Method for synthesizing anti-malarial drug lumefantrine

Abstract

The invention provides a method for synthesizing an anti-malarial drug lumefantrine, and relates to the technical field of chemical engineering. The preparation method comprises the following steps: carrying out reduction reaction on 4-acetylchloro-2, 7-dichlorofluorene and a reducing agent in an organic solvent to obtain an intermediate product; in an organic solvent in the presence of alkali, cyclizing the intermediate product to obtain 2, 7-dichlorofluorene-4-ethylene oxide; the product is subjected to a reaction with di-n-butylamine, and Alpha-(di-n-butylamine methyl)-2, 7-dichlorofluorene-4-methanol is obtained; and carrying out condensation reaction on the product and p-chlorobenzaldehyde to obtain the lumefantrine. The preparation technology is improved, n-butyl alcohol is adopted as a solvent, an intermediate in each step in the whole preparation process is not taken out, one-pot preparation of the lumefantrine is achieved, many devices such as reaction kettles, centrifugal machines and drying ovens are omitted for industrial production, corresponding human input is reduced, the product cycle is shortened, and the production cost is reduced. Factory profit is achieved to the maximum extent, and social resources are saved.

Description

Technical Field

[0001] This application relates to the field of chemical synthesis technology, and more specifically, to a method for synthesizing the antimalarial drug phenylfluorenol. Background Technology

[0002] Lumefrantrine is a racemic fluorene derivative of (Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-alpha-[(di-n-butylamino)methyl]-9H-fluorene-4-methanol. It was developed by the Chinese Academy of Military Medical Sciences and is my country's first antimalarial drug. Lumefrantrine exhibits excellent activity against malaria parasites, showing a very high kill rate against chloroquine-resistant and falciparum malaria parasites, and also has a significant killing effect on the intraerythral stage of both animal and human falciparum malaria parasites. Its advantages include no drug resistance or cross-resistance, low toxicity, and long-lasting antimalarial effect, but it has the disadvantage of a relatively slow onset of action. Researchers at the Chinese Academy of Military Medical Sciences combined it with artemether, which has a rapid onset of action, high kill rate, and is prone to relapse, to create a combination antimalarial drug, achieving a very satisfactory antimalarial effect. The ratio of artemether to fluorenol is 1:6. It has been included in the WHO's list of methylbenzene antimalarial drugs, and its usage is increasing year by year.

[0003] Malaria is a disease transmitted by mosquitoes and caused by Plasmodium, a type of protozoan. It is prevalent in tropical countries, with Africa, particularly sub-Saharan Africa, Southeast Asia (including Yunnan province in China), and South America being the most severely affected regions. Children under five years of age, who lack immunity to the disease, are more susceptible and have a higher mortality rate. Several forms of malaria exist, including tropical malaria (caused by Plasmodium falciparum), vivax malaria (caused by Plasmodium vivax or Plasmodium ovale), and malaria malaria (caused by Plasmodium malariae). Tropical malaria is the most severe form, leading to serious complications and cerebral malaria, which can cause coma and ultimately death.

[0004] The earliest report on the synthesis of fluoreneol was submitted by Deng Rongxian's team at the Academy of Military Medical Sciences (Novel Synthetic Process of the Antimalarial Drug fluoreneol, CN 1029680C). The route involved a five-step reaction: fluorene was chlorinated in glacial acetic acid to obtain 2,7-dichlorofluorene; then, it was acylated with aluminum trichloride to obtain 2,7-dichloro-4-chloroacetyl-fluorene; subsequently, it was reduced with potassium borohydride and cyclized with strong potassium oxide to obtain 2,7-dichloro-4-epoxyethylene-fluorene; this compound reacted with di-n-butylamine at high temperature to give α-(di-n-butylamino)-2,7-dichloro-4-fluorenemethanol; finally, this compound was condensed with p-chlorobenzaldehyde in ethanol to obtain fluoreneol, with a yield of approximately 15%. Subsequent reports on the synthesis of fluoreneol and its intermediates have all followed this patent in terms of route and steps.

[0005] However, the above methods still have many problems in the preparation of benzyl fluoreneol, such as long process routes, complicated operation, and difficult treatment, resulting in low equipment utilization, low total yield, low production capacity, and a lot of waste. Summary of the Invention

[0006] The purpose of this application is to provide a method for synthesizing the antimalarial drug phenfluorol. This method adopts a one-pot preparation process, which is simple, safe and environmentally friendly, with high equipment utilization, short cycle, high production capacity, and good product purity, making it suitable for industrial production.

[0007] To solve the above-mentioned technical problems, the technical solution adopted in this application is as follows: This application provides a method for synthesizing the antimalarial drug phenfluoreneol, wherein the structural formula of phenfluoreneol is shown in Formula I. Formula I; The preparation method includes the following steps: S1. In an organic solvent, 4-acetyl chloride-2,7-dichlorofluorene (compound of formula II) is reduced with a reducing agent to give the intermediate product 2-chloro-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol (compound of formula III). Formula II; Formula III; S2. In an organic solvent in the presence of a base, the above intermediate product (compound of formula III) is cyclized to obtain 2,7-dichlorofluorene-4-epoxyethylene (compound of formula IV). Formula IV; S3. In an organic solvent in the presence of a base, the above-mentioned 2,7-dichlorofluorene-4-epoxyethylene (compound IV) is reacted with di-n-butylamine to obtain Alpha-(di-n-butylaminemethyl)-2,7-dichlorofluorene-4-methanol (compound V). Formula V; S4. In an organic solvent in the presence of a base, the above-mentioned Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol (compound V) is subjected to a condensation reaction with p-chlorobenzaldehyde. After the reaction, a crude product is obtained by crystallization, and after purification, the benzenefluorene alcohol is obtained.

[0008] Compared with the prior art, the embodiments of this application have at least the following advantages or beneficial effects: 1. This application improves the preparation process using 4-acetylchloro-2,7-dichlorofluorene, employing n-butanol as a one-step solvent, unlike the traditional use of methanol or ethanol. n-Butanol is not miscible with water, so water washing can be used to remove impurities after two-phase or three-phase reactions. Therefore, intermediates at each step of the entire preparation process are not removed, achieving a "one-pot" production of benzylfluoreneol. This reduces the need for many reaction vessels, centrifuges, ovens, and other equipment in industrial production, thereby reducing manpower input and shortening the product cycle, maximizing factory profits and saving social resources.

[0009] 2. In addition, during the preparation process, although Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol (compound V) has basic functional groups, it is insoluble in acidic water under n-butanol solvent conditions, but soluble in n-butanol. The improved process of this application uses acid washing to remove impurities, so that it is not necessary to take it out at each step, and the purification is achieved at each step. Attached Figure Description

[0010] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0011] Figure 1 This is a diagram illustrating the synthetic route of phenylfluorenol in Example 1 of this application; Figure 2 This is the NMR spectrum of the product of Embodiment 1 of this application; Figure 3 This is the mass spectrum of the product in Example 1 of this application; Figure 4 for Figure 3 The mass spectrum corresponding to the chromatographic peak at retention time of 1.355 min; Figure 5 This is a physical image of the product in Embodiment 1 of this application. Detailed Implementation

[0012] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0013] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The present application will now be described in detail with reference to specific embodiments.

[0014] A method for synthesizing the antimalarial drug phenfluorenol, wherein the structural formula of phenfluorenol is shown in Formula I. Formula I; The preparation method includes the following steps: S1. In an organic solvent, the compound of formula II is reduced with a reducing agent to obtain the compound of formula III; Formula II; Formula III; S2. In an organic solvent in the presence of a base, the above compound III is cyclized to obtain compound IV; Formula IV; S3. In an organic solvent in the presence of a base, the above compound IV is reacted with di-n-butylamine to obtain compound V; Formula V; S4. In an organic solvent in the presence of an alkali, the above-mentioned compound V is subjected to a condensation reaction with p-chlorobenzaldehyde. After the reaction, crystallization is performed to obtain a crude product, which is then purified to obtain the benzenefluorenol.

[0015] In some embodiments of this application, the organic solvent in steps S1-S4 above is n-butanol, and the mass ratio of n-butanol to compound II is (4-6):1 w / w.

[0016] In some embodiments of this application, the reducing agent in step S1 above is sodium borohydride and / or potassium borohydride; the amount of the reducing agent added is in an equivalent ratio of (0.35-0.45):1 eq to the compound of formula II; the temperature of the reduction reaction is 10-20℃, and the reaction time is 4-6h.

[0017] In some embodiments of this application, the base in step S2 above is sodium bicarbonate and / or potassium bicarbonate; the amount of base added is in the equivalent ratio of (1.5-2.0):1 eq to the compound of formula II.

[0018] In some embodiments of this application, the temperature of the cyclization reaction in step S2 is 80-90°C and the reaction time is 3-5 hours.

[0019] In some embodiments of this application, the base in step S3 above is sodium carbonate and / or potassium carbonate, and the amount of base added is in an equivalent ratio of (1.5-2.0):1 eq to the compound of formula II.

[0020] In some embodiments of this application, the amount of di-n-butylamine used in step S3 above is in an equivalent ratio of (1.5-2.0):1 eq to the compound of formula II, the reaction temperature is 90-100℃, and the reaction time is 5-7 h. After the reaction, a 10% hydrochloric acid solution and saturated sodium chloride are added sequentially to wash the product.

[0021] In some embodiments of this application, the base in step S4 is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide, and the amount of base added is in an equivalent ratio of 1:(1.0-1.5)eq to the compound of formula II.

[0022] In some embodiments of this application, the equivalence ratio of p-chlorobenzaldehyde to compound II in step S4 is (1.05-1.25):1 eq, the condensation reaction temperature is 50-60°C, and the reaction time is 4-7 h.

[0023] In some embodiments of this application, the solvent used for purification in step S4 above is ethanol and / or n-butanol.

[0024] The features and performance of this application will be further described in detail below with reference to the embodiments. Example 1

[0025] This embodiment provides a method for synthesizing the antimalarial drug phenfluorol, the synthetic route of which is as follows: Figure 1 As shown, the specific steps are as follows: S1, Synthesis of 2,7-dichlorofluorene-4-epoxyethylene ( Figure 1 Compound 4): Preparation of sodium borohydride aqueous solution as reducing agent: At room temperature, add 50g ice water and 4g sodium hydroxide, stir until dissolved, add 4.24g (0.35eq) sodium borohydride, stir until dissolved, and pour into a constant pressure funnel for later use; In a 1L reaction flask equipped with a mechanical stirrer and a constant-pressure dropping funnel, add 100g of 4-acetyl chloride-2,7-dichlorofluorene ( Figure 1 Compound 2) and 500g n-butanol were added and stirred. A prepared sodium borohydride solution was then added dropwise. After the addition was complete, the mixture was kept at 15℃ for 5 hours, with the concentration of the starting material 4-acetyl chloride-2,7-dichlorofluorene ≤0.3%. 40.4g (2.0 eq) of sodium bicarbonate was added, and the mixture was stirred and heated to 85℃ for 4.5 hours, maintaining the intermediate state (…). Figure 1 Compound 3) ≤1%, add 200g water, the system is dissolved, the aqueous layer is separated while hot, the organic layer is a n-butanol solution or suspension of 2,7-dichlorofluorene-4-epoxyethylene (precipitated by cooling), HPLC 98%, directly proceed to the next step of reaction.

[0026] S2, Synthesis of Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol Figure 1 Compound 5): In the n-butanol system of 2,7-dichlorofluorene-4-epoxyethylene obtained in the previous step, stir and add 51.0 g (1.5 eq) of sodium carbonate, then add 62.2 g (1.5 eq) of di-n-butylamine (1.5 equivalent) dropwise. After the addition is complete, heat to 93℃ and react until the raw material 2,7-dichlorofluorene-4-epoxyethylene is ≤0.5%. Add 200 g of water to wash, then add 200 g of 10% hydrochloric acid to wash, then add 100 g of saturated sodium chloride to wash, to obtain an n-butanol solution of Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol with a purity of 90% by HPLC. Directly proceed to the next step. S3, Synthetic phenylfluorene alcohol ( Figure 1 Compound 1): In a n-butanol solution of Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol, add sodium hydroxide 19.3 g (1.5 eq) and stir. Then add 47.4 g (1.05 eq) of p-chlorobenzaldehyde dropwise. After the addition is complete, heat to 55 °C and react until the raw material Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol is ≤0.5%. Cool to 0 °C, add seed crystals, stir and crystallize overnight. Filter to obtain crude benzyl fluorene alcohol.

[0027] Take 300g of crude benzyl fluorene alcohol, heat to 65℃ and stir for 2h, cool to room temperature and stir for 1h, filter, add 350g of ethanol to the filter cake and reflux and stir for 1h, cool to room temperature and filter to obtain refined benzyl fluorene alcohol, 106.9g of light yellow solid, yield 63.0%, HPLC 99.7%, maximum impurity 0.15%.

[0028] The NMR spectrum of the phenylfluorene alcohol prepared in this embodiment is shown below. Figure 2 Shown: 1H NMR in CDCl3: δ7.72 (d, 2H, 2x Ar-H), 7.61 (d, 1H, Ar-H) 7.57 (s, 1H, Ar-H), 7.47 (s, 5H, 4xAr-H&C=CH-), 7.33 (dd, 1H, Ar-H), 5.33 (dd, IH, ArCH(OH)CH2N-), 4.55 (brd, 1H,-OH), 2.89 (dd, 1H, CH(OH)CH2N-), 2.69-2.54&2.52-2.45 (2 xm, 5H, CH(OH)CHN(CH2-)CH2-), 1.50-1.37 (m, 8H, N(CH2CH2CH2CH3)2), 0.96 (t, 6H , 2 x -CH3). Mass spectrum as shown Figure 3The figure shows (top: DAD 254 nm detection mass spectrometry; middle: DAD 214 nm detection mass spectrometry; bottom: MSD total ion current mass spectrometry). Figure 4 for Figure 3 The mass spectrum corresponding to the chromatographic peak at retention time of 1.355 min: MS m / s 530.2 [M+H] + . Example 2

[0029] This embodiment provides a method for synthesizing the antimalarial drug phenfluorol, the specific steps of which are as follows: Synthesis of S1,2,7-dichlorofluorene-4-epoxyethylene: Preparation of potassium borohydride aqueous solution: At room temperature, add 50g ice water and 4g sodium hydroxide, stir until dissolved, add 6.05g (0.35eq) potassium borohydride, stir until dissolved, and pour into a constant pressure funnel for later use; In a 1L reaction flask equipped with a mechanical stirrer and a constant-pressure dropping funnel, add 100g of 4-acetyl chloride-2,7-dichlorofluorene and 500g of n-butanol. Stir and start adding the prepared potassium borohydride solution dropwise. After the addition is complete, maintain the temperature at 18℃ for 6 hours, keeping the concentration of the starting material 4-acetyl chloride-2,7-dichlorofluorene ≤0.3%. Add 40.4g (2.0 eq) of sodium bicarbonate, stir and heat to 88℃, react for 4 hours, keeping the concentration of the intermediate state (compound of formula 3) ≤1%. Add 200g of water, and the system is dissolved. Separate the aqueous layer while hot. The organic layer is a n-butanol solution or suspension of 2,7-dichlorofluorene-4-epoxyethylene (precipitated by cooling). HPLC accuracy is 98%. Proceed directly to the next reaction step.

[0030] Synthesis of S2, Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol: In the n-butanol system of 2,7-dichlorofluorene-4-epoxyethylene obtained in the previous step, stir and add 66.5 g (1.5 eq) of potassium carbonate, then add 62.2 g (1.5 eq) of di-n-butylamine (1.5 equivalent) dropwise. After the addition is complete, heat to 95℃ and react until the raw material 2,7-dichlorofluorene-4-epoxyethylene is ≤0.5%. Add 200 g of water to wash, then add 200 g of 10% hydrochloric acid to wash, then add 100 g of saturated sodium chloride to wash, to obtain an n-butanol solution of Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol with a purity of 90% by HPLC. Directly proceed to the next step. Synthesis of S3, phenylfluorene alcohol: In a n-butanol solution of Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol, add 27.0 g (1.5 eq) of potassium hydroxide and add 47.4 g (1.05 eq) of p-chlorobenzaldehyde dropwise. After the addition is complete, heat to 53 °C and react until the raw material Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol is ≤0.5%. Then cool to -3 °C, add seed crystals, stir and crystallize overnight, filter to obtain crude benzylfluorene alcohol.

[0031] Add 300g of crude benzyl fluorene alcohol, heat to 66℃ and stir for 2 hours, cool to room temperature and stir for 1 hour, filter, add 350g of ethanol to the filter cake and reflux and stir for 1 hour, cool to room temperature and filter to obtain refined benzyl fluorene alcohol, 110.3g of light yellow solid, yield 65.0%, HPLC ≥ 99.6%, maximum impurity ≤ 0.17%.

[0032] In summary, the method for synthesizing the antimalarial drug phenfluoreneol according to the embodiments of this application has the following advantages: 1. This application improves the preparation process by using 4-acetylchloro-2,7-dichlorofluorene and adopts n-butanol as the solvent for one-step production, unlike the traditional use of methanol or ethanol solvent. n-Butanol is not miscible with water, so water washing can be used to remove impurities after two-phase or three-phase reaction. Therefore, the intermediates in each step of the entire preparation process are not removed, realizing the "one-pot" production of phenfluoreneol. This reduces the need for many reaction vessels, centrifuges, ovens and other equipment in industrial production, reduces the corresponding manpower input and shortens the product cycle, maximizing factory profits and saving social resources.

[0033] 2. In addition, during the preparation process, although Alpha-(di-n-butylaminomethyl)-2,7-dichlorofluorene-4-methanol (compound V) has a basic functional group, it is insoluble in acidic water under n-butanol, but soluble in n-butanol. The improved process of this application uses acid washing to remove impurities, so that it is not necessary to take it out at each step, and the purification is achieved at each step.

[0034] The embodiments described above are some, but not all, of the embodiments of this application. The detailed description of the embodiments of this application is not intended to limit the scope of the claimed application, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

Claims

1. A method for synthesizing the antimalarial drug phenfluoreneol, characterized in that, The structural formula of the benzylfluoreneol is shown in Formula I. Formula I; The preparation method includes the following steps: S1. In an organic solvent, the compound of formula II is reduced with a reducing agent to obtain the compound of formula III; Formula II; Formula III; S2. In an organic solvent in the presence of a base, the above compound III is cyclized to obtain compound IV; Formula IV; S3. In an organic solvent in the presence of a base, the above compound IV is reacted with di-n-butylamine to obtain compound V; Formula V; S4. In an organic solvent in the presence of a base, the above-mentioned compound V is subjected to a condensation reaction with p-chlorobenzaldehyde. After the reaction, crystallization is performed to obtain a crude product, which is then purified to obtain benzenefluorenol as shown in Formula I.

2. The method for synthesizing the antimalarial drug phenfluoreneol according to claim 1, characterized in that, The organic solvent used in steps S1-S4 is n-butanol, and the mass ratio of the amount of n-butanol added to the compound of formula II is (4-6):1 w / w.

3. A method for synthesizing the antimalarial drug phenfluoreneol according to claim 1, characterized in that, The reducing agent in step S1 is sodium borohydride and / or potassium borohydride; the equivalence ratio of the amount of reducing agent added to the compound of formula II is (0.35-0.45):1 eq; the temperature of the reduction reaction is 10-20℃, and the reaction time is 4-6h.

4. A method for synthesizing the antimalarial drug phenfluoreneol according to claim 1, characterized in that, The base in step S2 is sodium bicarbonate and / or potassium bicarbonate; the amount of base added is in the equivalent ratio of (1.5-2.0):1 eq to the compound of formula II.

5. The method for synthesizing the antimalarial drug phenfluorol according to claim 4, characterized in that, The cyclization reaction in step S2 is carried out at a temperature of 80-90℃ for 3-5 hours.

6. A method for synthesizing the antimalarial drug phenfluoreneol according to claim 1, characterized in that, The base in step S3 is sodium carbonate and / or potassium carbonate, and the equivalence ratio of the amount of base added to the compound of formula II is (1.5-2.0):1 eq.

7. A method for synthesizing the antimalarial drug phenfluoreneol according to claim 6, characterized in that, In step S3, the amount of di-n-butylamine used is in an equivalent ratio of (1.5-2.0):1 eq to the compound of formula II, the reaction temperature is 90-100℃, and the reaction time is 5-7h.

8. A method for synthesizing the antimalarial drug phenfluoreneol according to claim 1, characterized in that, The base in step S4 is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide, and the equivalence ratio of the amount of base added to the compound of formula II is (1.0-1.5):1 eq.

9. A method for synthesizing the antimalarial drug phenfluoreneol according to claim 8, characterized in that, In step S4, the equivalence ratio of p-chlorobenzaldehyde to compound II is (1.05-1.25):1 eq, the condensation reaction temperature is 50-60℃, and the reaction time is 4-7h.

10. The method for synthesizing the antimalarial drug phenfluoreneol according to claim 1, characterized in that, The solvent used for purification in step S4 is ethanol and / or n-butanol.

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