JPH0246023B2 - 33 AMINOO2*22JIMECHIRUPUROPANOORUJUDOTAIOYOBISONOSEIZOHO - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a 3-amino-2,2-dimethylpropanol derivative and a method for producing the same. More specifically, the present invention relates to 3-(N-alkyl-N-aralkyl)amino-2,2-dimethylpropanol, its acetoacetate derivatives, and methods for producing the same.

The 3-amino-2,2-dimethylpropanol derivative provided by the present invention has physiological activity in itself and is a compound that can be used not only as a pharmaceutical but also as an intermediate for pharmaceuticals.

(Prior Art) 3-Aminopropanols not only have physiological activity in themselves, but also various pharmaceuticals that have 3-aminopropanol or the like as a side chain group and are obtained from 3-aminopropanol as a raw material are also known. (Pharmacia Review (No. 9) Chemistry Aiming for Drug Discovery, p. 124 (1982) Pharmaceutical Society of Japan) In addition, there are various types that have an N,N-dialkyl-2,2-dimethylpropanol group as a physiologically active side chain. Examples of modifications of prototype compounds are known [MS Newman et al., Journal of
Medicinal Chemistry Vol. 10, p. 1003 (1972)]. As mentioned above, 3-amino-2,2-dimethylpropanols are considered to be important in medicinal chemistry as physiologically active atomic groups. However, part 2
3-, which has two methyl groups in the positions and an amino group substituted with an alkyl group and an aralkyl group.
(N-alkyl-N-aralkyl amino)-2,
The 2-dimethylpropanol derivative and its production method are unknown in the literature and unknown.

(Object of the invention) The object of the present invention is to create a novel 3-
An object of the present invention is to provide an amino-2,2-dimethylpropanol derivative and a method for producing the same. The 3-amino-2,2-dimethylpropanols provided by the present invention are not only physiologically active compounds themselves, but also 4-phenyl-1,4- which is useful as a therapeutic agent for cardiovascular diseases. It is a compound that can also be an intermediate for dihydropyridine-3,5-dicarboxylic acid ester derivatives.

(Structure and effects of the invention) The 3-amino-2,2-dimethylpropanol derivative provided by the present invention has the following formula [] [In the formula, R ₁ is a C ₁ to C ₄ lower alkyl group, R ₂ is the same or different one or two halogen atoms, a hydroxyl group, a C ₁ to _{C 4} lower alkyloxy group, C ₁ to C ₄
a benzyl group substituted with a lower dialkylamino group or unsubstituted, or the same or different one or two halogen atoms, a hydroxyl group, a C ₁ to C ₄ lower alkyloxy group, a C ₁ to C ₄ lower dialkyl Phenethyl group substituted with amino group or unsubstituted, R ₃ is hydroxyl group or CH ₃ COCH ₂ CO ₂
- represents. ] A 3-amino-2,2-dimethylpropanol derivative or an acid addition salt thereof.

In the 3-amino-2,2-dimethylpropanol derivative or acid addition salt thereof, R ₁ is, for example,
Methyl, ethyl, n-propyl, iso-propyl,
Represents a lower alkyl group such as n-butyl, and R ₂ is
A benzyl group or a phenethyl group; a benzyl group or a phenethyl group is a halogen atom such as chlorine, bromine, iodine, or fluorine; a hydroxyl group; a C ₁ to _{C 4} lower alkyloxy group such as a methoxy group or an ethoxy group;
For example, it may have one or two substituents of a C ₁ to _{C 4} lower dialkylamino group such as a dimethylamino group, and in the case of two substituents, they may be the same or different. . 3-amino- of the present invention
The 2,2-dimethylpropanol derivative may be an acid addition salt thereof. Examples of the acid addition salt include the amino group in the 3-amino-2,2-dimethylpropanol derivative and mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid. Examples include organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Examples include salts with monovalent or divalent organic carboxylic acids such as acetic acid, fumaric acid, maleic acid and tartaric acid.

Specific examples of the 3-amino-2,2-dimethylpropanol derivative provided by the present invention include the following compounds.

3-(N-benzyl-N-methylamino)-2,
2-dimethylpropanol, 3-(N-benzyl-N-propylamino)-
2,2-dimethylpropanol, 2,2-dimethyl-3-(N-methyl-N-phenethylamino)propanol, 2,2-dimethyl-3-(N-isopropyl-N
-phenethylamino)propanol, 2,2-dimethyl-3-(N-4-nitrobenzyl-N-methylamino)propanol, 2,2-dimethyl-3-(N-2,4,6-trichlorobenzyl-N- ethylamino)-propanol, 2,2-dimethyl-3-(N-4-methoxybenzyl-N-methylamino)propanol, 2,2-dimethyl-3-(N-4-dimethylaminobenzyl-N-methylamino) ) propanol, 2,2-dimethyl-3-(N-4-acetamidophenethyl-N-methylamino)propanol, acetoacetic acid = 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl Ester, acetoacetic acid = 3-(N-benzyl-N-ethylamino)-2,2-dimethylpropyl ester, acetoacetic acid = 3-(N-4-fluorobenzyl-
N-methylamino)-2,2-dimethylpropyl ester, acetoacetic acid = 3-(N-3,5-dichlorobenzyl-N-isopropylamino)-2,2-dimethylpropyl ester, acetoacetic acid = 3-(N -3,5-dinitrophenethyl-N-methylamino)-2,2-dimethylpropyl ester, acetoacetic acid =3-(N-4-methoxycarbonylbenzyl-N-methylamino)-2,2-dimethylpropyl ester.

In the 3-amino-2,2-dimethylpropanol derivative of the present invention, R ₃ is a hydroxyl group, that is, the following formula [-a] [In the formula, R ₁ and R ₂ are the same as defined above. ] The 3-amino-2,2-dimethylpropanol derivative or its acid addition salt represented by the following formula [] [In the formula, R ₁ represents a lower alkyl group, and R ₂ represents a substituted or unsubstituted benzyl group or a substituted or unsubstituted phenethyl group. ] An amine compound represented by or its acid addition salt and the following formula [] It can be produced by reductive condensation with 3-hydroxy-2,2-dimethylpropionaldehyde represented by or a dimer thereof.

In the amine compound represented by the above formula [] or its acid addition salt, the definitions and specific examples of R ₁ and R ₂ are the same as those described in detail above.

3-hydroxy- represented by the above formula []
2,2-dimethylpropionaldehyde may be a monomer or a dimer. That is, 3
-Hydroxy-2,2-dimethylpropionaldehyde has an equilibrium relationship between the two, as shown in the reaction formula below, and the equilibrium equation can be unilaterally shifted to the right or left by treatment with heat or acid. Hans―Jiirgen Arpe: Chemiker Zeitung97
Volume 54 (1973)].

According to the invention, 3-hydroxy-2,2-dimethylpropionaldehyde can be used in the form of monomers or dimers or mixtures thereof.

Amine compound represented by the above formula [] and 3-hydroxy-2,2- represented by the above formula []
A 3-amino-2,2-dimethylpropanol derivative represented by the above formula [-a] can be produced by reductively condensing dimethylpropionaldehyde in the presence of a reducing agent. The amine compound represented by the above formula [] and a substantially equivalent amount of 3-hydroxy-2,2-dimethylpropionaldehyde of the above formula [] can be subjected to a condensation reaction. Such a condensation reaction is carried out in the presence of acids such as mineral acids such as hydrochloric acid and sulfuric acid; or organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and organic carboxylic acids such as trichloroacetic acid and trifluoroacetic acid. You can do it below. The amount of these acids can range from a catalytic amount (0.01 equivalent) to a large excess amount (10 equivalent). The condensation reaction can be carried out at a temperature of 0 to 150°C, preferably 10 to 100°C. Examples of reducing agents that can be used together during condensation include metal hydrogen complex compounds such as NaBH ₄ and NaBH ₃ CN. The 3-amino-2,2-dimethylpropanol derivative represented by the above formula [-a] produced by reductive condensation can be easily purified by conventional procedures such as extraction, distillation, recrystallization, chromatography, etc. be able to.

The 3-amino-2,2-dimethylpropanol derivative can be purified and isolated as a free base using conventional procedures, or as an acid addition salt from the reaction mixture, or after isolation and purification of the free base using conventional procedures. It can also be obtained as an acid addition salt.

According to the present invention, the 3-amino-2,2-dimethylpropanol derivative of the above formula [-a] or its acid addition salt has the following formula [] 3-Hydroxy-2,2-dimethylpropionaldehyde or its dimer represented by the following formula [] H ₂ N-R ² ... [] [In the formula, R ² is a substituted or unsubstituted benzyl group or a substituted Or it represents an unsubstituted phenethyl group. ] It can also be produced by condensing with a primary amine derivative represented by the following, followed by reduction, and alkylating the nitrogen atom.

According to the present invention, 3- expressed by the above formula []
Hydroxy-2,2-dimethylpropionaldehyde (either monomer or dimonomer) is added with a primary amine represented by the above formula [] (R ² is the same as defined above) in the presence of a solvent or The condensation reaction can be carried out at a temperature of 0° to 150°C, preferably room temperature to 120°C, in the absence of a copolymer. Although the condensation reaction proceeds without a catalyst, mineral acids such as hydrochloric acid and sulfuric acid; and organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid are allowed to coexist in an amount of 0.01 to 10 equivalents, preferably 0.1 to 5 equivalents. Preferably, 0.5 to 10 equivalents of an inorganic alkali such as caustic soda, caustic potassium, potassium carbonate, soda carbonate, etc.
It is also possible to coexist 0.8 to 5 equivalents. The condensation product is treated with a reducing agent such as NaBH ₄ , NaBH ₃ CN,
Metal hydrogen complex compounds such as LiBH ₃ CN, LiAlH ₄ ; For example, reduction with hydrogen gas in the presence of a catalytic reduction catalyst such as Pd, Pt; For example, Zn/CH ₃ CO ₂ H, Li/liquid ammonia, Na/liquid It can be reduced with metals such as ammonia. Reducing agents are e.g.
A reductive condensation reaction can also be carried out by allowing a metal hydrogen complex compound such as NaBH ₄ or NaBH ₃ CN to coexist during the condensation reaction. The reduced compound and e.g. R ₁ −
Nitrogen atoms can be alkylated by reacting with alkyl halides such as Cl, R ₁ -Br, R ₁ I, or the reduced compound can be reacted with HCHO or (HCHO)n, CH ₃ CHO, CH ₃ CH ₂ CHO and
Nitrogen atoms can also be alkylated in the coexistence of reducing substances such as HCO ₂ H, Zn/CH ₃ CO ₂ H, etc. All of these reaction operations and reaction conditions can be selected from conventionally known methods.

In the 3-amino-2,2-dimethylpropanol derivative of the present invention, R ₃ is CH ₃ COCH ₂ CO ₂ -, that is, the above formula [-b] [In the formula, R ₁ and R ₂ are the same as defined above. ] The compound represented by the following formula [] is added to the 3-amino-2,2-dimethylpropanol derivative represented by the above formula [-a] or its acid addition salt. It can be produced by reacting the diketene represented by

3-amino- represented by the above formula [-a]
A 2,2-dimethylpropanol derivative or its acid addition salt and diketene are mixed without a solvent or in the presence of an aprotic organic solvent such as benzene, toluene, dichloroethane, carbon tetrachloride, dioxane, THF, etc.
The ester derivative of acetoacetic acid represented by the above formula [-b] can be produced by carrying out the reaction under heating at 30 to 150°C, preferably 50 to 120°C. According to the present invention, the reaction conditions are determined from the conventionally known literature [Organic Synthesis; Vol. 42, p. 28; Iwanami et al.
al: Chem.Pharm.Bull.Volume 27, page 1426 (1979), etc.]
can be selected from within the range of reaction conditions.

3-Amino-2,2-dimethylpropyl ester of acetoacetic acid provided by the present invention [-
b] using the Hantzsch reaction, the corresponding 4-phenyl-1, which is useful as a therapeutic drug for cardiovascular system diseases.
It can be easily converted into a 3-amino-2,2-dimethylpropyl ester derivative of 4-dihydropyridine-3,5-dicarboxylic acid.

According to the present invention, the 3-amino-2,2-dimethylpropanol derivative of the above formula [-a] has the following formula [] [In the formula, R ₁ and R ₂ are the same as defined above. ] It can also be produced by reducing 3-amino-2,2-dimethylpropionaldehyde represented by:

3-Amino-2,2-dimethylpropionaldehyde of the above formula [] can be produced by a known method [JAFaust: Journal of American
Chemical Society Vol. 81, p. 2214 (1959)]. As the reducing agent that can be used in this production method, for example, metal hydrogen complex compounds such as NaBH ₄ , NaBH ₃ CN, LiAlH ₄ , etc. are preferably used. The reaction conditions are
-20° to 100°C, preferably -10° to 80°C,
The reaction can be carried out by a conventional method used for reactions of metal hydrogen complex compounds. Isolation and purification are carried out using conventional methods such as extraction, recrystallization, distillation,
A chromatography method or the like can be used.

The 3-amino-2,2-dimethylpropanol derivative produced by the production method detailed above can be used with other useful compounds, such as 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivatives. It is a compound that can be converted and is also useful as a compound that itself has pharmacological activity.

The present invention will be explained in more detail below with reference to Examples.

Example 1 N-methylbenzylamino hydrochloride (27.2 g) was added to isopropanol (78 ml), followed by isobutyraldehyde (12.4 g) and paraformaldehyde (11.4 g), and the mixture was heated under reflux for 6 hours. The solvent was removed from the reaction mixture under reduced pressure (20 mmHg, about 30°C) to obtain a residue. The residue was dissolved in CH ₃ OH (200 ml), and NaBH ₄ (12 g) was added little by little while stirring under ice cooling. The mixture was returned to room temperature and stirred for 3 hours. CH ₃ OH was distilled off from the reaction mixture, and 20%
After adding NaOH aqueous solution (40ml), extract with _Et2O ,
The Et ₂ O layer was separated, washed with water, dried, and the solvent was removed.
The resulting residue was distilled under reduced pressure.

Collect the fraction with a boiling point of 122-124° (2 mmHg),
-(N-benzyl-N-methylamino)-2,2
-26.6g (75.6%) of dimethylpropanol was obtained.

The physical property values are as follows: NMR (CDCl ₃ ) δppm: 7.2 (s, 5H), 5.65 (bs,
1H) 3.48 (s, 2H), 3.38 (s, 2H), 2.42
(s, 2H), 2.18 (s, 3H), 0.93 (s, 6H), IR υcm ^-1 _nax (Neat): 3400, 2980, 1450, 1360,
1040 MS (m/e): 207 (M ⁺ ) Hydrochloride mp 143-145℃ Example 2 3-Hydroxy-2,2-dimethylpropionaldehyde dimer (1.02 g) and N-methylbenzylamine 1.21 g were anhydrous. In addition to methanol (20ml), add p-toluenesulfonic acid (600mg) under ice cooling.
was added followed by NaBH ₃ CN (950 mg).
Stir overnight at room temperature. The solvent was distilled off under reduced pressure, 20% NaOH (5 ml) was added to the residue, and the mixture was extracted with CH ₂ Cl ₂ .
After separating the _two CH ₂ Cl layers, washing with water and drying, the solvent was removed, and the resulting colorless oil was subjected to silica gel chromatography to obtain 3-(N-benzyl-N-methylamino)-2, 2-dimethylpropanol (930 mg, 45%) was obtained. The physical properties of this product were the same as those of Example 1.

Example 3 3-Hydroxy-2,2-dimethylpropionaldehyde (monomer) (1.02 g) and benzylamine (1.07 g) were added to 10 ml of anhydrous CH ₃ OH.
Next, the reaction solution was cooled on ice and added with NaBH ₃ CN (471 mg).
-Toluenesulfonic acid (873mg) was added and stirred for 30 minutes. The mixture was returned to room temperature and stirred for 12 hours. The solvent was distilled off, 5 ml of 20% NaOH aqueous solution was added to the residue, and extracted with ether. The ether layer was separated, washed with water, dried, and the solvent was distilled off. Residue [NMR, δppm
(CDCl ₃ ): 7.2 (S, 5H), 3.81 (S, 2H), 3.48
(S, 2H), 2.50 (S, 2H), 1.8 (BS, 1H), 0.99
(S,6H)] (1.7 g) was obtained. 30% on residue
HCHO (2 ml) and HCO ₂ H (90%) (1.27 g) were added, and the mixture was heated under reflux (bath temperature: 120°C) for 2 hours. The low boiling point fraction is removed under reduced pressure, the residue is distilled under reduced pressure, and the fraction with a boiling point of 122-124° (2 mmHg) is collected.
(N-benzyl-N-methylamino)-2,2-
1.44 g (70%) of dimethylpropanol was obtained. The physical properties were the same as in Example 1.

Example 4 3-Hydroxy-2,2-dimethylpropionaldehyde (0.51 g) was dissolved in dry benzene,
Benzylamine was then added. The condensation reaction was accompanied by an exothermic reaction. Benzene was distilled off at normal pressure, anhydrous CH ₃ OH (5 ml) was added to the residue, and then
NaBH ₃ CN (314 mg) and 1.8N-HCl/CH ₃ OH 3.6 ml
The mixture was added and stirred at room temperature for 48 hours. The solvent was distilled off, 20% NaOH aqueous solution (5 ml) was added to the residue, and the mixture was extracted with ether. The ether layer was separated, washed with water, dried, the ether was distilled off, 30% formalin (1 ml) and HCO ₂ H (0.7 ml) were added to the residue, and the mixture was heated at a bath temperature of 120°C.
After heating under reflux for 1.5 hours, the low boiling point fraction was removed under reduced pressure. The residue was distilled to give 3-(N-benzyl-
0.6 g of N-methylamino)-2,2-dimethylpropanol was obtained. The physical properties were the same as in Example 1.

Example 5 2,2-dimethyl-3-(N-benzyl-N-
methylamino)-2,2-dimethylpropanol
2.07g was dissolved in 1ml of benzene and heated to 70°C. 1.0 g of diketene was slowly added dropwise to this solution. After stirring for 1.5 hours, the solvent was distilled off, the residue was subjected to silica gel chromatography, and the hexane-ethyl acetate elution fraction was concentrated to obtain the desired acetoacetic acid-[2,2-dimethyl-3-(N-) Benzyl-N
-Methylamino)-2,2-dimethylpropyl]
2.8 g of ester (oil) was obtained.

Physical properties NMR (CDCl ₃ ) δppm: 7.35 (s, 5H), 3.95
(s, 2H), 3.57 (s, 2H), 3.38 (s, 2H),
2.28 (s, 2H), 2.18 (s, 3H), 2.15 (s,
3H), 0.89 (s, 6H), IR υcm ^-1 max (Neat) 3000, 1720, 1640, 1450,
1360, 1310, 1250, 1150, 1030 MS (m/e): 291 (M ⁺ ) Reference example 3-chloro-2-nitrobenzaldehyde 185
mg, 118 mg of methyl 3-aminocrotonate, and acetoacetic acid obtained in Example 5 -[2,2-dimethyl-
292 mg of 3-(N-benzyl-N-methylamino)propyl]ester was dissolved in 1 ml of isopropanol and heated under reflux in the dark for 12 hours. The solvent was distilled off and the residue was subjected to silica gel chromatography to obtain 2,6-dimethyl-4-(3'-
Chlor-2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[(2,2-dimethyl-3-(N
-benzyl-N-methylamino)propyl] ester was collected.

Physical properties NMR (CDCl ₃ ) δppm: 7.4 to 7.0 (brs, 8H),
6.15 (brs, 1H), 5.28 (s, 1H), 3.92 (s,
2H), 3.60 (s, 3H), 3.41 (s, 2H), 2.21
(s, 8H), 2.04 (s, 3H), 0.80 (s, 6H) Hydrochloride IR (KBr) υcm ^-1 max: 3400, 1684, 1536,
1480 mp182―187゜

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ₁ is a C ₁ to C ₄ lower alkyl group, R ₂ is the same or different one or two halogen atoms, a hydroxyl group, a C ₁ to _{C 4} lower alkyloxy group, C ₁ to C ₄
a benzyl group substituted with a lower dialkylamino group or unsubstituted, or the same or different one or two halogen atoms, a hydroxyl group, a C ₁ to C ₄ lower alkyloxy group, a C ₁ to C ₄ lower dialkyl Phenethyl group substituted with amino group or unsubstituted, R ₃ is hydroxyl group or CH ₃ COCH ₂ CO ₂
- represents. ] A 3-amino-2,2-dimethylpropanol derivative or an acid addition salt thereof. 2 The following formula [] [In the formula, R ₁ is a C ₁ to C ₄ lower alkyl group, R ₂
are the same or different and are one or two halogen atoms,
Hydroxyl group, C1 _{- C4} lower alkyloxy group, C1 _- C4
C ₄ lower dialkylamino group substituted or unsubstituted benzyl group or the same or different 1 or 2 halogen atoms, hydroxyl group, C ₁ -
It represents a phenethyl group substituted with a C ₄ lower alkyloxy group or a C ₁ to _{C 4} lower dialkylamino group or unsubstituted. ] An amine compound or its acid addition salt represented by the following formula [] 3-hydroxy-2,2-dimethylpropionaldehyde or its dimer represented by the following formula [
-a] [In the formula, R ₁ and R ₂ are the same as defined above. ] A method for producing a 3-amino-2,2-dimethylpropanol derivative or an acid addition salt thereof. 3 The following formula [] 3-Hydroxy-2,2-dimethylpropionaldehyde represented by the following formula [] H ₂ N-R ² ... [] [wherein R ² is the same or different and represents one or two halogen atoms, a hydroxyl group, C ₁ to _C4 lower alkyloxy group, _C1 to _C4 lower dialkylamino group substituted or unsubstituted benzyl group, or the same or different 1 or 2 halogen atoms,
Hydroxyl group, C1 _{- C4} lower alkyloxy group, C1 _- C4
Represents a phenethyl group substituted with a C ₄ lower dialkylamino group or unsubstituted. ] The following formula [-a], which is characterized by condensing with a primary amine derivative represented by and then reducing, and alkylating the nitrogen atom [In the formula, R ₁ and R ₂ are the same as defined above. ] A method for producing a 3-amino-2,2-dimethylpropanol derivative or an acid addition salt thereof. 4 The following formula [-a] [In the formula, R ₁ and R ₂ are the same as defined above. ] The 3-amino-2,2-dimethylpropanol derivative or its acid addition salt represented by the following formula [] The following formula [-b] characterized by reacting diketene represented by [In the formula, R ₁ and R ₂ are the same as defined above. ] A method for producing a 3-amino-2,2-dimethylpropanol derivative or an acid addition salt thereof. 5 The following formula [] [In the formula, R ₁ and R ₂ are the same as defined above. ] The following formula [-a] is characterized by reducing 3-amino-2,2-dimethylpropionaldehyde represented by [In the formula, R ₁ and R ₂ are the same as defined above. ] A method for producing a 3-amino-2,2-dimethylpropanol derivative or an acid addition salt thereof.