JPH0978277A - Production of 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially produce a specific 3-amino-2-hydroxy-1,1,1- trifluoromethyl compound by allowing a specific 2-aminoaldehyde compound to reductively coupling-react with iodotrifluoromethane. SOLUTION: 2-aminoaldehyde compound expressed by general formula 1 (R expresses H, a 1-30C alkyl group, a 6-35C aryl group and each of P<1> and R<2> expresses H, an amino group protecting group or phthaloyl group) is allowed to reductively coupling-react with CF3 I by an electrode reaction using a consumable electrode such as Zn. The electrode reaction is performed by using Ni or the like as an anode, tetrabutylammonium bromide or the like as a supporting electrolyte and N,N-dimethylformamide or the like as a reaction solvent. If necessary, the amino group protecting group is eliminated from the reaction product. As a result, the 3-amino-2-hydroxy-1,1,1,-trifluoromethyl compound expressed by general formula 2 (each of P<1> 0 and P<2> 0 expresses H, an amino group protecting group or phthaloyl group) is obtained at high yield.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 3-amino-2-
More specifically, it relates to a method for producing a hydroxy-1,1,1-trifluoromethyl compound, and more specifically, (3S) -N, N-dibenzyl-3-amino- whose steric configuration at the asymmetric carbon at the 3-position is the S-configuration. 4-methyl-1,1,1-trifluoromethyl-2 (S) -pentanol and (3S) -N,
N-dibenzyl-3-amino-4-methyl-1,1,1
-A method for producing trifluoromethyl-2 (R) -pentanol.

[0002]

BACKGROUND OF THE INVENTION 3-Amino-2 represented by the general formula (2)
-Hydroxy-1,1,1-trifluoromethyl compounds are important intermediates in pharmaceuticals.

[0003]

Embedded image

In the formula, R is a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group having 1 to 30 carbon atoms, an aryl group having 6 to 35 carbon atoms, or 7 to 3 carbon atoms.
Represents an aralkyl group of 6. P ₀ ¹ and P ₀ ^{2 each} independently represent a hydrogen atom or an amino group-protecting group, or P ₀ ¹ ,
P ₀ ² together represents a phthaloyl group.

Among them, (3S) -3-amino-4-methyl-1,1,1-trifluoromethyl-2-pentanol (Compound A) is used, for example, in Journal of Medicinal Chemistry. Me
dicinal Chemistry) Volume 35, 641
HLE (Hu as described in page (1992).
It is a very useful compound as an intermediate of a chronic bronchitis drug showing man Leukocyte elastase) inhibition.

[0006]

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The following methods are known as conventional methods for producing 3-amino-4-methyl-1,1,1-trifluoromethyl-2-pentanol (Compound A) and its derivatives. . (1) A method of coupling 2-methyl-1-nitropropane and trifluoroacetaldehyde ethyl hemiacetal with potassium carbonate and then reducing the nitro group by hydrogenation (JP-A-5-244694). ,
Alternatively, a method of reducing a nitro group with lithium aluminum hydride (EP-0819305).

(2) A method obtained by trifluoroacetylation from N-benzoylvaline via an oxazolone compound using trifluoroacetic anhydride, decarboxylation, and reduction of the ketone body (Journal of Medicinal Chemistry ( Journal of Medicinal
Chemistry, 33, 394 (1990)
Year)). (3) As an example of using trifluoromethane iodide, a method of preparing a CF ₃ ZnI reagent with activated zinc and reacting it with peptidyl aldehyde at a low temperature (−20 ° C.) (Tetrahedron Letters (Tetrahedron
Letters, 33, 4279 (1992).
Year)).

[0009]

Of the above methods,
The method (1) is not suitable for industrial production because it uses nitroalkane, which has a risk of explosion, and uses trifluoroacetaldehyde ethyl hemiacetal, which is difficult to operate. In the method of (2), the product is produced in a racemic form with a low yield (about 20%), and their resolution is required. In the method (3), since a large amount of zinc and CF ₃ I are used for the aldehyde, there are problems such as post-treatment of a large amount of zinc waste as an industrial manufacturing method. Therefore, 3-amino- which solves the above-mentioned problems and is industrially producible
It has been desired to develop a method for producing 4-methyl-1,1,1-trifluoromethyl-2-pentanol.

In view of the above, it is an object of the present invention to provide a method for producing a 3-amino-4-methyl-1,1,1-trifluoromethyl compound which can be industrially produced. .

[0011]

Means for Solving the Problems The gist of the present invention is the general formula (1);

Embedded image (In the formula, R represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group having 1 to 30 carbon atoms, an aryl group having 6 to 35 carbon atoms, or an aralkyl group having 7 to 36 carbon atoms. P ¹ and P ² independently represent a hydrogen atom or an amino group-protecting group, or P ¹ and P ² together represent a phthaloyl group, provided that P ¹ and P ² are At the same time, a 2-aminoaldehyde compound represented by the formula (1) is hydrogen atom, and trifluoromethane iodide is reductively coupled by an electrode reaction using a consumable electrode to remove the amino-protecting group. With or without separation, the compound represented by the general formula (2):

[Chemical 6] (In the formula, R is the same as above. P ₀ ¹ and P ₀ ² are independently
Represents a hydrogen atom or an amino group-protecting group, or
P ₀ ¹ and P ₀ ² together represent a phthaloyl group. ) In the production of the 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound. The present invention is described in detail below.

The 2-aminoaldehyde compound used in the present invention is represented by the above general formula (1).

R is a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group having 1 to 30 carbon atoms, an aryl group having 6 to 35 carbon atoms, or 7 to 3 carbon atoms.
6 represents an aralkyl group, for example, H-, CH _3- , C
H ₃ (CH _{2) n} - [where n is an integer of 1 to 29], (CH
_{3) 2 CH -, (CH} 3) 3 C-CH 2 -, (CH 3)
_{2 CH (CH 2) -,} Ph- [Ph is a phenyl group],
Ph (CH _{2) m} - [m is an integer from 1 to 9] and the like can be given. Of these, a hydrogen atom, a methyl group, an isopropyl group, and a benzyl group are preferable.

The above P ¹ and P ² independently represent a hydrogen atom or an amino group-protecting group. However, the case where P ¹ and P ² are simultaneously hydrogen atoms is excluded. The amino protecting group is
There is no particular limitation as long as it is a protecting group usually used as an amino-protecting group. For example, Protective Groups in Organic Synthesis, Second Edition (Protec
live Groups in Organic Sy
nthesis, 2nd Ed. ), By Theodora W. Green,
John Willie and Sons (John Wil
ey & Sons) (1990) 309-3
Examples thereof include an acetyl group and a benzyl group as described on page 84. Among them, it is preferable that P ¹ and P ² are both benzyl groups. Above P ¹ , P
^{In the case where 2} is a phthaloyl group when both are taken together,
It is a form of the amino-protecting group.

Next, the conditions of the manufacturing method of the present invention will be described. First, the 2-aminoaldehyde compound represented by the general formula (1) can be prepared, for example, from the corresponding amino acid by reduction of aminonitrile or carboxylic acid ester or oxidation of alcohol. For the reduction, for example, diisobutylaluminum hydride (DIBA
H), lithium aluminum hydride (LiAlH ₄ ) or the like can be used as the reducing agent.

The above-mentioned oxidation is not particularly limited, and for example, conventional Jones oxidation, Collins oxidation, PCC oxidation, Swan (Swe).
rn) oxidation, TEMPO oxidation, etc. can be used, and N
Protected amino alcohols can be converted to aldehydes.

Next, the 2-aminoaldehyde compound represented by the general formula (1) is subjected to a reductive coupling reaction to give 3-amino-2-hydroxy-formula represented by the general formula (2).
The process of producing a 1,1,1-trifluoromethyl compound will be described. The above 3-amino-2-hydroxy-1,
The 1,1-trifluoromethyl compound is prepared by an electrode reaction using CF ₃ I as a reagent.

The anode of the electrode used in the above electrode reaction is not particularly limited, and examples thereof include zinc, magnesium and aluminum. Of these, zinc is preferred. The cathode is not particularly limited, and examples thereof include nickel, stainless steel, carbon and platinum. Of these, nickel is preferable. The shape of the electrode is not particularly limited, and for example, a plate shape,
Examples thereof include a rod shape and a foam shape.

The supporting electrolyte used in the above electrode reaction is not particularly limited, and examples thereof include tetrabutylammonium bromide, tetrabutylammonium iodide, and tetrabutylammonium tetrafluoroborate. Of these, tetrabutylammonium bromide is preferred. The amount of the supporting electrolyte added is preferably 0.01 to 5 molar equivalents relative to the 2-aminoaldehyde compound. 0.
If it is less than 01 molar equivalent, the reaction takes a long time, and if it exceeds 5 molar equivalent, the solubility of other reaction substrates is inhibited,
It is not preferable in terms of reaction time and yield. More preferably,
It is 0.2 to 0.5 molar equivalent.

The concentration of the 2-aminoaldehyde compound used in the present invention in the solution is not particularly limited, but it is usually 0.
It is carried out at a concentration of 02 to 5 molar.

The amount of trifluoromethane iodide used in the present invention is preferably 1 to 10 molar equivalents relative to the 2-aminoaldehyde compound. If it is less than 1 molar equivalent, the reaction will not be completed, and even if it is used in excess of 10 molar equivalent, improvement of the reaction yield is not expected. More preferably,
It is 1 to 5 molar equivalents.

The reaction solvent used in the present invention is not particularly limited, and examples thereof include N, N-dimethylformamide (DMF) and N, N-dimethylacetamide (DM).
A), acetonitrile, tetramethylurea, N-methylpyrrolidone, hexamethylphosphorous triamide (HM
PT), tetrahydrofuran, etc. can be mentioned.
Of these, N, N-dimethylformamide is preferable.
These may be used alone or in combination of two or more.

In the present invention, the reaction is carried out under constant current conditions. As the above-mentioned constant current condition, it is preferable to apply 0.5 to 15 F / mol to the 2-aminoaldehyde compound. 0.
If the amount is less than 5 F / mol, the reaction is not completed, and even if the current exceeds 15 F / mol, the yield of the reaction cannot be further improved, and the amount of by-products increases. More preferably, 2.0 to
It is 3.0 F / mol.

As the reaction operation, for example, a 2-aminoaldehyde compound and a supporting electrolyte are dissolved in the above solvent,
It can be carried out by dissolving trifluoromethane iodide in a reaction solvent under conditions of −60 to 50 ° C., preferably −20 to 0 ° C., and applying current while stirring. The reaction is preferably carried out under anhydrous conditions after drying the solvent and the like.

The post-treatment of the above reaction is carried out, for example, by the following method. After the reaction, diluted hydrochloric acid, an aqueous solution of ammonium chloride, etc. are added to the reaction solution, and the mixture is extracted with a solvent such as ethyl acetate, diethyl ether, toluene, and further diluted hydrochloric acid,
Wash with an aqueous solution of ammonium chloride 2-3 times. The extract is washed with saturated saline, dried with a desiccant such as sodium sulfate, magnesium sulfate, etc., and then filtered off, and the filtrate is concentrated, followed by a general method such as recrystallization or column chromatography. The N-protected 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound represented by the general formula (2) can be separated.

Next, the step of removing the amino-protecting group of the 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound represented by the general formula (2) will be described. The step of removing the amino-protecting group is an optional step. N-protected 3-amino-2-hydroxy-1,
Examples of the step of deprotecting the 1,1-trifluoromethyl compound include, for example, Protective Groups in
Organic Synthesis, 2nd Edition (Protecti
ve Groups in Organic Synt
hesis, 2nd Ed. ), Theodora W
Thedra W. Green, John Wiley and Sons (John Wiley)
& Sons) Publishing (1990) 309-3 of the same book
The deamination method described on page 84 can be used.

For example, P ₀ ¹ and P ₀ ² are benzyl groups, N, N-dibenzyl-3-amino-2-hydroxy-
In the case of a 1,1,1-trifluoromethyl compound, deprotection by a hydrogenation method using Pd / C or the like as a catalyst in a solvent such as methanol or ethanol is carried out to 3
-Amino-2-hydroxy-1,1,1-trifluoromethyl compound can be obtained. The deprotection by the hydrogenation method is performed at room temperature and atmospheric pressure, and the catalyst such as Pd / C is the N, N-dibenzyl-3-amino-2-hydroxy-1,1,1-trifluoromethyl compound. It is preferable to use 5 to 10% by weight.

In the case of the debenzylation reaction by the above hydrogenation method, N, N-dibenzyl-3-amino-used for the reaction is used.
The concentration of the 2-hydroxy-1,1,1-trifluoromethyl compound is not particularly limited, but is usually 0.1 to 1 molar.

In the present invention, (3S) and (3
R) -3-Amino-2-hydroxy-1,1,1-trifluoromethyl compound can be produced without optical resolution. When L-valine is used as the amino acid, (3S) -3-amino-4-methyl-1,1,1
-Trifluoromethyl-2-pentanol can be obtained.

It can be obtained by reacting an aminoaldehyde in which the amino group of L-valine is benzyl-protected (3S).
-N, N-dibenzyl-3-amino-1,1,1-trifluoromethyl-2-pentanol is a novel compound and is an important compound as a precursor of compound A.

Further, from other optically active amino acids, for example, N-protected aminoaldehyde corresponding to L-phenylalanine, L-alanine and the like, by the same method,
The 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound can be prepared.

In the present invention, the configuration of the asymmetric carbon at the 2-position does not affect the usefulness as an intermediate, so that it is not necessary to pay particular attention to the stereoselectivity of the reaction in the present invention.

[0033]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 Production of (3S) -N, N-dibenzyl-3-amino-4-methyl-1,1,1-trifluoromethyl-2-pentanol The electrode was a zinc plate (5 cm × 5 cm) on the anode. 5 cm) and a nickel plate (5 cm x 5 cm) is used for the cathode. Argon-substituted (2S) -N, N-dibenzyl-2-amino-3-methylbutyraldehyde (5.74 g, 20.4 mmo)
l) and tetrabutylammonium bromide (0.32 g, 1
(3 mmol) in a DMF solution containing trifluoromethane iodide (12 g, 61.3 mmol) was dissolved at −15 ° C., and a current of 2.5 F / mol was applied at a constant current of 0.3 A while stirring. Ammonium chloride aqueous solution was added to the reaction solution,
It was extracted with ethyl acetate. Further, after washing twice with an ammonium chloride aqueous solution and once with a saturated sodium chloride aqueous solution,
It was dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by silica gel chromatography, (3S) -N, N-
Dibenzyl-3-amino-4-methyl-1,1,1-trifluoromethyl-2-pentanol (3.8 g, 1
0.8 mmol, yield 53%) was obtained. ¹ H-NMR (CDCl ₃ ) δ; 7.4-7.2 (m,
10H), 4.1-4.0 (m, 1H), 3.8-3.
7 (d, 4H), 3.2 (bs, 1H), 2.7 (d
d, 1H), 2.3-2.2 (m, 1H), 1.25
(D, 3H), 0.97 (d, 3H)

Reference Example 1 Preparation of (2S) -N, N-dibenzyl-2-amino-3-methylbutyraldehyde Dimethyl sulfoxide (7) was added to dichloromethane (150 ml) containing oxalyl chloride (7.4 g, 58.3 mmol). A dichloromethane (30 ml) solution containing 0.25 g, 92.8 mmol) was added dropwise at -78 ° C, and the mixture was stirred for 10 minutes. Then, a solution of (2S) -N, N-dibenzyl-2-amino-3-methylbutanol (12.5 g, 44.2 mmol) in dichloromethane (60 ml) prepared from L-valine by a general method was added for 30 minutes. Drop by
The mixture was further stirred for 1 hour. Triethylamine (1
7.9 g, 177 mmol) was added and the mixture was stirred at 0 ° C. for 20 minutes, water (200 ml) was added, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The filtrate is concentrated and purified by silica gel chromatography, (2S)-
N, N-dibenzyl-2-amino-3-methylbutyraldehyde (11.5 g, 40.9 mmol, yield 92)
%) Was obtained. ¹ H-NMR (CDCl ₃ ) δ; 9.8 (s, 1H),
7.4-7.2 (m, 10H), 4.0 (d, 2H),
3.7 (d, 2H), 2.7 (dd, 1H), 2.3-
2.2 (m, 1H), 1.08 (d, 3H), 0.87
(D, 3H)

Example 2 Preparation of (3S) -3-amino-4-methyl-1,1,1-trifluoromethyl-2-pentanol (3S) -N, N-dibenzyl-3-amino-4- Methyl-1,1,1-trifluoromethyl-2-pentanol (3.8 g, 10.8 mmol) was added to ethanol (20
After dissolving in 0 ml), the system was replaced with nitrogen, and Pd / C (10
% W / w, 0.68 g) was added. After replacing the system with hydrogen,
Stir vigorously under a hydrogen atmosphere. After the consumption of hydrogen ceased, Pd / C was filtered and the filtrate was concentrated. The concentrate was dissolved in 50 ml of ether and blown with hydrochloric acid gas to give (3S) -3-amino-4-methyl-1,1,1-.
Trifluoromethyl-2-pentanol hydrochloride (2.2
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ; 5.2-5.5 (b
d, 2H), 4.1-4.0 (m, 1H), 3.2 (b)
s, 1H), 2.7 (dd, 1H), 2.3-2.2
(M, 1H), 1.25 (d, 3H), 0.97 (d,
3H) Elemental analysis value (C ₆ H ₁₃ ClF ₃ NO)

[0037]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, by reacting an N-protected 2-aminoaldehyde compound derived from an amino acid with trifluoromethane iodide under electrode reaction conditions, N-protected 3 -Amino-2-hydroxy-1,1,1-trifluoromethyl compound can be prepared, so that from the amino aldehyde in which the amino group of L-valine is benzyl-protected, (3S) -3-amino-4-methyl- 1,1,1-trifluoromethyl-2-
Pentanol (Compound A) can be produced and can provide useful intermediates for pharmaceuticals.

Claims (8)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group having 1 to 30 carbon atoms, an aryl group having 6 to 35 carbon atoms, or an aralkyl group having 7 to 36 carbon atoms. P ¹ and P ² independently represent a hydrogen atom or an amino group-protecting group, or P ¹ and P ² together represent a phthaloyl group, provided that P ¹ and P ² are At the same time, a 2-aminoaldehyde compound represented by the formula (1) is hydrogen atom, and trifluoromethane iodide is reductively coupled by an electrode reaction using a consumable electrode to remove the amino-protecting group. With or without separation, the compound of the general formula (2): (In the formula, R is the same as above. P ₀ ¹ and P ₀ ² are independently,
Represents a hydrogen atom or an amino group-protecting group, or
P ₀ ¹ and P ₀ ² together represent a phthaloyl group. ) The production of a 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound, characterized by obtaining a 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound Law. 2. The method for producing a 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound according to claim 1, wherein the consumable electrode is zinc. 3. P ¹ and P ² are independently a substituted or unsubstituted linear or branched alkyl group having 1 to 30 carbon atoms or an aryl group having 6 to 35 carbon atoms. 3-amino-2-hydroxy-1, as described in Item 1 or 2,
Process for producing 1,1-trifluoromethyl compound. 4. The 3-amino-2-hydroxy-group according to claim ¹ , wherein P ¹ and P ² are both benzyl groups.
Process for producing 1,1,1-trifluoromethyl compound. 5. The method according to claim 1, wherein R is an isopropyl group.
3-amino-2-hydroxy-1, described in 2, 3 or 4.
Process for producing 1,1-trifluoromethyl compound. 6. 3-amino-2-hydroxy-1,1,
The method for producing a 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound according to claim 5, wherein the configuration at the asymmetric carbon at the 3-position of the 1-trifluoromethyl compound is S-configuration. 7. The 3-amino- according to claim 4, wherein the amino-protecting group is eliminated after the reductive coupling reaction.
Process for producing 4-methyl-1,1,1-trifluoromethyl compound. 8. The method for producing a 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound according to claim 7, wherein R is an isopropyl group.