A novel preparation method of naphthofuramate
Through one-step carbonylation reaction, the use of cheap metal nickel catalyst and gas CO as the carbonaceous source is used to directly synthesize naphthalate, solving the problems of cumbersome and high cost in the prior art, and achieving efficient and low-cost naphthalate production.
Patent Information
- Application Number
- CN202210644707.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-06-08
- Publication Date
- 2025-08-19
- Estimated Expiration
- 2042-06-08
AI Technical Summary
The existing synthesis methods of naphthalate are cumbersome and costly, with low synthesis efficiency, making it difficult to achieve simplification and cost reduction.
The synthesis route was simplified by the one-step carbonylation reaction using cheap metal nickel catalyst and gas CO as the carbonyl source.
The efficient synthesis of naphthalfuromidate is achieved, which reduces production costs, improves synthesis efficiency, and avoids the use of expensive transition metal catalytic systems.
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Abstract
Description
Technical Field
[0001] The present invention relates to a method for synthesizing naphthofuram. Background Art
[0002] Nafuramide, also known as clarithromycin, is a peripheral vasodilator. It is used to treat various conditions caused by cerebrovascular disease, such as cerebral metabolic disorders, stroke sequelae, and Alzheimer's disease. It is also widely used for peripheral vascular disease, intermittent diarrhoea, painful spasms, vasculitis, capillaritis, diabetic arteriopathic artery disease, and nutritional ulcers.
[0003] The current industrial manufacturing methods for naphthofuram have the disadvantages of high production costs and complicated procedures. Most current synthesis methods require 5-6 steps, which greatly reduces the synthesis efficiency. In the past two decades, chemists have also made new attempts to synthesize naphthofuram, with the aim of making the synthesis route simpler and more cost-effective, but these new attempts have mainly focused on a single step in the synthesis route. To this end, we have also further studied and improved the synthesis method of naphthofuram, designed a four-component carbonylation reaction of 1-allylnaphthalene, tetrahydrofuran, and diethylaminoethanol, and directly synthesized naphthofuram through a one-step method, greatly shortening the synthesis route.
[0004] In summary, this paper describes a novel nickel-catalyzed carbonylation esterification of olefins to prepare naphthofuramin esters. Summary of the Invention
[0005] The object of the present invention is to provide a method for synthesizing naphthofuram.
[0006]
[0007] Reaction Equation 1: Synthesis of naphthofuram ester
[0008] The specific operation steps are as follows (reaction equation 1):
[0009] The reaction is carried out in a 300 ml autoclave. The catalyst, catalyst promoter, and alcohol are weighed. Peroxide and tetrahydrofuran are injected under a nitrogen atmosphere. The reaction is placed in a carbon monoxide atmosphere at 70-150°C, preferably 110-130°C. The reaction time is 10-36 hours, preferably 18-24 hours. After the reaction is completed, naphthofuram ester 4 is isolated.
[0010] The catalyst is nickel di(acetylacetonate), nickel acetate, nickel chloride, or nickel iodide, preferably nickel di(acetylacetonate). The catalyst promoter is 6,6'-dimethyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, or 2,2'-bipyridine, preferably 4,4'-dimethyl-2,2'-bipyridine.
[0011] The molar ratio of alcohol to nickel di(acetylacetonate) and 6,6'-dimethyl-2,2'-bipyridine is 100:1:1-100:20:20, preferably 100:5:5-100:10:10.
[0012] The gas pressure of carbon monoxide is 1 to 30 atmospheres, preferably 1 to 10 atmospheres.
[0013] The present invention has the following advantages:
[0014] First, the one-step process replaces the traditional multi-step reaction, eliminating the need for complex steps, reducing costs and significantly improving synthesis efficiency. Second, the carbonylation synthesis of naphthofuram esters does not require expensive transition metal catalysis systems. Third, the carbonyl gas CO is used as the carbonyl source, which is inexpensive and readily available.
[0015] The invention uses gaseous CO as a carbonyl source and, under the action of a catalytic amount of a cheap metal nickel catalyst, obtains the product of ether naphthyl furan ester with high atomic utilization and high efficiency. DETAILED DESCRIPTION
[0016] In order to better understand the present invention, the following examples are provided for illustration:
[0017]
[0018] Example 1
[0019] The reaction was carried out in a 300 ml autoclave. First, nickel diacetylacetonate (0.015 mmol) and 4,4'-dimethyl-2,2'-bipyridine (0.015 mmol) were added to a 4 ml glass vial and mixed. Under a nitrogen atmosphere, 1.5 ml of tetrahydrofuran was added as a solvent, and diethylaminoethanol 3 (0.3 mmol) and di-tert-butyl peroxide (0.75 mmol) were injected to obtain a mixture. The vial was capped with a rubber cap. The reaction vial was placed in a high-pressure reactor, and carbon monoxide was replaced in the high-pressure reactor by filling it with 5 atmospheres of carbon monoxide. At this time, the carbon monoxide in the reactor was connected to the interior of the vial through the needle. The reaction was then carried out at 120° C. for 22.0 hours. After the reaction was completed, naphthofuram ester 4 was obtained by column chromatography separation with a yield of 46%. The compound was identified by nuclear magnetic resonance (H and C) and high-resolution mass spectrometry.
[0020] The test data is as follows:
[0021] 4: 1H NMR (400MHz, CDCl3) δ8.10–7.99(m,1H),7.83(d,J=9.8Hz,1H),7.72(d,J=8.0Hz,1H),7.5 6–7.42(m,2H),7.42–7.28(m,2H),4.12–3.94(m,2H),3.92–3.72(m,2H),3.72–3.57(m,1H ),3.48–3.31(m,1H),3.33–3.20(m,1H),3.19–3.04(m,0.6H),3.04–2.88(m,0.4H),2.51– 2.29(m,6H),2.11–1.89(m,3H),1.89–1.78(m,2H),1.51–1.32(m,1H),0.99–0.83(m,6H).
[0022] 13 C NMR (100MHz, CDCl3) δ175.6,135.2,133.9,131.9,128.7,127.2,127.1,126.0,125.5,125.3,123.7,123.7,77.3, 77.2,67.6,67.5,62.3,50.7,47.6,47.4,44.5,44.1,38.2,38.0,36.4,35.9,31.6,31.4,25.6,25.5,11.9,11.8.
[0023] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 24 H 34 NO3 384.2533; Found:384.2538.
[0024] Example 2
[0025] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operation process and conditions are the same as Example 1), the difference is that the catalytic agent of the reaction is changed to 2,2'-bipyridine, the yield of the target product naphthofuramin ester will be 23%, and the raw material olefin will remain.
[0026] Example 3
[0027] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operating process and conditions are the same as in Example 1), the difference is that the reaction temperature is reduced to 100 degrees Celsius, and the yield of the target product naphthofuramin ester is reduced to 21%.
[0028] Example 4
[0029] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the amount of peroxide in the reaction is reduced to 2 equivalents, and the yield of the target product naphthofuramin ester is reduced to 38%, at which time the raw material is fully converted.
[0030] Example 5
[0031] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is changed to nickel chloride, and the yield of the target product naphthofuramin ester is reduced to 14%, at which time the raw materials are fully converted.
[0032] Example 6
[0033] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the carbon monoxide pressure of the reaction is increased to 10 bar, and the yield of the target product naphthofuramin ester is 44%, at which time the raw material is fully converted.
[0034] Comparative Example 1
[0035] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the reaction temperature is reduced to 60 degrees Celsius, the yield of the target product naphthofuramin ester is reduced to 0%, and a large amount of raw materials remain.
[0036] Comparative Example 2
[0037] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is changed to copper acetate, the yield of the target product naphthofuramin ester is reduced to 0%, and a large amount of raw materials remain.
[0038] Comparative Example 3
[0039] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the co-catalyst of the reaction is changed to triphenylphosphine, the yield of the target product naphthylfuran ester is reduced to 3%, and the raw materials are fully converted.
[0040] Comparative Example 4
[0041] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operating process and conditions are the same as in Example 1), the difference is that the peroxide in the reaction is removed, the yield of the target product naphthofuramin ester is reduced to 0%, and a large amount of raw materials remain.
[0042] Comparative Example 5
[0043] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operating process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is removed, the yield of the target product naphthofuramin ester is reduced to 0%, and a large amount of raw materials remain.
Claims
1. A method for preparing naphthofuramin, characterized in that: The naphthyl furan ester product is prepared from 1-allyl naphthalene 1, tetrahydrofuran 2, carbon monoxide and diethylaminoethanol 3, and the reaction formula is as follows: ； The specific steps are as follows: The reaction is carried out in a high-pressure reactor. The catalyst and catalyst promoter are weighed. Tetrahydrofuran (2), 1-allylnaphthalene (1), diethylaminoethanol (3), and peroxide are sequentially injected into the mixture under a nitrogen atmosphere to obtain a mixture. The mixture is placed in a reactor or the mixture is mixed or prepared directly in the reactor. The atmosphere in the reactor is replaced with carbon monoxide gas. The reaction is carried out at 70-150° C. for 10-36 hours. After the reaction is completed, naphthofuramate is isolated. The peroxide is one or more of hydrogen peroxide, cumene hydroperoxide, tert-butyl perbenzoate, and di-tert-butyl peroxide; The catalyst is one or more of nickel di(acetylacetonate), nickel acetate, nickel chloride, and nickel iodide; The catalyst auxiliary agent is one or more of 6,6'-dimethyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine and 2,2'-bipyridine.
2. The preparation method according to claim 1, characterized in that: The reaction temperature is 110-130°C; the reaction time is 18-24 hours; The peroxide is di-tert-butyl peroxide; The catalyst is nickel di(acetylacetonate); The catalyst auxiliary agent is 4,4'-dimethyl-2,2'-bipyridine.
3. The preparation method according to claim 1, characterized in that: The molar ratio of diethylaminoethanol 3 to the catalyst and catalyst auxiliary is 100:1:1-100:20:
20.
4. The preparation method according to claim 3, characterized in that: The molar ratio of diethylaminoethanol 3 to the catalyst and catalyst auxiliary is 100:5:5-100:10:
10.
5. The preparation method according to claim 1, characterized in that: The molar ratio of diethylaminoethanol 3 to peroxide is 1:1-1:
5.
6. The preparation method according to claim 5, characterized in that: The molar ratio of diethylaminoethanol 3 to peroxide is 1:2-1:
3.
7. The preparation method according to claim 1, characterized in that: The atmospheric pressure of carbon monoxide is 1-30 atmospheres; The total volume of the reaction substrate, catalyst, co-catalyst and peroxide shall not exceed 50% of the volume of the high-pressure reactor.
8. The preparation method according to claim 7, characterized in that: The atmospheric pressure of carbon monoxide is 1-10 atmospheres.
9. The preparation method according to claim 1, characterized in that: The above tetrahydrofuran 2 serves as both a solvent and a reaction substrate in the reaction; the amount of tetrahydrofuran 2 used is 0.1-2.0 ml per 0.3 mmol of diethylaminoethanol 3.
10. The preparation method according to claim 9, characterized in that: The amount of tetrahydrofuran 2 used is 1.0 - 1.8 ml per 0.3 mmol of diethylaminoethanol 3.