JPH0710816A - Production of high-purity aminoolefins - Google Patents

Abstract

PURPOSE:To easily obtain aminoolefins in high purity by deprotecting the phthaloyl group of a compound having double bond and phthaloyl group and/or its acid addition salt with hydrazine in nitrogen atmosphere. CONSTITUTION:Aminoolefins having high purity can be produced by deprotecting a compound having double bond and phthaloyl group and/or its acid addition salt in nitrogen atmosphere. Especially aminoolefins of the formula III can be produced in high purity from a compound of the formula I [R is H or group of the formula II (R<1> is hydroxymethyl, formyl or disubstituted aminomethyl)] and/or its acid addition salt by this reaction. Aminoolefins are useful as production intermediates for pharmaceuticals, agrochemicals, various functional materials, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing high-purity amino olefins. Amino olefins are compounds useful as intermediates for the production of pharmaceuticals, agricultural chemicals, various functional materials and the like.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a primary amine, Gab which hydrolyzes an N-substituted phthalimide obtained from a halide and potassium phthalimide is used.
The Riel method and the Ing-Manske method of deprotecting an N-substituted phthalimide obtained from a halide and potassium phthalimide with hydrazine are generally used.

However, the former Gabriel method is economically disadvantageous because (1) the reaction time is long, (2) the yield of the product is low, and (3) the purity of the product is low and the purification is performed. Therefore, there is a problem that the post-treatment is burdened, and it cannot be said to be an industrial method.

On the other hand, the latter Ing-Manske method is
The reaction time, yield, purity, etc. are advantageous over the Gabriel method. However, since hydrazine used in the reaction originally has a reducing action, when an N-substituted phthalimide having a double bond and a phthaloyl group and / or an acid addition salt thereof is used as a raw material, the desired product is obtained. In addition to the amino olefins, the double bond-reduced amine compound is by-produced. For example, the general formula (I)

[0005]

[Chemical 5]

[Wherein R is hydrogen, or

[0007]

[Chemical 6]

(R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group). ] When the compound represented by and / or its acid addition salt is used as a starting material, the compound of the general formula (II)

[0009]

[Chemical 7]

[Wherein R is hydrogen, or

[0011]

[Chemical 8]

(R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group). ] In addition to the amino olefins represented by the general formula (III)

[0013]

[Chemical 9]

[Wherein R is hydrogen, or

[0015]

[Chemical 10]

(R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group). ] The amine compound represented by

However, the amino olefins, which are the desired products, and the amine compounds, which are by-products, are structurally very similar and therefore have very close physical properties, making separation very difficult. Is. This often causes a problem when the above-mentioned amino olefins are used as a raw material for a drug or the like which is required to have a very high purity. That is, when an aminoolefin containing an amine compound produced by reduction of a double bond as an impurity is used as a raw material, the reaction of the aminoolefin which is the original raw material proceeds, and the amine compound which is an impurity also progresses. Since they react in the same manner, a compound having a similar structure derived from an amine compound is by-produced in the intended final product. Moreover, since this by-product has a structure similar to that of the intended final product, separation and removal are not easy, which is a very problematic problem. For example, amino olefins represented by the above general formula (II) are known as intermediates for the production of anti-peptic ulcer agents, but [WO92 / 1
No. 3854], and in this case, a compound derived from the amine compound represented by the general formula (III), which is a by-product obtained by reducing the double bond, is used as a final product in the drug substance of the anti-peptic ulcer drug. This is a serious problem because it is by-produced as an impurity and the separation and removal of this impurity are not easy.

For the above reasons, it has been desired to develop a method for producing high-purity amino olefins.

[0019]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies in view of the problems of the conventional production method, and as a result, have found that the compound having a double bond and a phthaloyl group and / or its acid addition salt. When deprotecting the phthaloyl group of with hydrazine to produce amino olefins, by reacting under a nitrogen atmosphere, by-products of the amine compound in which the double bond is reduced are suppressed, and the target amino olefins are increased. They have found that they can be obtained with a purity and arrived at the present invention.

That is, according to the present invention, when deprotecting the phthaloyl group of a compound having a double bond and a phthaloyl group and / or an acid addition salt thereof with hydrazine, the reaction is carried out under a nitrogen atmosphere. It is a method for producing olefins. Further, a compound having a double bond and a phthaloyl group and / or an acid addition salt thereof is represented by the general formula (I)

[0021]

[Chemical 11]

[Wherein R is hydrogen, or

[0023]

[Chemical 12]

(R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group). ] The phthalimide compound and / or acid addition salt thereof represented by the formula:

[0025]

[Chemical 13]

[Wherein R is hydrogen, or

[0027]

[Chemical 14]

(R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group). ] It is a manufacturing method of high purity amino olefins which are amino olefins represented by these.

The compound having a double bond and a phthaloyl group and / or its acid addition salt, which is a raw material of the present invention, is
For example, it can be easily obtained by reacting a halogenated olefin with potassium phthalimide and, if necessary, reacting with an acid. For example, the above general formula (I)
And the acid addition salt thereof are represented by the general formula (IV)

[0030]

[Chemical 15]

[Wherein X represents halogen, R represents hydrogen,
Or

[0032]

[Chemical 16]

(R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group). ] The halogenated olefins represented by the following formula (V)

[0034]

[Chemical 17]

It can be obtained by reacting with potassium phthalimide represented by and reacting with an acid as the case requires. Here, the acid is a commonly used inorganic acid and organic acid, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, oxalic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, Examples thereof include phthalic acid.

The compound having a double bond and a phthaloyl group and / or an acid addition salt thereof can be deprotected by reacting with hydrazine to convert it into an amino olefin which is a desired product. it can. For example, in the case of the compound represented by the above general formula (I) and / or its acid addition salt, the above general formula (I
It can be converted into amino olefins represented by I).

The amount of hydrazine used in the present invention is preferably 1 to 10 equivalents based on the compound having a double bond and a phthaloyl group and / or its acid addition salt as a raw material. When the amount is less than 1 equivalent, the deprotection of the phthaloyl group is not sufficiently performed, which causes a decrease in yield and the like, which is not preferable. Further, if more than 10 equivalents are used, the reaction does not change so much and it is economically disadvantageous, which is not preferable. More preferably, 3 equivalents to
7 equivalents.

The reaction of the present invention is carried out under a nitrogen atmosphere, whereby the double bond is reduced, whereby the by-product of the amine compound produced can be suppressed, and the desired product, amino olefins, can be increased. It can be obtained in purity.

A solvent is preferably used in the reaction of the present invention. As the solvent, for example, benzene, toluene, aromatic hydrocarbons such as xylene, hexane, aliphatic hydrocarbons such as cyclohexane, carbon tetrachloride, chloroform, halogenated hydrocarbons such as methylene chloride, methanol, ethanol, Alcohols such as propanol and diols such as 1,4-butanediol and 1,4-butenediol can be used.

The reaction temperature in the present invention is 30 ° C to 12 ° C.
The temperature is preferably 0 ° C. A temperature lower than 30 ° C is not preferable because a sufficient reaction rate cannot be obtained.
Further, if the temperature is higher than 120 ° C., the decomposition becomes severe and the yield is lowered. More preferably, it is 70 ° C to 100 ° C.

[0041]

The present invention will be described in more detail with reference to the following examples. Example 1 (A) 4- [4- (1-piperidinylmethyl) pyridyl
2-oxy] -cis-2-butenyl-1-amine
Manufacturing

[0042]

[Chemical 18]

N- {4- [4- (1-piperidinylmethyl) pyridyl-2-oxy] butyl} phthalimide-free N- {4- [4- (1-piperidinylmethyl)
Pyridyl-2-oxy] -cis-2-butenyl} phthalimide maleate (HPLC purity 99.97%)
3.00 g (5.91 mmol) was added to 16.20 g (179.76 mmol) of 1,4-butanediol and dissolved while hot, and under a nitrogen atmosphere, 80% hydrazine monohydrate 1.85 g (29.56 mmol). ) Is added, and 80 ° C to 9
The mixture was stirred at 0 ° C for 2 hours and 20 minutes.

After cooling, the reaction-terminated liquid contained 45.0 m of toluene.
1L was added and 1N-sodium hydroxide aqueous solution 20.0 ml
Once, and twice with 5.0 ml, and once with a mixed solution of 5.0 ml of saturated saline and 5.0 ml of water, and the organic layer was collected. Further, wash water is combined and toluene 15.
The organic layer was extracted twice with 5.0 ml of 1N-sodium hydroxide aqueous solution, 2.5 ml of saturated saline and 2.5 ml of water.
The organic layer was collected by washing once with ml of the mixed solution. The collected organic layers were combined and dried over 20.00 g of anhydrous sodium sulfate, then filtered, the solvent was distilled off, and the residue was vacuum dried to give 4- [4-
(1-Piperidinylmethyl) pyridyl-2-oxy]-
Obtained cis-2-butenyl-1-amine. (B) N- {4- [4- (1-piperidinylmethyl) pi
Lysyl-2-oxy] -cis-2-butenyl} -2-
Production of (furfurylsulfinyl) acetamide

[0045]

[Chemical 19]

4- [4- (1-Piperidinylmethyl) pyridyl-2-oxy] -cis-2-obtained in (A)
Butenyl-1-amine with 35.0 ml of toluene and 2-
(Furfurylsulfinyl) acetic acid-p-nitrophenyl (HPLC purity 98.32%) 1.92 g (6.21 m)
mol) was added, and the mixture was stirred at room temperature for 14 hours and 30 minutes.

The reaction-terminated liquid was used as a 15% acetic acid aqueous solution 30.0 m
It was extracted once with 1 and twice with 20.0 ml, and the aqueous layer was collected. 7.00 g of anhydrous potassium carbonate (50.6
5 mmol) was added to make it alkaline. Ethyl acetate 4
The organic layer was collected by extracting once with 0.0 ml and twice with 35.0 ml. The recovered organic layer was washed once with 20.0 ml of 1N-sodium hydroxide solution, 4 times with 10.0 ml, and with water 10.
Wash once with 0 ml and once with saturated saline 10.0 ml,
After drying over 20.00 g of anhydrous sodium sulfate, it was filtered and the solvent was distilled off. To the residue was added 40.0 ml of ethanol to replace the solvent, and the solvent was distilled off, followed by vacuum drying to obtain N- {4.
-[4- (1-Piperidinylmethyl) pyridyl-2-oxy] -cis-2-butenyl} -2- (furfurylsulfinyl) acetamide was obtained.

As described above, 4-obtained in (A)
[4- (1-Piperidinylmethyl) pyridyl-2-oxy] -cis-2-butenyl-1-amine is N- {4
-[4- (1-Piperidinylmethyl) pyridyl-2-oxy] -cis-2-butenyl} -2- (furfurylsulfinyl) acetamide was derived and contained in it by analysis by HPLC. N- {4- [4
-(1-Piperidinylmethyl) pyridyl-2-oxy]
The proportion of butyl} -2- (furfurylsulfinyl) acetamide was analyzed, and 4- [4- (1-piperidinylmethyl) pyridyl-2- was produced as a by-product of the reduction of the double bond in the reaction (A). The production rate of [oxy] butyl-1-amine was analyzed. The results are shown in Table 1. In the table, "final product" means N- {4- which is a product of the reaction of (B).
It is [4- (1-piperidinylmethyl) pyridyl-2-oxy] -cis-2-butenyl} -2- (furfurylsulfinyl) acetamide, and the "reduced form" is the reaction of (A). 4- [4- (1-piperidinylmethyl) pyridyl-2 produced by reduction of the double bond in
N- {4- [4- (1-piperidinylmethyl) pyridyl-2-oxy] butyl} -2- (furfurylsulfinyl) derived from -oxy] butyl-1-amine according to the following reaction scheme: It is acetamide.

[0049]

[Chemical 20]

Comparative Example 1 The same operation as in Example 1 (A) was carried out except that the reaction was carried out in an open system instead of under a nitrogen atmosphere. The results are shown in Table 1.

Example 2 In (A) of Example 1, as a reaction solvent, 16.20 g (179.76 mmol) of 1,4-butanediol was replaced with cis-2-butene-1,4-diol 16.2.
Completely the same operation was performed except that 0 g (183.86 mmol) was used. The results are shown in Table 1.

Comparative Example 2 In (A) of Example 1, as the reaction solvent, 16.20 g (179.76 mmol) of 1,4-butanediol was replaced by cis-2-butene-1,4-diol 16.2.
The same procedure was performed except that 0 g (183.86 mmol) was used and the reaction was performed in an open system instead of under a nitrogen atmosphere. The results are shown in Table 1.

Example 3 (A) 4- [4- (1-piperidinylmethyl) pyridyl
2-oxy] -cis-2-butenyl-1-amine
Manufacturing

[0054]

[Chemical 21]

N- {4- [4- (1-piperidinylmethyl) pyridyl-2-oxy] butyl} phthalimide-free N- {4- [4- (1-piperidinylmethyl)
Pyridyl-2-oxy] -cis-2-butenyl} phthalimide maleate (HPLC purity 99.97%)
3.00 g (5.91 mmol) of toluene 20.76
g, ethanol 1.92 g and potassium carbonate aqueous solution 1
5.0 ml (2.04 g of anhydrous potassium carbonate (14.76
It was added to the two-layer system mixed solution containing (mmol)), shaken vigorously, neutralized and extracted. After separating the organic layer, water 5.4m
After washing with 1 and drying with anhydrous sodium sulfate (10.00 g), the mixture was filtered, the solvent was distilled off, and the residue was vacuum dried to obtain N- {4-
2.37 g of [4- (1-piperidinylmethyl) pyridyl-2-oxy] -cis-2-butenyl} phthalimide
Got The recovery rate was quantitative.

To this residue was added 20.76 g of toluene and 3.60 g of ethanol, and under a nitrogen atmosphere, 1.85 g (29.56 mmol) of 80% hydrazine monohydrate was added, and the mixture was heated at 80 ° C. to 90 ° C. for 20 hours. Stir for minutes.

After cooling, the reaction-terminated liquid contained 20.0 m of toluene.
1L was added and 1N-sodium hydroxide aqueous solution 20.0 ml
Once, and twice with 5.0 ml, and once with a mixed solution of 5.0 ml of saturated saline and 5.0 ml of water, and the organic layer was collected. Further, wash water is combined and toluene 15.
The organic layer was extracted twice with 5.0 ml of 1N-sodium hydroxide aqueous solution, 2.5 ml of saturated saline and 2.5 ml of water.
The organic layer was collected by washing once with ml of the mixed solution. The collected organic layers were combined and dried over 20.0 g of anhydrous sodium sulfate,
Filter, evaporate the solvent, dry under vacuum and then 4- [4- (1-
Piperidinylmethyl) pyridyl-2-oxy] -cis
2-Butenyl-1-amine was obtained. (B) N- {4- [4- (1-piperidinylmethyl) pi
Lysyl-2-oxy] -cis-2-butenyl} -2-
Production of (furfurylsulfinyl) acetamide

[0058]

[Chemical formula 22]

4- [4- (1-piperidinylmethyl) pyridyl-2-oxy] -cis-2-obtained in (A)
Butenyl-1-amine with 35.0 ml of toluene and 2-
(Furfurylsulfinyl) acetic acid-p-nitrophenyl (HPLC purity 98.32%) 1.92 g (6.21 m)
mol) was added, and the mixture was stirred at room temperature for 14 hours and 30 minutes.

After completion of the reaction, a 15% aqueous acetic acid solution (30.0 m)
It was extracted once with 1 and twice with 20.0 ml, and the aqueous layer was collected. 7.00 g of anhydrous potassium carbonate (50.6
5 mmol) was added to make it alkaline. Ethyl acetate 4
The organic layer was collected by extracting once with 0.0 ml and twice with 35.0 ml. The recovered organic layer was washed once with 20.0 ml of 1N-sodium hydroxide solution, 4 times with 10.0 ml, and with water 10.
Wash once with 0 ml and once with saturated saline 10.0 ml,
After drying over 20.0 g of anhydrous sodium sulfate, it was filtered and the solvent was distilled off. To the residue was added 40.0 ml of ethanol to replace the solvent, and the solvent was distilled off, followed by vacuum drying to obtain N- {4-.
[4- (1-Piperidinylmethyl) pyridyl-2-oxy] -cis-2-butenyl} -2- (furfurylsulfinyl) acetamide was obtained. The results are shown in Table 1.

Comparative Example 3 In Example 3 (A), the same operation was performed except that the reaction was performed in an open system instead of under a nitrogen atmosphere. The results are shown in Table 1.

[0062]

[Table 1]

[0063]

According to the present invention, amino olefins, which have been difficult to obtain with high purity by the conventional method, can be easily prepared.
And it became possible to obtain it with high purity.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hirotsune Kondo 2805 Imafuku Nakadai, Kawagoe City, Saitama Prefecture Central Glass Co., Ltd. Tokyo Research Laboratory (72) Inventor Yoshiyuki Kikuchi 2805 Imafuku Nakadai, Kawagoe City, Saitama Prefecture Central Glass Co., Ltd. Tokyo Research Center

Claims (2)

[Claims] 1. Production of high-purity amino-olefins, characterized in that when deprotecting the phthaloyl group of a compound having a double bond and a phthaloyl group and / or its acid addition salt with hydrazine, the reaction is carried out under a nitrogen atmosphere. Method. 2. A compound having a double bond and a phthaloyl group and / or an acid addition salt thereof is represented by the general formula (I): [In the formula, R is hydrogen, or (R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group.). ] It is a phthalimide compound and / or its acid addition salt represented by these,
The product has the general formula (II): [In the formula, R is hydrogen, or (R ¹ represents a hydroxymethyl group, a protected hydroxymethyl group, a formyl group, a protected formyl group or a disubstituted aminomethyl group.). ] The manufacturing method of the high purity amino olefins of Claim 1 which are amino olefins represented by these.