JPS61186387A - Production of aminated phthalide-isoquinoline - Google Patents

Abstract

PURPOSE:The reduction of a nitrophthalide-isoquinoline with NaBH2S3 or LiBH4 enables industrially advantageous production of the title compound which is used as a medicine without use of a metallic catalyst. CONSTITUTION:A nitro compound of formula III, resulting from condensation reaction between a tetrahydroisoquinolien of formula I (R<1>, R<2> are H, lower alkoxy; R<7> is lower alkyl) and a nitrophthalide of formula II (at least one of R<3>'-R<6>' are nitro), is reduced with NaBH2S3 or LiBH4, preferably in an amount of 1.5-2mol to give the objective compound of formula IV (at least one of R<3>-R<6> is amino). The reduction reaction is carried out in a solvent of 3-20 times the weight of the reactant at 20-60 deg.C for 0.5-30hr. The resultant amino compound is epimerized, when needed, to increase the content of isomer A.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing aminated 7-thalide isoquinolite 7, and more specifically, aminated phthalide-ink 1ζ-7 which is useful as a pharmaceutical. The present invention relates to an industrially advantageous method for producing the same.

[Conventional technology]

The following general formula (1) (In the above formula, R1 and R8 represent a hydrogen atom or a lower alkoxy group, and at least one of R3, R4, Ha, and R6 is an amino group, and the remainder is a hydrogen atom or a lower alkoxy group. and R? represents a lower alkyl group) /R8-J'R8 epiform (hereinafter referred to as
Form A) is particularly useful as a medicine for liver diseases or allergic diseases.

This amino compound [l] is usually a tetrahydroisoquinoline represented by the following general formula (in the above formula, R1, HR and R7 are the same as defined in the above general formula (1)) and a tetrahydroisoquinoline represented by the following general formula ( ff]V (In the above formula, at least one of Te, Rs', R4', R" and H R" is a nitro group, and the remaining residues represent a hydrogen atom or a lower alkoxy group.) By condensation reaction with phthalides, the following general formula (I
) (In the above formula, R1, HM, R?, R', R4'
, R@' and -' are as defined in the general formulas (I[) and (IV) above. ) can be produced by obtaining a nitro compound represented by the following formula and then subjecting this nitro compound to reduction treatment. In this condensation reaction, in addition to the A form of the nitro compound (If), /Re-J'S
Since R-form (hereinafter referred to as B-form) is also produced, it is necessary to epimolize the mixture of A-form and B-form of the nitro compound before or after reduction to obtain a mixture with a high content of A-form. .

As a method for reducing the nitro compound of the general formula [Watari] shown above, a method of reducing using a reducing agent consisting of a combination K of tin chloride and hydrochloric acid (British Patent No. r73.ri3!) has been known. There is. However, this method requires the use of a large amount of tin chloride, and since the amino compound in the mixture obtained in this reaction is an acid salt, usually
This is brought into a schiff-free state by adding an alkali and extracted with an organic solvent, but in this case, a large amount of the tin component used for reduction precipitates as fine powder, making it extremely difficult to filtrate this metal component. In addition, a method (4?Kaisho!≦-Jj, No. 1117) in which a nitro compound similar to the general formula shown above is reduced with hydrogen in the presence of a palladium catalyst is also known, but this method cannot be used at normal pressure. Since the reduction reaction did not proceed well, it had to be carried out under pressure, and therefore it was necessary to use a pressure-resistant device as the reaction equipment.

[Problems to be Solved by the Invention and Means Therefor] In view of the above circumstances, the present inventors have found that the nitro compound of the general formula (II) can be easily reduced under normal pressure, and
As a result of various studies in order to obtain a reduction method that would facilitate the treatment of the mixture after reduction, we found that % NaBHlBg or L was used as the reducing agent.
The inventors completed the present invention by discovering that when iBH4 is used, the reduction reaction proceeds well without the use of a metal catalyst, and in this case, the target product in the reaction mixture can be directly extracted and recovered. did.

That is, the gist of the present invention is a method for producing an amino compound represented by the general formula (1) by reducing the nitro compound represented by the general formula (1), using 18 g of NaBH or LiBH4 as a reducing agent, The present invention relates to a method for producing aminated phthalide-isoquinolines, which is characterized in that the reaction is carried out without using a catalyst.

[Structure of the invention]

The present invention will be explained in detail below.

(Raw material) In the present invention, the nitro compound of the general formula CI) is reduced, and the nitro compound is usually combined with a tetrahydroisoquinoline of the general formula
It can be obtained by a condensation reaction between ff) and ff7tide. This condensation reaction is usually carried out using, for example, methanol or ethanol.

In this condensation reaction, the A-form and the B-form are formed due to the difference in the steric configuration of the hydrogen atoms bonded to the condensation positions of the nitro-7-thalides (IV), that is, the 1- and 7-position carbon atoms (R8 and SR). A mixture of is obtained.

Therefore, in the present invention, A of the nitro compound with
The mixture of isomer and B isomer is then subjected to reduction treatment to obtain the amino compound of the general formula (1) shown above. However, since it is the A of the amino compound that is ultimately useful as a medicine, the amino compound after the reduction treatment is By epimerizing the compound, it is necessary to convert the B form of the amino compound to the Mu form. In some cases, the nitro compound of general formula (II) may be subjected to epimerization treatment in advance.

A nitro compound with a high content of mu-isomers is obtained, and then.

There is no problem in reducing this. However, in the case of the present invention, the former is preferable because the yield of the final A-form amine compound is higher.

(Reducing agent) In the present invention, as a reducing agent, NaB horse 81 or L
The use of iBH4 is an essential requirement.

In short, by using this reducing agent, the nitro compound of the general formula CI) can be reduced satisfactorily under normal pressure without using a catalyst, and the process for treating the reaction mixture is simplified. It is.

The amount of the reducing agent used is usually %i, i-J times the nitro compound of the general formula (It), preferably i, z ~
If the amount used is too small, the nitro group cannot be reduced sufficiently, and it is preferable that the effect be the same even if the amount is too large.

(Reaction Solvent) The reduction reaction of the present invention is usually carried out in an organic solvent or an aqueous solution thereof. Examples of this solvent include ethers such as diethyl ether, diglyme, and tetrahydro-7rane, dimethylformamide, and dimethylsulfonate. Examples include oxides and aqueous solutions thereof. The amount of these solvents used is usually 2.
~10 times by weight, preferably 3 to 20 times by weight.

(Reaction Conditions) Since the reduction reaction of the present invention proceeds well under normal pressure, there is no need to carry out the reaction under increased pressure which requires a pressure-resistant reactor, and it is usually industrially desirable to carry out the reaction under normal pressure. In some cases, it may be carried out under pressure.

In addition, the source temperature of the two reactions is usually 0°C to 100T, preferably 20°C to ≦θ°C. If this temperature is too low, the reaction rate is slow and the target temperature cannot be efficiently reached. General formula (1
) cannot be obtained, and conversely, if the content is too high, more by-products will be produced, which is not preferable. The reaction time is usually 30 hours.

(Operating procedure) As a method for carrying out the present invention, for example, a nitro compound and an organic solvent as raw materials are charged into a reactor, and while being kept at a predetermined temperature under stirring, diluted with an organic solvent as necessary. This can be done by dropping a reducing agent.

Since the reaction of the present invention is an exothermic reaction, it is desirable to adjust the temperature of the reducing agent dropwise so that the temperature within the system is maintained within a certain range as heat is removed from the reaction system.

(Treatment of reaction mixture) As a method for separating the amino compound, which is the target product (from the mixture after the reaction), it is usually preferable to mix water and an organic solvent to this mixture and extract the amino compound into the organic phase. . That is, the reducing agent is decomposed into a metal salt and hydrogen, and the metal salt remains in the aqueous phase, making it possible to separate the amino compound. Furthermore, if a large amount of reducing agent remains in the mixture after the reaction, it is desirable to add an inorganic acid to the mixture to decompose the remaining reducing agent, if necessary. The organic solvent for extracting amino compounds is usually dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as clobenzene and dichlorobenzene are preferred. The amount of solvent used is usually 0.2-fold by weight based on the reaction mixture.

Further, the amount of water to be mixed is usually 0.7 to 10 times the weight of the organic solvent.

The organic phase containing the desired product obtained by the above-mentioned extraction is usually treated with a high-boiling aliphatic alcohol, such as the halogenated hydrocarbon, such as methanol, ethanol, propatool, etc. It is desirable to distill off the halogenated hydrocarbon and replace the solvent. Of the amine compounds of the general formula (1) produced during this treatment, only Form A is precipitated as crystals. Therefore, Form A, which is useful as a medicine, can be recovered by filtering this mixture. Further, this mixture is preferable because it can be subsequently subjected to an epimolization treatment in order to convert the dissolved three forms to the A form. The amount of aliphatic alcohol used may be any amount that can disperse Form A of the amino compound, and is usually about the same amount as the amount of solvent used in the epinorization treatment described below.

(Ebimerization) If the amine compound, which is the target product recovered as described above, is the A-isomer alone which has been epimerized before reduction, it can be used as a product as it is, but a mixture of the A-isomer and the three amine compounds can be used as a product. If so, it is necessary to epimerize this amino compound.

This ebimerization is usually carried out by stirring the amine compound in an aliphatic lower alcohol such as methanol, ethanol, propatool, or an aqueous solution thereof at a temperature of 20,100°C. The amount of aliphatic lower alcohol used is usually 3 to 20 times the weight of the amino compound.If the temperature of the emmolization treatment is too high, a product with a high content of isomer A cannot be obtained, and vice versa. If the resistance is low, the reaction rate is slow and undesirable.

Through this emmolization treatment, the three isomers are converted to the A-form, and although the three are dissolved, the A-form is precipitated as crystals, so by filtering the mixture after the treatment, the A-form is can only be collected.

〔Effect of the invention〕

According to the present invention, by reducing the nitro compound of the general formula (n) using a specific reducing agent, the reduction reaction proceeds favorably under normal pressure without using a catalyst, which is preferable. . Therefore, the operation of extracting and separating the desired product from the mixture after the reaction is simple, and its industrial value is great.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Example 1-2 (Condensation reaction) A compound of the general formula (I[[) in which R1 is a hydrogen atom, R2 is a methoxy group, and R7 is a methyl group was placed in a 20'Oxi glass-backed reactor equipped with a stirrer and a temperature controller. (Col I Runin) 2 J, 7 f (/00 rnmol
), in the general formula (IV) shown above, Rν, R4', R''
Compound j where is an ethoxy group and Ra' is a nitro group
/, /f (100 mmol) and methanol 1 Or
d was charged, and the reaction was carried out at a temperature of to° C. for one hour while stirring.

After the reaction was completed, it was cooled to a temperature of 20° C., and the precipitated target product having the following structural formula was recovered. In addition, the yield of the desired product based on the raw material cotalunin is ψ7! Among them, the A-form content was φHirotchi, and the B-form content was Za%.

N01 (Reduction reaction) Nitro compound 2 A, j f (jOrrmo
1) and tetrahydrofuran 10-, and while stirring under reflux, add the reducing agent shown in Table 1/00! n
A suspension prepared by adding mol of tetrahydro 7 run Jim was added dropwise over 1 hour, and the mixture was further stirred at the same temperature for 1 hour to carry out a reduction reaction.

The conversion rate of the nitro compound and the selectivity of the amino compound after the reaction were measured, and the results shown in Table 1 were obtained.

Table 1 (Separation of amino compounds) 3! After adding thihydrochloric acid until the pH of the mixture became 1 or less, an extraction process was performed and an organic phase containing an amino compound was recovered.

Methanol was added to the organic phase thus recovered and distilled to a solvent volume of 100 rxl.
A solvent exchange was performed from dichloromethane to methanol.

(Epimolization) A methanol slurry of the amino compound obtained by the above method and caustic soda≠ and Gt were charged into a 100 m glass reactor similar to the above, and the reaction was carried out at a temperature of 40°C for 10 hours with stirring. The mixture was filtered to collect crystals of Form A.

In this method, when the content and content rate of isomer A and isomer B in the mixture after reaction are determined, isomer A2 J, Of (ri≦
, a%), 3 bodies 0. ! r f (J, 4'%)
Met. Furthermore, the purity of the recovered crystalline CA substance was approximately 100%, and its yield was 1% based on the nitro compound used in the reduction reaction.

Sender: Mitsubishi Chemical Industries, Ltd. Representative Patent Attorney Hase - 1 other person

Claims (1)

[Claims] (1) The following general formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ...... [II] (In the above formula, R^1 and R^2 represent a hydrogen atom or a lower alkoxy group, and R^ At least one of 3', R^4', R^5' and R^6' is a nitro group, the rest represent a hydrogen atom or a lower alkoxy group, and R^7 represents a lower alkyl group.) The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼……[I] It has the same meaning as [I], and R^3, R^4, R^5 and R^6 have the same meaning as the above general formula [II] except that the nitro group is an amino group. As defined in [II].) In the method for producing the amino compound represented by
A method for producing aminated phthalide-isoquinolines, characterized in that the reaction is carried out using iBH_4 without using a metal catalyst.