A process for the preparation of propamidine

Abstract

The application discloses a method for preparing propafenone, and belongs to the technical field of drug synthesis. The method comprises the following steps: (1) taking 4-bromoguaiacol as raw material to perform etherification reaction with N,N-diethylchloroacetamide to obtain an intermediate A; (2) performing cross coupling reaction on the intermediate A and dipropyl malonate under the catalysis of a copper / oxamide ligand combination system to obtain an intermediate B; and (3) performing decarboxylation on the intermediate B by heating to obtain the propafenone. The raw material is cheap and easy to obtain, the route is short, the operation is simple, and the method has good industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing propanediol. Background Technology

[0002] Propanediol (Puran), chemical formula C 18 H 27 NO5 is a colorless or pale yellow oily liquid.

[0003] Propanedidil, a derivative of eugenol, is a non-barbiturate, ultra-short-acting intravenous anesthetic. Clinically, its anesthetic effect is rapid; a single intravenous injection is sufficient to induce sleep in the patient. However, its duration of deep anesthesia is relatively short, typically lasting only about five minutes. These characteristics make it ideal for short-duration anesthesia in surgical examinations and it can also be used as an induction anesthetic in major clinical surgeries, and it has long been widely used in many countries. Therefore, developing efficient, low-cost, and simple preparation techniques is currently a key focus of research on the synthetic process of propanedidil.

[0004] Bayer first described the synthesis of propanedidium in patent document GB906250. Propanedidium was obtained in one step by etherification of homovanillic acid ester with chloroacetamide. The disadvantages are that homovanillic acid ester is expensive, leading to high production costs, and the use of hazardous reagents such as metallic sodium poses safety risks during production.

[0005]

[0006] Patent document GB571395 discloses a method that uses 4-hydroxy-3-methoxybenzyl alcohol as a starting material, reacts with chloroacetamide in an etherification reaction, then converts benzyl alcohol to benzyl chloride, then converts it to acid through cyanidation / hydrolysis, and finally esterifies it with propanol to obtain propanedidium. This method is not only long, but also requires the use of highly toxic substances such as sodium cyanide, which limits its application.

[0007]

[0008] US Patent document US20030153554 reports a five-step reaction process using guaiacol as the starting material, involving hydroxyalkylation, acetylation, palladium / carbon hydrogenation reduction, esterification, and etherification to obtain the final product. This route uses inexpensive and widely available o-methoxyphenol (guaiacol) as the starting material, but it also has drawbacks such as a long route, a low overall yield of only 28%, and the need for a high-risk palladium-catalyzed high-pressure hydrogenation reduction operation.

[0009]

[0010] The representative methods for preparing propanedidium disclosed in these documents no longer fully meet the requirements of current pharmaceutical industrial production in terms of the availability of starting materials, safety of reaction conditions, cost, and yield. Therefore, it is very important to develop new propanedidium preparation technologies. Summary of the Invention

[0011] To address the shortcomings of existing technologies, this invention aims to provide a highly economical method for preparing propanil. The invention uses 4-bromoguaiacol as the starting material, sequentially undergoing etherification under alkaline conditions, copper-catalyzed cross-coupling, and thermal decarboxylation to obtain propanil. 4-bromoguaiacol can be conveniently obtained through the bromination of guaiacol at low cost. Therefore, the process of this invention has advantages such as readily available and inexpensive raw materials, a short process route, simple operation, and high overall yield.

[0012] This invention provides a method for preparing propanil, wherein the method uses 4-bromoguaiacol as the starting material, reacts in the presence of a copper / oxalamide ligand combination system, and then decarboxylates upon heating to obtain propanil.

[0013] Specifically, the method includes the following steps:

[0014] (1) 4-bromoguaiacol and N,N-diethylchloroacetamide undergo etherification in the presence of a base to give intermediate A;

[0015] (2) In a solvent, under the catalysis of a copper / oxalamide ligand combination system, in the presence of a base, intermediate A is cross-coupled with dipropyl malonate to obtain intermediate B;

[0016] (3) The intermediate B is thermally decarboxylated to obtain propanediol.

[0017] The reaction process is shown in reaction formula I below:

[0018]

[0019] Formula I

[0020] In step (1), the amount of N,N-diethylchloroacetamide used is 1-1.2 molar equivalents relative to 4-bromoguaiacol.

[0021] In step (1), the alkali includes, but is not limited to, potassium carbonate.

[0022] In step (2), the solvent includes one or more of the following: aromatic solvents such as toluene, ether solvents such as dioxane, amide solvents such as dimethylformamide, alcohol solvents such as propanol, and sulfone solvents such as dimethyl sulfoxide; preferably, it is an ether solvent.

[0023] In step (2), the ligand in the copper / oxalamide ligand combination system is oxalamide, which has chelating coordination function as shown in structural formula 1:

[0024]

[0025] Formula 1

[0026] R 1 R 2 Each is independently hydrogen or C1-C4 alkyl; preferably, it is H or methyl;

[0027] R 3 It can be alkyl, aryl, or heteroaryl, with no particular structural limitation, but preferably a sterically hindered substituted phenyl group, including but not limited to 2-methylphenyl, 2-isopropylphenyl, 2-tert-butylphenyl, 2,6-diethylphenyl, 2,6-diisopropylphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, mestrimethylphenyl, 2-methoxyphenyl, 2-dimethylaminophenyl, and mestrimethoxyphenyl, etc.

[0028] The side chain (i.e. the dashed part in the structural formula) is an alkyl or aryl group and a heteroaryl group with a heteroatom Y that can coordinate with copper, including but not limited to, preferably 2-(dimethylamino)ethyl, 2-(dimethylamino)propyl, 2-pyridimethylene, 2-(2-pyridin)ethyl;

[0029] Y includes O, N, and S; preferably, it is N.

[0030] In step (2), the alkali includes one or more of alkali metal phosphates, carbonates, alkoxides, and hydroxides; preferably, it is cesium carbonate and sodium tert-butoxide; more preferably, it is sodium tert-butoxide.

[0031] In step (2), the copper catalyst in the copper / oxalamide ligand combination system includes one or more of cuprous chloride, cuprous bromide, cuprous iodide, copper chloride, copper bromide, copper sulfate, copper acetylacetone, and copper acetate; preferably, it is cuprous chloride, cuprous bromide, and cuprous iodide; more preferably, it is cuprous iodide.

[0032] In step (2), the temperature of the reaction is not lower than 100°C.

[0033] Step (2) in the preparation method of propanediol described in this invention is the core inventive point.

[0034] In one specific embodiment, the method includes the following steps:

[0035] (1) Using acetonitrile as solvent, 4-bromoguaiacol and N,N-diethylchloroacetamide were refluxed and etherified in the presence of potassium carbonate to obtain intermediate A; the amount of N,N-diethylchloroacetamide relative to 4-bromoguaiacol was 1-1.2 molar equivalents.

[0036] (2) Under nitrogen protection, using dioxane or the like as solvent, and catalyzed by a copper / oxalamide ligand combination system, intermediate A and dipropyl malonate are heated to reflux to obtain intermediate B, with dipropyl malonate having a molar amount of 1.5-2 times that of intermediate A.

[0037] (3) Using dimethyl sulfoxide as solvent, intermediate B was heated to 160°C to decarboxylate to obtain propanediol.

[0038] The present invention also provides an intermediate, the structure of which is as follows:

[0039]

[0040] The present invention also provides a method for preparing intermediate A, wherein 4-bromoguaiacol and N,N-diethylchloroacetamide are subjected to an etherification reaction in the presence of a base to obtain intermediate A.

[0041] The alkali includes, but is not limited to, potassium carbonate.

[0042] The amount of N,N-diethylchloroacetamide used is 1-1.2 molar equivalents relative to 4-bromoguaiacol.

[0043] The present invention also provides a method for preparing intermediate B, wherein intermediate A is cross-coupled with dipropyl malonate in a solvent, under the catalysis of a copper / oxalamide ligand combination system, and in the presence of a base to obtain intermediate B.

[0044] The definitions of the solvent, alkali, and copper / oxalamide ligand combination system are the same as those for the foregoing definitions.

[0045] The present invention also provides the application of the intermediate in the preparation of propanil, other biopharmaceuticals, etc.

[0046] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0047] This invention synthesizes a novel intermediate A or B. The method described in this invention uses inexpensive and readily available starting material 4-bromoguaiacol; it involves etherification under alkaline conditions, cross-coupling under copper catalysis, and decarboxylation upon heating, making the operation simple; the process route is short, and the final product yield can reach over 70%. Attached Figure Description

[0048] Figure 1 HPLC chromatogram of propantheline products. Detailed Implementation

[0049] The present invention will be further described in detail below with reference to embodiments, but the embodiments of the present invention are not limited thereto. Variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention and are protected by the appended claims. The processes, conditions, reagents, experimental methods, etc., for carrying out the present invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations. The data given in the following embodiments include the synthetic operations and reaction conditions and products.

[0050] Example 1: Preparation of Intermediate A

[0051] Under nitrogen protection, 4-bromo-2-methoxyphenol (0.2 mol, 40.6 g), K₂CO₃ (41.5 g, 0.3 mol, 1.5 eq.), and 250 mL of acetonitrile were added to a 500 mL three-necked flask equipped with a mechanical stirrer. The mixture was stirred thoroughly at room temperature and heated to reflux in an oil bath. N,N-diethylchloroacetamide (36.0 g, 0.24 mol, 1.20 eq.) was slowly added through a dropping funnel, and the mixture was refluxed for 5 hours. The reaction solution was cooled to room temperature, and the solvent was recovered by rotary evaporation. 100 mL of water was added to the residue, and the mixture was heated and stirred under reflux for 30 minutes. After cooling to room temperature, the aqueous phase was discarded, and the residue was washed with water until neutral to obtain 59.7 g of a pale yellow oily product, with a yield of 93%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 6.94 (s, 1H), 6.92 (d, J = 2.8 Hz,1H), 6.77 (d, J = 8.8 Hz, 1H), 4.65 (s, 2H), 3.79 (s, 3H), 3.36-3.30 (m, 4H), 1.13 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ(ppm): 166.6, 150.2, 146.9, 123.4, 115.5, 115.3, 113.9, 68.4, 56.0, 41.4,40.3, 14.2, 12.7.

[0052] Example 2

[0053] The operation of Example 2 was the same as that of Example 1 of the present invention, except that the amount of N,N-diethylchloroacetamide was adjusted to 30g (0.2mol, 1.0eq.), and 53.9g of intermediate A was obtained as a pale yellow oily viscous liquid with a yield of 84%.

[0054] Example 3 Preparation of Intermediate B

[0055] Under nitrogen protection, intermediate A (31.6 g, 0.1 mol), CuI (0.95 g, 5 mmol, 5 mol%), bis(pyridine-2-methyl)oxalamide (1.35 g, 5 mmol, 5 mol%), Cs₂CO₃ (65 g, 0.2 mol, 2.0 eq.), dipropyl malonate (37.5 g, 0.2 mol, 2.0 eq.), and dioxane (250 mL) prepared in the embodiments of the present invention were added sequentially to a 500 mL reaction flask equipped with a mechanical stirrer. After purging the air with nitrogen, the mixture was heated to 100 °C and refluxed with stirring for 6 hours (the reaction can proceed at 100 °C or higher). The reaction solution was cooled to room temperature, 100 mL of water was added, and the mixture was neutralized to neutral with 2 M hydrochloric acid and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the crude product. The crude product was adsorbed onto silica gel to form free-flowing powder particles, and then extracted with ethyl acetate / petroleum ether to remove the extractant, yielding 25.5 g of pale yellow oily liquid, with a yield of 60%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 6.99 (s,1H), 6.89 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.71 (s, 2H), 4.54(s, 1H), 4.15 – 4.05 (m, 4H), 3.86 (s, 3H), 3.42-3.34 (m, 4H), 1.68-1.59 (m,4H), 1.17 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 168.3, 167.0, 149.3, 147.6, 126.5,121.9, 113.8, 112.80, 68.5, 67.3, 57.4, 55.8, 41.5, 40.3, 21.8, 14.2, 12.7,10.2.

[0056] Example 4

[0057] The operation of Example 4 was the same as that of Example 3 of the present invention, except that the amount of dipropyl malonate was adjusted to 28g (0.15mol, 1.5eq.), and 21.7g of intermediate B was obtained as a pale yellow oily viscous liquid with a yield of 51%.

[0058] Example 5

[0059] The operation of Example 5 was the same as that of Example 3 of the present invention, except that the amount of ligand bis(pyridine-2-methyl)oxalamide was adjusted to 10 mol%, and 28.7 g of intermediate B was obtained as a pale yellow oily viscous liquid with a yield of 68%.

[0060] Examples 6-10

[0061] The operations in Examples 6-10 are the same as those in Example 3 of the present invention, but the solvents used are different. The results are listed in Table 1.

[0062] Table 1. Molar yield of intermediate B when using different solvents

[0063]

[0064] Examples 11-17

[0065] The operations in Examples 11-17 are the same as those in Example 3 of the present invention, but the copper salt catalyst used is different. The results are listed in Table 2.

[0066] Table 2. Molar yield of intermediate B when using different copper salts as catalysts.

[0067]

[0068] Examples 18-23

[0069] The operations of Examples 18-23 are the same as those of Example 3 of the present invention, but the alkali used is different. The results are listed in Table 3.

[0070] Table 3. Molar yield of intermediate B when using different bases

[0071]

[0072] Examples 24-43

[0073] The operations in Examples 24-43 were the same as those in Example 3 of the present invention, but the oxalamide ligands used were different. The results are listed in Table 4.

[0074] Table 4. Molar yield of intermediate B when using different oxalamide ligands

[0075]

[0076] Example 44

[0077] Synthesis of Propanediol

[0078] 42.5 g of intermediate B, 12 g of sodium chloride, 200 mL of DMSO, and 20 mL of water were added to a 500 mL round-bottom flask. After stirring until homogeneous, the reaction mixture was heated and stirred in a 160 °C oil bath for 12 hours. Most of the solvent was evaporated under reduced pressure. The remaining reaction solution was cooled to room temperature, and 200 mL of water was added. Extraction was performed with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. After adsorption onto silica gel, a free-flowing powder was formed. The powder was extracted with petroleum ether / ethyl acetate, and the extractant was evaporated to obtain 31 g of a colorless oily liquid, with a yield of 94% and an HPLC purity >98%.

[0079] Colorless oily liquid (31 g, 94%); 1 H NMR (400 MHz, CDCl3) δ (ppm): 6.88 (d, J =8.4 Hz, 1H), 6.82 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.69 (s, 2H), 4.03 (t, J= 6.4 Hz, 2H), 3.84 (s, 3H), 3.53 (s, 2H), 3.42-3.34(m, 4H), 1.67-1.58 (m,2H), 1.17 (t, J = 7.2 Hz,3H), 1.11 (t, J = 7.2 Hz,3H), 0.89 (t, J = 7.2 Hz,3H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 171.7, 167.0, 149.4, 146.7, 128.0,121.4, 114.2, 112.9, 68.7, 66.4, 55.8, 41.5, 40.9, 40.2, 21.9, 14.2, 12.8,10.3.

[0080] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0081] As used in this invention, the terms "comprising" and "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0082] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0083] The above embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made based on the essence of the content of the present invention are covered within the scope of protection of the present invention.

Claims

1. A method for preparing propanyldipropionate, characterized in that, The method uses 4-bromoguaiacol as the starting material, reacts in the presence of a copper / oxalamide ligand system, and then decarboxylates upon heating to obtain propanildi.

2. The preparation method according to claim 1, characterized in that, The method includes the following steps: (1) 4-bromoguaiacol and N,N-diethylchloroacetamide undergo etherification in the presence of a base to give intermediate A; (2) In a solvent, under the catalysis of a copper / oxalamide ligand combination system, in the presence of a base, intermediate A obtained in step (1) is cross-coupled with dipropyl malonate to obtain intermediate B; (3) The intermediate B obtained in step (2) is thermally decarboxylated to obtain propanediol; The reaction process is shown in reaction formula I below: Equation I.

3. The preparation method according to claim 2, characterized in that, In step (1), the amount of N,N-diethylchloroacetamide used is 1-1.2 molar equivalents relative to the 4-bromoguaiacol.

4. The preparation method according to claim 2, characterized in that, In step (2), the copper catalyst in the copper / oxalamide ligand combination system includes one or more of cuprous chloride, cuprous bromide, cuprous iodide, copper chloride, copper bromide, copper sulfate, copper acetylacetone, and copper acetate.

5. The preparation method according to claim 2, characterized in that, In step (2), the ligand in the copper / oxalamide ligand combination system is oxalamide with chelating coordination function, as shown in structural formula 1 below: Formula 1 R 1 R 2 Each is independently hydrogen or C1-C4 alkyl; R 3 It is alkyl, aryl, or heteroaryl; the side chain is an alkyl or aryl or heteroaryl with a heteroatom Y that can coordinate with copper; Y includes O, N, and S.

6. The preparation method according to claim 2, characterized in that, In step (2), the base includes one or more of alkali metal phosphates, carbonates, alkoxides and hydroxides; and / or, the solvent includes one or more of aromatic solvents, ether solvents, amide solvents, alcohol solvents and sulfone solvents.

7. The preparation method according to claim 2, characterized in that, In step (2), the temperature of the reaction is not lower than 100°C.

8. An intermediate, characterized in that, The structure of the intermediate is as follows: 。 9. A method for preparing an intermediate, characterized in that, The preparation method of intermediate A is as follows: 4-bromoguaiacol and N,N-diethylchloroacetamide are subjected to etherification reaction in the presence of base to obtain intermediate A; And / or, intermediate B is prepared by cross-coupling intermediate A with dipropyl malonate in a solvent, under the catalysis of a copper / oxalamide ligand combination system, in the presence of a base, to obtain intermediate B.

10. The use of the intermediate according to claim 8 in the preparation of propanediol.

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