JP3439797B2 - Method for producing amine derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an amine derivative useful as an intermediate for producing antibacterial compounds.

[0002]

The compound represented by Chemical formula 11 has excellent antibacterial activity and high safety, and is expected as an excellent antibacterial agent. Its characteristic is that it has a cis-2-fluorocyclopropyl group at the 1-position, which is 1,2-cis-2-
Constructed from fluorocyclopropylamine.

[0003]

[Chemical 11]

[0004] 1,2-cis-2-fluoro-cyclopropylamine was prepared from fluorocyclopropylamine derivative of the formula V, a compound of this formula V, cis-2-fluoro-cyclopropane carboxylic acid, alcohol It is prepared by treatment with triethylamine and diphenylphosphoryl azide in the presence (JP-A-2-231475).
issue).

On the other hand, as a method of converting a carboxylic acid derivative into an amine derivative, a method of treating an acid azide compound in the presence of alcohol is known.

[0006]

The production method using diphenylphosphoryl azide, which is a fluorocyclopropylamine derivative, has the problems that this reagent is expensive and that the phosphorus-containing waste liquid derived from this reagent is treated.

On the other hand, cis-2-fluorocyclopropanecarboxylic acid is converted into an acid halide or a mixed acid anhydride and then treated with a metal azide, the resulting acid azide compound is extracted with an organic solvent, and the extract is dried. By removing the solvent and then treating with the addition of alcohol, the desired product is obtained from the carboxylic acid in a yield of about 50 to 65%. That is, it was revealed that the fluorocyclopropylamine derivative can be produced by a classical method using a metal azide.

However, since this method requires an operation of concentrating and isolating the intermediate acid azide compound, there is a risk of explosion and the operability is poor. Therefore, for the purpose of avoiding this concentration operation, the toluene extract of the acid azide compound was used as it was for the reaction in the presence of alcohol, but the desired product was obtained only in a yield of about 30 to 55%.

Therefore, using an inexpensive metal azide,
1,2-cis-2 with excellent safety and operability, and efficient
-Development of synthetic method of fluorocyclopropylamine derivative has been desired.

[0010]

Means for Solving the Problems As a result of earnest studies, the present inventors have found that when a rearrangement reaction of a compound of formula IV to a compound of formula V is carried out in the presence of a dehydrating agent, the desired compound The present invention has been completed by finding out that

That is, the present invention provides formula I

[0012]

[Chemical 12] By reacting a metal azide with a reactive derivative of the compound represented by the formula IV

[0013]

[Chemical 13] A compound of formula V, characterized in that it is converted to a compound of formula V and treated with this compound in the presence of alcohol and a dehydrating agent

[0014]

[Chemical 14] (Wherein R ² represents an alkyl group having 1 to 6 carbon atoms or a benzyl group which may have a substituent).

The present invention also relates to the process according to claim 1, wherein the reactive derivative derived from the compound represented by the formula I is an acid anhydride or an acid halide, and the acid anhydride is represented by the formula II.

[0016]

[Chemical 15] (In the formula, R ¹ represents an alkyl group.) The above-mentioned production method, which is a compound represented by the formula.

The present invention also provides a compound of formula IV
It relates to a process for preparing a compound of formula V, characterized in that it is treated in the presence of alcohol and a dehydrating agent.

The present invention further provides a 2-fluorocyclopropanecarboxylic acid having the formula

[0019]

Embedded image A compound represented by the formula XCO ₂ R ¹ (wherein R ¹ represents an alkyl group and X represents a halogen atom) is reacted to convert into a compound represented by the formula II, It relates to a process for producing a compound represented by the formula V, which comprises reacting the compound with a metal azide to convert the compound into a compound represented by the formula IV, and treating the compound in the presence of an alcohol and a dehydrating agent.

The method of the present invention will be described below.

First, the step of producing an acid azide compound will be described.

When the acid azide compound used in the present invention is produced, the carboxylic acid compound represented by the formula I may be converted into a reactive derivative, and this reactive derivative may be reacted with a metal azide. Here, the reactive derivative of the carboxylic acid compound represented by the formula I is a compound in which the carboxylic acid substituent portion of the compound represented by the formula I is converted into a substituent having higher reactivity. Examples of such compounds include acid anhydrides, acid halides and active esters.
This reactive derivative may be isolated and purified after production, or may be used in the next step without isolation and purification.

The cis-2-fluorocyclopropanecarboxylic acid that can be used in the method of the present invention has isomers having an enantiomeric relationship, and the carboxylic acid may be a racemate or one of the isomers. The enantiomer alone may be used.

As the acid anhydride, a mixed acid anhydride is usually used,
The acyl moiety that is more easily eliminated may be bonded to cis-2-fluorocyclopropanecarboxylic acid. As such an acid anhydride, an acid anhydride with carbonic acid represented by the formula II is most common. The acid anhydride with carbonic acid is most commonly prepared by reacting a halogenocarbonic acid (formic acid) ester with the above carboxylic acid. For example, it may be prepared by a method described in the literature (ORGANIC SYNTHESIS, 51 , p48). This reaction is usually carried out in the presence of a base, but the base may be either organic or inorganic. Carbonates, hydrogencarbonates and the like of alkali metals or alkaline earth metals, and tertiary alkylamines, dialkylanilines, heterocyclic compounds and the like can be used. This reaction is usually carried out in the presence of a solvent, but there is no particular limitation as long as it is inert to the reaction. Hydrocarbons, ketones, ethers, halogenated hydrocarbons and the like may be used.

The acid halide, represented by formula III, can be prepared from the carboxylic acid by commonly used methods. An acid chloride is generally used as the acid halide. To prepare the acid chloride, for example, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, etc. may be reacted. The reaction may be carried out by mixing a carboxylic acid and a reagent and heating at room temperature or heating. At this time, the reaction may be carried out in a solvent inert to the reaction. Examples of such a solvent include hydrocarbons and halogenated hydrocarbons. For example, benzene, chloroform, methylene chloride,
For example, ethylene chloride.

[0026]

[Chemical 17]

The active ester may be a commonly known one, and examples thereof include paranitrophenyl ester.

As the metal azide, an alkali metal azide or an alkaline earth metal azide may be used.
That is, sodium azide, potassium azide, lithium azide, calcium azide and the like are used, but of these, sodium azide is most commonly used.

The reaction of the metal azide with the acid halide or acid anhydride is generally carried out in a solvent miscible with water under cooling. Specifically, the acid halide or acid anhydride may be dissolved or suspended in an organic solvent, and an aqueous solution of a metal azide may be added thereto while cooling. The reaction temperature may be in the range of ice-cooling to room temperature, but it is usually preferable to carry out the reaction under ice-cooling. As the reaction solvent, alcohols, acetone or the like may be used.

After the reaction, the reaction solution may be diluted with water and then the acid azide compound formed in the organic solvent may be separated by extraction. The extraction solvent used may be a commonly used one. The extraction solvent may be one that is immiscible with water, has a relatively high boiling point, and is inert to the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, lower aliphatic hydrocarbons such as hexane, heptane and cyclohexane, and halogenated hydrocarbons such as dichloroethane. Among these, aromatic hydrocarbons are preferable, and toluene is particularly preferable. The amount of the extraction solvent used may be determined based on the weight of cis-2-fluorocyclopropanecarboxylic acid, and for example, it may be used in the range of 1 ml to 30 ml per gram of the carboxylic acid.

The method of the present invention is characterized in that the reaction of the next step is carried out using the acid azide extract itself.
It goes without saying that the method for concentrating and isolating the azide compound as described above can be applied.

The thermal rearrangement reaction of the present invention will be described below. That is, it is a feature of the present invention that the azide compound extract described above is used as it is and treated in the presence of an alcohol and a dehydrating agent.

Various kinds of dehydrating agents can be used in the method of the present invention. For example, a porous (or crystalline) zeolite compound, an anhydrous inorganic salt and the like may be used. Examples of the anhydrous inorganic base include sodium sulfate, calcium sulfate, magnesium sulfate and the like. In addition to the above, as the inorganic compound, silica gel, alumina and the like, and in addition, phosphorus pentoxide, calcium oxide, calcium hydride, calcium chloride, potassium carbonate and the like can be used in some cases.

A zeolite compound is preferably used as the dehydrating agent used in the present invention, but molecular sieves are most commonly used as the zeolite compound. Various types of molecular sieves can be used in the present invention. For example, the molecular sieves 3A or 4A may be in the form of beads, pellets (for example, 1/8, 1/16, etc.) or powder.
Of these, powdery molecular sieves 4A are preferable, and more preferable are those sufficiently dried under reduced pressure at 200 ° C. or higher.

The amount of the molecular sieve used depends on the raw material
-2-It may be used in the range of 10% to 300% by weight with respect to fluorocyclopropanecarboxylic acid, but usually it is used.
100% is enough.

Examples of alcohols used in the method of the present invention include primary alcohols such as ethyl alcohol and 1-propanol, secondary alcohols such as isopropyl alcohol, and tertiary alcohols such as t-butyl alcohol and t-amyl alcohol. It may be benzyl alcohol. In the case of benzyl alcohol, it may have a substituent, but for example, an alcohol in which the phenyl group is substituted with an alkyl group, an alkoxyl group, a halogen atom or the like can be used. For example, 4-methoxybenzyl alcohol,
4-methylbenzyl alcohol, 4-chlorobenzyl alcohol and the like.

The amount of alcohol to be used may be determined by using the weight of cis-2-fluorocyclopropanecarboxylic acid as a guide. For example, if it is used in the range of 1 ml to 30 ml per gram of the carboxylic acid. Good.

The reaction temperature will vary slightly depending on the alcohol and extraction solvent used, but it is usually carried out within the range of 50 ° C to 100 ° C.

The reaction time may be in the range of 4 hours to 24 hours, and is usually completed in about 4 hours.

As the actual operation of the reaction, compound IV is extracted with an extraction solvent, and this extract is gradually added dropwise to the mixture of alcohol and dehydrating agent under heating, or the extract and alcohol are dehydrated. In addition, the temperature may be raised and the reaction may be performed under heating.

[0041]

The present invention will be described below with reference to examples, but the present invention is not limited thereto.

Example 1 2.08 g of cis-2-fluorocyclopropanecarboxylic acid was dissolved in 10.4 ml of acetone,
Under ice cooling, 3.07 ml of triethylamine was added, and the mixture was stirred for 10 minutes. Here, 2.39 g of ethyl chlorocarbonate was added to acetone 10.4.
Add the solution dissolved in ml at 0 ℃ or below,
Stir for 30 minutes 1-Ethoxycarbonyloxycarbonyl-2
-Fluorocyclopropane ( ¹ H-NMR (CDCl ₃ ) δ (p
pm): 1.39 (3H, t, J = 7 Hz), 1.21- 1.57 (1H, m), 1.66
-2.11 (2H, m), 4.37 (2H, q, J = 7.2 Hz), 4.89 (1H,
dm, J = 65.6 Hz)). Next, an aqueous solution prepared by dissolving 1.95 g of sodium azide in 10.4 ml of water was added at 0 ° C. or below, and the mixture was stirred for 1 hour under ice cooling. After reaction, the reaction mixture was added with 20.8 ml of cold water.
Cis-2-fluorocyclopropylcarbonylazide was extracted with 41.6 ml of toluene ( ¹ H-NMR (CDCl ₃ ) δ
(ppm): 1.09-1.46 (1H, m), 1.66-2.17 (2H, m), 4.80
(1H, dm, J = 65.6 Hz)). Meanwhile, t-butanol 41.6 m
and 2.0 g of molecular sieve 4A powder were heated to 75 ° C., and the above toluene extract was added dropwise thereto over 30 minutes, followed by stirring at about 80 ° C. for 4 hours. After the reaction, the molecular sieves were filtered off, and the solvent was distilled off under reduced pressure to remove cis.
1.77 g (yield 79%) of -1- (tertiary-butoxycarbonylamino) -2-fluorocyclopropane was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.6-1.3 (2H,
m), 1.46 (9H, s), 2.50-2.76 (1H, m), 4.62 (1H, dm, J
= 65 Hz), 4.5-5.0 (1H, br)

Reference Example 1 2.77 g of cis-1- (tertiary-butoxycarbonylamino) -2-fluorocyclopropane obtained in Example 1 was dissolved in 14 ml of toluene, and an equivalent amount (equal mol) of para was added. Toluenesulfonic acid monohydrate was added, and the mixture was heated with stirring for 2 hours. After the reaction, the reaction solution was cooled and the precipitated crystals were collected by filtration to give 3.71 g (yield 95%) of parafluorotoluenesulfonate of 2-fluorocyclopropylamine.
Got

¹ H-NMR (CD ₃ OD) δ (ppm): 1.17-1.29 (2 H,
m), 2.36 (3H, s), 2.64-2.69 (1H, m), 4.84 (1H, ddt,
J = 3.9, 63.5, 5.3 Hz), 7.23 (2H, d, J = 8.0 Hz), 7.
70 (2H, d, J = 8.0 Hz) mp: 168.5-170.5 ℃ (decomposition)

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-63-264461 (JP, A) JP-A-2-231475 (JP, A) JP-A-63-277655 (JP, A) JP-A-2- 88535 (JP, a) JP flat 5-163232 (JP, a) United States Patent 3079403 (US, a) (58 ) investigated the field (Int.Cl. ^7, DB name) C07C 271/56 C07C 269/02 CA (STN) REGISTRY (STN)

Claims (9)

(57) [Claims] 1. Formula I By reacting a metal azide with a reactive derivative of a compound represented by the formula IV A compound of the formula V ## STR3 ## characterized by treating this compound in the presence of an alcohol and a dehydrating agent. (In the formula, R ² represents an alkyl group having 1 to 6 carbon atoms or a benzyl group which may have a substituent.) 2. The process according to claim 1, wherein the reactive derivative derived from the compound represented by the formula I is an acid anhydride or an acid halide. 3. The acid anhydride has the formula II The method according to claim 2, which is a compound represented by the formula (wherein R ¹ represents an alkyl group). 4. The formula IV: A compound of formula V characterized in that it is treated in the presence of an alcohol and a dehydrating agent. (In the formula, R ² represents an alkyl group having 1 to 6 carbon atoms or a benzyl group which may have a substituent.) 5. A compound represented by the formula: XCO ₂ R ¹ (wherein R ¹ represents an alkyl group and X represents a halogen atom) is added to 2-fluorocyclopropanecarboxylic acid. Reaction of formula II (In the formula, R ¹ represents an alkyl group), the compound is converted to a compound represented by the formula IV A compound of formula V characterized in that this compound is treated in the presence of an alcohol and a dehydrating agent. (In the formula, R ² means an alkyl group or a benzyl group which may have a substituent.) 6. The method according to claim 1, wherein the alcohol is tertiary butyl alcohol or benzyl alcohol which may have a substituent. 7. The method according to claim 1, 2, 3, 4, 5, or 6, wherein the dehydrating agent is a zeolite compound. 8. The method according to claim 1, 2, 3, 4, 5, 6, or 7, wherein the metal azide is sodium azide. 9. A compound of formula I in which the fluorine atom and the substituent —NHCO ₂ R ² are on the same side of the plane of the cyclopropane ring.
V is a compound of claim 1, 2, 3, 4, 5, 6, 7,
Or the production method according to 8.