Synthesis method of 6-(piperazine-1-yl)-2-naphthaldehyde

Abstract

The invention relates to the field of chemical synthesis, and discloses a synthesis method of 6-(piperazine-1-yl)-2-naphthaldehyde, which comprises the following steps: (1) dissolving 6-bromo-2-naphthaldehyde in an organic solvent, adding N-BOC-piperazine, a palladium catalyst, a phosphine ligand and alkali in an inert atmosphere, heating to perform a coupling reaction, and performing post-treatment to obtain a compound A; (2) in an inert atmosphere, carrying out BOC protecting group removal reaction on the compound A under the condition of an acid solution, filtering, washing and drying to obtain a compound B; and (3) dissolving the compound B in water, adding a saturated sodium bicarbonate solution to adjust the pH value to 7-8, separating out a precipitate, filtering and drying to obtain a target compound. The preparation method provided by the invention is simple in operation steps, high in product yield, safe and efficient.

Description

Technical Field

[0001] The present application relates to the field of chemical synthesis, and more specifically to a method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde. Background Art

[0002] 6-(piperazine-1-yl)-2-naphthaldehyde is an important organic intermediate, which is widely used in drug synthesis and material science. It has a wide range of application prospects in many fields such as medicine, pesticides and material science. However, the existing methods for preparing 6-(piperazine-1-yl)-2-naphthaldehyde have many shortcomings.

[0003] Patent CN103214358A discloses a method for synthesizing 6-hydroxy-2-naphthaldehyde, which uses cheap and readily available ethyl naphthol as a raw material and undergoes bromination, reduction, methylation, Grignard reaction, demethylation and other reactions to obtain 6-hydroxy-2-naphthaldehyde. The method has complicated reaction steps and requires a multi-step complex reaction process, which not only increases the difficulty of operation, but also easily leads to a decrease in the yield of the product, while introducing more impurities, increasing the cost and difficulty of subsequent separation and purification.

[0004] Therefore, it is of great practical significance to develop a method for preparing 6-(piperazine-1-yl)-2-naphthaldehyde with simple reaction steps, safety, high efficiency, low cost and suitable for industrial production. Summary of the invention

[0005] In order to solve the problems in the prior art, the present invention aims to provide a method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde. The preparation method provided by the present invention has simple operation steps, is safe and efficient, has low cost and is suitable for industrial production.

[0006] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0007] The present invention provides a method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde, and the preparation method comprises the following steps:

[0008] (1) dissolving 6-bromo-2-naphthaldehyde in an organic solvent, adding N-BOC-piperazine, a palladium catalyst, a phosphine ligand and a base under an inert atmosphere, heating to carry out a coupling reaction, and post-treating to obtain compound A;

[0009] (2) Under an inert atmosphere, compound A is subjected to a BOC protecting group removal reaction in an acidic solution, and then filtered, washed, and dried to obtain compound B;

[0010] (3) Compound B was dissolved in water, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, a precipitate was precipitated, and the precipitate was filtered and dried to obtain the target compound.

[0011] As a preferred technical solution, in step (1), the organic solvent is any one of toluene, xylene or 1,4-dioxane or a combination of at least two thereof, and the mass volume ratio of 6-bromo-2-naphthaldehyde to the organic solvent is 1 g:8 to 12 mL.

[0012] As a preferred technical solution, in step (1), the organic solvent is toluene.

[0013] As a preferred technical solution, the molar ratio of 6-bromo-2-naphthaldehyde to N-BOC-piperazine in step (1) is 1:(1.1-1.3).

[0014] The applicant has found that when the molar ratio of 6-bromo-2-naphthaldehyde to N-BOC-piperazine is 1:(1.1-1.3), the two can fully contact and react, and the reaction rate is in a relatively ideal state. When 6-bromo-2-naphthaldehyde is excessive, side reactions such as self-coupling may occur, generating other impurities and reducing the purity of the target product; when N-BOC-piperazine is excessive, some unnecessary side reactions may also occur, such as reacting with other substances in the reaction system, or generating some multi-substituted products, which will reduce the purity of the product.

[0015] As a preferred technical solution, the palladium catalyst in step (1) is any one of palladium acetate, palladium chloride or tetrakistriphenylphosphine palladium, or a combination of at least two thereof, and the phosphine ligand is any one of BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine), Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene) or DPPF (1,1'-bis(diphenylphosphino)ferrocene), or a combination of at least two thereof.

[0016] As a preferred technical solution, the palladium catalyst in step (1) is palladium acetate, and the phosphine ligand is BINAP.

[0017] As a preferred technical solution, the molar ratio of 6-bromo-2-naphthaldehyde, palladium catalyst and phosphine ligand in step (1) is 1: (0.05-0.15): (0.2-0.4).

[0018] As a preferred technical solution, the molar ratio of 6-bromo-2-naphthaldehyde, palladium acetate and BINAP in step (1) is 1: (0.08-0.12): (0.25-0.35).

[0019] Palladium acetate is a catalyst for the reaction, and its dosage will affect the reaction rate and activity. BINAP, as a ligand, complexes with palladium acetate to enhance the catalytic activity of palladium. The applicant has found through a large number of experiments that when the molar ratio of 6-bromo-2-naphthaldehyde, palladium acetate, and BINAP is 1: (0.08-0.12): (0.25-0.35), the palladium catalyst-ligand complex is in the best active state, promoting the efficient coupling reaction of 6-bromo-2-naphthaldehyde and N-Boc-piperazine. The possible reason is that the two phosphine atoms of BINAP can effectively coordinate with the palladium atom in the center of palladium acetate to form a stable and highly active complex. This complex can better activate the substrate molecules and promote the reaction. If the ratio is not appropriate, it may not be possible to form an ideal catalytically active species, resulting in reduced catalyst activity and a slowed reaction rate.

[0020] As a preferred technical solution, the base in step (1) is any one of cesium carbonate, potassium carbonate or potassium phosphate, or a combination of at least two thereof, and the molar ratio of 6-bromo-2-naphthaldehyde to the base is 1:(1.5-2.5).

[0021] As a preferred technical solution, the base in step (1) is cesium carbonate.

[0022] As a preferred technical solution, the molar ratio of 6-bromo-2-naphthaldehyde to cesium carbonate in step (1) is 1:(1.8-2.2).

[0023] As a preferred technical solution, the heating temperature in step (1) is 100-120° C., and the reaction time is 11-13 h.

[0024] As a preferred technical solution, the acidic solution in step (2) is an ethyl acetate solution of hydrogen chloride, a dichloromethane solution of trifluoroacetic acid or a methanol solution of sulfuric acid, the reaction temperature is room temperature, the reaction time is 11 to 13 hours, and the mass volume ratio of compound A to the acidic solution is 1 g: 8 to 12 mL.

[0025] As a preferred technical solution, the acidic solution in step (2) is a solution of hydrogen chloride in ethyl acetate.

[0026] As a preferred technical solution, the inert atmosphere is any one of nitrogen, argon or helium, or a combination of at least two of them.

[0027] As a preferred technical solution, the inert atmosphere is nitrogen.

[0028] As a preferred technical solution, the post-treatment step in step (1) comprises: after the reaction is completed, the reaction solution is filtered through diatomaceous earth, ethyl acetate-water solution is added for extraction, the organic phases are combined, washed and dried to obtain a crude product; the crude product is chromatographed on a silica gel column and eluted to obtain compound A.

[0029] In the present invention, in step (1), LCMS is used to monitor the amount of 6-bromo-2-naphthaldehyde in the reaction system. When 6-bromo-2-naphthaldehyde cannot be detected, the reaction is completed.

[0030] Beneficial Effects

[0031] 1. The present invention synthesizes 6-(piperazine-1-yl)-2-naphthaldehyde through three main reactions of coupling reaction, BOC protecting group removal reaction and neutralization reaction. In the reaction process, no expensive and difficult to recover special catalyst is used, thereby reducing production costs and improving yield.

[0032] 2. The reaction conditions of the present invention are mild and only need to be carried out under conventional heating, room temperature and other conditions. The requirements for reaction equipment are not high and no special high-temperature and high-pressure equipment is required. The present invention is safe and reliable and is conducive to the implementation of large-scale industrial production.

[0033] 3. The present invention controls the molar ratio of 6-bromo-2-naphthaldehyde, palladium acetate and BINAP to be 1:(0.08-0.12):(0.25-0.35), so that the palladium catalyst-ligand complex is in an optimal active state, promotes the efficient coupling reaction of 6-bromo-2-naphthaldehyde and N-Boc-piperazine, and greatly improves the yield of 6-bromo-2-naphthaldehyde. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is a reaction equation diagram of Example 1 of the present application;

[0035] Figure 2 The hydrogen nuclear magnetic resonance spectrum of compound A obtained in step (1) of Example 1 of the present application;

[0036] Figure 3 The hydrogen nuclear magnetic resonance spectrum of compound B obtained in step (2) of Example 1 of the present application;

[0037] Figure 4 The hydrogen nuclear magnetic resonance spectrum of 6-(piperazine-1-yl)-2-naphthaldehyde obtained in step (3) of Example 1 of the present application;

[0038] Figure 5 This is the HPLC detection chart of 6-(piperazine-1-yl)-2-naphthaldehyde obtained in step (3) of Example 1 of the present application;

[0039] Figure 6This is the hydrogen nuclear magnetic resonance spectrum of the debrominated molecule 2-naphthaldehyde obtained in Comparative Example 1 of the present application. DETAILED DESCRIPTION

[0040] The experimental methods in the following examples of the present invention, where no specific conditions are specified, are usually carried out under conventional conditions or under conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0041] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] Example 1

[0043] This embodiment specifically provides a synthesis method and preparation method of 6-(piperazine-1-yl)-2-naphthaldehyde, and the materials involved in the preparation method are shown in Table 1:

[0044] Table 1

[0045]

[0046]

[0047] The specific steps are as follows:

[0048] (1) 10 g of 6-bromo-2-naphthaldehyde was added to a 250 mL three-necked flask, 100 mL of toluene was added to dissolve, 9.51 g of N-BOC-piperazine, 27.72 g of cesium carbonate, 0.96 g of palladium acetate and 7.95 g of BINAP were added under a nitrogen atmosphere, the oil bath was heated to 100 ° C, and stirred for 12 h. The amount of 6-bromo-2-naphthaldehyde in the reaction system was detected by LCMS. When 6-bromo-2-naphthaldehyde could not be detected, the reaction was complete. 20 g of diatomaceous earth was used for filtration, 300 mL of water and 150 mL of ethyl acetate were added to the liquid phase, and the organic phases were combined. Washed with saturated brine and dried over anhydrous sodium sulfate to obtain an orange-brown oily crude product. The crude product was eluted by column chromatography, petroleum ether and ethyl acetate to obtain 10.5 g of yellow solid compound A. LCMS purity 95%, yield 68.88%.

[0049] 1HNMR (400MHz, DMSO) δ10.02(s,1H),8.38(s,1H),7.99(d,J=9.2Hz,1H),7.79(d,J=5.7Hz,2H),7.50 (dd,J=9.2,2.5Hz,1H),7.28(d,J=2.2Hz,1H),3.51(d,J=5.5Hz,4H),3.40–3.35(m,4H)1.44(s,9H).

[0050] The H NMR spectrum of compound A is shown in Figure 2 shown.

[0051] (2) Under nitrogen atmosphere, compound A obtained in step (1) was added with 100 mL of 4 M HCl ethyl acetate, stirred at room temperature for 12 h, filtered, and the filter cake was washed with ethyl acetate 2 to 3 times. After drying, 11.5 g of orange solid compound B was obtained. LCMS purity was 98%, and the yield was 95.10%.

[0052] 1 HNMR(400MHz,DMSO)δ10.04(s,1H),9.21(s,2H),8.42(s,1H),8.04(d,J=9.1Hz,1H),7.88– 7.78(m,2H),7.53(dd,J=9.1,2.4Hz,1H),7.37(s,1H),3.63(d,J=5.1Hz,4H),3.28(s,4H).

[0053] The H NMR spectrum of compound B is shown in Figure 3 shown.

[0054] (3) Compound B was dissolved in 1000 mL of water at room temperature, and a saturated sodium bicarbonate solution was added to adjust the pH to 7-8. A yellow precipitate was precipitated, which was filtered and dried to obtain 7.9 g of yellow solid 6-(piperazine-1-yl)-2-naphthaldehyde with a purity of 97% and a yield of 73.42%.

[0055] 1 HNMR (400MHz, CDCl3) δ10.07(s,1H),8.20(s,1H),7.88(dd,J=8.5,1.8Hz,2H),7.73(d,J=8.6Hz ,1H),7.35(dd,J=9.1,2.4Hz,1H),7.13(d,J=2.2Hz,1H),3.41–3.33(m,4H),3.14–3.07(m,4H).

[0056] The H NMR spectrum of 6-(piperazine-1-yl)-2-naphthaldehyde is as follows Figure 4 As shown, HPLC detection diagram is shown in Figure 5shown.

[0057] Comparative Example 1

[0058] The difference from Example 1 is that in step (1), the palladium catalyst palladium acetate and the phosphine ligand BINAP are replaced by 3.11 g DPPF palladium dichloride (0.1 eq).

[0059] Reaction results: The reaction system is relatively complex, with most of the bromine-depleted molecule 2-naphthaldehyde.

[0060] 1 HNMR (400MHz, dmso) δ10.14(s,1H),8.57(s,1H),8.15(d,J=8.0Hz,1H),8.04(dd,J=13.6,8.4Hz,2H),7.89(d,J=8.5Hz,1H),7.74–7.61(m,2H).

[0061] The H NMR spectrum of 2-naphthaldehyde molecule is as follows Figure 6 shown.

[0062] Comparative Example 2

[0063] The difference from Example 1 is that in step (1), the palladium catalyst palladium acetate and the phosphine ligand BINAP are replaced by 4.92 g tetrakistriphenylphosphine palladium (0.1 eq).

[0064] Reaction results: The raw materials reacted completely, the reaction system was relatively complex, and most of it was the debrominated molecule 2-naphthaldehyde.

[0065] Comparative Example 3

[0066] The difference from Example 1 is that in step (1), the palladium catalyst palladium acetate and the phosphine ligand BINAP are replaced by 0.96 g palladium acetate (0.1 eq) and 9.34 g DPPF palladium dichloride (0.3 eq).

[0067] Reaction results: The raw materials reacted completely, and the yield was only 8%.

[0068] Comparative Example 4

[0069] The difference from Example 1 is that in step (1), the substrate 6-bromo-2-naphthaldehyde is replaced by 6-fluoro-naphthalene-2-carboxaldehyde, the organic solvent toluene is replaced by dioxane, and the palladium catalyst palladium acetate and the phosphine ligand BINAP are replaced by 1.07 g DPPF palladium dichloride (0.1 eq).

[0070] Reaction result: The reaction failed and no product was generated.

[0071] Comparative Example 5

[0072] This embodiment specifically provides a synthesis method and preparation method of 6-(piperazine-1-yl)-2-naphthaldehyde, and the materials involved in the preparation method are shown in Table 2:

[0073] Table 2

[0074]

[0075] The specific steps are as follows:

[0076] Add 2g of 2-bromo-6-fluoronaphthalene into a three-necked flask containing 20mL of tetrahydrofuran, cool to -72°C under nitrogen protection, slowly drop 5.332mL of n-butyllithium, stir for 30min, then slowly drop 1.032mL of N,N-dimethylformamide, return to room temperature and stir for 2h, take a sample and point the plate, the reaction of the raw materials is complete.

[0077] Reaction results: The reaction system is messy and purification is difficult. Considering the cost and operational safety, this route was abandoned.

Claims

1. A method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde, characterized in that: The synthesis method comprises the following steps: (1) dissolving 6-bromo-2-naphthaldehyde in an organic solvent, adding N-BOC-piperazine, a palladium catalyst, a phosphine ligand and a base under an inert atmosphere, heating to carry out a coupling reaction, and post-treating to obtain compound A; (2) Under an inert atmosphere, compound A is subjected to a BOC protecting group removal reaction in an acidic solution, and then filtered, washed, and dried to obtain compound B; (3) Compound B was dissolved in water, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, a precipitate was precipitated, and the precipitate was filtered and dried to obtain the target compound.

2. A method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: In step (1), the organic solvent is any one of toluene, xylene or 1,4-dioxane or a combination of at least two thereof, and the mass volume ratio of 6-bromo-2-naphthaldehyde to the organic solvent is 1 g:8-12 mL.

3. A method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: The molar ratio of 6-bromo-2-naphthaldehyde to N-BOC-piperazine in step (1) is 1:(1.1-1.3).

4. A method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: The palladium catalyst in step (1) is any one of palladium acetate, palladium chloride or tetrakistriphenylphosphine palladium or a combination of at least two thereof, and the phosphine ligand is any one of BINAP, Xantphos or DPPF or a combination of at least two thereof.

5. A method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: The molar ratio of 6-bromo-2-naphthaldehyde, palladium catalyst and phosphine ligand in step (1) is 1: (0.05-0.15): (0.2-0.4).

6. A method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: The base in step (1) is any one of cesium carbonate, potassium carbonate or potassium phosphate or a combination of at least two thereof, and the molar ratio of 6-bromo-2-naphthaldehyde to the base is 1:(1.5-2.5).

7. The method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: The heating temperature in step (1) is 100-120° C., and the reaction time is 11-13 hours.

8. The method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: In step (2), the acidic solution is an ethyl acetate solution of hydrogen chloride, a dichloromethane solution of trifluoroacetic acid or a methanol solution of sulfuric acid, the reaction temperature is room temperature, the reaction time is 11 to 13 hours, and the mass volume ratio of compound A to the acidic solution is 1 g: 8 to 12 mL.

9. The method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: The inert atmosphere is any one of nitrogen, argon or helium, or a combination of at least two of them.

10. The method for synthesizing 6-(piperazine-1-yl)-2-naphthaldehyde according to claim 1, characterized in that: The post-treatment step in step (1) comprises: after the reaction is completed, filtering the reaction solution through diatomaceous earth, adding ethyl acetate-water solution for extraction 2 to 3 times, combining the organic phases, washing and drying to obtain a crude product; and subjecting the crude product to silica gel column chromatography and eluting to obtain compound A.

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