JP4568398B2 - Hexahydroisoindoline acid addition salt and method of use thereof - Google Patents

Hexahydroisoindoline acid addition salt and method of use thereof Download PDF

Info

Publication number
JP4568398B2
JP4568398B2 JP2000080736A JP2000080736A JP4568398B2 JP 4568398 B2 JP4568398 B2 JP 4568398B2 JP 2000080736 A JP2000080736 A JP 2000080736A JP 2000080736 A JP2000080736 A JP 2000080736A JP 4568398 B2 JP4568398 B2 JP 4568398B2
Authority
JP
Japan
Prior art keywords
hexahydroisoindoline
cis
acid
addition salt
represented
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
JP2000080736A
Other languages
Japanese (ja)
Other versions
JP2001261644A (en
Inventor
哲聖 上條
孝志 柳
菊池  健
Original Assignee
キッセイ薬品工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by キッセイ薬品工業株式会社 filed Critical キッセイ薬品工業株式会社
Priority to JP2000080736A priority Critical patent/JP4568398B2/en
Publication of JP2001261644A publication Critical patent/JP2001261644A/en
Application granted granted Critical
Publication of JP4568398B2 publication Critical patent/JP4568398B2/en
Application status is Expired - Fee Related legal-status Critical
Anticipated expiration legal-status Critical

Links

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention is a general formula useful as a raw material for producing pharmaceuticals.
[0002]
[Chemical 9]
[0003]
(Wherein X represents an acid residue of phosphoric acid or acetic acid, n is 1, 2 or 3, provided that when X is an acid residue of acetic acid, n represents 1) The present invention relates to a hydroisoindoline / acid addition salt and a method of using the same.
[0004]
Specifically, the present invention relates to a pharmaceutical, for example, a formula having a hypoglycemic action and useful as a therapeutic agent for diabetes.
[0005]
Embedded image
[0006]
And a cis-hexahydroisoindoline / acid addition salt represented by the above general formula (I), which is useful as a raw material for producing the benzylsuccinic acid derivative represented by formula (I) or a pharmacologically acceptable salt thereof.
[0007]
Furthermore, the present invention is a compound useful as a pharmaceutical raw material using the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I).
[0008]
Embedded image
[0009]
A method for producing cis-hexahydroisoindoline represented by formula (1) and a cis-hexahydroisoindoline / acid addition salt represented by the general formula (I), and having a blood glucose lowering action, as a therapeutic agent for diabetes The present invention relates to a useful process for producing a benzylsuccinic acid derivative represented by the formula (II) or a pharmacologically acceptable salt thereof.
[0010]
[Prior art]
The benzylsuccinic acid derivative represented by the above formula (II) and a pharmacologically acceptable salt thereof have an insulin secretion promoting action and a blood glucose lowering action and are useful compounds as a therapeutic agent for diabetes (Japanese Patent Laid-Open No. Hei 4-). No. 356459).
[0011]
Organic compounds often have isomers, and the pharmacological effects are often different depending on the isomers. Therefore, in the case of pharmaceuticals, it is required to have a single isomer as much as possible, particularly from the side-effect side. . Furthermore, in the case of pharmaceuticals, from the aspect of ensuring safety, it is required to confirm the safety when all impurities are contained in a certain level or more. That is, when the maximum daily dose of the drug is 2 g or less, confirmation of safety is required for impurities present exceeding 0.1%. Therefore, it is desired that the impurities be 0.1% or less. Therefore, the starting material of the pharmaceutical is also 0.1% or less in impurity content, that is, a purity of 99.%, unless it is an easily removable impurity. 9% or more is preferable.
[0012]
Methods for obtaining a single isomer are roughly classified into a method using a single isomer raw material and a method of purifying with a final product or an appropriate intermediate. And, since the method of purifying with a final product or an intermediate requires extra steps and labor, and the efficiency is deteriorated, a method of using a single isomer at the raw material stage is desired.
[0013]
The benzyl succinic acid derivative represented by the formula (II) is an isomer in which the benzyl succinic acid moiety is in the S configuration and the hexahydroisoindoline moiety is cis, but in addition, the benzyl succinic acid moiety in the S configuration is hexahydro There are isomers in which the isoindoline moiety is trans and the benzyl succinic acid moiety is in the R configuration and the hexahydroisoindoline moiety is cis or trans.
[0014]
When the benzyl succinic acid moiety is in the S configuration and the hexahydroisoindoline moiety is a trans isomer, the final benzyl succinic acid derivative represented by the formula (II) or a pharmacologically acceptable product thereof is acceptable. Even if the salt is purified by recrystallization, the impurities cannot be removed. Therefore, when purifying after producing the final product, it must be converted to a final product after derivatizing the final product into a purifiable derivative, and the yield must be reduced. It had been. Accordingly, there has been a demand for a method using a raw material having the highest possible purity and less impurity generation. However, as described below, a method for producing a benzyl succinic acid derivative represented by the above formula (II) can be used. -Regarding hexahydroisoindoline, it has been difficult to obtain high-purity so far.
[0015]
As a method for producing cis-hexahydroisoindoline used as a raw material for producing the benzyl succinic acid derivative represented by the formula (II), for example, cis-1,2,3,6-tetrahydrophthalimide is used, lithium aluminum hydride is used, and the like. And cis-3a, 4,7,7a-tetrahydroisoindoline, and then catalytic reduction using platinum oxide has been reported (Journal of Organic Chemistry (J. Org Chem.), 20, 1687-1694, 1955). However, in this method, about 5% of a trans isomer is produced simultaneously with the cis isomer, and only a product having an insufficient purity to be used as a raw material for producing a pharmaceutical product can be obtained.
[0016]
Several methods have also been reported as methods for producing high-purity cis-hexahydroisoindoline. For example, a method in which cis-1,2,3,6-tetrahydrophthalimide is catalytically reduced in the presence of palladium to obtain cis-hexahydrophthalimide, and then reduced using lithium aluminum hydride (WO94 / 03437). , A method of reducing cis-hexahydrophthalimide using a borane reagent (JP-A-10-287648), a method of catalytic reduction of isoindoline in the presence of ruthenium, rhodium or palladium (JP-A-11-71349) ) Etc. have been reported.
[0017]
These methods were developed as a method for producing high-purity cis-hexahydroisoindoline, but nevertheless, by-products and contamination of a small amount of trans form are inevitable, and the purity as a pharmaceutical raw material is low. Only insufficiency can be obtained, or the purity is high, but special equipment or expensive reagents are required, or the operation is dangerous, all in terms of purity, cost, safety, etc. There are some problems.
[0018]
For example, in the method described in JP-A-11-71349 using a catalyst such as ruthenium, rhodium or palladium, the by-product of the trans isomer is as small as about 0.1 to 0.5%, but another impurity 2 -About 0.3 to 4% of methylcyclohexylmethylamine is produced as a by-product, and the purity of cis-hexahydroisoindoline is inadequate at about 96 to 99.3%. Impurities are not removed and the purity is not improved at all.
[0019]
As described above, the methods for producing cis-hexahydroisoindoline reported so far are inadequate in the purity of cis-hexahydroisoindoline as a raw material for producing pharmaceuticals, or the production method itself is There is a problem as an industrial method. Therefore, there has been a demand for a method for easily obtaining high-purity cis-hexahydroisoindoline that is suitable as a raw material for producing pharmaceuticals by a simple operation.
[0020]
Regarding cis-hexahydroisoindoline / acid addition salts, hydrochlorides and picrates have been reported so far (J. Org. Chem., 20, pp. 1687-1694 (1955); -287648). However, no phosphate or acetate has been reported, such as the cis-hexahydroisoindoline / acid addition salt represented by the formula (I) of the present invention, and the formula of the present invention There is no description suggesting that the cis-hexahydroisoindoline / acid addition salt represented by (I) has good crystallinity and excellent purification efficiency.
[0021]
[Problems to be solved by the invention]
A method that has been reported so far as a method for producing cis-hexahydroisoindoline, which is a raw material for producing a benzylsuccinic acid derivative represented by the above formula (II), which has a hypoglycemic action and is useful as a therapeutic agent for diabetes, In addition, there are not a few trans isomers, and only raw materials with insufficient purity can be obtained as raw materials for pharmaceuticals, or high purity, but requires special equipment or expensive reagents, and operation In any case, there is a problem as a method for producing a pharmaceutical raw material or an industrial method in terms of purity, cost or safety.
[0022]
Hexahydroisoindoline is a liquid and can be distilled, but the boiling points of the cis isomer and the trans isomer are very close, and it is difficult to separate the cis isomer and the trans isomer by distillation. It is impossible to increase the purity of cis-hexahydroisoindoline by distillation purification.
[0023]
For example, according to the above-mentioned JP-A No. 11-71349, the by-product trans form and 2-methylcyclohexylmethylamine content are determined by purifying the reaction solution after completion of the reaction and post-treatment according to a conventional method, followed by distillation. There is no difference between products and impurities are not reduced at all even by distillation.
[0024]
The problem to be solved by the present invention is a pharmaceutical, for example, a benzylsuccinic acid derivative represented by the above formula (II) or a pharmacologically acceptable salt thereof, which has a hypoglycemic action and is useful as a therapeutic agent for diabetes. A highly pure cis-hexahydroisoindoline, which is extremely useful as a raw material for producing a benzyl succinate represented by the above formula (II), which is useful as a pharmaceutical. It is to provide a method for producing an acid derivative or a pharmacologically acceptable salt thereof.
[0025]
[Means for Solving the Problems]
The present inventors have provided a highly pure cis-hexahydro compound that is useful as a raw material for producing a benzylsuccinic acid derivative represented by the above formula (II) that has a blood glucose lowering action and is useful as a therapeutic agent for diabetes. As a result of diligent research to develop a method for easily and efficiently obtaining isoindoline, among various cis-hexahydroisoindoline / acid addition salts, it is represented by the general formula (I) of the present invention. The cis-hexahydroisoindoline / acid addition salt has very good crystallinity, crystallized in a suitable solvent, and recrystallized in a suitable solvent as necessary, thereby causing impurities such as trans isomers. By using this cis-hexahydroisoindoline / acid addition salt, extremely high purity, which is useful as a raw material for pharmaceuticals, is represented by the formula (III). The cis - to obtain a finding that it is possible to obtain hexahydroterephthalic isoindoline efficiently.
[0026]
The present inventors further use the cis-hexahydroisoindoline / acid addition salt to provide a highly pure benzylsuccinic acid derivative represented by the above formula (II) and a pharmacologically useful compound thereof. The knowledge that an acceptable salt can be efficiently produced by a simple method has been obtained, and the present invention has been achieved.
[0027]
That is, the present inventors appropriately inactivate impurities that cannot be removed by ordinary methods such as distillation purification, for example, cis-hexahydroisoindoline containing a small amount, for example, about 0.1 to 5% of trans-hexahydroisoindoline. By dissolving in an organic solvent, adding phosphoric acid or acetic acid to crystallize it, and recrystallizing as necessary, impurities can be almost completely removed, and those having a purity of 99.9% or more can be easily obtained. Moreover, it has been found that it can be obtained in a high yield.
[0028]
Then, using the cis-hexahydroisoindoline / acid addition salt represented by the above general formula (I) obtained as described above, it is treated with an appropriate basic substance to release the addition acid. The cis-hexahydroisoindoline represented by the above formula (III), which is useful as a pharmaceutical raw material, can be obtained by processing according to a conventional method. By using an indoline / acid addition salt, a highly pure benzylsuccinic acid derivative represented by the above formula (II) and a pharmacologically acceptable salt thereof are efficiently produced by a simple method. I found that I could do it.
[0029]
The cis-hexahydroisoindoline acid addition salt represented by the general formula (I) of the present invention is a novel acid addition salt, and is excellent in cis-hexahydroisoindoline acid addition salt. It has crystallinity.
[0030]
For example, acid addition salts of mineral acids such as hydrochloric acid, sulfuric acid and boric acid can be obtained as crystals, but the purification ability is poor and the removal efficiency of impurities such as trans isomers is low. In addition, among organic acid addition salts, acid addition salts such as L-malic acid, L-lactic acid, citric acid, malonic acid, methanesulfonic acid and benzoic acid cannot be obtained as crystals, and acid addition of succinic acid Although the salt can be obtained as crystals, it is highly deliquescent and difficult to recrystallize, and cannot be purified. Furthermore, although organic acid addition salts such as L-tartaric acid, succinic acid, maleic acid, fumaric acid, and p-toluenesulfonic acid can be obtained as crystals, purification ability is similar to that of mineral acid acid addition salts. The removal efficiency of impurities such as trans isomers is low.
[0031]
As described above, most of the various cis-hexahydroisoindoline / acid addition salts are not obtained as crystals, or have poor purification ability and low removal efficiency of impurities such as trans isomers. Only the acid addition salt represented by the general formula (I) has specifically good characteristics, and this is crystallized in a suitable inert organic solvent, and recrystallized as necessary. It is surprising to exhibit the excellent action and effect of efficiently removing impurities such as the body.
[0032]
As described above, the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention exhibits an excellent action and effect that impurities such as a trans isomer can be efficiently removed. In the production of high-purity cis-hexahydroisoindoline useful as a pharmaceutical raw material, the high-purity benzylsuccinic acid derivative represented by the formula (II) useful as a pharmaceutical and its pharmacological properties It is a very useful compound as a raw material for the production of acceptable salts.
[0033]
As described above, since the boiling points of cis-hexahydroisoindoline and trans-hexahydroisoindoline are very close to each other, it is impossible to remove the trans form by distillation purification. Also, most of the cis-hexahydroisoindoline / acid addition salts are not obtained as crystals or have poor purification ability.
[0034]
On the other hand, the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention is crystallized in a suitable inert organic solvent, and recrystallized as necessary. As a result, it is possible to remove the trans-body and other impurities efficiently and almost completely. For example, when the content of the trans isomer and other impurities is about 1% or less, the impurity content can be reduced to 0.01% or less simply by crystallization in an inert organic solvent, A high yield of 80% to 90% can be obtained. Even when impurities are contained in an amount of about 3 to 5%, after recrystallization, recrystallization is repeated once or twice to obtain a material having a purity of 99.9% or more in a yield of about 70 to 80%. Can do.
[0035]
As described above, the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention has very good crystallinity and is crystallized in a suitable inert organic solvent. By recrystallizing as necessary, trans-hexahydroisoindoline and other impurities that cannot be removed by distillation purification can be removed almost completely and efficiently.
[0036]
Among the cis-hexahydroisoindoline acid addition salts represented by the general formula (I) of the present invention, the general formula
[0037]
Embedded image
[0038]
A phosphoric acid addition salt of cis-hexahydroisoindoline represented by (wherein n represents 1, 2 or 3) is preferred.
[0039]
Embedded image
[0040]
Most preferred is cis-hexahydroisoindoline phosphate represented by:
[0041]
The cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention can be easily produced according to a known acid addition salt production method. That is, cis-hexahydroisoindoline containing a small amount of trans-hexahydroisoindoline and other impurities is dissolved in a suitable inert organic solvent, and an appropriate amount of phosphoric acid or acetic acid is added under heating and stirring. The mixture is stirred for crystallization and recrystallized as necessary.
[0042]
In this case, it is needless to say that the impurities contained in cis-hexahydroisoindoline are preferably as small as possible, but it is sufficient if the impurity content is about 5%.
[0043]
The cis-hexahydroisoindoline used for the production can be produced according to a known method, for example, the method described in JP-A No. 11-71349.
[0044]
Examples of the inert organic solvent that can be used for crystallization or recrystallization of the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention include alcohols such as methanol, ethanol, and isopropanol, and acetone. , Ketones such as methyl ethyl ketone, esters such as ethyl acetate and isopropyl acetate, ethers such as isopropyl ether, hydrocarbons such as hexane, cyclohexane, methylcyclohexane and toluene, or a mixed solvent thereof or a solvent thereof and water A mixed solvent can be mentioned, and it is appropriately selected and used depending on the kind of cis-hexahydroisoindophosphoric acid addition salt.
[0045]
For example, in the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I), X is an acid residue of phosphoric acid, and n is 1, which is represented by the formula (IAa) In the case of crystallization of cis-hexahydroisoindoline / phosphate, an alcohol or a mixed solvent of alcohols is preferable. Among them, a methylcyclohexane / alcohol mixed solvent is preferable, and a methylcyclohexane / modified ethanol mixed solvent is most preferable. Is preferred. In the case of recrystallization, a mixed solvent of alcohols and water is preferable, and a modified ethanol / water mixed solvent is most preferable.
[0046]
The cis-hexahydroisoindoline / acid addition salt represented by the general formula (I), wherein X is an acid residue of acetic acid
[0047]
Embedded image
[0048]
In the case of crystallization of cis-hexahydroisoindoline / acetate represented by formula (1), esters, hydrocarbons, or a mixed solvent thereof is preferable, and a methylcyclohexane / ethyl acetate mixed solvent is particularly preferable. In the case of recrystallization, a mixed solvent of esters and hydrocarbons, particularly an ethyl acetate / hexane mixed solvent is most preferable.
[0049]
The mixing ratio of the mixed solvent is appropriately determined depending on the type of the solvent. In the case of a methylcyclohexane / ethanol mixed solvent as a crystallization solvent, a mixing ratio of 1: 4 to 2: 1 is preferable. In the case of ethyl acetate mixed solvent, a mixing ratio of about 2: 1 is preferred. A 80: 1 mixing ratio is preferred for the recrystallized modified ethanol / water mixed solvent, and a 2: 1 mixing ratio is preferred for the ethyl acetate / hexane mixed solvent. The amount of the crystallization solvent used varies depending on the kind of the solvent and acid, the amount of hexahydroisoindoline, etc., but it is generally sufficient to use about 500 to 1000 mL with respect to 100 g of hexahydroisoindoline.
[0050]
Using the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention, the cis-hexa represented by the formula (III) having a high purity, which is useful as a raw material for producing pharmaceuticals. In order to suitably carry out the process for producing hydroisoindoline, the cis-hexahydroisoindoline / acid addition salt represented by the above general formula (I) is mixed with a suitable inert organic solvent such as methylcyclohexane and water. The mixture is treated with a basic substance such as potassium hydroxide in a mixed solvent to remove the addition acid, and the organic layer is separated and washed, and then the solvent is distilled off by a conventional method, followed by distillation if necessary.
[0051]
As a solvent in this production method, an inert organic solvent that does not interact with cis-hexahydroisoindoline and has a relatively low boiling point, for example, a mixed solvent of hydrocarbons such as hexane, cyclohexane, methylcyclohexane, and water. Examples of the basic substance include inorganic bases such as sodium hydroxide, potassium hydroxide, and potassium carbonate.
[0052]
Further, the benzylsuccinic acid derivative represented by the above formula (II) and its pharmacology, which is useful as a pharmaceutical, using the cis-hexahydroisoindoline / acid addition salt represented by the above general formula (I) of the present invention. An acceptable salt production method can be carried out as follows.
[0053]
For example, the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) may be used as it is or after the addition acid is removed by the above-described method or the like, After preparing hexahydroisoindoline, in the presence or absence of a basic substance, the general formula
[0054]
Embedded image
[0055]
(Wherein R represents a protecting group for a carboxyl group) a benzyl succinic acid monoester derivative represented by formula
[0056]
Embedded image
[0057]
The reactive functional derivative of (3S) -3-methoxycarbonyl-4-phenylbutyric acid represented by, for example, acid chloride, and then the carboxyl protecting group is removed, and neutralization or salt conversion is performed as necessary. By doing so, the benzyl succinic acid derivative represented by the above formula (II) and its pharmacologically acceptable salt can be produced with extremely high purity.
[0058]
The basic substance used in the above production method may be any substance used in ordinary amidation reactions, and examples thereof include organic bases such as triethylamine and pyridine and inorganic bases such as potassium carbonate and sodium hydroxide. It can be appropriately selected depending on the type of reactive functional derivative of the benzyl succinic acid monoester derivative used, the type of reaction solvent, and the like. The reaction solvent may be an inert solvent that does not interact with the raw materials to be used. For example, hydrocarbons such as toluene, esters such as ethyl acetate, and the like, mixed solvents thereof, and water and Can be mentioned. These reaction solvents can also be appropriately selected according to the type of reactive functional derivative of the benzyl succinic acid monoester derivative used, the type of basic substance, and the like.
[0059]
As described above, in this production method, the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention is directly converted to the benzyl succinic acid monomony represented by the general formula (IV). Depending on the type of reactive functional derivative of the benzyl succinic acid monoester derivative used, the type of reaction solvent and basic substance, etc. A cis-hexahydroisoindoline represented by the formula (III) may be produced by treating with a basic substance in a suitable inert solvent to remove the addition acid, and then subjected to the reaction.
[0060]
Use of the cis-hexahydroisoindoline / acid addition salt represented by the general formula (I) of the present invention, which is useful as a pharmaceutical, and the benzyl succinic acid derivative represented by the formula (II) and its pharmacologically acceptable Examples of the reactive functional derivative of the benzylsuccinic acid monoester derivative represented by the general formula (IV) as another raw material in the above-described method for producing a salt include an acid halide, a mixed acid anhydride, an acid An anhydride, an active ester, etc. can be mentioned.
[0061]
Such a reactive functional derivative is prepared as a reactive functional derivative by producing a benzyl succinic acid monoester derivative represented by the above general formula (IV) by a method as described below and the like, according to a conventional method. By induction, it can be easily manufactured. For example, an acid chloride in an acid halide is prepared by converting a benzylsuccinic acid monoester derivative represented by the general formula (IV) into an inert organic solvent such as toluene in the presence of a small amount of N, N-dimethylformamide. It can be easily produced by reacting with thionyl at room temperature.
[0062]
As the benzyl succinic acid monoester derivative represented by the general formula (IV), a monoester in which one of the carboxyl groups is protected with a lower alkyl such as methyl or ethyl, an aralkyl such as benzyl ester or other protective group for a carboxyl group Can be mentioned. These derivatives are partly known substances and can be easily produced by a known method or a method analogous thereto. For example, in the benzyl succinic acid monoester derivative represented by the general formula (IV), (3S) -3-methoxycarbonyl-4-phenyl represented by the formula (IVA), wherein R is a methyl group Butyric acid can be produced by the method described in Angewante Hemi International Edition (Angew. Chem. Int. Ed.), 37, 1931 (1998).
[0063]
In the benzyl succinic acid monoester derivative represented by the general formula (IV), R is a benzyl group.
[0064]
Embedded image
[0065]
(3S) -3-benzyloxycarbonyl-4-phenylbutyric acid represented by the formula can be produced, for example, by the method described in JP-A-4-35659.
[0066]
DETAILED DESCRIPTION OF THE INVENTION
The content of the present invention is explained in more detail by the following examples. The trans-hexahydroisoindoline content in the examples was calculated from the results of gas chromatography analysis under the following conditions.
[0067]
Column used: J & W CAM (diameter 0.25 mm × length 30 m, film thickness 0.25 μm)
Column temperature: 110 ° C
Inlet temperature: 150 ° C
Carrier gas: helium
Flow rate: 31 cm / sec
Detector: Hydrogen flame ionization detector
Detector temperature: 200 ° C
Split ratio: 1: 100
[0068]
【Example】
Example 1
Cis-Hexahydroisoindoline phosphate
7.83 g (62.5 mmol) of cis-hexahydroisoindoline having a trans-hexahydroisoindoline content of 0.25% was dissolved in 56 mL of a mixed solvent of methylcyclohexane / denatured ethanol (1: 1), and the mixture was heated and stirred at 65 ° C. To the flask, 7.20 g (62.5 mmol) of 85% phosphoric acid was added dropwise, and after inoculation, the mixture was stirred for 3 hours under cooling. The precipitated crystals were filtered, washed with 3.0 mL of a mixed solvent of methylcyclohexane / denatured ethanol (1: 1), and cis-hexahydroisoindoline / phosphate having a trans-hexahydroisoindoline content of 0.02%. 0 g was obtained.
[0069]
Elemental analysis value (%): C8H15NHThreePOFour
Theoretical value C: 43.05 H: 8.13 N: 6.28
Measured value C: 42.87 H: 8.17 N: 6.37
1H-NMR (CDThreeOD) δ ppm:
1.34-1.62 (6H, m), 1.64-1.76 (2H, m), 2.30-2.44 (2H, m), 3.06-3.16 (2H, m ), 3.22-3.34 (2H, m)
[0070]
Example 2
Cis-Hexahydroisoindoline phosphate
Cis-hexahydroisoindoline 5.00 g (39.9 mmol) having a trans-hexahydroisoindoline content of 1.93% is dissolved in 20 mL of methylcyclohexane and 25 mL of denatured ethanol, and heated with stirring at 65 ° C. with 85% phosphoric acid 4 .60 g (39.9 mmol) was added dropwise, and after inoculation, the mixture was stirred for 3 hours under cooling. The precipitated crystals were filtered and washed with 10 mL of a mixed solvent of methylcyclohexane / denatured ethanol (1: 1) to obtain 7.84 g of cis-hexahydroisoindoline phosphate having a trans-hexahydroisoindoline content of 0.17%. Obtained.
[0071]
The above-described cis-hexahydroisoindoline phosphate (5.00 g) having a trans-hexahydroisoindoline content of 0.17% was dissolved in 22 mL of denatured ethanol and 0.28 mL of water, and then stirred overnight under cooling. The precipitated crystals were filtered and washed with 5.0 mL of denatured ethanol to obtain 4.81 g of cis-hexahydroisoindoline phosphate having a trans-hexahydroisoindoline content of 0.03%.
[0072]
Example 3
Cis-Hexahydroisoindoline phosphate
Separately prepared in the same manner as in Example 1 or 2, 1.22 g of cis-hexahydroisoindoline phosphate having a trans-hexahydroisoindoline content of 0.05% was added to 4.9 mL of denatured ethanol and 0.065 mL of water. After being dissolved in the mixed solvent by heating, the mixture was stirred overnight under cooling. The precipitated crystals are filtered and washed with 1.0 mL of a denatured ethanol / water (80: 1) mixed solvent to obtain 1.15 g of cis-hexahydroisoindoline / phosphate having a trans-hexahydroisoindoline below the detection limit. It was.
[0073]
Example 4
Bis (cis-hexahydroisoindoline) / phosphate / dihydrate
Dissolve 2.50 g (20 mmol) of cis-hexahydroisoindoline having a trans-hexahydroisoindoline content of 0.22% in a mixed solvent of 8.8 mL of methylcyclohexane and 8.8 mL of isopropanol, and 85% with heating and stirring at 50 ° C. 1.15 g (10 mmol) of phosphoric acid was added dropwise, and the mixture was stirred overnight under cooling. The precipitated crystals were collected by filtration and then washed with 4.0 mL of a mixed solution of methylcyclohexane / isopropanol (1: 1) to give bis (cis-hexahydroisoindoline) with a trans-hexahydroisoindoline content of 0.05%. 3.14 g of phosphate dihydrate was obtained.
[0074]
Elemental analysis value (%): C16H30N2・ HThreePOFour・ 2H2O
Theoretical value C: 49.99 H: 9.70 N: 7.29
Actual value C: 49.81 H: 9.45 N: 7.04
1H-NMR (CDThreeOD) δ ppm:
1.34-1.60 (6H, m), 1.62-1.74 (2H, m), 2.26-2.40 (2H, m), 3.02-3.14 (2H, m) ), 3.16-3.28 (2H, m)
[0075]
Example 5
Cis-Hexahydroisoindoline acetate
Dissolve 2.50 g (20.0 mmol) of cis-hexahydroisoindoline having a trans-hexahydroisoindoline content of 0.22% in 13.2 mL of a mixed solvent of methylcyclohexane / ethyl acetate (2: 1) and heat at 70 ° C. While stirring, 1.15 mL (20.1 mmol) of acetic acid was added dropwise, and after inoculation, the mixture was stirred overnight under cooling. The precipitated crystals were filtered, washed with 2.0 mL of a mixed solvent of methylcyclohexane / ethyl acetate (2: 1), and 3.15 g of cis-hexahydroisoindoline / acetate having a trans-hexahydroisoindoline content of 0.01%. Got.
[0076]
1H-NMR (CDThreeOD) δ ppm:
1.35-1.75 (8H, m), 1.90 (3H, s), 2.25-2.40 (2H, m), 3.00-3.35 (4H, m)
[0077]
Example 6
Cis-Hexahydroisoindoline acetate
Separately produced in the same manner as in Example 5, cis-hexahydroisoindoline / acetate 2.37 g having a trans-hexahydroisoindoline content of 0.09% was mixed with 4.0 mL of ethyl acetate and 2.0 mL of hexane. After heating and dissolving, the mixture was stirred overnight under cooling. The precipitated crystals were filtered and washed with 1.0 mL of a mixed solvent of ethyl acetate / hexane (2: 1) to give 2.01 g of cis-hexahydroisoindoline / acetate having a trans-hexahydroisoindoline content of 0.01%. Obtained.
[0078]
Example 7
Cis-Hexahydroisoindoline
Separately prepared in the same manner as in Example 3, transcyclohexahydroisoindoline is below the detection limit, 10.0 g of cis-hexahydroisoindoline phosphate, 30 mL of methylcyclohexane, 12 mL of water, and 8.90 g of potassium hydroxide. In addition, the mixture was stirred at room temperature for 30 minutes and then separated. The aqueous layer was extracted twice with 10 mL of methylcyclohexane, and the solvent of the combined organic layer was distilled off under reduced pressure, followed by distillation under reduced pressure, whereby cis-hexahydroisoindoline 4 having trans-hexahydroisoindoline below the detection limit was obtained. .59 g was obtained.
[0079]
1H-NMR (CDClThree) Δ ppm:
1.20-1.70 (8H, m), 1.92 (1H, brs), 2.00-2.15 (2H, m), 2.70-2.85 (2H, m), 2. 85-3.00 (2H, m)
[0080]
Example 8
Bis [(2S) -2-benzyl-3- (cis-hexahydroisoindoline-2-ylcarbonyl) propionic acid] calcium dihydrate
Dissolve 4.98 g of (3S) -3-methoxycarbonyl-4-phenylbutyric acid in 30 mL of toluene, add 0.10 mL of N, N-dimethylformamide and 1.95 mL of thionyl chloride with stirring under ice cooling, and add 5% under ice cooling. For 30 minutes at room temperature.
[0081]
A toluene solution of (3S) -3-methoxycarbonyl-4-phenylbutyric acid chloride obtained above was separately prepared in the same manner as in Example 1 or 2, and had a trans-hexahydroisoindoline content of 0.02%. To a solution prepared by dissolving 5.50 g of cis-hexahydroisoindoline phosphate and 15.5 g of potassium carbonate in 60 mL of water at room temperature, the solution was added dropwise over 20 minutes with water-cooling and stirring.
[0082]
After the dropwise addition, the mixture was stirred for 30 minutes under water cooling, stirred for 30 minutes at room temperature, and then separated. The aqueous layer was extracted with 20 mL of toluene, and the combined organic layer was washed sequentially with 10 mL each of a saturated aqueous sodium hydrogen carbonate solution, 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate by filtration, the solvent was distilled off under reduced pressure to give 7.38 g of (2S) -2-benzyl-3- (cis-hexahydroisoindoline-2-ylcarbonyl) propionate as a colorless oil. Got.
[0083]
1H-NMR (CDClThree) Δ ppm:
1.20-1.60 (8H, m), 2.10-2.35 (3H, m), 2.55-2.65 (1H, m), 2.75-2.85 (1H, m ), 3.00-3.10 (1H, m), 3.10-3.45 (5H, m), 3.60-3.70 (3H, m), 7.15-7.30 (5H) , M)
[0084]
Dissolve 7.38 g of methyl (2S) -2-benzyl-3- (cis-hexahydroisoindoline-2-ylcarbonyl) propionate in 17 mL of isopropanol, add 26 mL of 1 mol / L sodium hydroxide aqueous solution with stirring at room temperature, Stir overnight at room temperature.
[0085]
After adding 60 mL of water to the reaction solution, a solution prepared by dissolving 1.60 g of calcium chloride in 10 mL of water was added dropwise with stirring at 45 ° C. After stirring at 45 ° C. for 1 hour, the mixture was stirred overnight under cooling and the precipitated crystals were collected by filtration and washed with 50 mL of water to obtain 6.95 g of white crystals. 3. Recrystallize 5.00 g of this crystal from methanol / water to give bis [(2S) -2-benzyl-3- (cis-hexahydroisoindoline-2-ylcarbonyl) propionic acid] calcium dihydrate. 45 g was obtained.
[0086]
1H-NMR (CDClThree) Δ ppm:
1.15-1.50 (16H, m), 1.90-2.40 (6H, m), 2.55-3.10 (14H, m), 3.20-3.50 (6H, m) ), 7.10-7.30 (10H, m)
[0087]
In addition, when the impurity content rate of the crystal | crystallization obtained above was confirmed by the following related substance confirmation method, the content rate of the trans body was 0.01%.
[0088]
Related substances confirmation method
100 mg of the sample is dissolved in 100 mL of a water / methanol (4/3) mixed solution to obtain a sample solution. 15 μL of the sample solution is weighed and tested by the liquid chromatograph method under the following conditions to determine the ratio of each related substance peak area to the total peak area.
[0089]
Operating conditions
Detector: UV absorption photometer (measurement wavelength: 210 nm)
Column used: SUPELCOSIL ABZ + Plus (SUPELCO, diameter 4.6 mm × length 150 mm, silica gel particle size 5 μm)
Column temperature: 35 ° C
Flow rate: 1.2 mL / min
Area measurement range: 30 minutes from the start of measurement
Mobile phase: Add 33 volumes of acetonitrile and 1 volume of n-amyl alcohol to 66 volumes of water. This solution is adjusted to pH 2.0 with phosphoric acid.

Claims (4)

  1. General formula
    (Wherein X represents an acid residue of phosphoric acid or acetic acid, n is 1, 2 or 3, provided that when X is an acid residue of acetic acid, n represents 1) Hydroisoindoline / acid addition salt.
  2. General formula
    The cis-hexahydroisoindoline / acid addition salt according to claim 1, represented by (wherein n represents 1, 2 or 3).
  3. formula
    The cis-hexahydroisoindoline / acid addition salt according to claim 2 represented by the formula:
  4. General formula
    (Wherein X represents an acid residue of phosphoric acid or acetic acid, n is 1, 2 or 3, provided that when X is an acid residue of acetic acid, n represents 1) Hydroisoindoline / acid addition salt is treated with a basic substance to release the addition acid.
    The manufacturing method of cis-hexahydroisoindoline represented by these.
JP2000080736A 2000-03-22 2000-03-22 Hexahydroisoindoline acid addition salt and method of use thereof Expired - Fee Related JP4568398B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2000080736A JP4568398B2 (en) 2000-03-22 2000-03-22 Hexahydroisoindoline acid addition salt and method of use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2000080736A JP4568398B2 (en) 2000-03-22 2000-03-22 Hexahydroisoindoline acid addition salt and method of use thereof

Publications (2)

Publication Number Publication Date
JP2001261644A JP2001261644A (en) 2001-09-26
JP4568398B2 true JP4568398B2 (en) 2010-10-27

Family

ID=18597797

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2000080736A Expired - Fee Related JP4568398B2 (en) 2000-03-22 2000-03-22 Hexahydroisoindoline acid addition salt and method of use thereof

Country Status (1)

Country Link
JP (1) JP4568398B2 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001261645A (en) * 2000-03-22 2001-09-26 Kissei Pharmaceut Co Ltd (3s)-3-methoxycarbonyl-4-phenylbutyryl chloride and method for using the same
JP4000113B2 (en) * 2002-01-22 2007-10-31 キッセイ薬品工業株式会社 (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt and method of use thereof
KR20050083977A (en) * 2002-11-25 2005-08-26 신닛폰 리카 가부시키가이샤 Process for producing cyclic amine
JP2007526342A (en) * 2005-01-03 2007-09-13 テバ ファーマシューティカル インダストリーズ リミティド Olmesartan medoxomil with low levels of impurities
WO2010016584A1 (en) 2008-08-07 2010-02-11 杏林製薬株式会社 Process for production of bicyclo[2.2.2]octylamine derivative
CA2737296A1 (en) * 2008-09-16 2010-03-25 Kyorin Pharmaceutical Co., Ltd. Method for purifying aminoacetylpyrrolidinecarbonitrile derivative and salt thereof
WO2010107029A1 (en) 2009-03-19 2010-09-23 国立大学法人京都大学 Molecular probe precursor for pancreatic islet imaging and use of same
CN102911108A (en) * 2012-11-16 2013-02-06 葛长乐 Preparation method of trans-perhydro-isoindazole and salt thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04356459A (en) * 1991-04-25 1992-12-10 Kissei Pharmaceut Co Ltd New benzylsuccinic acid derivative
JPH10101629A (en) * 1996-10-01 1998-04-21 Nippon Soda Co Ltd Production of optically active butyric acid derivative
JPH10182602A (en) * 1996-11-01 1998-07-07 Mitsui Chem Inc New pyrrolidinone derivative
JPH11193270A (en) * 1997-12-26 1999-07-21 Koei Chem Co Ltd Production of optically active 1-methyl-3-piperidinemethanol
JP2001261645A (en) * 2000-03-22 2001-09-26 Kissei Pharmaceut Co Ltd (3s)-3-methoxycarbonyl-4-phenylbutyryl chloride and method for using the same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4063386B2 (en) * 1998-01-29 2008-03-19 キッセイ薬品工業株式会社 Rapid-release oral pharmaceutical composition

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04356459A (en) * 1991-04-25 1992-12-10 Kissei Pharmaceut Co Ltd New benzylsuccinic acid derivative
JPH10101629A (en) * 1996-10-01 1998-04-21 Nippon Soda Co Ltd Production of optically active butyric acid derivative
JPH10182602A (en) * 1996-11-01 1998-07-07 Mitsui Chem Inc New pyrrolidinone derivative
JPH11193270A (en) * 1997-12-26 1999-07-21 Koei Chem Co Ltd Production of optically active 1-methyl-3-piperidinemethanol
JP2001261645A (en) * 2000-03-22 2001-09-26 Kissei Pharmaceut Co Ltd (3s)-3-methoxycarbonyl-4-phenylbutyryl chloride and method for using the same

Also Published As

Publication number Publication date
JP2001261644A (en) 2001-09-26

Similar Documents

Publication Publication Date Title
EP1481964B1 (en) Stable salts of novel derivatives of 3,3-diphenylpropylamines
JP5632279B2 (en) Preparation method and polymorph of ivabradine hydrochloride
RU2009128C1 (en) Hydrochlorides of derivatives of 1-benzyl-4 (1-indanon) -methylpiperidine
US5091567A (en) Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid
CA2420003A1 (en) Process for making n-aryl-anthranilic acids and their derivatives
EP1792899B1 (en) Process for production of optically active amine derivatives
JP5202635B2 (en) Processes and intermediates for the preparation of integrase inhibitors
Burgess et al. Manipulation of substrate-controlled diastereoselectivities in hydroborations of acyclic allylamine derivatives
EP0633254A1 (en) Novel isoxazole derivative and salt thereof
CN101575309A (en) Method for synthesizing (S)-oxiracetam
AU748360B2 (en) Novel intermediates and processes for the preparation of optically active octanoic acid derivatives
CN1268611C (en) Method of preparing 4-hydroxy pyrrolidone-2-acetamine
KR101135336B1 (en) New process for the synthesis of agomelatine
KR100421073B1 (en) Preparation of substituted perhydroisoindoles
JP2691442B2 (en) Novel proline derivatives
HU209723B (en) Process for producing of piperazine derivatives
US5986129A (en) Process for producing rhein and diacerhein
HU186024B (en) Process for preparing new carboxylic acid amides
CN106478482A (en) A kind of synthetic method of Oxiracetam
WO2007072087A2 (en) Novel process for production of highly pure polymorph (i) donepezil hydrochloride
EP0366301B1 (en) Preparation of 1,4-diazabicyclo [3.2.2]nonane
US5371237A (en) Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide
SI9400049A (en) N-substituted derivatives of n-methyl-3-(p-trifluoromethyl- phenoxy)-3-phenylpropylamine and process for their preparation
WO2011101861A1 (en) Process for preparation of dpp-iv inhibitors
EP0357126B1 (en) Tetracyclic antidepressants

Legal Events

Date Code Title Description
A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20060620

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20100330

A521 Written amendment

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20100525

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20100727

A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20100809

R150 Certificate of patent or registration of utility model

Free format text: JAPANESE INTERMEDIATE CODE: R150

FPAY Renewal fee payment (event date is renewal date of database)

Free format text: PAYMENT UNTIL: 20130813

Year of fee payment: 3

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

LAPS Cancellation because of no payment of annual fees