CN101693690A - N,N-substituent-1-(1H-pyrazole-3-yl) methylamine and preparation method thereof - Google Patents

Abstract

The invention relates to a method for preparing N,N-substituent-1-(1H-pyrazole-3-yl) methylamine, which is realized in a way that: in the presence of a reducing agent, a compound V disclosed in the specification reacts in an organic solvent to obtain a compound disclosed as a formula A. The method is safe and simple, and is suitable for large-scale production. R1, R2 and R3 are substituent groups.

Description

N, N-substituted-1-(1H-pyrazol-3-yl)methanamine and its preparation method

technical field

The present invention relates to N, N-substituted-1-(1H-pyrazol-3-yl)methanamines, their intermediates and their synthesis methods.

Background technique

N,N-substituted-1-(1H-pyrazol-3-yl)methanamine (such as formula A) is an intermediate of some anti-HIV drugs and anti-inflammatory drugs (US2002383509).

The preparation method of N, N-substituted-1-(1H-pyrazol-3-yl)methanamine derivatives can be seen in US 2004186292; WO2006026305; Tetrahedron, 64(33), 7745, 2008; Synthetic Communications, 25(5), 761, 1995; Journal of the Chemical Society, Chemical Communications, (13), 528, 1975, etc.

Among the methods of N,N-substituted-1-(1H-pyrazol-3-yl)methanamine, the method of patent US2004186292 is widely used. In the method, substituted alkyne is used as a raw material, and a substituent diazomethane is cyclo-added, and one-step reaction is performed to obtain N, N-substituted-1-(1H-pyrazol-3-yl)methanamine. However, there are raw materials that are not easy to get, and the diazomethane that the required raw materials replace has high toxicity, is explosive, and is not easy to operate, which restricts this method in the large-scale preparation of N, N-substituted-1-(1H-pyrazol-3-yl) Application on methylamine.

Reaction 1

At the same time, the patent US2004186292 also provides a method for synthesizing 3-substituted pyrazoles with readily available raw materials. The method takes methyl ketone and 1,1-dimethoxy-N,N-dimethylmethylamine as raw materials, and reacts in DMF to obtain 3-(dimethylamino)-2-ene-1 substituted-ketone , and further react with hydrazine hydrate to obtain 3-substituted-pyrazole derivatives. However, there are rare raw materials, and this patent does not use this method to prepare N, N-substituted-1-(1H-pyrazol-3-yl)methylamine.

Reaction 2

In addition, this patent also provides a third method for preparing 3-substituted-pyrazole derivatives, which also has the problem of scarce raw materials.

Reaction 3

Contents of the invention

Technical problem: The purpose of this invention is to provide N, N-substituted-1-(1H-pyrazol-3-yl)methanamine and its preparation method, to find mild conditions, safe and simple, suitable for large-scale preparation of N, N-substituted- The synthetic route of 1-(1H-pyrazol-3-yl)methanamine, to overcome the above-mentioned defect that exists in prior art route.

Technical solution: the present invention provides a compound represented by formula A,

Wherein R ₁ , R ₂ and R ₃ are substituents, specifically, R ₁ is hydrogen, methyl, ethyl, isopropyl; R ₂ and R ₃ can be the same or different and represent methyl respectively (R ₂ ≠ R ₃ ), ethyl, propyl.

The compound shown in the formula A is obtained by the following reaction: in the presence of a reducing agent, the compound shown in the formula V is reduced in an organic solvent, R ₁ , R ₂ and R ₃ are as defined above,

The reducing agent is sodium borohydride, zinc borohydride, potassium borohydride or potassium tri-sec-butyl borohydride tetrahydrofuran solution.

Described organic solvent is methanol, ethanol, isopropanol organic solvent, and the mixture of above-mentioned organic solvent.

The reaction temperature is 25-30°C.

The compound shown in the formula V described in the above reaction is obtained by the following reaction: the addition reaction of the compound shown in the formula IV and an amine in an organic solvent, R ₁ , R ₂ and R ₃ are as defined above,

The organic solvent is methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol, 3-pentanol or any mixture of the above-mentioned various organic solvents.

The reaction temperature of the addition reaction is 20°C-40°C.

The compound shown in the formula IV described in the above reaction is obtained by the following reaction: the compound shown in the formula III reacts with an acid in water, R ₁ , R ₂ and R ₃ are as defined above,

The acid is one of formic acid, acetic acid, hydrochloric acid, phosphoric acid or a mixture thereof in any ratio.

The reaction temperature of the reaction is 20°C-25°C.

The compound shown in formula III described in the above reaction is obtained by reacting compound II and compound D in an organic solvent, R ₁ , R ₂ and R ₃ are as defined above,

Wherein R ₄ and R ₅ are substituents, specifically, they may be the same or different and represent methyl (R ₄ ≠ R ₅ ), ethyl, and propyl respectively.

The organic solvent is methanol, ethanol, isopropanol organic solvents, and any mixture of the above organic solvents.

The reaction temperature of the reaction is 20°C-40°C.

The compound represented by formula II in the above reaction is obtained by reacting compound B and compound C, R ₁ , R ₂ , R ₃ R ₄ and R ₅ are as defined above,

The reaction temperature of the reaction is 80°C-100°C.

Beneficial effects: the present invention uses compounds B and C as raw materials, undergoes condensation, nucleophilic addition and its reverse reaction to obtain compound IV, and the nucleophilic addition reaction of IV and amine, after the reducing agent is reduced, a total of five steps of reaction to obtain N, N-substituted-1-(1H-pyrazol-3-yl)methanamine.

The present invention is a brand-new synthesis route of N, N-substituted-1-(1H-pyrazol-3-yl)methanamine, through condensation, nucleophilic addition and its reverse reaction, nucleophilic addition reaction, reduction, a total of five steps The reaction route is short, the raw materials are readily available, and the operation is simple.

Detailed ways

The present invention will be further described below in conjunction with specific examples, but the present invention is not limited.

In the following preparation examples, NMR is measured by Bruker AMX-400 and INVOA-600 NMR instruments, TMS is the internal standard, and the chemical shift unit is ppm; silica gel 200-300 mesh is used for column chromatography, produced by Qingdao Ocean Chemical Factory ; The TLC silica gel plate is HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Factory; the boiling range of petroleum ether is 60-90°C; the color is developed by using ultraviolet lamp and iodine tank. If the operation method is not specified in the preparation examples, the concentration refers to evaporating the solvent in the solution of the prepared compound with a rotary evaporator; the drying refers to drying the prepared compound with a DHG-9240A constant temperature drying oven at 60°C.

The preparation of embodiment 14-(dimethylamino)-1,1-dimethoxybutyl-3-ene-2-one (formula II)

Mix 1,2-propanediketal (130g, 1.1mol) and 1,1-dimethoxy-N,N-dimethylmethylamine (134g, 1.1mol) and react at 100°C for 2h. After cooling, it was concentrated to give 4-(dimethylamino)-1,1-dimethoxybutyl-3-en-2-one (II) (144 g, 76%) as a red oil. ¹ H NMR (CDCl ₃ , 300 MHz), 3.1 (d, 6H), 3.4 (s, 6H), 4.56 (s, 1H), 5.34 (d, 1H), 7.74 (d, 1H).

The preparation of embodiment 23-(dimethoxymethyl)-1H-pyrazole (formula III)

Add II (144g, 0.83mol) to hydrazine hydrate (83.2g, 1.66mol) and react at room temperature for 24h. Washed with saturated brine (50ml×3), extracted with ethyl acetate (40ml×3), dried over anhydrous sodium sulfate, concentrated to obtain 3-(dimethoxymethyl)-1H-pyrazole ( III) (113 g, 95%). ¹ H NMR (CDCl ₃ , 300 MHz), δ 7.58 (1H, d), 6.34 (1H, d), 5.62 (1H, s), 3.37 (6H, s).

The preparation of embodiment 31H-pyrazole-3-formaldehyde (formula IV)

Mix III (116g, 0.83mol), acetic acid (25g, 0.41mol) and water (100ml) and react at room temperature for 48h. Filter and dry to obtain the dimer of 1H-pyrazole-3-carbaldehyde as a yellow solid, add the dimer to pyrimidine (200ml) heated to 50°C and stir until completely dissolved to obtain 1H-pyrazole-3-carbaldehyde monomer solution (IV) (68 g, 87%). ¹ H NMR (Pyridine-d ₆ , 300 MHz), δ 10.38 (1H, t), 7.95 (1H, dd), 7.06 (1H, d).

The preparation of embodiment 41H-pyrazole-3-formaldehyde (formula IV)

Mix III (116g, 0.83mol), formic acid (19g, 0.41mol) and water (100ml) and react at room temperature for 24h. 1H-Pyrazole-3-carbaldehyde (IV) (67 g, 85%) was obtained by filtration and dried as a yellow solid.

The preparation of embodiment 51H-pyrazole-3-formaldehyde (formula IV)

Mix III (116g, 0.83mol), hydrochloric acid (40ml) and water (100ml) and react at room temperature for 24h. 1H-Pyrazole-3-carbaldehyde (IV) (50 g, 63%) was obtained by filtration and dried as a yellow solid.

The preparation of embodiment 6N-((1H-pyrazol-3-yl) methylene) methylene methylamine (formula V)

Dissolve IV (68g, 0.7mol) in methylamine ethanol solution (100ml), stir at room temperature for 48h, and concentrate under reduced pressure to obtain N-((1H-pyrazol-3-yl)methylene) as a yellow semisolid Methylenemethylamine (V) (53 g, 69%).

The preparation of embodiment 7N-methyl-1-(1H-pyrazol-3-yl)methanamine (formula A)

Dissolve V (76g, 0.7mol) in ethanol (100ml), slowly add sodium borohydride (54g, 1.4mol) under ice bath, remove the ice bath after addition, stir at room temperature for 15h, concentrate to obtain N-methyl- 1-(1H-pyrazol-3-yl)methanamine (A) (51 g, 68%). ¹ H NMR (CDCl ₃ , 300 MHz), δ 7.52 (1H, d), 6.14 (1H, d), 3.75 (2H, s), 3.5 (3H, s).

The preparation of embodiment 8N-methyl-1-(1H-pyrazol-3-yl)methanamine (formula A)

Dissolve IV (68g, 0.7mol) in methylamine ethanol solution (100ml), slowly add sodium borohydride (54g, 1.4mol) under ice bath, remove the ice bath after addition, stir at room temperature for 15h, concentrate to obtain N- Methyl-1-(1H-pyrazol-3-yl)methanamine (A) (52 g, 70%).

The preparation of embodiment 9N-methyl-1-(1H-pyrazol-3-yl)methanamine (formula A)

Dissolve IV (68g, 0.7mol) in methylamine ethanol solution (100ml), slowly add potassium borohydride (76g, 1.4mol) under ice bath, remove the ice bath after addition, stir at room temperature for 15h, and concentrate to obtain N- Methyl-1-(1H-pyrazol-3-yl)methanamine (A) (55 g, 73%).

The preparation of embodiment 10N-((1H-pyrazol-3-yl) methyl)-N-methylethylamine (formula A)

Dissolve IV (68g, 0.7mol) in isopropylamine (72ml, 0.84mol) ethanol solution (100ml), slowly add sodium borohydride (54g, 1.4mol) under ice bath, remove the ice bath after addition, and stir at room temperature for 15h , concentrated to give N-((1H-pyrazol-3-yl)methyl)-N-methylethylamine (A) (65 g, 67%). ¹ H NMR (CDCl ₃ , 300MHz), δ7.39(1H,d), 6.27(1H,d), 3.69(2H,s), 2.32(2H,m), 2.27(3H,s), 1.56(3H , s).

Claims (10)

1. A N, N-substituted-1-(1H-pyrazol-3-yl)methanamine, characterized in that the N,N-substituted-1-(1H-pyrazol-3-yl)methanamine is Compound shown in formula A,

_R is hydrogen, methyl, ethyl or isopropyl; R ₂ is methyl R ₂ ≠ R ₃ and R ₃ ≠ H, ethyl or isopropyl; R ₃ is methyl R ₂ ≠ R ₃ and R ₂ ≠ H, ethyl or isopropyl. 2. a kind of N as claimed in claim 1, the preparation method of N-substituted-1-(1H-pyrazol-3-yl)methanamine is characterized in that, described formula A compound is the compound shown in formula V In the presence of a reducing agent, in an organic solvent, the reaction temperature is 25°C-30°C. 3. according to claim 2, the preparation method of N, N-substituted-1-(1H-pyrazol-3-yl) methylamine is characterized in that, described reducing agent is sodium borohydride, zinc borohydride, Potassium borohydride or potassium tri-sec-butyl borohydride tetrahydrofuran solution; the organic solvent is methanol, ethanol, isopropanol organic solvent or a mixture of the above organic solvents. 4. according to claim 2 or 3 described N, the preparation method of N-substituted-1-(1H-pyrazol-3-yl)methanamine, is characterized in that, the compound shown in described formula V, is by formula The compound shown in IV and amine are prepared by reacting in an organic solvent at a reaction temperature of 20°C-40°C,

5. according to claim 4, the preparation method of N, N-substituted-1-(1H-pyrazol-3-yl) methylamine is characterized in that, described organic solvent is methanol, ethanol, propanol, iso Propanol, butanol, sec-butanol, tert-butanol, 1-pentanol or 3-pentanol, or a mixture of the above-mentioned various organic solvents. 6. according to claim 4 or 5 described N, the preparation method of N-substituted-1-(1H-pyrazol-3-yl)methanamine, is characterized in that, the compound N shown in described formula IV, N- Substituted-1-(1H-pyrazol-3-yl)methylenemethanamine is obtained by reacting the compound represented by formula III in acid at a reaction temperature of 20°C-40°C,

7. according to claim 6, the preparation method of N, N-substituted-1-(1H-pyrazol-3-yl)methanamine is characterized in that said acid is one of formic acid, acetic acid, hydrochloric acid or phosphoric acid species or any mixture thereof. 8. according to the preparation method of the 1-substituted-1H-pyrazole-3-carbaldehyde described in claim 6 or 7, it is characterized in that, compound 3-(alkoxy substituent methyl)- 1-substituent-1H-pyrazole, obtained by addition reaction of the compound shown in formula II in a mixed solution of water and organic solvent at a reaction temperature of 20°C-40°C,

9. according to claim 8, the preparation method of N, N-substituted-1-(1H-pyrazol-3-yl) methylamine is characterized in that described organic solvent is methyl alcohol, ethanol or isopropanol organic solvent, and any ratio mixture of the above-mentioned organic solvents. 10. according to claim 8 or 9 described N, the preparation method of N-substituted-1-(1H-pyrazol-3-yl)methanamine, is characterized in that, compound 3-(alkane) shown in the formula II Oxygen substituent methyl)-1-substituent-1H-pyrazole is obtained by reacting compound B and compound C at a reaction temperature of 80°C-100°C,