CN116574014A

CN116574014A - Preparation method of zolmitriptan intermediate

Info

Publication number: CN116574014A
Application number: CN202310613940.7A
Authority: CN
Inventors: 史海超; 褚杰; 花凯; 娄亮; 赵宗民; 李铁军
Original assignee: Shandong Ruishun Pharmaceutical Co ltd
Current assignee: Shandong Ruishun Pharmaceutical Co ltd
Priority date: 2023-05-25
Filing date: 2023-05-25
Publication date: 2023-08-11

Abstract

The invention provides a preparation method of an zolmitriptan intermediate, which comprises the following steps: the method comprises the steps of taking sulfuric acid aqueous solution as a solvent, taking concentrated nitric acid or fuming nitric acid as a nitrifying reagent, and performing nitration reaction on L-phenylalanine in a microchannel reactor to obtain 4-nitro-L-phenylalanine. The 4-nitro-L-phenylalanine is subjected to reduction reaction to prepare the 4-nitro-L-amphetamine alcohol. The method for preparing 4-nitro-L-phenylalanine reduces the consumption of concentrated sulfuric acid or mixed acid, reduces the cost, and is more beneficial to environmental protection; the reaction condition is mild, the realization and control are easy, the preparation period is short, the purification is simple, the energy consumption is low, and the cost is further reduced; good reaction selectivity, less byproducts and high yield and purity of target products. The method for preparing 4-nitro-L-amphetamine alcohol is safe, environment-friendly, reduces the generation of waste liquid and has low cost; few impurities, simple purification steps and high yield and purity of the target product.

Description

Preparation method of zolmitriptan intermediate

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an zolmitriptan intermediate.

Background

Zolmitriptan (Zolmitriptan), chemical name: (S) -4- [ [3- [2- (dimethylamino) ethyl ]]Indol-5-yl]Methyl group]-2-oxazolidinones of formula C ₁₆ H ₂₁ N ₃ O ₂ Molecular weight 287.36, having a chemical structure represented by formula 1:

zolmitriptan (Zolmitriptan) was first developed by Wellcom corporation, england, for the acute treatment of moderate and severe migraine with or without symptoms of aura. Zolmitriptan patent (US 5466699) was first obtained on 12 months of 1991. And then assigned to UK Jielikang (Zenece) and sold for the first time in the Federal of English in 3 months 1997 under the trade name Zomig. The FDA approved 11 th 1997 for market in the united states. And then sold in member countries of the European Union, such as Germany, netherlands, denmark, etc. The dosage forms on the market include tablets, dispersible tablets, buccal tablets, capsules and the like.

Zolmitriptan is a novel, efficient and specific drug for treating acute migraine, is a highly selective 5-HT1B/1D receptor agonist, and can relieve the attack of migraine by activating 5-HT1 receptor to cause vasoconstriction and inhibit release of neuropeptides. The pharmacological study results showed that: zolmitriptan not only can control peripheral blood flow of brain, but also can act on pain center of brain, thereby playing a role in treating migraine.

At present, a plurality of patents and documents at home and abroad report on a synthesis method of zolmitriptan. The existing zolmitriptan has more synthetic routes, and most of the zolmitriptan takes L-phenylalanine or 4-nitro-L-phenylalanine as a starting material, and the target compound is obtained through 7-9 steps of reaction. The relevant synthetic routes are summarized as follows:

the synthesis route I is as follows:

this route starts from 4-nitro-L-phenylalanine, first with MeOH and SOCl ₂ Reacting to form ester, and then passing through NaBH ₄ Reducing to obtain corresponding alcohol; closing the ring of alcohol and phosgene under alkaline conditions to obtain a compound 5; compound 5 via H ₂ Reduction of nitro group by Pd/C to give Compound 6; diazotizing the compound 6 to obtain a compound 7; the compound 7 and 4-chlorobutyraldehyde glycol undergo a rearrangement reaction to generate an indole cycloamino compound, and the compound and NaBH ₃ CN/HCHO reaction to obtain target compound 1.

The synthesis route II is as follows:

the process uses L-phenylalanine as a starting material, and the L-phenylalanine and nitric acid are subjected to nitration reaction under the catalysis of sulfuric acid to generate a compound 2. Compound 2 is catalyzed by Lewis acid boron trifluoride and an expensive boron trifluoride dimethyl sulfide reaction is used to produce compound 4. Compound 4 is cyclized with phosgene to obtain compound 5. And then go through H ₂ Reduction and diazotization of/Pd/C gives compound 7. The compound 7 and 3-cyano diethyl acetal undergo condensation reaction, then cyclize under the action of p-toluenesulfonic acid to generate indole compound, finally in H ₂ Reacting with dimethylamine under the catalysis of Pd/C to generate the target compound 1.

The synthesis route III:

the route uses L-phenylalanine as a starting material, and comprises the steps of first preparing a solution in HNO ₃ And H is ₂ SO ₄ Para-nitration under the action of (2) to give compound (2) with MeOH and SOCl ₂ The reaction gives an esterified product 3, which is prepared by NaBH ₄ Reduction to obtain hydroxyBase compound 4. And (3) carrying out cyclization reaction with solid phosgene (triphosgene) to obtain a compound 5. Reducing nitro group by hydrazine hydrate to obtain a compound 6; and diazotizing to obtain the compound 7. The target compound 1 is prepared by the Fischer (Fischer) indole synthesis reaction of the compound 7 and 4- (dimethylamino) butyraldehyde diethanol.

In the synthetic route, the intermediate compound 2 and the intermediate compound 4 with the same structure are prepared by different methods or conditions; the compound is an important structural fragment for preparing zolmitriptan and is an important intermediate for preparing zolmitriptan.

However, the method for preparing the intermediate compound 2, namely 4-nitro-L-phenylalanine has the advantages of large consumption of concentrated sulfuric acid and concentrated nitric acid, large waste acid production, environmental protection and high cost; the reaction temperature is lower, the reaction condition is harsh, the energy consumption is high, the reaction period is long, and the cost is further increased; the nitration reaction has poor selectivity, more ortho-position byproducts, complicated purification steps and low yield and purity of target products. The method for preparing the intermediate compound 4, namely 4-nitro-L-amphetamine alcohol, adopts a method of firstly esterifying and then reducing the nitrified L-phenylalanine, the esterification of amino acid is generally hydrochloric acid or thionyl chloride for catalytic esterification, the two are strong acid and volatile, the equipment and personnel are extremely unfriendly, more acid waste liquid is generated in the post-treatment, a large amount of dangerous waste is generated, and the requirements of current green production are not met; and a large amount of impurities are generated, and the yield and purity of the target product are low. The prior art also reports a method for reducing alpha-amino acid into alpha-amino alcohol in one step, but the reaction degree of a target product is poor, the yield is lower, the impurities are more, and the purity is lower; the product yield is further reduced by purifying for a plurality of times to obtain the product meeting the requirements, the production cost of the product is increased, a large amount of solvent is used by purifying for a plurality of times, the treatment pressure of the organic solvent is further increased, and the environmental protection and the waste liquid treatment are not facilitated.

The present invention has been made to solve the above-described problems.

Disclosure of Invention

Aiming at the defects existing in the prior art, the invention provides a preparation method of an zolmitriptan intermediate. The method for preparing the intermediate compound 2, namely 4-nitro-L-phenylalanine, reduces the consumption of concentrated sulfuric acid or mixed acid (concentrated sulfuric acid and concentrated nitric acid), reduces the production of strong acid waste liquid, reduces the cost, and is more beneficial to environmental protection; the reaction condition is mild, the realization and control are easy, the preparation period is short, the purification is simple, the energy consumption is low, and the cost is further reduced; good reaction selectivity, less byproducts and high yield and purity of target products. The method for preparing the intermediate compound 4, namely 4-nitro-L-amphetamine alcohol, is safe, environment-friendly, reduces the generation of waste liquid and has low cost; few impurities, simple purification steps and high yield and purity of the target product.

The technical scheme of the invention is as follows:

a preparation method of a zolmitriptan intermediate 4-nitro-L-phenylalanine comprises the following steps: the method comprises the steps of taking sulfuric acid aqueous solution as a solvent, taking concentrated nitric acid or fuming nitric acid as a nitrifying reagent, and performing nitration reaction on L-phenylalanine in a microchannel reactor to obtain 4-nitro-L-phenylalanine.

According to the invention, the mass fraction of the aqueous sulfuric acid solution is preferably 75 to 98%, preferably 75 to 85%.

According to the invention, the mass fraction of nitric acid in the concentrated nitric acid or fuming nitric acid is preferably 64-97%.

According to the invention, the mass ratio of the aqueous sulfuric acid solution to the L-phenylalanine is preferably 1-5:1, preferably 1-2:1.

According to the invention, the molar ratio of the nitrifying agent concentrated nitric acid or fuming nitric acid to L-phenylalanine is 1-2:1; preferably 1:1.

According to the invention, the nitration temperature is preferably from-5 to 30℃and preferably from 5 to 20 ℃.

According to the invention, the nitration time is preferably from 20 seconds to 300 seconds, preferably from 28 seconds to 60 seconds.

According to the invention, the microchannel reactor is commercially available.

According to the present invention, a preferred method for producing 4-nitro-L-phenylalanine comprises the steps of: dissolving L-phenylalanine in sulfuric acid aqueous solution to obtain L-phenylalanine solution; and respectively and simultaneously introducing the L-phenylalanine solution and concentrated nitric acid or fuming nitric acid into a micro-channel reactor, and performing nitration reaction on the L-phenylalanine to obtain the zolmitriptan intermediate 4-nitro-L-phenylalanine.

Preferably, the flow rate of the L-phenylalanine solution is 0.5-2ml/min; the flow rate of the concentrated nitric acid or fuming nitric acid is 0.3-1ml/min; preferably, the flow rate of the L-phenylalanine solution is 1ml/min; the flow rate of the concentrated nitric acid or fuming nitric acid is 0.6ml/min.

According to the present invention, preferably, the method for post-treating the reaction liquid obtained by the nitration reaction comprises the steps of: and (3) introducing the reaction solution into water with the temperature below 10 ℃, fully and uniformly mixing, and filtering, washing and drying to obtain the 4-nitro-L-phenylalanine.

A preparation method of a zolmitriptan intermediate 4-nitro-L-amphetamine alcohol comprises the following steps: 4-nitro-L-phenylpropanol (chemical name, (S) -2-amino-3- (4-nitrophenyl) propanol) is prepared by reduction reaction of the obtained 4-nitro-L-phenylalanine (chemical name, (S) -2-amino-3- (4-nitrophenyl) propionic acid) in a solvent in the presence of a reducing agent.

According to a preferred embodiment of the invention, the solvent consists of solvent a and solvent B;

the solvent A is one or the combination of more than two of tetrahydrofuran, methyltetrahydrofuran, methanol or ethanol; preferably, the solvent A is tetrahydrofuran;

the solvent B is one or the combination of more than two of toluene, dimethylbenzene or dioxane; preferably, the solvent B is toluene;

the volume ratio of the solvent A to the solvent B is 1:0.5-10, preferably 1:1-4.

Preferably, solvent A and solvent B are added prior to the addition of 4-nitro-L-phenylalanine, or solvent A is added prior to the addition of 4-nitro-L-phenylalanine and solvent B is added after the addition of 4-nitro-L-phenylalanine.

According to the invention, the ratio of the mass of 4-nitro-L-phenylalanine to the volume of the solvent is preferably 0.01-0.1g/mL.

According to a preferred embodiment of the invention, the reducing agent is sodium borohydride, potassium borohydride, sodium borohydride-wayEasily-basic acid, potassium borohydride-Lewis acid, potassium borohydride-iodine, sodium borohydride-H ₂ SO ₄ Or potassium borohydride-H ₂ SO ₄ One of them.

Preferably, the lewis acid is one or a combination of more than two of aluminum chloride, zinc chloride, lithium chloride, nickel chloride, palladium chloride or calcium chloride.

Preferably, the molar ratio of sodium borohydride or potassium borohydride to Lewis acid in the sodium borohydride-Lewis acid or potassium borohydride-Lewis acid is 1-6:1, preferably 2-4:1, more preferably 2:1; in the potassium borohydride-iodine and the sodium borohydride-iodine, the molar ratio of the sodium borohydride or the potassium borohydride to the iodine is 1-3:1, preferably 1-1.5:1, more preferably 1.1:1; sodium borohydride-H ₂ SO ₄ Potassium borohydride-H ₂ SO ₄ In which sodium or potassium borohydride and H ₂ SO ₄ The molar ratio of (2) is 1-3:1, preferably 1-1.5:1, more preferably 1.1:1.

According to the invention, the molar ratio of 4-nitro-L-phenylalanine to reducing agent is preferably 1:1-8.

According to the present invention, preferably, 4-nitro-L-phenylalanine may be added to the reaction system at one time or in divided portions.

According to the present invention, 4-nitro-L-phenylalanine is preferably produced as described above.

According to the invention, the preparation method of the zolmitriptan intermediate 4-nitro-L-amphetamine comprises the following steps:

adding a reducing agent and 4-nitro-L-phenylalanine into the solvent A; then adding a solvent B, and reacting to obtain an zolmitriptan intermediate 4-nitro-L-amphetamine alcohol;

or, adding a reducing agent into the solvent A, and adding 4-nitro-L-phenylalanine in batches; then adding a solvent B, and reacting to obtain the zolmitriptan intermediate 4-nitro-L-amphetamine.

Preferably, the step of heating and refluxing is further included after the reducing agent and the 4-nitro-L-phenylalanine are added into the solvent A; the heating reflux reaction temperature is 60-66 ℃ and the reaction time is 1-5h.

Preferably, the method further comprises the step of heating and refluxing before adding the 4-nitro-L-phenylalanine in batches; alternatively, the method may further comprise a step of heating and refluxing after the 4-nitro-L-phenylalanine is added in portions; the heating reflux reaction temperature is 60-66 ℃ and the reaction time is 1-5h.

Preferably, the reaction temperature after adding the solvent B is 66-140 ℃, preferably 80-100 ℃; the reaction time is 2 to 24 hours, preferably 6 to 12 hours.

Preferably, when 4-nitro-L-phenylalanine is added in portions, it is added in 2-4 portions and is added over 5-15 minutes.

According to the present invention, a method for post-treating a reaction solution obtained by reducing 4-nitro-L-phenylalanine comprises the steps of:

stirring and cooling the reaction liquid to room temperature, dripping water for quenching, filtering, extracting the water phase with toluene or ethyl acetate, merging the organic phases, drying the organic phases through anhydrous magnesium sulfate or anhydrous sodium sulfate, filtering, and concentrating under reduced pressure until the organic phases are dried to obtain 4-nitro-L-amphetamine;

or, stirring and cooling the reaction liquid to room temperature, cooling the reaction liquid to 0-10 ℃ by ice water, and filtering to remove solids; dropwise adding a sodium hydroxide aqueous solution into the obtained filtrate, and filtering to remove generated solids; separating the obtained filtrate, extracting the water phase with toluene or ethyl acetate, mixing the organic layers, drying the organic phase with anhydrous magnesium sulfate or anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain 4-nitro-L-amphetamine;

or, stirring and cooling the reaction liquid to room temperature, cooling the reaction liquid to 0-10 ℃ by ice water, and filtering to remove solids; washing the obtained filtrate with water, separating the liquid, and concentrating the organic layer under reduced pressure to dryness to obtain the 4-nitro-L-amphetamine alcohol.

The synthetic route of the invention is as follows:

the invention has the technical characteristics that:

preparation of 4-nitro-L-phenylalanine:

through research improvement, the invention adjusts the concentration and the dosage of the concentrated sulfuric acid of the solvent, reduces the dosage of the concentrated sulfuric acid or the mixed acid (the concentrated sulfuric acid and the concentrated nitric acid) of the solvent, reduces the dosage from 3-4 times of the conventional dosage to 1-2 times of the conventional dosage, avoids generating a large amount of strongly acidic waste liquid, is environment-friendly and has low cost.

Meanwhile, the use of the nitrifying reagent is reduced through optimizing the proportion, the molar quantity of nitric acid for nitrifying is reduced to 1:1 through adopting a microchannel reactor, the nitrifying reaction temperature is controlled stably and well, the reaction is carried out at a higher, mild and easily-realized reaction temperature, the reaction period is short, meanwhile, the risk of out-of-control of the nitrifying temperature can be completely controlled, and the reaction is safe, green and environment-friendly, and the cost is further reduced.

After the process is improved, the isomer of the nitrified product is effectively controlled, the nitrified product prepared by the process reported in the literature contains about 10% -20% of o-nitro isomer, after the process is improved, the para-nitrified product (namely 4-nitro-L-phenylalanine) with high purity can be obtained by using the method of the invention without purification or simple post-treatment, the reaction selectivity is good, the purity of the product can reach more than 97%, and the isomer is greatly reduced to within 3.5%. The purity can be directly used for reaction without further refining.

The highest nitration reaction yield of L-phenylalanine is 68% in Zymtriptan synthesis process research of Zhongmiatriptan university paper, and other prior documents report that the yield is not more than 60%. The improved process of the invention improves the production efficiency and the yield of the nitrified product, and the yield is improved to more than 88% from less than 60% due to avoiding the production of nitrified isomers, thereby shortening the production time, reducing the production cost and reducing the discharge and the treatment of a large amount of acid hazardous wastes.

The nitration reaction is a reaction process of introducing nitro into organic compound molecules, the mechanism of the reaction process is mainly divided into two types, the nitration of aliphatic compounds is generally realized through free radical processes, the reaction processes are complex, and different systems can be different; the reaction history is typical of electrophilic substitution reactions for aromatic compounds. In the reaction, the hydroxyl group of nitric acid is protonated and dehydrated to form nitroxyl cation (NO ₂ And then carrying out electrophilic aromatic substitution reaction with benzene ring, and removing one molecule of hydrogen ions. The common nitrifying reagent is concentrated nitric acid, fuming nitric acid, concentrated sulfuric acid and mixed acid of concentrated sulfuric acid and nitric acid are common dehydrating agents, and the existence of strong acid materials has strict requirements on reaction equipment. The heat release enthalpy in the nitration reaction is increased, the strong heat release reaction is realized, the vast majority of reaction heat exceeds 600J/g, the reaction is very severe, and the material flushing or explosion accident is easily caused by out-of-control, so the nitration reaction is also classified as a dangerous supervision process. In order to control the reaction rate, heat generated by the reaction is timely led out, the nitration reaction needs to be cooled and controlled, and the temperature is difficult to control and also can not generate nitrated isomer or polynitro products, so that the purity of the products is reduced, and the cost is increased. According to the invention, after the microchannel reactor is used, the contact time and concentration of the nitrifying reagent and the reaction raw materials can be effectively controlled, the heat dissipation area is increased, and the reacted product is led out and quenched in time; the invention effectively inhibits the occurrence of side reaction and improves the selectivity and conversion rate of the reaction by adopting the micro-channel reactor. And meanwhile, the amount of materials for contact reaction is reduced, so that the exothermic heat of the reaction is effectively controlled, and the reaction is safer and more controllable.

Preparation of 4-nitro-L-amphetamine alcohol:

the method for preparing 4-nitro-L-amphetamine from the nitrified 4-nitro-L-phenylalanine is summarized in domestic and foreign literature reports, the method for preparing 4-nitro-L-amphetamine by esterification and then reduction of the nitrified 4-nitro-L-phenylalanine is adopted, the esterification of amino acid is generally hydrochloric acid or thionyl chloride for catalytic esterification, the two are strong acid and volatile, the method is extremely unfriendly to equipment and personnel, more acid waste liquid is generated by post-treatment, a large amount of dangerous waste is generated, and the method does not meet the requirements of current green production.

According to the literature, the two-step yield of 4-nitro-L-amphetamine alcohol prepared in WO9118897A1 is only 37.0%; the two-step yield disclosed in Zaomitriptan synthesis and technological improvement published by Zhangling, quhaole and Zhou Shujing is about 79.4%, which is the highest yield in the prior art. But prepared by using the process disclosed in "synthesis of zolmitriptan and process improvement", the reported method was not repeated, the single step yield of 4-nitro-L-amphetamine was found to be only 40.2%, and the purity of 4-nitro-L-amphetamine was very low due to the large amount of sodium hydroxide solution used in the reduction process to neutralize the salt of 4-nitro-L-phenylalanine in the previous step; the yield of the preparation of 4-nitro-L-amphetamine alcohol by the two-step method is only about 55-67%.

In the preparation of 4-nitro-L-amphetamine, the use of sodium borohydride/potassium borohydride+Lewis acid to reduce nitrated L-phenylalanine to nitro-L-amphetamine in one step has not been reported in literature.

The inventors have tried to apply various reduction methods to the preparation of alpha-amino acid to alpha-amino alcohol by one-step reduction, and found in experiments that according to the literature preparation, the reaction time is prolonged to 3 days, the reaction is still not completed, the product yield is very low, only about 40%, and a large amount of unreacted materials are contained in the obtained product, so that the product yield is low and the quality is poor. In order to obtain the product meeting the requirements, multiple purifications are needed, the product yield is further reduced, the product production cost is increased, multiple purifications also cause the use of a large amount of solvents, the treatment pressure of the organic solvent is further increased, and the environmental protection and the waste liquid treatment are not facilitated.

According to the invention, a high boiling point solvent toluene or xylene and the like are added when 4-nitro-L-phenylalanine is reduced by a one-step method, so that the reaction temperature is increased, the reaction energy is further increased, the reaction is completely carried out in a short time, all 4-nitro-L-phenylalanine is reduced into 4-nitro-L-amphetamol by one step, the conversion rate is greatly increased, and the yield is increased to 80-90%. Meanwhile, as the preparation of the ester is not carried out any more, the use of strong acid volatile materials such as HCl, sulfoxide chloride and the like is avoided, the influence on the environment is reduced, the equipment is corroded, the method is friendly to operators, the production of waste liquid is reduced, the environmental protection is facilitated, and the concept of green chemistry is practiced.

In the preparation, it is found that when simple tetrahydrofuran or alcohols are used as solvents and a sodium borohydride/potassium borohydride+Lewis acid system is used for reduction, the 4-nitro-L-phenylalanine has a low reaction degree and cannot be completely reacted, and a large amount of unreacted 4-nitro-L-phenylalanine residues cause the 4-nitro-L-amphetamine to have a low yield which is less than 40%. The invention improves the process, adds a proper amount of toluene or dimethylbenzene in the reaction system after the initial stage of the reaction or the reaction is carried out for a period of time, and moderately increases the reaction temperature; after the continuous reaction is carried out for a period of time, the 4-nitro-L-phenylalanine is completely reacted, and the yield of the 4-nitro-L-amphetamine is improved to 80-90%.

The invention has the following beneficial effects:

1. the preparation method of 4-nitro-L-phenylalanine reduces the consumption of concentrated sulfuric acid and nitrifying reagent by using the microchannel reactor, reduces the production of strong acid waste liquid, reduces the cost and is more beneficial to environmental protection; the reaction condition is mild, the realization and control are easy, the preparation period is short, the purification is simple, the energy consumption is low, and the cost is further reduced; good reaction selectivity, less byproducts, high yield and purity of target products, and suitability for industrial production.

2. In the preparation of the 4-nitro-L-amphetamine alcohol, the two-step reaction of esterifying and reducing the alcohol is simplified into one step, so that the preparation time is shortened; the method is safe, green and environment-friendly, reduces the generation of three wastes (especially the neutralization and emission of hydrochloric acid gas) and has low cost; few impurities, simple purification steps, high yield and purity of target products, and suitability for industrial production.

Drawings

FIG. 1 is an HPLC chart of the product prepared in example 1;

FIG. 2 is an HPLC plot of the product prepared in example 2;

FIG. 3 is an HPLC plot of the product prepared in example 3;

FIG. 4 is an HPLC plot of the product prepared in example 4;

FIG. 5 is an HPLC plot of the product prepared in example 10;

FIG. 6 is an MS spectrum of the product prepared in example 10;

FIG. 7 is a product of example 10 ¹ HNMR nuclear magnetic patterns;

FIG. 8 is an HPLC plot of the product prepared in example 11;

FIG. 9 is an HPLC plot of the product prepared in example 14;

FIG. 10 is an HPLC plot of the product prepared in example 18;

FIG. 11 is an HPLC plot of the product prepared in example 19;

FIG. 12 is an HPLC plot of the product prepared in example 20;

FIG. 13 is an HPLC plot of the product prepared in comparative example 1;

FIG. 14 is an HPLC plot of the product prepared in comparative example 3.

Detailed Description

The present invention is further illustrated by the following specific examples, but it should be understood that these examples are for the purpose of more detailed description only and should not be construed as limiting the invention in any way.

In the examples, the reagents used, as such are commercially available without specific description; the methods used, unless otherwise specified, are all prior art.

The micro-channel reactor in the embodiment is an existing commercial device and is matched with a double-plunger high-pressure constant-flow infusion pump for a multi-module micro-reactor unit.

Examples 1 to 6

Compound 2: preparation of 4-nitro-L-phenylalanine, channel flow rate investigation

50g of concentrated sulfuric acid (98 wt.%) were added dropwise to 10g of water under stirring and cooled with ice water, and the mixture was cooled to room temperature. 60g (0.36 mol) of L-phenylalanine was slowly added thereto with continued cooling, and stirred until the solid was dissolved, to obtain an L-phenylalanine solution. The L-phenylalanine solution (at 20 ℃ C.) was introduced into the reactor through the channel 1 at a set flow rate of 1ml/min.

Simultaneously, 34.8g (0.36 mol) of concentrated nitric acid (65 wt%) at 20 ℃ is fed into the micro-channel reactor through the channel 2, and the flow rate is set to be 0.6ml/min; the temperature of the reaction cavity of the micro-channel is controlled to be 5-10 ℃, and the mixing reaction time in the micro-channel reactor is kept to be 28 seconds. After the reaction, the material liquid is pumped into water which is pre-cooled to 0 ℃, stirred for 30min, filtered, washed with water until the pH is about 7, and dried at 70 ℃ to obtain 71.6g of yellow solid with the yield of 93.8%.

The HPLC chart of the product obtained in this example is shown in FIG. 1, and the purity of the target product is 97.29% and the isomer content is 2.20%.

According to the same method, the experimental results of the compound 2 (4-nitro-L-phenylalanine) prepared by setting different flow rates are as follows:

examples

Channel 1

Channel 2

Feeding amount

Yield of

Yield is good

Purity of

Isomers of

Remarks

1

1ml/min

0.6ml/min

60g

71.6g

93.8％

97.29％

2.20％

FIG. 1

2

1ml/min

0.3ml/min

60g

70.3g

92.1％

97.60％

1.80％

FIG. 2

3

1ml/min

0.8ml/min

60g

68.9g

90.3％

96.61％

2.81％

FIG. 3

4

1ml/min

60g

69.1g

90.5％

96.10％

3.59％

FIG. 4

5

0.5ml/min

0.6ml/min

60g

67.5g

88.4％

96.14％

2.12％

-

6

2ml/min

0.6ml/min

60g

67.9g

88.9％

95.89％

2.05％

-

From the above examples, the nitrified product prepared by the method of the present invention has a high yield of more than 85% when the flow rate of the L-phenylalanine solution (channel 1) is 0.5 to 2ml/min and the flow rate of the concentrated nitric acid (channel 2) is 0.3 to 1ml/min.

Concentrated nitric acid (lane 2) sulfuric acid is preferably 0.6ml/min, and L-phenylalanine (lane 1) sulfuric acid is preferably 1ml/min.

Examples 7 to 9

Compound 2: preparation of 4-nitro-L-phenylalanine

60g of concentrated sulfuric acid (98 wt.%) were added dropwise to 16ml of water under stirring and cooled with ice water, and the mixture was cooled to room temperature. 60g (0.36 mol) of L-phenylalanine was slowly added under ice water cooling, and stirred until the solid was dissolved, to obtain an L-phenylalanine solution. The L-phenylalanine solution was fed into the microchannel reactor through channel 1 at a flow rate of 1ml/min.

Simultaneously, 34.8g (0.36 mol) of concentrated nitric acid (65 wt%) was introduced into the microchannel reactor through channel 2 at a flow rate of 0.6ml/min; the temperature of the reaction chamber of the micro-channel is controlled, and the reaction time in the micro-channel reactor is kept to be 60 seconds. After the reaction, pumping the material liquid into water which is precooled to 0 ℃, stirring for 30min, filtering, washing with water to pH of about 7, and drying the solid at 60 ℃ to obtain yellow solid.

According to the same method, the experimental results of the compound 2 (4-nitro-L-phenylalanine) prepared by setting different temperatures are as follows:

the examples show that the reaction can produce the required product at the reaction temperature of 5-20 ℃.

Comparative example 1

Reference "synthesis and Process improvement of zolmitriptan" prepares 4-nitro-L-phenylalanine.

Compound 2: preparation of 4-nitro-L-phenylalanine

In the low-temperature cooling circulation bath, 21.2g of water is added into a reaction bottle, 133.6g of concentrated sulfuric acid is added dropwise under the condition of cooling, and 50g of L-phenylalanine is added continuously under the condition of cooling. And (3) dropwise adding a mixed solution of 12.5ml of fuming nitric acid and 12.5ml of concentrated sulfuric acid, wherein the temperature is controlled to be not more than 20 ℃ in the dropwise adding process, and the temperature is raised to 30 ℃ after the dropwise adding, so that the reaction is carried out for 3 hours.

The reaction solution was poured into 500ml of ice water, the pH of the solution was adjusted to about 7 by adding ammonia water, suction filtration was performed, and the solid was washed with 30ml of water to obtain 47.3g of a yellow solid, and the yield was 74.3%.

The HPLC chart of the product obtained in this comparative example is shown in FIG. 13, and the purity of the target product is 85.19% and the isomer content is 11.14%.

The preparation method of the invention has obvious advantages compared with the preparation results of literature methods, and the following table is shown in detail:

conclusion: compared with the conventional kettle-type nitration method, the novel method for preparing the product has the advantages of high yield, high purity of the target product, good isomer control, higher safety, higher efficiency and lower cost.

Examples 10 to 20

Compound 4: preparation of 4-nitro-L-amphetamine alcohol

200ml of tetrahydrofuran (solvent A) and 34.0g (0.25 mol) of zinc chloride (reducing agent 1) were added to a reaction flask, 27.0g (0.5 mol) of potassium borohydride (reducing agent 2) was added with stirring, and the mixture was heated to reflux (60℃to 66 ℃) for 2 hours. The heating was turned off and the temperature was slightly lowered to 60℃and 21.0g (0.1 mol) of 4-nitro-L-phenylalanine (Compound 2) prepared in the method of example 2 was added to the reaction mixture in 3 batches, each batch of about 7g, and the addition was completed for about 10 minutes, preventing the addition from being carried out by a vigorous reaction.

After the addition, 200ml of toluene (solvent B) was added to the reaction mixture and heated to 85℃and the reaction was continued for 10 hours with heat preservation, and the heating was stopped. The reaction solution was cooled to room temperature with stirring, and then cooled to 0 to 10℃with ice water. Suction filtration to remove solids (if necessary with celite filtration). 150ml of 20wt% sodium hydroxide aqueous solution was slowly added dropwise thereto over a period of Bi Jiaoban min. Filtering, removing the generated solid again, and separating filtrate. The aqueous phase was extracted with toluene 50ml×3 times, and the organic layers were combined and dried over anhydrous magnesium sulfate. The drying agent was filtered and the organic layer was distilled to dryness to give 17.3g of orange solid in 88.3% yield.

The HPLC chart of the product obtained in this example is shown in FIG. 5, and the purity is 99.13%.

The mass spectrum of the obtained product is shown in FIG. 6, and the peak with mass-to-charge ratio m/z= 197.1 is compound 4 (C ₉ H ₁₂ N ₂ O ₃ Exact Mass:196.1 Molecular ion [ M+H ]] ⁺ Peak, compound 4 molecular weight correct; the nuclear magnetic pattern is shown in fig. 7, and the data are as follows: ¹ H NMR(600MHz，DMSO，δ)：1.36(s，2H，NH ₂ )，2.50-2.57(m，1H，NCH)，2.83-2.91(m，2H，ArCH ₂ )，3.20-3.28(m，2H，OCH ₂ )，4.67(s，1H，OH)，7.50(d，J＝9Hz，2H，ArH)，8.15(dd，J＝7.2Hz，2.4Hz，2H，ArH).

4-nitro-L-amphetamine was prepared according to the above method under different combinations of reducing agents, solvent combinations, etc., and the conditions not shown in the table are as described above, and the experimental results are shown in the table below. The yield and quality of the obtained target product are higher than those of the product prepared by the prior process method.

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* Remarks: the dimethylbenzene mainly comprises a mixture of 45-70wt% of m-xylene, 15-25wt% of p-xylene and 10-15wt% of o-xylene, and is commercially available.

As can be seen from the above table, the solvent A is one or more of tetrahydrofuran, methyltetrahydrofuran, methanol or ethanol, and the solvent B is one or more of toluene, xylene or dioxane, so that a sample meeting the requirements can be prepared. Solvent A is preferably tetrahydrofuran and solvent B is preferably toluene. The volume ratio of the solvent A to the solvent B is 1:0.5-10, preferably 1:1-4.

The reducing agent is sodium borohydride, potassium borohydride, sodium borohydride-Lewis acid, potassium borohydride-iodine, sodium borohydride-H ₂ SO ₄ Or potassium borohydride-H ₂ SO ₄ Can be used for preparing samples meeting the requirements.

Comparative examples 2 to 4

Compound 4: preparation of 4-nitro-L-amphetamine alcohol

200ml of the reaction solvent and 34.0g (0.25 mol) of zinc chloride were added to the reaction flask, 27.0g (0.5 mol) of potassium borohydride was added under stirring, and the mixture was heated to reflux (60℃to 66 ℃) for 2 hours. The heating was turned off and the temperature was slightly lowered to 60℃and 21.0g (0.1 mol) of 4-nitro-L-phenylalanine (Compound 2) prepared in the method of example 2 was added to the reaction mixture in 3 batches, each batch of about 7g, and the addition was completed for about 10 minutes, preventing the addition from being carried out by a vigorous reaction.

After the addition, the reaction is carried out for 10 hours with heat preservation, and the heating is stopped. The reaction solution was cooled to room temperature with stirring, and then cooled to 0 to 10℃with ice water. Suction filtration to remove solids (if necessary with celite filtration). 150ml of 20wt% sodium hydroxide aqueous solution was slowly added dropwise thereto over a period of Bi Jiaoban min. Filtering, removing the generated solid again, and separating filtrate. The aqueous phase was extracted with toluene 50ml×3 times, and the organic layers were combined and dried over anhydrous magnesium sulfate. The drying agent is filtered, and the organic layer is distilled to dryness to obtain orange solid.

The conditions of reducing agent, reaction solvent type and the like are changed to prepare 4-nitro-L-amphetamine alcohol according to the method, and the conditions not related in the table are as follows:

the experimental results show that when tetrahydrofuran, absolute ethyl alcohol and toluene are independently used, the yield of the prepared product is low, the quality is poor, and the product which can be applied to the large-scale production cannot be obtained.

Claims

1. A method for preparing an zolmitriptan intermediate, comprising the steps of:

(1) Taking sulfuric acid aqueous solution as a solvent and concentrated nitric acid or fuming nitric acid as a nitrifying reagent, and performing nitrifying reaction on L-phenylalanine in a microchannel reactor to obtain 4-nitro-L-phenylalanine;

(2) 4-nitro-L-amphetamine is prepared by reduction reaction of 4-nitro-L-phenylalanine in a solvent in the presence of a reducing agent.

2. The process for the preparation of an intermediate of zolmitriptan according to claim 1, wherein in step (1), the process for the preparation of 4-nitro-L-phenylalanine comprises the steps of: dissolving L-phenylalanine in sulfuric acid aqueous solution to obtain L-phenylalanine solution; and respectively and simultaneously introducing the L-phenylalanine solution and concentrated nitric acid or fuming nitric acid into a micro-channel reactor, and performing nitration reaction on the L-phenylalanine to obtain the zolmitriptan intermediate 4-nitro-L-phenylalanine.

3. The process for the preparation of an intermediate of zolmitriptan according to claim 2, wherein the flow rate of the L-phenylalanine solution is 0.5-2ml/min; the flow rate of the concentrated nitric acid or fuming nitric acid is 0.3-1ml/min; preferably, the flow rate of the L-phenylalanine solution is 1ml/min; the flow rate of the concentrated nitric acid or fuming nitric acid is 0.6ml/min.

4. A process for the preparation of an intermediate of zolmitriptan according to claim 1, characterized in that in step (1) it comprises any one of the following conditions:

i. the nitration temperature is-5-30 ℃, preferably 5-20 ℃;

ii. The nitration time is 20 seconds to 300 seconds, preferably 28 seconds to 60 seconds.

5. A process for the preparation of an intermediate of zolmitriptan according to claim 1, wherein in step (2) the solvent consists of solvent a and solvent B;

6. The process for preparing zolmitriptan intermediate according to claim 1, wherein in step (2), the reducing agent is sodium borohydride, potassium borohydride, sodium borohydride-lewis acid, potassium borohydride-iodine, sodium borohydride-H ₂ SO ₄ Or potassium borohydride-H ₂ SO ₄ One of them.

7. The process for the preparation of an intermediate of zolmitriptan according to claim 1, wherein in step (2), the molar ratio of 4-nitro-L-phenylalanine to reducing agent is 1:1-8.

8. The process for preparing an intermediate of zolmitriptan according to claim 5, wherein in step (2), the solvent A and the solvent B are added before the addition of 4-nitro-L-phenylalanine, or the solvent A is added before the addition of 4-nitro-L-phenylalanine and the solvent B is added after the addition of 4-nitro-L-phenylalanine.

9. The process for the preparation of an intermediate of zolmitriptan according to claim 1, wherein in step (2), the process for the preparation of an intermediate of zolmitriptan comprises the steps of:

10. A process for the preparation of an intermediate of zolmitriptan according to claim 9, comprising any one of the following conditions:

i. the step of heating and refluxing is further included after the reducing agent and the 4-nitro-L-phenylalanine are added into the solvent A;

ii. The method can also comprise the step of heating and refluxing before adding the 4-nitro-L-phenylalanine in batches; alternatively, the method may further comprise a step of heating and refluxing after the 4-nitro-L-phenylalanine is added in portions;

iii, the reaction temperature after adding the solvent B is 66-140 ℃, preferably 80-100 ℃; the reaction time is 2 to 24 hours, preferably 6 to 12 hours;

iv, when 4-nitro-L-phenylalanine is added in batches, the addition is carried out in batches of 2-4 and the addition is completed in 5-15 minutes.