A method for synthesizing 3-methoxytyramine

Abstract

The application discloses a synthesis method of 3-methoxy tyramine and belongs to the technical field of organic synthesis. The method is directly synthesizing 4-hydroxy-3-methoxy phenylacetonitrile by reacting 4-hydroxy-3-methoxy benzyl alcohol with sodium cyanide in the presence of a phase transfer catalyst (such as a crown ether); then, the target product 3-methoxy tyramine is prepared by a hydrogenation reduction reaction under the catalysis of a Raney nickel or a Raney cobalt. The method avoids the high-risk chlorination process in the prior art, shortens the reaction route, and replaces the expensive palladium-carbon catalyst with a cheap non-noble metal catalyst. The process has the advantages of easy availability of raw materials, low cost (about 50% reduction in cost), high total yield (more than 85%), safety and environmental protection, and the like, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more particularly to a method for synthesizing pesticide intermediates, specifically a method for synthesizing 3-methoxytyramine. Background Technology

[0002] 3-Methoxytyramine (CAS No: 554-52-9) is an important fine chemical intermediate, mainly used in the synthesis of the fungicide diyrylamide. Diyrylamide (CAS No: 374726-62-2) is a novel amygdalin fungicide developed and produced by Syngenta, Switzerland. It exhibits stable control effects against most oomycete diseases and possesses excellent activity, while also being safe for crops, humans, wildlife, and the environment. As of 2022, its global annual sales were approximately US$120 million. With its patent protection expiring recently (May 14, 2021), it is poised to become one of the fungicide products developed by domestic and international pesticide companies. 3-Methoxytyramine is a key intermediate for this product, and its market has significant potential for further expansion.

[0003] From the perspective of retrosynthesis, and based on a comprehensive review of literature and patent search results, the synthesis methods of 3-methoxytyramine can be mainly divided into three categories.

[0004] 1. Original research route using vanillin as raw material

[0005] Syngenta, the original developer of dimethicone, clearly described the synthesis method of the intermediate 3-methoxytyramine in the literature Bio & Med Chem, 2008, 16:1531-1545, PestManag Sci 63, 2007, 57-62 and patents WO2007020381 and WO2003042166. Using vanillin as a raw material, it first undergoes an addition reaction with sodium cyanide to obtain the intermediate vanillylmandelinnitrile, and then undergoes palladium-catalyzed hydrogenation under strongly acidic conditions to obtain the product 3-methoxytyramine, as shown in the figure below.

[0006]

[0007] The inventors conducted research on this route and confirmed its feasibility, but several problems exist. These include: the addition reaction in step one is carried out under weakly acidic conditions, and sodium cyanide may release hydrogen cyanide gas, greatly increasing the reaction risk; step one is an equilibrium reaction, and the raw material vanillin cannot be completely converted, with a yield of only 85%; step two is carried out under strongly acidic conditions, and the metal catalyst is not resistant, resulting in too few reuses. In actual trials, it was found that palladium on carbon needs to be added after four reuses. Of the three problems, the first two can be improved without affecting scale-up production through process optimization, equipment matching, interlocking dripping, and alarm devices. The third problem, palladium on carbon can only be reused four times, leading to a significant increase in product production costs. According to a rough estimate, the raw material cost reaches 231 CNY / kg, of which palladium on carbon accounts for 63% of the cost, making it uneconomical.

[0008] 2. Henry's reaction route using vanillin as a raw material

[0009] Literature searches revealed numerous studies in J. Org. Chem., 1953, 18, 1: 1–3., Bioorg. Med. Chem., 2011, 19: 783-788., J. Am. Chem. Soc., 1951, 73, 12, 5555–5557., J. Am. Chem. Soc., 1931, 53(10): 3865–3867., and patents CN113956263A, CN114573508B, and CN116731005B, all of which describe the use of vanillin as a raw material, which undergoes a Henry reaction with nitromethane to generate the intermediate vanillylnitrostyrene. This intermediate is then reduced in one or two steps to obtain the product 3-methoxytyramine, as illustrated below.

[0010]

[0011] The inventors investigated this route, screening Henry's reaction conditions using a parallel reactor. Under the same or similar substrate reaction conditions reported in literature and patents, the reaction results were poor; the reaction solution was black and opaque, with tar-like solids formed. Central control monitoring showed chaotic HPLC spectra with numerous extraneous peaks and no dominant peak. The analysis suggested that the presence of the phenolic hydroxyl groups on the vanillin substrate significantly interfered with the reaction, and that the generated product was overly reactive, exhibiting a tendency to polymerize and continue tandem reactions, resulting in poor actual reaction performance. Therefore, this route was deemed unfeasible and the research was abandoned.

[0012] 3. The classic route using vanillin as a raw material

[0013] Shandong Kangqiao Biotechnology Co., Ltd. reported a method for synthesizing dimethicone in its patent CN 102584621 B, which involves the synthesis of the key intermediate 3-methoxytyramine. Using vanillin as a raw material, the product 3-methoxytyramine is obtained through chlorination, cyano substitution, and catalytic hydrogenation, as shown in the figure below. Similar synthetic methods have been described in the literature European Journal of Medicinal Chemistry 45 (2010) 11–18., Chemistry of Natural Compounds., 1990, 26: 54-59., and J. Org. Chem. 2006, 71, 3, 992–1001.

[0014]

[0015] This route involves classical reactions, but it also has drawbacks such as the excessive irritation and poor stability of the benzyl chloride intermediate, the high equipment requirements of the strongly acidic environment of the chlorination step, and the large amount of waste. The entire route is a three-step reaction, and the yield is slightly low.

[0016] In summary, the three synthetic routes for 3-methoxytyramine are as follows: Route 1 (Syngenta's original route) has the main problem of excessively high raw material costs; Route 2 is technically infeasible; and Route 3 (Kangqiao's patented route) has the main problems of prominent safety and environmental issues and low yield. Therefore, it is necessary to develop a synthetic method that is economically, technically, safely, and environmentally feasible. Summary of the Invention

[0017] The purpose of this invention is to provide a method for synthesizing 3-methoxytyramine, so as to solve the problems of high cost, poor safety and large amount of waste in the prior art.

[0018] The technical solution adopted by this invention to solve its technical problem is:

[0019] A method for synthesizing 3-methoxytyramine, comprising the following steps: (1) mixing 4-hydroxy-3-methoxybenzyl alcohol, a cyaniding agent, and a phase transfer catalyst in an organic solvent to carry out a substitution reaction to obtain the intermediate 4-hydroxy-3-methoxyphenylacetonitrile; (2) carrying out a hydrogenation reduction reaction of the intermediate 4-hydroxy-3-methoxyphenylacetonitrile in a solvent in the presence of a metal catalyst and a basic additive to obtain the product 3-methoxytyramine. The specific reaction is illustrated below.

[0020]

[0021] Preferably, in step (1), the phase transfer catalyst is a crown ether compound; preferably 18-crown-6 or 15-crown-5. This allows the hydroxyl group of benzyl alcohol to be directly substituted by a cyano group under mild conditions, avoiding the step of introducing chlorine atoms.

[0022] Preferably, in step (1), the mass of the phase transfer catalyst is 0.5%-5% of the mass of 4-hydroxy-3-methoxybenzyl alcohol, preferably 1%-2%; the cyaniding agent is sodium cyanide or potassium cyanide; the molar ratio of 4-hydroxy-3-methoxybenzyl alcohol to the cyaniding agent is 1:1.1-1:2, more preferably 1:1.2.

[0023] Preferably, in step (1), the organic solvent is N,N-dimethylformamide (DMF), and the amount of organic solvent used is 3-10 times (preferably 5 times) the mass of 4-hydroxy-3-methoxybenzyl alcohol; the reaction temperature is 100℃-130℃, and the reaction time is 4-10h. More preferably, in step (1), the reaction temperature is 110℃, and the reaction time is 4-5h.

[0024] Preferably, in step (2), the metal catalyst is selected from palladium on carbon, Raney-Ni, or Raney-Co; the amount of the metal catalyst is 5% to 20% of the mass of 4-hydroxy-3-methoxyphenylacetonitrile. Preferably, it is 10%. Using Raney-Ni or Raney-Co as the catalyst replaces the expensive palladium on carbon, significantly reducing costs.

[0025] Preferably, in step (2), the alkaline additive is ammonia or an ammonia-methanol solution; the solvent is a C1-C4 alkyl alcohol, such as methanol, ethanol, isopropanol, etc., preferably methanol.

[0026] Preferably, in step (2), the hydrogen pressure of the hydrogenation reduction reaction is 1.5-3.0 MPa, the reaction temperature is 40℃-100℃, and the reaction time is 6-12 h. More preferably, the temperature is 90-100℃. More preferably, the reaction time is 8-10 h, at which point the corresponding phenomenon is that the hydrogen pressure in the hydrogenation reactor no longer decreases.

[0027] Preferably, the post-processing of step (1) includes: after the reaction is completed, the solvent is recovered under reduced pressure, the pH is adjusted to 6.5-7.5, extraction, washing, decolorization, and concentration to obtain the crude intermediate product; the post-processing of step (2) includes: after the reaction is completed, the catalyst is removed by filtration, the filtrate is concentrated, and the product is obtained by recrystallization using a crystallization solvent; the crystallization solvent is preferably a mixed solvent of ethyl acetate and cyclohexane, or a mixed solvent of ethyl acetate and n-heptane.

[0028] Preferably, the post-processing method of step (1) is as follows: after passing the central control test, about 80-85% of the solvent N,N-dimethylformamide is recovered under high vacuum and reduced pressure. Citric acid aqueous solution is added to adjust the pH of the reaction solution to 6.5-7.5. After extraction twice with methyl tert-butyl ether, the organic phases are combined, washed with saturated brine, decolorized with activated carbon, concentrated under reduced pressure to recover the solvent, and the crude product is directly used in the next step.

[0029] Preferably, the post-processing method in step (2) is as follows: after the central control is qualified, the residual ammonia is recovered by depressurization, the filter is filtered after room temperature depressurization, the filter cake is washed three times with a small amount of methanol, the filtrate is concentrated to recover methanol, the crude product is obtained, and then crystallized in a mixed solvent system of ethyl acetate and cyclohexane to obtain pure 3-methoxytyramine.

[0030] Preferably, in step (2), the amount of solvent used is 4-12 times (preferably 4 times) the mass of 4-hydroxy-3-methoxyphenylacetonitrile; the amount of alkaline additive used is 1%-10% of the mass of 4-hydroxy-3-methoxyphenylacetonitrile. More preferably, the amount of alkaline additive (calculated as pure ammonia) used is 8%-10%.

[0031] The beneficial effects of this invention are:

[0032] 1. The original route in the prior art (Syngenta route) requires weakly acidic conditions in the cyanation addition step, which causes the highly toxic sodium cyanide to easily convert into volatile hydrogen cyanide (HCN) gas and escape, posing a huge threat to operators and the environment; the chlorination route in the prior art (Concor route) involves a strongly acidic or highly corrosive chlorination environment, and the generated benzyl chloride intermediate has strong irritant properties and instability. In contrast, step (1) of this invention utilizes a phase transfer catalyst system to directly achieve the cyano substitution of hydroxyl groups in a non-acidic (neutral or weakly alkaline) organic solvent environment. This reaction environment effectively inhibits the generation and escape of hydrogen cyanide gas from a chemical principle perspective, while also avoiding the use of highly corrosive reagents and the generation of unstable intermediates, making the reaction process more controllable and significantly reducing safety risks and environmental pressure.

[0033] 2. Step (2) of this invention successfully developed a non-precious metal catalytic system, using inexpensive and readily available skeletal nickel or cobalt catalysts to replace the expensive palladium on carbon (Pd / C) catalyst in the original research route. This solves the problem of high cost caused by the easy poisoning, short lifespan, and limited number of reuses (only about 4 times) of palladium on carbon catalysts in strongly acidic systems. According to calculations, the total raw material cost of the route of this invention is only about 117 CNY / kg, which is about 50% of the cost of the original research process, making it highly competitive in the market.

[0034] 3. This invention uses 4-hydroxy-3-methoxybenzyl alcohol as the starting material and requires only two reaction steps to obtain the target product, avoiding multiple cumbersome operations. After process optimization, the overall yield of the two-step reaction can be stably maintained above 85% (based on vanillin), and the intermediates and products have high purity, simple post-processing, and low emissions, demonstrating excellent prospects for industrial application. Detailed Implementation

[0035] The technical solution of the present invention will be further described in detail below through specific embodiments. It should be understood that the implementation of the present invention is not limited to the following embodiments, and any modifications and / or alterations made to the present invention will fall within the protection scope of the present invention.

[0036] In this invention, unless otherwise specified, all parts and percentages are by weight, and the equipment and raw materials used are commercially available or commonly used in the art. Unless otherwise specified, the methods in the following embodiments are conventional methods in the art.

[0037] Unless otherwise specified, the reagents used in the following examples can be purchased from a regular biochemical reagent store.

[0038] Example 1

[0039] (1) Synthesis of intermediate 4-hydroxy-3-methoxyphenylacetonitrile

[0040] 4-Hydroxy-3-methoxybenzyl alcohol (31 g, 0.2 mol, 1.0 eq) and solvent N,N-dimethylformamide (100 g) were added to a 500 ml dry three-necked flask. While stirring, catalyst 18-crown-6 (0.31 g, 0.01 m%), sodium cyanide solid (11.8 g, 0.24 mol, 1.2 eq; a gas mask must be worn before adding the materials, and all equipment involved must be thoroughly quenched with sodium hypochlorite solution before further treatment) and the remaining solvent N,N-dimethylformamide (50 g) were added sequentially. The temperature was raised to 110 °C, and the reaction was maintained at this temperature for 4 h. After cooling and vacuum distillation to recover about 120-125 g of solvent, the pH was adjusted to 7 with citric acid aqueous solution, and the mixture was extracted twice with methyl tert-butyl ether. The organic phases were combined, washed with saturated brine, decolorized with activated carbon, and concentrated to dryness to obtain 33.0 g of a pale yellow oily substance. HPLC analysis showed a content of 94.3% and a yield of 95.4%.

[0041] The product was sent for LC-MS analysis, and the molecular weight (negative ion mode) was 162.0309, which matches the product's 163.06.

[0042] (2) Synthesis of the product 3-methoxytyramine

[0043] In a 500ml stainless steel autoclave, the following were added sequentially: 32.8g of 4-hydroxy-3-methoxyphenylacetonitrile (94.3% purity, 0.190mol, 1.0eq), Raney-Ni (3.3g, 10%m), ammonia-methanol solution (16ml, 20% mass concentration, 10%m), and methanol (132g). After the addition was complete, the mixture was purged with nitrogen and hydrogen three times, then pressurized to 2.0MPa with hydrogen gas, heated to 90℃, and maintained at the same pressure. At 2.5 MPa, after about 8 hours of reaction, the absorption of hydrogen essentially ceased. The reaction was then stopped, the temperature was lowered, the pressure was released, and nitrogen was purged for 0.25 hours. The mixture was filtered, and the filter cake was washed three times with methanol. The filtrate was distilled at atmospheric pressure to recover methanol. The residue in the reactor was crystallized from ethyl acetate and cyclohexane, filtered, and dried to obtain 29.2 g of colorless to pale yellow crystals. HPLC analysis showed a purity of 98.9%, mp = 155.5-156.5℃. The yield of the single-step reaction was 91.14%, and the yield of the two-step reaction was 86.59%.

[0044] H-NMR (CDCl3) δ (ppm): 2.32-2.55 (m, 2H); 2.60 (t, 2H); 2.61-3.72 (broad, 3H); 3.52 (s, 3H); 6.30-6.96 (m, 3H).

[0045] Example 2

[0046] (1) Synthesis of intermediate 4-hydroxy-3-methoxyphenylacetonitrile

[0047] Add 124 g (0.8 mol, 1.0 eq) of 4-hydroxy-3-methoxybenzyl alcohol and 400 g (4,N-dimethylformamide) of solvent to a 2000 ml dry three-necked flask. While stirring, add 15-crown-5 catalyst (1.24 g, 0.01 m%) and sodium cyanide solid (47.2 g, 0.96 mol, 1.2 eq). Wear a respirator before adding the materials, and thoroughly drench all containers and equipment with sodium hypochlorite solution after adding the materials. (After quenching and further processing) and the remaining solvent N,N-dimethylformamide (200g), the mixture was heated to 110℃ and reacted for 4 hours. After cooling and vacuum distillation to recover about 480-500g of solvent, the pH was adjusted to 7 with citric acid aqueous solution, and the mixture was extracted twice with methyl tert-butyl ether. The organic phases were combined, washed with saturated brine, decolorized with activated carbon, and concentrated to dryness to obtain 134.2g of a light yellow oily substance. HPLC analysis showed a content of 93.1% and a yield of 95.7%.

[0048] The product was sent for LC-MS analysis, and the molecular weight (negative ion mode) was 162.0309, which matches the product's 163.06.

[0049] (2) Synthesis of the product 3-methoxytyramine

[0050] In a 2000ml stainless steel autoclave, 134g of 4-hydroxy-3-methoxyphenylacetonitrile (93.1% purity, 0.764mol, 1.0eq), 13.4g of Raney-Co (10%m), 13.4g of ammonia (10%m), and 536g of methanol were added sequentially. After the addition was completed, nitrogen and hydrogen were purged three times. Then, hydrogen was introduced to pressurize the autoclave to 2.0MPa, and the temperature was raised to 90℃, while the pressure was maintained at 2.5MPa. After about 8 hours, the reaction basically stopped absorbing hydrogen. The reaction was then stopped, the temperature was lowered, the pressure was released, and nitrogen was purged for 0.25 hours. The mixture was filtered, and the filter cake was washed three times with methanol. The filtrate was distilled at atmospheric pressure to recover methanol. The residue in the reactor was crystallized out with a mixed solvent of ethyl acetate and n-heptane. After filtration and drying, 116.3 g of colorless to pale yellow crystals were obtained. The purity was 99.3% according to HPLC, with mp = 155.1-156.3℃. The single-step yield was 90.4%, and the overall yield of the two-step reaction was 86.52%.

[0051] I-NMR (CDCl3) δ (ppm): 2.32-2.55 (m, 2H); 2.60 (t, 2H); 2.61-3.72 (broad, 3H); 3.52 (s, 3H); 6.30-6.96 (m, 3H).

[0052] Example 3

[0053] (1) Synthesis of intermediate 4-hydroxy-3-methoxyphenylacetonitrile

[0054] 4-Hydroxy-3-methoxybenzyl alcohol (3100g, 20.1mol, 1.0eq) and solvent N,N-dimethylformamide (10kg) were added to a 50L glass-jacketed reactor. While stirring, catalyst 18-crown-6 (31g, 0.01m%), sodium cyanide solid (1180g, 24.1mol, 1.2eq; a gas mask must be worn before adding the materials, and all equipment involved must be thoroughly quenched with sodium hypochlorite solution before further treatment), and the remaining solvent N,N-dimethylformamide (5kg) were added sequentially. The temperature was raised to 110℃, and the reaction was maintained at this temperature for 4 hours. After cooling and vacuum distillation to recover approximately 12-12.5kg of solvent, the pH was adjusted to 7 with citric acid aqueous solution. Extraction was performed twice with methyl tert-butyl ether, and the organic phases were combined. After washing with saturated brine and decolorization with activated carbon, the mixture was concentrated to dryness, yielding 3335g of a pale yellow oily substance. HPLC analysis showed a content of 94.2% and a yield of 95.8%.

[0055] (2) Synthesis of the product 3-methoxytyramine

[0056] In a 50L stainless steel autoclave, the following were added sequentially: 3330g of 4-hydroxy-3-methoxyphenylacetonitrile (94.2% purity, 19.2mol, 1.0eq), Raney-Ni (333g, 10%m), ammonia-methanol solution (1600ml, 20% mass concentration, 10%m), and methanol (13.32kg). After the addition was complete, nitrogen and hydrogen were purged three times. Then, hydrogen was introduced to pressurize the autoclave to 2.0MPa, and the temperature was raised to 90℃. The pressure was maintained at this level. At 2.5 MPa, after about 8 hours of reaction, the absorption of hydrogen essentially ceased. The reaction was then stopped, the temperature was lowered, the pressure was released, and nitrogen was purged for 0.25 hours. The mixture was filtered, and the filter cake was washed three times with methanol. The filtrate was distilled at atmospheric pressure to recover methanol. The residue in the reactor was crystallized from ethyl acetate and cyclohexane, filtered, and dried to obtain 2988 g of colorless to pale yellow crystals. HPLC analysis showed a purity of 98.84%, mp = 155.5-156.5℃. The yield of the single-step reaction was 92.01%, and the yield of the two-step reaction was 88.14%.

[0057] In summary, the method of this invention directly cyanides vanillin in one step, avoiding the highly polluting and risky chlorination process and reducing the number of reaction steps. It uses an inexpensive skeletal nickel / cobalt catalyst, and the overall process yield is increased to over 85% (based on vanillin). The total raw material cost (only 117 CNY / kg) is approximately 50% of the original process, resulting in a significant cost reduction. The product quality is high, with high purity of intermediates and product, and it is easy to purify.

[0058] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on its differences from other embodiments. Similar or identical parts between embodiments can be referred to interchangeably. For the apparatus disclosed in the embodiments, since it corresponds to the method disclosed in the embodiments, the description is relatively simple; relevant parts can be referred to in the method section.

[0059] The above provides a detailed description of the synthesis method of 3-methoxytyramine provided by this invention. Specific examples have been used to illustrate the principles and implementation methods of this invention. The descriptions of the above embodiments are merely for the purpose of helping to understand the method and core ideas of this invention. It should be noted that those skilled in the art can make various improvements and modifications to this invention without departing from its principles, and these improvements and modifications also fall within the protection scope of the claims of this invention.

Claims

1. A method for synthesizing 3-methoxytyramine, characterized in that, The method includes the following steps: (1) mixing 4-hydroxy-3-methoxybenzyl alcohol, a cyaniding agent and a phase transfer catalyst in an organic solvent to carry out a substitution reaction to obtain the intermediate 4-hydroxy-3-methoxyphenylacetonitrile; (2) carrying out a hydrogenation reduction reaction of the intermediate 4-hydroxy-3-methoxyphenylacetonitrile in a solvent in the presence of a metal catalyst and an alkaline additive to obtain the product 3-methoxytyramine.

2. The synthesis method according to claim 1, characterized in that, In step (1), the phase transfer catalyst is a crown ether compound.

3. The synthesis method according to claim 2, characterized in that, In step (1), the mass of the phase transfer catalyst is 0.5%-5% of the mass of 4-hydroxy-3-methoxybenzyl alcohol; the cyanating agent is sodium cyanide or potassium cyanide; and the molar ratio of 4-hydroxy-3-methoxybenzyl alcohol to the cyanating agent is 1:1.1-1:

2.

4. The synthesis method according to claim 1, characterized in that, In step (1), the organic solvent is N,N-dimethylformamide (DMF), and the amount of organic solvent used is 3-10 times the mass of 4-hydroxy-3-methoxybenzyl alcohol; the reaction temperature is 100℃-130℃, and the reaction time is 4-10h.

5. The synthesis method according to claim 1, characterized in that, In step (2), the metal catalyst is selected from palladium on carbon, nickel skeleton (Raney-Ni), or cobalt skeleton (Raney-Co); the amount of the metal catalyst is 5% to 20% of the mass of 4-hydroxy-3-methoxyphenylacetonitrile.

6. The synthesis method according to claim 1, characterized in that, In step (2), the alkaline additive is ammonia or an ammonia-methanol solution; the solvent is a C1-C4 alkyl alcohol.

7. The synthesis method according to claim 1, characterized in that, In step (2), the hydrogen pressure of the hydrogenation reduction reaction is 1.5-3.0 MPa, the reaction temperature is 40℃-100℃, and the reaction time is 6-12 h.

8. The synthesis method according to claim 1, characterized in that, The post-processing of step (1) includes: after the reaction is completed, the solvent is recovered under reduced pressure, the pH is adjusted to 6.5-7.5, extraction, washing, decolorization, and concentration to obtain the crude intermediate product; the post-processing of step (2) includes: after the reaction is completed, the catalyst is removed by filtration, the filtrate is concentrated, and the product is obtained by recrystallization using a crystallization solvent.

9. The synthesis method according to claim 1, characterized in that, In step (2), the amount of solvent used is 4-12 times the mass of 4-hydroxy-3-methoxyphenylacetonitrile; the amount of alkaline additive used is 1%-10% of the mass of 4-hydroxy-3-methoxyphenylacetonitrile.

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