A preparation method of rupatadine fumarate

Abstract

The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing rupatadine fumarate. The method for preparing rupatadine fumarate of the present invention comprises the following steps: S1, reacting nitrogenmethylloratadine, phenyl chloroformate, and an organic amine in an organic solvent to obtain compound I; the structural formula of compound I being: #imgabs0#; S2, reacting compound I with a base in an organic solvent to obtain desloratadine; S3, reacting desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride, and an organic amine in an organic solvent to obtain rupatadine; and S4, reacting rupatadine with fumaric acid in a salt-forming solvent to obtain rupatadine fumarate. The method for preparing rupatadine fumarate of the present invention has mild reaction conditions, short reaction time, a short route, simple operation, high yield, high product purity, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a preparation method of rupatadine fumarate. Background Art

[0002] Rupatadine fumarate, chemical name 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate, has the structural formula:

[0003]

[0004] Rupatadine fumarate is an antihistamine and a widely used antiallergic drug in clinical practice, primarily for desensitization of various allergic diseases. It also plays an important role in the treatment of dermatological conditions such as urticaria, allergic rhinitis, and allergic asthma. Rupatadine fumarate belongs to the third-generation tricyclic antihistamine class. Its pharmacological effects primarily stem from rupatadine, which has dual antihistamine and platelet-activating factor (PAF) antagonism properties. Fumaric acid has inhibitory effects on Escherichia coli and Staphylococcus aureus, and also exhibits anti-tumor, anti-electroshock, analgesic, and antitussive properties.

[0005] Rupatadine fumarate is a potent antiallergic drug developed by Uriach Pharmaceuticals of Spain. In 1993, Uriach Pharmaceuticals applied for a patent for rupatadine fumarate, publication number ES2087818. This patent discloses a synthetic route for rupatadine fumarate: nitrogen-methyl loratadine is reacted with ethyl chloroformate to produce loratadine, which is then reacted under alkaline conditions to produce desloratadine. Desloratadine is then condensed with 5-methylnicotinic acid to produce rupatadine amide. The resulting amide is then reduced to produce rupatadine, which is then salted with fumaric acid to produce rupatadine fumarate. While this route addresses the challenges of synthesizing rupatadine fumarate, it is long and complex, requiring hydrogen-generating reagents such as sodium borohydride, placing high demands on production equipment. Furthermore, the highly toxic ethyl chloroformate used is environmentally unfriendly.

[0006] Currently, there are many synthetic routes for the preparation of rupatadine fumarate, but most of them have defects such as long routes, low yields, harsh reaction conditions, and low product purity.

[0007] In view of this, the present invention is proposed. Summary of the Invention

[0008] The present invention aims to provide a method for preparing rupatadine fumarate, which has mild reaction conditions, short reaction time, short route, simple operation, high yield and high product purity, and is suitable for large-scale industrial production.

[0009] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are adopted:

[0010] The present invention provides a method for preparing rupatadine fumarate, comprising the following steps:

[0011] S1, nitrogen methyl loratadine, phenyl chloroformate and an organic amine react in an organic solvent to obtain compound I;

[0012] The structural formula of the compound I is:

[0013] S2, reacting the compound I with a base in an organic solvent to obtain desloratadine;

[0014] S3, reacting the desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride and an organic amine in an organic solvent to obtain rupatadine;

[0015] S4, the rupatadine and fumaric acid react in a salt-forming solvent to obtain rupatadine fumarate. Further, step S1 includes at least one of the following features (1) to (6);

[0016] (1) The organic amine includes triethylamine;

[0017] (2) The organic solvent includes toluene;

[0018] (3) the molar ratio of the nitrogen methyl loratadine to the phenyl chloroformate is 1:(1.15-1.25);

[0019] (4) The molar ratio of the nitrogen-methyl loratadine to the organic amine is 1:(0.095-0.15);

[0020] (5) The dosage ratio of the nitrogen-methyl loratadine and the organic solvent is 1 g: 8 to 12 mL;

[0021] (6) The reaction conditions are: reflux reaction for 6 to 8 hours.

[0022] Furthermore, in step S1, after the reaction, the process further comprises: sequentially performing concentration and recrystallization.

[0023] Preferably, after the concentration, recrystallization is performed using isopropanol and / or acetonitrile to obtain the compound I.

[0024] Furthermore, in step S2, at least one of the following features (1) to (5) is included;

[0025] (1) The alkali comprises sodium hydroxide and / or potassium hydroxide;

[0026] (2) The organic solvent includes toluene and / or N,N-dimethylformamide;

[0027] (3) The molar ratio of the compound I to the base is 1:(4-8);

[0028] (4) The ratio of the compound I to the organic solvent is 1 g: 14-16 mL;

[0029] (5) The reaction conditions are: reflux reaction for 7 to 9 hours.

[0030] Furthermore, in step S2, after the reaction, the process further comprises: extracting, concentrating and recrystallizing in sequence.

[0031] Preferably, after the reaction, water is added for extraction, and the organic phase is collected. After the organic phase is concentrated, it is recrystallized using ethyl acetate and / or 4-methyl-2-pentanone to obtain the desloratadine.

[0032] Furthermore, step S3 includes at least one of the following features (1) to (5);

[0033] (1) The organic amine includes triethylamine;

[0034] (2) The organic solvent includes N,N-dimethylformamide;

[0035] (3) the molar ratio of the desloratadine to the 3-chloromethyl-5-methylpyridine hydrochloride is 1:(1.05-1.2);

[0036] (4) The molar ratio of the desloratadine to the organic amine is 1:(4-5);

[0037] (5) The usage ratio of the desloratadine and the organic solvent is 1 g: 9-12 mL.

[0038] Furthermore, in step S3, the reaction temperature is 60-80° C., and the reaction time is 55-65 min.

[0039] Furthermore, in step S3, after the reaction, the step further includes: extracting and concentrating in sequence.

[0040] Preferably, after the reaction, an extractant is added for extraction, the organic phase is collected, and the organic phase is concentrated to obtain the rupatadine.

[0041] Furthermore, in step S3, the extractant includes an aqueous solution of ethyl acetate and potassium dihydrogen phosphate.

[0042] Preferably, the volume ratio of the ethyl acetate to the aqueous solution of potassium dihydrogen phosphate is 1:(1-2);

[0043] Preferably, the concentration of the aqueous solution of potassium dihydrogen phosphate is 0.05 to 0.067 g / mL.

[0044] Furthermore, step S4 includes at least one of the following features (1) to (4);

[0045] (1) The molar ratio of the desloratadine to the fumaric acid is 1:(1-1.1);

[0046] (2) the salt-forming solvent comprises ethanol and / or ethyl acetate;

[0047] (3) The ratio of the fumaric acid to the salt-forming solvent is 1 g: 90-110 mL;

[0048] (4) The reaction temperature is 60-80°C.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] The preparation method of rupatadine fumarate of the present invention comprises the following steps: using nitrogenmethylloratadine as a starting material, using phenyl chloroformate instead of highly toxic ethyl chloroformate, and reacting under alkaline conditions to generate compound I; then reacting compound I under alkaline conditions to generate desloratadine; reacting desloratadine with 3-chloromethyl-5-methylpyridine hydrochloride to obtain rupatadine, and directly salifying rupatadine to obtain rupatadine fumarate. The method has mild reaction conditions, short reaction time, short reaction route, simple operation, low equipment requirements, environmental friendliness, good safety, and can obtain rupatadine fumarate in high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0052] Figure 1 This is a liquid chromatogram of rupatadine fumarate prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0053] The technical scheme of the present invention will be clearly and completely described below in conjunction with the accompanying drawings and specific embodiments, but it will be understood by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. Those who do not specify specific conditions in the embodiments are carried out according to normal conditions or the conditions recommended by the manufacturer. Those whose reagents or instruments are not specified by the manufacturer are conventional products that can be purchased commercially.

[0054] The following is a detailed description of a method for preparing rupatadine fumarate according to an embodiment of the present invention.

[0055] In some embodiments of the present invention, a method for preparing rupatadine fumarate is provided, comprising the following steps:

[0056] S1, nitrogen methyl loratadine, phenyl chloroformate and an organic amine react in an organic solvent to obtain compound I;

[0057] The structural formula of compound I is:

[0058] S2, compound I and a base react in an organic solvent to obtain desloratadine;

[0059] S3, desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride and an organic amine react in an organic solvent to obtain rupatadine;

[0060] S4, rupatadine and fumaric acid react in a salt-forming solvent to obtain rupatadine fumarate.

[0061] The preparation method of rupatadine fumarate of the present invention comprises the following steps: using nitrogenmethylloratadine as a starting material, using phenyl chloroformate instead of highly toxic ethyl chloroformate, and reacting under alkaline conditions to generate compound I; reacting compound I under alkaline conditions to generate desloratadine; reacting desloratadine with 3-chloromethyl-5-methylpyridine hydrochloride to obtain rupatadine, and directly salifying rupatadine without further purification to generate rupatadine fumarate; and the method has mild reaction conditions, a short reaction route, a short reaction time, simple operation, low equipment requirements, environmental friendliness, good safety, and can obtain rupatadine fumarate in high yield and high purity.

[0062] In some embodiments of the present invention, nitrogen methyl loratadine, chemical name is 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-benzo[5,6]cycloheptane[1,2-b]pyridine, and has the structural formula: The structural formula of phenyl chloroformate is: Desloratadine, chemical name is 8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]heptane[1,2-b]pyridine; its structural formula is The structure of 3-chloromethyl-5-methylpyridine hydrochloride is Rupatadine, chemical name is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, and its structural formula is The structural formula of fumaric acid is Rupatadine fumarate, chemical name is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate, with the structural formula

[0063] In some embodiments of the present invention, in step S1, the organic amine includes triethylamine.

[0064] In some embodiments of the present invention, in step S1, the organic solvent includes toluene.

[0065] In some embodiments of the present invention, in step S1, the molar ratio of nitrogen-methyl loratadine to phenyl chloroformate is 1:(1.15-1.25); preferably, the molar ratio of nitrogen-methyl loratadine to phenyl chloroformate is 1:1.2.

[0066] In some embodiments of the present invention, in step S1, the molar ratio of nitrogen-methyl loratadine to the organic amine is 1:(0.095-0.15); preferably, the molar ratio of nitrogen-methyl loratadine to the organic amine is 1:0.1.

[0067] In some embodiments of the present invention, in step S1, the usage ratio of nitrogen-methyl loratadine to the organic solvent is 1 g:8-12 mL; preferably, the usage ratio of nitrogen-methyl loratadine to the organic solvent is 1 g:10 mL.

[0068] In some embodiments of the present invention, in step S1, the reaction conditions are: reflux reaction for 6 to 8 hours.

[0069] In some embodiments of the present invention, in step S1, after the reaction, the step further comprises: sequentially performing concentration and recrystallization; preferably, after concentration, recrystallization is performed using isopropanol and / or acetonitrile to obtain Compound I; preferably, recrystallization is performed using isopropanol.

[0070] In some specific embodiments of the present invention, in step S1, after the reaction, the solid is concentrated under reduced pressure at 55-65° C., and then isopropanol and / or acetonitrile are added for recrystallization to obtain Compound I; preferably, isopropanol is added for recrystallization.

[0071] In some specific embodiments of the present invention, in step S1, the volume ratio of nitrogen-methyl loratadine to isopropyl alcohol and / or acetonitrile is 1 g: 5-10 mL.

[0072] In some embodiments of the present invention, in step S1, the reaction yield is greater than 80%, and the purity of the compound I obtained after recrystallization is greater than 99.5%.

[0073] In some embodiments of the present invention, in step S2, the base includes sodium hydroxide and / or potassium hydroxide; preferably, the base includes potassium hydroxide.

[0074] In some embodiments of the present invention, in step S2, the organic solvent includes toluene and / or N,N-dimethylformamide; preferably, the organic solvent includes toluene.

[0075] In some embodiments of the present invention, in step S2, the molar ratio of compound I to the base is 1:4 to 8; typically but not limitatively, for example, the molar ratio of compound I to the base can be 1:4, 1:4, 1:5, 1:6, 1:7, 1:8 or a range consisting of any two thereof.

[0076] In some embodiments of the present invention, in step S2, the usage ratio of compound I to the organic solvent is 1 g:14-16 mL; preferably, the usage ratio of compound I to the organic solvent is 1 g:15 mL.

[0077] In some embodiments of the present invention, in step S2, the reaction conditions are: reflux reaction for 7 to 9 hours; preferably, the reaction time is 8 hours.

[0078] In some embodiments of the present invention, in step S2, after the reaction, the process further comprises: extracting, concentrating and recrystallizing in sequence; preferably, after the reaction, water is added for extraction, the organic phase is collected, and after the organic phase is concentrated, ethyl acetate and / or 4-methyl-2-pentanone is used for recrystallization to obtain desloratadine; preferably, ethyl acetate is used for recrystallization.

[0079] In some specific embodiments of the present invention, in step S2, a reaction liquid is obtained after the reaction, and water is added to the reaction liquid for extraction; preferably, the volume ratio of the reaction liquid to water is 1:0.8-1.2.

[0080] In some specific embodiments of the present invention, in step S2, the ratio of the solid obtained after concentration to ethyl acetate is 1 g: 5-15 mL.

[0081] In some embodiments of the present invention, in step S2, the reaction yield is greater than 75%, and the purity of desloratadine after recrystallization is greater than or equal to 99.5%.

[0082] In some embodiments of the present invention, in step S3, the organic amine includes triethylamine.

[0083] In some embodiments of the present invention, in step S3, the organic solvent includes N,N-dimethylformamide.

[0084] In some embodiments of the present invention, in step S3, the molar ratio of desloratadine to 3-chloromethyl-5-methylpyridine hydrochloride is 1:(1.05-1.2); typically but not limitatively, for example, the molar ratio of desloratadine to 3-chloromethyl-5-methylpyridine hydrochloride can be 1:1.05, 1:1.1, 1:1.15, 1:1.25 or a range of any two thereof.

[0085] In some embodiments of the present invention, in step S3, the molar ratio of desloratadine to the organic amine is 1:4-5.

[0086] In some embodiments of the present invention, in step S3, the usage ratio of desloratadine to the organic solvent is 1 g:9-12 mL.

[0087] In some embodiments of the present invention, in step S3, the reaction temperature is 60-80°C, and the reaction time is 55-65 min; typically but not limitatively, for example, the reaction temperature is 60°C, 65°C, 70°C, 75°C, 80°C or a range consisting of any two thereof; preferably, the reaction temperature is 60°C, and the reaction time is 1 h.

[0088] In some embodiments of the present invention, in step S3, after the reaction, the process further comprises: sequentially performing extraction and concentration; preferably, after the reaction, adding an extractant for extraction, collecting the organic phase, and concentrating the organic phase to obtain rupatadine.

[0089] In some embodiments of the present invention, in step S3, the extractant includes ethyl acetate and an aqueous solution of potassium dihydrogen phosphate; preferably, the volume ratio of ethyl acetate to the aqueous solution of potassium dihydrogen phosphate is 1:(1-2); preferably 3:4; preferably, the concentration of the aqueous solution of potassium dihydrogen phosphate is 0.05-0.067 g / mL.

[0090] In some embodiments of the present invention, in step S3, a reaction solution is obtained after the reaction, and an extractant is added to the reaction solution for extraction; preferably, the volume ratio of the reaction solution to the extractant is 1:(6-8).

[0091] In some embodiments of the present invention, in step S4, the molar ratio of desloratadine to fumaric acid is 1:(1-1.1).

[0092] In some embodiments of the present invention, in step S4, the salt-forming solvent includes ethanol and / or ethyl acetate.

[0093] In some embodiments of the present invention, in step S4, the usage ratio of fumaric acid to salt-forming solvent is 1 g:90-110 mL; preferably 1 g:100-105 mL.

[0094] In some embodiments of the present invention, in step S4, the reaction temperature is 60-80° C.; preferably, the reaction time is 55-65 min.

[0095] Example 1

[0096] The preparation method of rupatadine fumarate provided in this embodiment comprises the following steps:

[0097] S1. The steps of synthesizing compound I from nitrogen-methyl loratadine are as follows:

[0098]

[0099] The specific steps include:

[0100] To a 250 mL four-necked flask at room temperature were added 10.0 g (30.78 mmol) of nitrogen-methyl loratadine, 100 mL of toluene, and 0.31 g (3.08 mmol) of triethylamine. The temperature was raised to reflux, and 5.76 g (36.94 mmol) of phenyl chloroformate was slowly added dropwise. After the addition was complete, the mixture was refluxed for 6 h, and detected by TLC (developing solvent: dichloromethane: methanol = 10:1, Rf = 0.32). After the reaction was completed, the mixture was concentrated to dryness under reduced pressure at 60 ° C. 50 mL of isopropanol was added for recrystallization to obtain 10.94 g of a light pink solid (Compound I) with a yield of 82.45% and a purity of 99.82%.

[0101] S2. The steps of synthesizing desloratadine from compound I are as follows:

[0102]

[0103] The specific steps include:

[0104] To a 250 mL four-necked flask at room temperature were added 10.0 g (23.21 mmol) of compound I, 150 mL of toluene and 5.21 g (92.84 mmol) of potassium hydroxide, and the temperature was raised to reflux for 8 h. TLC detection (developing solvent: n-heptane: ethyl acetate = 1:1, Rf = 0.35) was performed. After the reaction was completed, 150 mL of water was added for extraction, and the organic phase was collected. The organic phase was concentrated to dryness and 50 mL of ethyl acetate was added for recrystallization to obtain 5.59 g of an off-white crystalline solid (desloratadine) with a yield of 77.53% and a purity of 99.5%.

[0105] S3. The steps of synthesizing rupatadine fumarate from desloratadine are as follows:

[0106]

[0107] The specific steps include:

[0108] To a 250 mL four-necked flask were added 5.0 g (16.09 mmol) of desloratadine, 50 mL of DMF, 6.50 g (64.36 mmol) of triethylamine, and 3.01 g (16.89 mmol) of 3-chloromethyl-5-methylpyridine hydrochloride at room temperature. The temperature was raised to 60° C. and the reaction was allowed to proceed for 1 h. 150 mL of ethyl acetate was added, and the organic phase was extracted with an aqueous potassium dihydrogen phosphate solution (10 g of potassium dihydrogen phosphate dissolved in 200 mL of water). The organic phase was concentrated to dryness and dissolved in 100 mL of ethanol. The temperature was raised to 60° C., and 2.05 g (17.70 mmol) of fumaric acid was dissolved in 100 mL of ethanol to obtain a mixed solution. The mixed solution was added dropwise to the reaction system, stirred at 60° C. for 1 h, then cooled to 20-30° C. and filtered to obtain 6.64 g of a light pink solid (rupatadine fumarate) with a yield of 77.53% and a purity of 99.86%.

[0109] The liquid chromatogram of rupatadine fumarate prepared in this example is as follows: Figure 1 shown.

[0110] Example 2

[0111] The preparation method of rupatadine fumarate provided in this embodiment refers to Example 1, except that in step S1, 6.75 g (43.09 mmol) of phenyl chloroformate was slowly added dropwise to obtain 7.02 g of a pink solid (Compound I) with a yield of 52.9% and a purity of 99.58%.

[0112] Example 3

[0113] The preparation method of rupatadine fumarate provided in this example refers to Example 1, except that, in step S1, the temperature was raised to 90° C., and 5.76 g (36.94 mmol) of phenyl chloroformate was slowly added dropwise. After the addition was complete, the mixture was refluxed for 6 h to obtain 10.47 g of a light pink solid (Compound I) with a yield of 78.9% and a purity of 99.75%.

[0114] Example 4

[0115] The preparation method of rupatadine fumarate provided in this example is similar to that of Example 1, except that in step S1, 50 mL of isopropanol is replaced with 100 mL of isopropanol. 9.96 g of a light pink solid (Compound I) is obtained with a yield of 75.06% and a purity of 99.96%.

[0116] Example 5

[0117] The preparation method of rupatadine fumarate provided in this example refers to Example 1, except that in step S1, 50 mL of isopropyl alcohol is replaced with 50 mL of acetonitrile; 8.26 g of a light pink solid (Compound I) is obtained with a yield of 62.25% and a purity of 99.06%.

[0118] Example 6

[0119] The preparation method of rupatadine fumarate provided in this example refers to Example 1, except that in step S1, 50 mL of isopropanol was replaced with 50 mL of isopropanol and 50 mL of n-heptane. 11.21 g of a light pink solid (Compound I) was obtained with a yield of 84.48% and a purity of 98.03%.

[0120] Example 7

[0121] The preparation method of rupatadine fumarate provided in this example is similar to that of Example 1, except that in step S2, 5.21 g (92.84 mmol) of potassium hydroxide is replaced with 3.71 g (92.84 mmol) of sodium hydroxide. 5.73 g of an off-white crystalline solid (desloratadine) is obtained with a yield of 79.47% and a purity of 99.80%. However, the reaction time is relatively long, ranging from 18 to 20 hours.

[0122] Example 8

[0123] The preparation method of rupatadine fumarate provided in this example refers to Example 1, except that in step S2, 5.21 g (92.84 mmol) of potassium hydroxide is replaced with 3.90 g (69.63 mmol) of potassium hydroxide; 4.84 g of an off-white crystalline solid (desloratadine) is obtained with a yield of 66.71% and a purity of 98.8%.

[0124] Example 9

[0125] The preparation method of rupatadine fumarate provided in this embodiment refers to Example 1, except that in step S2, 100 mL of toluene was added to obtain 5.22 g of an off-white crystalline solid (desloratadine) with a yield of 71.90% and a purity of 98.90%.

[0126] Example 10

[0127] The preparation method of rupatadine fumarate provided in this example is similar to that of Example 1, except that in step S2, 50 mL of 4-methyl-2-pentanone is added for recrystallization; 5.65 g of an off-white crystalline solid (desloratadine) is obtained with a yield of 78.36% and a purity of 99.03%.

[0128] Example 11

[0129] The preparation method of rupatadine fumarate provided in this example refers to Example 1, except that in step S2, 5 mL of methanol and 50 mL of methyl tert-butyl ether were added for recrystallization; 2.05 g of an off-white crystalline solid (desloratadine) was obtained with a yield of 28.43% and a purity of 99.66%.

[0130] Example 12

[0131] The preparation method of rupatadine fumarate provided in this embodiment refers to Example 1, except that in step S3, the temperature is raised to 80° C. and the reaction is carried out for 1 hour to obtain 6.42 g of a light pink solid (rupatadine fumarate) with a yield of 75.03% and a purity of 99.28%.

[0132] Example 13

[0133] The preparation method of rupatadine fumarate provided in this example is similar to that of Example 1, except that in step S3, the mass of 3-chloromethyl-5-methylpyridine hydrochloride is 3.44 g (19.308 mmol); 7 g of a light pink solid (rupatadine fumarate) is obtained with a yield of 81.80% and a purity of 99.43%.

[0134] Example 14

[0135] The preparation method of rupatadine fumarate provided in this embodiment refers to Example 1, except that in step S3, the mass of triethylamine is 8.125 g (80.45 mmol); 6.7 g of light pink solid (rupatadine fumarate) is obtained with a yield of 80.61% and a purity of 99.58%.

[0136] Example 15

[0137] The preparation method of rupatadine fumarate provided in this embodiment refers to Example 1, except that in step S3, the mass of fumaric acid is 1.86 g (16.09 mmol); 6.1 g of light pink solid (rupatadine fumarate) is obtained with a yield of 72.33% and a purity of 99.57%.

[0138] Example 16

[0139] The preparation method of rupatadine fumarate provided in this example refers to Example 1, except that in step S3, the organic phase is concentrated to dryness and dissolved in 100 mL of ethyl acetate; 6.78 g of a light pink solid (rupatadine fumarate) is obtained with a yield of 79.22% and a purity of 99.49%.

[0140] Example 17

[0141] The preparation method of rupatadine fumarate provided in this embodiment refers to that of Example 1, except that in step S3, after dissolution, the temperature is raised to 80° C.; 6.78 g of a light pink solid (rupatadine fumarate) is obtained with a yield of 79.2% and a purity of 99.55%.

[0142] Comparative Example 1

[0143] The preparation method of rupatadine fumarate provided in this comparative example refers to Example 1, except that no triethylamine is added in step S1; 10.16 g of a pink solid (Compound I) is obtained with a yield of 76.6% and a purity of 99.64%.

[0144] Comparative Example 2

[0145] The preparation method of rupatadine fumarate provided in this comparative example refers to Example 1, except that, in step S2, the temperature was raised to 90° C. for 8 h, and the reaction could not proceed.

[0146] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing rupatadine fumarate, characterized in that: The steps include: S1, nitrogen methyl loratadine, phenyl chloroformate and an organic amine react in an organic solvent to obtain compound I; The structural formula of the compound I is: The reaction conditions are: reflux reaction for 6 to 8 hours; The organic amine includes triethylamine; The organic solvent includes toluene; The molar ratio of the nitrogen methyl loratadine to the phenyl chloroformate is 1:(1.15-1.25); The molar ratio of the nitrogen methyl loratadine to the organic amine is 1: (0.095-0.15); The usage ratio of the nitrogen-methyl loratadine and the organic solvent is 1 g: 8 to 12 mL; After the reaction, the method further comprises: sequentially performing concentration and recrystallization; After the concentration, recrystallization is performed using isopropanol to obtain the compound I; S2, reacting the compound I with a base in an organic solvent to obtain desloratadine; The organic solvent includes toluene and / or N,N-dimethylformamide; The molar ratio of the compound I to the base is 1:(4-8); The usage ratio of the compound I and the organic solvent is 1 g: 14-16 mL; The reaction conditions are: reflux reaction for 7 to 9 hours; After the reaction, water is added for extraction, and the organic phase is collected. After the organic phase is concentrated, it is recrystallized using ethyl acetate and / or 4-methyl-2-pentanone to obtain the desloratadine; S3, reacting the desloratadine, 3-chloromethyl-5-methylpyridine hydrochloride and an organic amine in an organic solvent to obtain rupatadine; The organic solvent includes N,N-dimethylformamide; The usage ratio of the desloratadine and the organic solvent is 1 g: 9 to 12 mL; After the reaction, an extractant is added for extraction, an organic phase is collected, and the organic phase is concentrated to obtain the rupatadine; The extractant includes an aqueous solution of ethyl acetate and potassium dihydrogen phosphate; The volume ratio of the ethyl acetate to the aqueous solution of potassium dihydrogen phosphate is 1:(1-2); The concentration of the aqueous solution of potassium dihydrogen phosphate is 0.05 to 0.067 g / mL; S4. The rupatadine and fumaric acid react in a salt-forming solvent to obtain rupatadine fumarate.

2. The method for preparing rupatadine fumarate according to claim 1, wherein: In step S2, the alkali includes sodium hydroxide and / or potassium hydroxide.

3. The method for preparing rupatadine fumarate according to claim 1, wherein: In step S3, at least one of the following features (1) to (3) is included; (1) The organic amine includes triethylamine; (2) the molar ratio of the desloratadine to the 3-chloromethyl-5-methylpyridine hydrochloride is 1:(1.05-1.2); (3) The molar ratio of the desloratadine to the organic amine is 1:(4-5).

4. The method for preparing rupatadine fumarate according to claim 1, wherein: In step S3, the reaction temperature is 60-80° C., and the reaction time is 55-65 min.

5. The method for preparing rupatadine fumarate according to claim 1, wherein: In step S4, at least one of the following features (1) to (4) is included; (1) The molar ratio of the desloratadine to the fumaric acid is 1:(1-1.1); (2) the salt-forming solvent comprises ethanol and / or ethyl acetate; (3) The ratio of the fumaric acid to the salt-forming solvent is 1 g: 90-110 mL; (4) The reaction temperature is 60-80°C.

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