carbon atoms; R ¹ is methyl, CH ² OH, CH 2 CH ² COR ² , CO ² R ³ , CONR ⁴ (R ⁵ ), hydroxyl, CH ² OR ² or CH 2 NR ⁴ (R ⁵ ); R ² is an alkyl group containing 1 to 5 carbon atoms; R ³ is a hydrogen atom or an alkyl group containing from 1 to 5 carbon atoms; R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen and alkyl groups containing from 1 to 5 carbon atoms; and ( a and b are both double bonds, or one of the bonds a or b is simple and the other of them is double, or both bonds a and b are simple, characterized in that it comprises lactonizing a compound of the general formula (1) wherein R ¹ , R ¹ , and b are as defined above; and Z is hydrogen, ammonium (NH ₄ ⁺⁾ cation, or a metal. cation, wherein said lactonization reaction proceeds under conditions such that the solubility of said compound of formula (1) and / or the solubility of said compound of formula (2) is not more than 0.5% by weight, thereby forming said compound of formula (1). (2) containing not more than 0,3 mole percent of the dimer of formula (3); R ¹ where R, R ¹ , a and b are as defined above. 2,2-dimethylpentane, hexane, iso-hexane, n-heptane, octane, isooctane, methylcyclopentane, ethylcyclopentane, propylcyclopentane, methylcyclohexane, ethylcyclohexane and propylcyclohexane. Process according to claim 1, characterized in that: R ¹ is methyl or hydroxyl; and Z is hydrogen or ammonium (NH ₄ ⁺⁾ cation. A process according to claim 1 or 2, characterized in that the medium used in said lactonization reaction comprises at least one substance selected from the group consisting of water, saturated hydrocarbons containing from 5 to 5 carbon atoms. 16 carbon atoms of the general formula _{CnH2n + 2} or _CnH2n and unsaturated hydrocarbons having 5 to 16 carbon atoms of the formula _CnH2n or _CnH2n _ _second . 4 4 4 4 4 4 4 4 4 4 4 4 4 · 4 9 A process according to claim 3, wherein the medium used in said lactonization reaction comprises water and at least one selected from the group consisting of C 5 -C 16 saturated hydrocarbons of the formula C _n H _{2 n + 2} or C _n H _2n and unsaturated hydrocarbons having 5 to 16 carbon atoms of the formula _CnH2n or _CnH2n - _2nd A process according to claim 3, wherein the medium used in said lactonization reaction comprises water. Process according to Claim 3 or 4, characterized in that the hydrocarbon medium used in said lactonization reaction comprises at least one substance selected from the group consisting of pentane, 2-methylpentane, Process according to any one of claims 1 to 6, characterized in that said lactonization reaction is carried out in an acid medium whose pH does not exceed 5. 8.. Process according to claim 7, characterized in that said acid medium whose pH does not exceed 5 is formed by adding at least one acid selected from the group consisting of formic acid, phosphoric acid, trifluoroacetic acid, sulfuric acid, 9 9 9 «9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 995 99 9 9 «9 10. hydrochloric acid, perchloric acid, p-toluenesulfonic acid and methanesulfonic acid. Process according to any one of claims 1 to 8, characterized in that: R is sec-butyl or 1,1-dimethylpropyl; R ¹ is methyl or hydroxyl; a and b are double bonds. A method according to claim 9, characterized in that: R is sec-butyl or 1,1-dimethylpropyl; R ¹ is methyl; Z is hydrogen; a and b are double bonds.