A method for preparing a high-purity pentoxifylline intermediate

Abstract

The invention discloses a method for preparing a high-purity pentoxifylline intermediate, wherein the prepared 6-bromo-2-hexanone crude product is reacted with an alkali metal bisulfite to generate a novel 6-halogenated-2-hydroxyhexane-2-sulfonic acid alkali metal salt, and then the 6-bromo-2-hexanone pure product is generated under the action of a hydrohalic acid or a base, without the need for rectification and purification, and the post-processing operation is simple, in line with the trend of green chemical industry, and has a good industrial production application prospect. At the same time, the present invention can effectively avoid the dimer impurities generated in the high-temperature distillation process, and the yield and purity are high, which provides favorable guarantees for the safety and effectiveness of preparing the finished drug pentoxifylline.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing a high-purity pentoxifylline key intermediate. Background Art

[0002] Pentoxifylline is an agent for improving cerebral circulation and peripheral vascular circulation disorders. It not only has the effect of dilating cerebral and peripheral blood vessels, improving blood circulation in the brain and limbs, but also can improve the oxidation capacity of hypoxic tissues. It is mainly used to improve cerebral circulation after ischemic stroke, and can also be used to treat peripheral vascular diseases such as chronic occlusive vasculitis with intermittent claudication, and can also be used to treat duodenal ulcers, viral hepatitis, lower extremity venous ulcers and other diseases. It is widely used clinically.

[0003] 6-halogenated-2-hexanone, the structural formula is As the key side chain of pentoxifylline, it is the key intermediate for the synthesis of pentoxifylline. US3737433A and US3422107A disclose the preparation method of the above intermediate, which comprises the following steps: the route uses ethyl acetoacetate as the raw material, and reacts with 1,3-dibromopropane through a cyclization reaction and a halogenation ring opening to generate the key intermediate 6-halogeno-2-hexanone. The reaction route is as follows:

[0004]

[0005] However, the above method has the following problems: the raw materials of the first step, ethyl acetoacetate and 1,3-dibromopropane cyclization product, have more impurities and need to be distilled and purified; the second step, the ring-opening reaction, has more impurities and still needs to be distilled and purified. At the same time, the second step product 6-halogenated-2-hexanone has poor thermal stability. During the high-temperature distillation process, polymerization reaction will occur to produce more polymerized impurities. The polymerized impurities react with theobromine and are introduced into the oxathione theobromine finished product, affecting the product quality. Since the polymerized impurities contain halogen atoms, the risk of introducing genotoxic impurities is greatly increased. At the same time, the distillation step has high requirements on the vacuum degree of the equipment, which increases the difficulty of industrial scale-up production.

[0006] In view of the shortcomings of the existing technology, it is urgent to develop an industrial production method for producing 6-halo-2-hexanone without distillation and purification. Summary of the invention

[0007] The purpose of the present invention is to provide a method for preparing a high-purity pentoxifylline intermediate 6-bromo-2-hexanone. The synthesis method of the present invention can significantly improve the purity and yield of 6-bromo-2-hexanone, avoid the distillation process of the intermediate and a large amount of polymerized impurities generated due to high temperature in the distillation process, and reduce the synthesis cost of pentoxifylline.

[0008] In order to achieve the above object, the present invention adopts the following technical solution:

[0009] A method for preparing a high-purity pentoxifylline intermediate comprises the following steps:

[0010] a) Preparation of crude pentoxifylline intermediate product: Compounds of formula I and II undergo condensation reaction in the presence of a base to generate compounds of formula III; compounds of formula III undergo ring-opening reaction in the presence of a hydrohalic acid and an alkali metal halide to generate crude pentoxifylline intermediate product of formula IV, the reaction formula is as follows:

[0011]

[0012] wherein X is independently F, Cl, Br or I;

[0013] b) Purification of crude pentoxifylline intermediate product: reacting the crude pentoxifylline intermediate product shown in the above formula IV with an alkali metal bisulfite in a mixed solvent of an organic solvent and water, filtering to obtain a compound of formula V after the reaction is completed; reacting the compound of formula V with a hydrohalogen acid or a base in a mixed solvent of an organic solvent and water, extracting and separating the liquids after the reaction, and concentrating the separated organic phase under reduced pressure to obtain a high-purity compound of formula IV, the reaction formula is as follows:

[0014]

[0015] Wherein, X is F, Cl, Br or I, and M is an alkali metal.

[0016] In step a), the base is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides. Preferably, the alkali metal carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate, the alkali metal bicarbonate is selected from sodium bicarbonate and potassium bicarbonate, and the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.

[0017] In some embodiments, after the reaction of the compound of formula I and the compound of formula II in step a) is completed, the mixture is concentrated under reduced pressure and then fractionated or not; in particular, it is preferred not to fractionate and directly proceed to the next step of reaction.

[0018] In some embodiments, the condensation reaction in step a) can be selected from alcohol, C1-C4 halogenated alkane, ethyl acetate and tetrahydrofuran, preferably methanol and ethanol.

[0019] In some embodiments, the reaction temperature of the condensation reaction in step a) is 40-100° C., preferably 60-90° C.; the reaction time is 5-15 h, preferably 10 h.

[0020] In some embodiments, in step a), the molar ratio of the compound of formula I to the compound of formula II in the condensation reaction is (1-3):1; the molar ratio of the alkali metal carbonate to the compound of formula II is (5-10):1.

[0021] In some embodiments, the hydrohalic acid in step a) is selected from HBr and HCl; and the alkali metal halide is selected from sodium bromide, potassium bromide, sodium chloride and potassium chloride.

[0022] In some embodiments, the reaction temperature of the ring-opening reaction in step a) is 50-100° C., preferably 80-90° C.; and the reaction time is 1-5 h.

[0023] In some embodiments, the molar ratio of the compound of formula III to the hydrohalic acid in the ring-opening reaction of step a) is (0.8-1.5):1; the molar ratio of the compound of formula III to the alkali metal halide is (0.5-1.5):1.

[0024] In some embodiments, after the condensation reaction in step a), the compound of formula III is obtained by filtration and concentration under reduced pressure; after the ring-opening reaction, the crude intermediate product of pentoxifylline shown in formula IV is obtained by extraction, washing and concentration under reduced pressure. The above post-treatment operations can use conventional methods and conditions in the art.

[0025] In some embodiments, the alkali metal bisulfite in step b) is selected from sodium bisulfite and potassium bisulfite; the molar ratio of the alkali metal bisulfite to the compound of formula IV is (1.5-3):1.

[0026] In some embodiments, the hydrohalic acid in step b) is selected from HBr and HCl.

[0027] In some embodiments, the base in step b) is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides. Preferably, the alkali metal carbonates are selected from sodium carbonate and potassium carbonate, the alkali metal bicarbonates are selected from sodium bicarbonate and potassium bicarbonate, and the alkali metal hydroxides are selected from sodium hydroxide and potassium hydroxide.

[0028] In some embodiments, in step b) during the preparation of the compound of formula V, the organic solvent is selected from alcohol, C1-C4 halogenated alkane, ethyl acetate and tetrahydrofuran, preferably methanol and ethanol; the volume mass ratio of the organic solvent to the compound of formula IV is (0.5-50) mL:1 g; the volume mass ratio of water to the compound of formula IV is (0.5-5) mL:1 g;

[0029] In some embodiments, in step b) of preparing the compound of formula V, the compound of formula IV is added dropwise, and the dropping temperature is controlled at 10 to 60°C, preferably 20 to 30°C; the reaction temperature is -10 to 60°C, preferably 20 to 30°C; and the reaction time is 1 to 5 hours.

[0030] In some embodiments, in step b) of preparing the compound of formula V, after the reaction is completed, filtering, slurrying, and drying under reduced pressure obtain a white solid.

[0031] In some embodiments, in step b) for preparing the compound of formula IV, the organic solvent is selected from alcohol, C1-C4 halogenated alkane, ethyl acetate and tetrahydrofuran, preferably dichloromethane and chloroform; the volume mass ratio of the organic solvent to the compound of formula V is (1-5) mL:1 g; the volume mass ratio of water to the compound of formula V is (1-20) mL:1 g; the molar ratio of the hydrohalic acid to the compound of formula V is (1-3):1.

[0032] In some embodiments, during the free reaction in step b) to prepare the compound of formula IV, the reaction temperature is 10-60°C, preferably 20-30°C; the reaction time is 0.5-5h, preferably 1-2h.

[0033] In some embodiments, in step b) of preparing the compound of formula V, the filter cake obtained after filtration is slurried with alcohol, preferably, the alcohol is selected from methanol and ethanol; the volume mass ratio of the alcohol to the compound of formula IV is (2-10) mL:1 g, and the slurrying time is 1-5 h.

[0034] In some embodiments, in the process of preparing the compound of formula IV in step b), the reaction mixture is first separated into an organic phase and an aqueous phase, and the aqueous phase is extracted and separated with a C1-C4 halogenated alkane, and then the organic phases are combined, washed with water, and concentrated under reduced pressure to obtain a high-purity compound of formula IV, the volume mass ratio of the C1-C4 halogenated alkane to the compound of formula V is (1-5) mL:1 g, and the volume mass ratio of water to the compound of formula V is (0.5-5) mL:1 g.

[0035] In particular, the use of alkali metal bisulfite method to purify 6-bromo-2-hexanone can effectively avoid the dimer impurities generated during the distillation process. The main impurity structure is as follows:

[0036]

[0037] The present invention has achieved the following beneficial effects:

[0038] 1) The present invention allows a crude 6-bromo-2-hexanone to react with an alkali metal bisulfite to generate a novel 6-halogenated-2-hydroxyhexane-2-sulfonic acid alkali metal salt, and then generates a high-purity 6-bromo-2-hexanone product under the action of a hydrohalic acid or a base. The method does not require rectification and purification, has simple post-treatment operations, reduces production costs, conforms to the trend of green chemical industry, and has good industrial production application prospects.

[0039] 2) The present invention adopts the alkali metal bisulfite method to purify 6-bromo-2-hexanone, which can effectively avoid the dimer impurities generated in the high-temperature distillation process, improve the yield and purity, and provide favorable guarantees for the safety and effectiveness of preparing the finished drug pentoxifylline. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0041] Figure 1 is the H NMR spectrum of sodium 6-bromo-2-hydroxyhexane-2-sulfonate;

[0042] Figure 2 This is the gas phase spectrum of 6-bromo-2-hexanone obtained in Example 1;

[0043] Figure 3 This is the gas phase spectrum of 6-bromo-2-hexanone obtained by distillation purification method in Comparative Example 1; DETAILED DESCRIPTION

[0044] Embodiments of the present invention are described in detail below, and examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0045] The endpoints and any values ​​of the scope described in the present invention are not limited to the precise scope or value, and these scopes or values ​​should be understood to include values ​​close to these scopes or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered as specifically disclosed in this article.

[0046] Example 1: Synthesis of 6-bromo-2-hexanone

[0047] Step 1: Synthesis of compound 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester:

[0048]

[0049] Add 200 mL of anhydrous ethanol to a three-necked flask, start stirring, and add anhydrous potassium carbonate (183.5 g, 1.33 mol), ethyl acetoacetate (66.5 g, 0.51 mol), and 1-bromo-3-chloropropane (35.0 g, 0.22 mol) in sequence. After the addition is complete, stir the mixture at 70 ° C for 10 hours. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, and the filter cake is rinsed with 90 mL of anhydrous ethanol. The filtrate is collected and concentrated under reduced pressure to obtain 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester as a brown-red liquid crude product 38.4 g, which is directly used in the next step reaction.

[0050] Step 2: Synthesis of crude compound 6-bromo-2-hexanone:

[0051]

[0052] Add 40% hydrobromic acid (50.6g, 0.25mol) to a three-necked flask, add sodium bromide (27.8g, 0.27mol), start stirring, heat to 80°C, dropwise add the above-mentioned crude product of 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester 38.4g, and stir for 0.5 hours. Stir the reaction solution at 85°C for 2 hours. After the reaction is completed, cool the reaction solution to room temperature, add 90mL of dichloromethane and 180mL of water to extract the liquid, collect the organic phase, wash the liquid with 120mL of water, collect the organic phase, and concentrate under reduced pressure to obtain 43.2g of 6-bromo-2-hexanone dark red liquid crude product.

[0053] Step 3: Preparation of compound 6-bromo-2-hydroxyhexane-2-sodium sulfonate:

[0054]

[0055] Add sodium bisulfite (41.9 g, 0.40 mol) to the reaction flask, add 48 mL of water, start stirring, control the temperature to 20°C, dropwise add 43.2 g of the above crude 6-bromo-2-hexanone, and stir for 0.5 hours after the dropwise addition. Continue to add 600 mL of anhydrous ethanol and stir for 1 hour. Cool to -10°C, stir for 1 hour, filter, beat the filter cake with 300 mL of anhydrous ethanol for 1 hour, filter with suction to obtain a solid wet product, and dry under reduced pressure to obtain an off-white solid of 6-bromo-2-hydroxyhexane-2-sulfonate sodium (54.9 g, purity 99.5%).

[0056] 1H NMR (D2O, 500Hz): 1.5 (s, 3H), 1.55-1.65 (m, 2H), 1.85-1.95 (m, 4H), 3.5-3.57 (t, 2H, J = 5Hz).

[0057] Step 4: Preparation of 6-bromo-2-hexanone:

[0058]

[0059] Sodium 6-bromo-2-hydroxyhexane-2-sulfonate (54.9 g, 0.19 mol) was added into a three-necked flask, and 65 mL of water and 130 mL of dichloromethane were added. Stirring was started, and 40% hydrobromic acid (60.7 g, 0.30 mol) was added dropwise at 20°C. After the addition was completed, stirring was performed for 1 hour, and the liquids were separated. The aqueous phase was extracted with 65 mL of dichloromethane, and the organic phases were combined and washed with 65 mL of water. The organic phase was collected and concentrated under reduced pressure to obtain 6-bromo-2-hexanone as a light brown liquid (32.65 g, the total yield of four steps was 81.8%, and the purity by HPLC was 98.2%).

[0060] HPLC: Rt = 15.973min, see Figure 2 .

[0061] MS (ESI): m / z = 180.2 [M + H] + .

[0062] Example 2: Synthesis of 6-chloro-2-hexanone

[0063] Step 1: Synthesis of compound 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester:

[0064]

[0065] Add 300 mL of anhydrous ethanol to a three-necked flask, start stirring, and add anhydrous sodium carbonate (165.4 g, 1.56 mol), ethyl acetoacetate (50.7 g, 0.39 mol), and 1-bromo-3-chloropropane (41.0 g, 0.26 mol) in sequence. After the addition is complete, stir the mixture at 80 ° C for 13 hours. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, and the filter cake is rinsed with 100 mL of anhydrous ethanol. The filtrate is collected and concentrated under reduced pressure to obtain 45.6 g of a brown-red liquid crude product of ethyl 3,4-dihydro-6-methyl-2H-pyran-5-carboxylate, which is directly used in the next step.

[0066] Step 2: Synthesis of crude compound 6-chloro-2-hexanone:

[0067]

[0068] Add 20% hydrochloric acid (50.4g, 0.28mol) to a three-necked flask, add sodium chloride (17.0g, 0.29mol), start stirring, heat to 80°C, drop 45.6g of crude ethyl 3,4-dihydro-6-methyl-2H-pyran-5-carboxylate, and stir for 1 hour. Stir the reaction solution at 80°C for 4 hours. After the reaction is completed, cool the reaction solution to room temperature, add 115mL of dichloromethane and 200mL of water, extract the liquid, collect the organic phase, wash the liquid with 135mL of water, collect the organic phase, and concentrate under reduced pressure to obtain 35.3g of crude 6-chloro-2-hexanone liquid.

[0069] Step 3: Preparation of compound 6-chloro-2-hydroxyhexane-2-sodium sulfonate:

[0070]

[0071] Add sodium bisulfite (60.3 g, 0.58 mol) to the reaction flask, add 80 mL of water, start stirring, control the temperature to 35 ° C, drop 35.3 g of 6-chloro-2-hexanone crude product, and stir for 1 hour after the dropwise addition. Continue to add 400 mL of anhydrous ethanol and stir for 2 hours. Cool to -10 ° C, stir for 1.5 hours, filter, and beat the filter cake with 250 mL of anhydrous ethanol for 1 hour, filter with suction to obtain a solid wet product, and dry under reduced pressure to obtain 6-chloro-2-hydroxyhexane-2-sulfonic acid sodium as a white solid (52.2 g, purity 99.3%).

[0072] Step 4: Preparation of 6-chloro-2-hexanone:

[0073]

[0074] Sodium 6-chloro-2-hydroxyhexane-2-sulfonate (52.2 g, 0.23 mol) was added to a three-necked flask, and 150 mL of water and 100 mL of dichloromethane were added. The mixture was stirred and 20% hydrochloric acid (73.0 g, 0.40 mol) was added dropwise at 35°C. The mixture was stirred for 3 hours and separated. The aqueous phase was extracted with 60 mL of dichloromethane, and the organic phases were combined and washed with 50 mL of water. The organic phases were collected and concentrated under reduced pressure to obtain 6-chloro-2-hexanone as a light yellow liquid (29.45 g, with a total yield of 84.6% in four steps and a purity of 98.0% by HPLC).

[0075] MS (ESI): m / z = 135.6 [M + H] + .

[0076] Comparative Example 1: Synthesis of 6-bromo-2-hexanone (purified by distillation based on Example 1)

[0077] Step 1: Synthesis of compound 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester

[0078]

[0079] Add 200 mL of anhydrous ethanol to a three-necked flask, start stirring, and add anhydrous potassium carbonate (183.5 g, 1.33 mol), ethyl acetoacetate (66.5 g, 0.51 mol), and 1-bromo-3-chloropropane (35.0 g, 0.22 mol) in sequence. After the addition is complete, stir the mixture at 70 ° C for 10 hours. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, and the filter cake is rinsed with 90 mL of anhydrous ethanol. The filtrate is collected and concentrated under reduced pressure to obtain 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester as a brown-red liquid crude product 38.4 g, which is directly used in the next step reaction.

[0080] Step 2: Synthesis of crude compound 6-bromo-2-hexanone:

[0081]

[0082] Add 40% hydrobromic acid (50.6g, 0.25mol) to a three-necked flask, add sodium bromide (27.8g, 0.27mol), start stirring, heat to 80°C, dropwise add the above crude product of 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester 38.4g, and stir for 0.5 hours. Stir the reaction solution at 85°C for 2 hours. After the reaction is completed, cool the reaction solution to room temperature, add 90mL of dichloromethane and 180mL of water to extract the liquid, collect the organic phase, wash the liquid with 120mL of water, collect the organic phase, and concentrate under reduced pressure to obtain a dark red liquid crude product of 6-bromo-2-hexanone, then vacuum distill at 130°C, collect the positive fraction at 94-98°C, and obtain 22.9g of 6-bromo-2-hexanone, with a total yield of 58.2% in two steps and a purity of 92.7%.

[0083] HPLC: Rt = 16.206min, see Figure 3 .

[0084] MS (ESI): m / z = 180.2 [M + H] + .

[0085] Comparative Example 2: 6-bromo-2-hexanone was synthesized by distillation purification method with reference to the method in existing literature (Zhang Ling et al., Synthesis of 6-bromo-2-hexanone, Qilu Pharmacy, Vol. 52, No. 3, pp. 168-169).

[0086] Step 1: Synthesis of compound 3,4-dihydro-6-methyl-2H-pyran-5-carboxylic acid ethyl ester

[0087]

[0088] Add 28.0 g (0.2 mol) of potassium carbonate, 35 ml of 95% ethanol, 20.2 g (0.1 mol) of 1,3-dibromopropane and 13.0 g (0.1 mol) of ethyl acetoacetate into a reaction flask, stir and heat to 60°C, then heat to reflux after the temperature stabilizes, react at 82°C for 5 h, evaporate the ethanol, add 75 ml of water to dissolve the salt, let stand to separate the layers, extract the aqueous layer with 12.5 ml of cyclohexane, combine the organic layers, add anhydrous sodium sulfate to dry, distill under reduced pressure, increase the vacuum to 1-10 mmHg, collect the bp105-108°C fraction after the column top temperature stabilizes, and obtain 12.6 g of ethyl 3,4-dihydro-6-methyl-2H-pyran-5-carboxylate with a yield of 74.1% and a HPLC purity of 95.3%.

[0089] Step 2: Synthesis of compound 6-bromo-2-hexanone:

[0090]

[0091] Add 12.6g of ethyl 3,4-dihydro-6-methyl-2H-pyran-5-carboxylate, 1.0g (0.0097mol) of sodium bromide and 1.0g (0.0058mol) of p-toluenesulfonic acid to a 500ml reaction bottle, stir at 10℃ and drop 14.0ml of 63% (0.11mol) hydrobromic acid solution, keep warm for 1h, and heat to reflux for 3h. Add an equal volume of ice water and let stand to separate. Extract the water layer with chloroform and combine the organic layers, wash with saturated sodium carbonate solution, add anhydrous sodium sulfate to dry, evaporate the chloroform at normal pressure, gradually reduce the pressure, and increase the vacuum to 1-10mmHg. After the column top temperature stabilizes, collect the bp94-98℃ fraction to obtain 11.3g of 6-bromo-2-hexanone, with a yield of 85.3% and an HPLC purity of 95.6%.

[0092] MS (ESI): m / z = 180.2 [M + H] + .

[0093] In summary, the present invention adopts the alkali metal bisulfite method to purify 6-bromo-2-hexanone, which can effectively avoid the dimer impurities generated in the high-temperature distillation process, and the total yield can reach 80% and the purity can reach 98%, which is better than the distillation purification method, and the post-treatment is simple, and only extraction, reduced pressure distillation and other operations are required, which is very suitable for industrial production.

[0094] The above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing a pentoxifylline intermediate, characterized in that The steps include: a) Preparation of crude pentoxifylline intermediate product: Compounds of formula I and II undergo condensation reaction in the presence of a base to generate compounds of formula III; compounds of formula III undergo ring-opening reaction in the presence of a hydrohalic acid and an alkali metal halide to generate crude pentoxifylline intermediate product of formula IV, the reaction formula is as follows: wherein X is independently Cl or Br; b) Purification of crude pentoxifylline intermediate product: reacting the crude pentoxifylline intermediate product represented by the above formula IV with alkali metal bisulfite in a mixed solvent of alcohol and water, filtering to obtain a compound of formula V after the reaction is completed; reacting the compound of formula V with a hydrohalogen acid or a base in a mixed solvent of an organic solvent and water, and after the reaction is completed, first separating the reaction mixture to obtain an organic phase and an aqueous phase, and extracting and separating the aqueous phase with a C1-C4 halogenated alkane, then combining the organic phases, washing with water, and concentrating under reduced pressure to obtain a compound of formula IV; the reaction formula is as follows: Wherein, X is Cl or Br, and M is an alkali metal; In step b) of preparing the compound of formula IV, the organic solvent is dichloromethane or chloroform.

2. The method according to claim 1, characterized in that: In step a), the base is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides; the hydrohalic acid is selected from HBr and HCl; and the alkali metal halide is selected from sodium bromide, potassium bromide, sodium chloride and potassium chloride.

3. The method according to claim 2, characterized in that: In step a), the alkali metal carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate, the alkali metal bicarbonate is selected from sodium bicarbonate and potassium bicarbonate, and the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.

4. The method according to any one of claims 1 to 3, characterized in that: The solvent of the condensation reaction in step a) is selected from alcohol, C1-C4 halogenated alkane, ethyl acetate and tetrahydrofuran; the reaction temperature of the condensation reaction is 40-100° C. and the reaction time is 5-15 hours; the molar ratio of the compound of formula I to the compound of formula II is (1-3):1; the molar ratio of the alkali metal carbonate to the compound of formula II is (5-10):

1.

5. The method according to claim 4, characterized in that: The alcohol is methanol or ethanol.

6. The method according to claim 1, characterized in that: The reaction temperature of the ring-opening reaction in step a) is 50-100° C., and the reaction time is 1-5 hours; the molar ratio of the compound of formula III to the hydrohalic acid is (0.8-1.5):1; and the molar ratio of the compound of formula III to the alkali metal halide is (0.5-1.5):

1.

7. The method according to claim 1, characterized in that: In step a), after the condensation reaction is completed, the compound of formula III is obtained by filtration and concentration under reduced pressure; after the ring-opening reaction is completed, the crude intermediate product of pentoxifylline shown in formula IV is obtained by extraction, washing and concentration under reduced pressure.

8. The method according to claim 1, characterized in that: In step b), the alkali metal bisulfite is selected from sodium bisulfite and potassium bisulfite, and the molar ratio of the alkali metal bisulfite to the compound of formula IV is (1.5-3):1; the hydrohalic acid is selected from HBr and HCl; and the base is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides.

9. The method according to claim 8, characterized in that: In step b), the alkali metal carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate, the alkali metal bicarbonate is selected from sodium bicarbonate and potassium bicarbonate, and the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.

10. The method according to claim 1, characterized in that: In the process of preparing the compound of formula V in step b), the alcohol is methanol or ethanol; the volume mass ratio of the alcohol to the compound of formula IV is (0.5-50) mL:1 g; the volume mass ratio of water to the compound of formula IV is (0.5-5) mL:1 g; the reaction temperature is -10-60° C.; and the reaction time is 1-5 h.

11. The method according to claim 1, characterized in that: In step b) of preparing the compound of formula IV, the volume mass ratio of the organic solvent to the compound of formula V is (1-5) mL:1 g; the volume mass ratio of water to the compound of formula V is (1-20) mL:1 g; the molar ratio of the hydrohalic acid to the compound of formula V is (1-3):1; the reaction temperature is 10-60° C.; and the reaction time is 0.5-5 h.

12. The method according to claim 1, characterized in that: In step b) during the preparation of the compound of formula V, the filter cake obtained after filtration is slurried with alcohol; the volume mass ratio of alcohol to the compound of formula IV is (2-10) mL:1 g, and the slurrying time is 1-5 h.

13. The method according to claim 12, characterized in that: The alcohol is selected from methanol and ethanol.

14. The method according to claim 1, characterized in that: In step b) of preparing the compound of formula IV, the volume mass ratio of the C1-C4 halogenated alkane to the compound of formula V is (1-5) mL:1 g, and the volume mass ratio of water to the compound of formula V is (0.5-5) mL:1 g.

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