Preparation method of erlotinib intermediate and erlotinib

Abstract

The invention relates to the technical field of chemical synthesis of medicines, in particular to an erlotinib intermediate and a preparation method of erlotinib. The invention relates to a preparation method of an erlotinib intermediate. The preparation method comprises the following steps: carrying out nitration reaction on a compound A and mixed acid in a continuous flow reactor to prepare an erlotinib intermediate B, the structural formulas of the compound A and the erlotinib intermediate B are respectively as follows: # imgabs0 #; the mixed acid comprises nitric acid and sulfuric acid; in the mixed acid, the mass fraction of the sulfuric acid is 65%-75%; the molar ratio of the nitric acid to the compound A is (4-4.8): 1. On the basis of the continuous flow reactor, the nitration reaction has high mononitration selectivity by adopting the specific reaction conditions of the nitration-sulfuric acid mixed nitration method, and meanwhile, the conversion rate of the raw materials and the yield of the product are also ensured and even improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to an erlotinib intermediate and a method for preparing erlotinib. Background Art

[0002] Non-small cell lung cancer is the most common type of lung cancer, accounting for about 80% of all lung cancer cases. Erlotinib, whose trade name is Tarceva and chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinolinamine, is a targeted anti-tumor drug jointly developed by Swiss Roche, American Océ Biopharmaceuticals and Genentech Pharmaceuticals, and its target is the epidermal growth factor receptor.

[0003] From the chemical structure of erlotinib, we can know that quinazoline is its main ring structure. The main difference between different erlotinib synthesis routes lies in the difference in the construction method of the quinazoline ring. A more common synthesis route of erlotinib is: using 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester as a raw material, through nitration, reduction, cyclization, chlorination, aniline substitution and other steps to synthesize the target product erlotinib. The specific synthesis route is as follows:

[0004]

[0005] In the prior art, the production process of each step is also a traditional batch process. Researchers focus more on the subsequent reduction, cyclization and other steps, while the step of obtaining the nitrated intermediate by nitration of the starting material has rarely received attention. As the first step of the synthesis of erlotinib, the selectivity of nitration, the conversion rate of the raw materials and the yield of the first step intermediate are of great significance to the yield and cost control of the entire erlotinib synthesis route.

[0006] In view of this, the present invention is proposed. Summary of the invention

[0007] An object of the present invention is to provide a method for preparing an erlotinib intermediate, so as to solve the technical problems of poor mononitration selectivity and low yield of the erlotinib intermediate in the prior art.

[0008] Another object of the present invention is to provide a method for preparing erlotinib.

[0009] In order to achieve the above-mentioned object of the present invention, the present invention provides a method for preparing an erlotinib intermediate, comprising the following steps:

[0010] Compound A and mixed acid are subjected to nitration reaction in a continuous flow reactor to prepare erlotinib intermediate B;

[0011] The structural formulas of the compound A and the erlotinib intermediate B are as follows:

[0012]

[0013] The mixed acid comprises nitric acid and sulfuric acid; in the mixed acid, the mass fraction of the sulfuric acid is 65% to 75%;

[0014] The molar ratio of the nitric acid to the compound A is (4-4.8):1.

[0015] In a specific embodiment of the present invention, the molar ratio of the nitric acid to the compound A is (4.2-4.6):1; in the mixed acid, the mass fraction of the sulfuric acid is 68%-72%.

[0016] In a specific embodiment of the present invention, the compound A is dissolved in a solvent in advance, and then nitrated with the mixed acid in a continuous flow reactor. Further, the solvent includes at least one of CH2Cl2, CHCl3, DMF and DMSO.

[0017] In a specific embodiment of the present invention, in the continuous flow reactor, the total flow rate of the compound A and the mixed acid is 30 to 50 mL / min, preferably 36 to 40 mL / min.

[0018] In a specific embodiment of the present invention, in the mixed acid, the molar ratio of the sulfuric acid to the nitric acid is (1.5-1.7):1.

[0019] In a specific embodiment of the present invention, the mixed acid is mainly prepared from sulfuric acid with a mass fraction of 65% to 75% and nitric acid with a mass fraction of more than 97%.

[0020] In a specific embodiment of the present invention, the temperature of the nitration reaction is 30-50°C.

[0021] In a specific embodiment of the present invention, the mixing residence time of the compound A and the mixed acid in the reaction zone of the continuous flow reactor is 40 to 80 seconds.

[0022] In a specific embodiment of the present invention, the continuous flow reactor comprises a Corning G1 continuous flow reactor.

[0023] In a specific embodiment of the present invention, the process further comprises: subjecting the material after the nitration reaction to static separation and collecting an organic layer; subjecting the organic layer to alkali washing and water washing, removing the solvent and collecting a solid.

[0024] The present invention also provides a method for preparing erlotinib, comprising the method for preparing any one of the above-mentioned erlotinib intermediates.

[0025] In a specific embodiment of the present invention, the method further comprises: subjecting the erlotinib intermediate to nitro reduction, cyclization, chlorination, and 3-ethynylaniline substitution reactions in sequence.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] (1) The preparation method of the erlotinib intermediate of the present invention is based on a continuous flow reactor and adopts specific reaction conditions of the nitric-sulfur mixed acid nitration method, so that the nitration reaction has high single nitration selectivity, and the conversion rate of the raw materials and the yield of the product are also guaranteed or even improved;

[0028] (2) The preparation method of erlotinib of the present invention is based on a simple and highly selective first step nitration reaction, which improves the yield of erlotinib product as a whole and reduces the cost accordingly. DETAILED DESCRIPTION

[0029] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be appreciated 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, all belong to the scope of protection of the present invention. If specific conditions are not indicated in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0030] Research has found that the existing conventional nitric-sulfur mixed acid nitration method has the following problems:

[0031] On the one hand, since the nitric-sulfur mixed acid nitration reaction is a heterogeneous reaction, it is easy to cause local overheating and lead to danger. In addition, the reaction materials themselves are explosive and dangerous, the nitrating agent is highly corrosive and oxidizing, and the nitration products and by-products are explosive. All these factors result in low heat transfer efficiency and great safety hazards in the case of a kettle reaction. On the other hand, the nitric-sulfur mixed acid nitration method reacts quickly and easily produces multiple nitrates, which not only results in poor single nitration selectivity but also increases production risks due to the generation of multiple nitrates.

[0032] Based on the above reasons, other methods are used in the prior art to replace the nitric-sulfuric acid nitration method to prepare the nitration product, but this will not only make the reaction system complicated, but also increase the cost.

[0033] In one aspect, the present invention provides a method for preparing an erlotinib intermediate, comprising the following steps:

[0034] Compound A and mixed acid are subjected to nitration reaction in a continuous flow reactor to prepare erlotinib intermediate B;

[0035] The structural formulas of compound A and erlotinib intermediate B are as follows:

[0036]

[0037] The mixed acid includes nitric acid and sulfuric acid; in the mixed acid, the mass fraction of sulfuric acid is 65% to 75%;

[0038] The molar ratio of nitric acid to compound A is (4-4.8):1.

[0039] The route for obtaining erlotinib intermediate B by nitration reaction of compound A with mixed acid is as follows:

[0040]

[0041] The preparation method of the erlotinib intermediate of the present invention is carried out in a continuous flow reactor, and the high heat and mass transfer efficiency of the continuous flow reactor is utilized to rapidly transfer the heat of the nitration reaction, thereby improving the safety factor. In addition, the nitric-sulfur mixed acid method is low in cost.

[0042] In addition, the present invention improves the selectivity of mononitration of compound A to a certain extent by using a mixed acid with a lower sulfuric acid concentration, and at the same time uses a higher molar ratio of nitric acid to compound A, combined with the extremely strong heat and mass transfer efficiency of the continuous flow reactor, to make up for the weak nitration capacity of sulfuric acid, while taking into account the improvement of the mononitration selectivity of the nitration reaction, as well as the conversion rate and yield of the reaction. This is of great significance for the improvement of the overall yield and reduction of the cost of subsequent erlotinib production.

[0043] For example, in different embodiments, the mass fraction of sulfuric acid in the mixed acid can be 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75% or a range consisting of any two of them.

[0044] For example, in different embodiments, the molar ratio of nitric acid to compound A can be 4:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1 or a range consisting of any two of them.

[0045] In a specific embodiment of the present invention, the molar ratio of nitric acid to compound A is (4.2-4.6):1; in the mixed acid, the mass fraction of sulfuric acid is 68%-72%.

[0046] In a specific embodiment of the present invention, compound A is dissolved in a solvent in advance, and then nitrated with a mixed acid in a continuous flow reactor. Further, the solvent includes at least one of CH2Cl2, CHCl3, DMF and DMSO.

[0047] In actual operation, compound A is dissolved in a solvent in advance to obtain a solution containing compound A; in the solution, the concentration of compound A can be 0.1 to 1 g / mL, preferably 0.4 to 0.6 g / mL.

[0048] For example, in different embodiments, in the solution, the concentration of compound A can be 0.1 g / mL, 0.2 g / mL, 0.5 g / mL, 0.8 g / mL, 1 g / mL, or a range consisting of any two of them.

[0049] In a specific embodiment of the present invention, in the continuous flow reactor, the total flow rate of compound A and the mixed acid is 30 to 50 mL / min, preferably 36 to 40 mL / min.

[0050] For example, in different embodiments, in a continuous flow reactor, the total flow rate of compound A and the mixed acid can be 30 mL / min, 32 mL / min, 35 mL / min, 38 mL / min, 40 mL / min, 42 mL / min, 45 mL / min, 48 mL / min, 50 mL / min or a range consisting of any two thereof.

[0051] The total flow rate is the sum of the flow rates of the solution containing compound A and the mixed acid.

[0052] In the continuous flow reactor, the molar ratio of nitric acid to compound A is maintained within a defined range, while the total flow rate is controlled within the above range, taking into account the selectivity, raw material conversion rate and yield of mononitration.

[0053] By controlling the total flow rate within the above range, both the mass transfer of the reaction system and the reaction efficiency are guaranteed, while taking into account the selectivity, raw material conversion rate and yield of the mononitration.

[0054] The method of the present invention achieves multiple performances by coordinating multiple parameters, such as reaction safety, product yield, single nitration selectivity, etc. However, simply increasing the amount of nitric acid in the prior art will lead to an increase in polynitration byproducts, which not only reduces the product yield and increases the production cost, but also causes safety risks in production.

[0055] In a specific embodiment of the present invention, in the mixed acid, the molar ratio of sulfuric acid to nitric acid is (1.5-1.7):1.

[0056] For example, in different embodiments, in the mixed acid, the molar ratio of sulfuric acid to nitric acid can be 1.5:1, 1.55:1, 1.6:1, 1.65:1, 1.7:1 or a range consisting of any two of them.

[0057] In a specific embodiment of the present invention, the mixed acid is mainly prepared from sulfuric acid with a mass fraction of 65% to 75% and nitric acid with a mass fraction of more than 97%.

[0058] In a specific embodiment of the present invention, the temperature of the nitration reaction is 30-50°C.

[0059] For example, in different embodiments, the temperature of the nitration reaction can be 30°C, 32°C, 35°C, 38°C, 40°C, 42°C, 45°C, 48°C, 50°C or a range consisting of any two thereof.

[0060] According to the preparation method of the present invention, the raw materials can be completely converted under the reaction condition of 30° C., the selectivity reaches 99.3%, and the temperature tolerance range is wide; at the same time, the reaction residence time only needs 65 seconds, and compared with the existing production process, the production efficiency is greatly improved.

[0061] In a specific embodiment of the present invention, the mixing residence time of compound A and the mixed acid in the reaction zone of the continuous flow reactor is 40 to 80 seconds, preferably 60 to 70 seconds.

[0062] For example, in different embodiments, the mixing residence time of compound A and the mixed acid in the reaction zone of the continuous flow reactor can be 40s, 45s, 50s, 55s, 60s, 65s, 70s, 75s, 80s or a range consisting of any two thereof.

[0063] In a specific embodiment of the present invention, the continuous flow reactor comprises a Corning G1 continuous flow reactor.

[0064] In a specific embodiment of the present invention, the process further comprises: subjecting the material after the nitration reaction to static separation and collecting an organic layer; subjecting the organic layer to alkali washing and water washing, removing the solvent and collecting a solid.

[0065] Among them, alkali washing and water washing can be carried out according to conventional experimental operations; the solvent can be removed by conventional reduced pressure distillation.

[0066] In actual operation, the method for preparing the erlotinib intermediate of the present invention may include the following steps:

[0067] The solution containing compound A and the mixed acid are respectively pumped into a continuous flow reactor at a certain flow rate to carry out nitration reaction; after the reaction is completed, the reacted material is discharged from the continuous flow reactor, and is allowed to stand for separation, and the organic phase is collected and washed with alkali and water, and then the solvent is removed to obtain the erlotinib intermediate B. The product can be further detected and analyzed by liquid chromatography.

[0068] The present invention also provides a method for preparing erlotinib, including the method for preparing any one of the above-mentioned erlotinib intermediates.

[0069] In a specific embodiment of the present invention, the method further comprises: subjecting the erlotinib intermediate to nitro reduction, cyclization, chlorination and 3-ethynylaniline substitution reactions in sequence.

[0070] Among them, the subsequent nitro reduction, cyclization, chlorination, and 3-ethynylaniline substitution reactions can be carried out according to existing conventional operations and will not be described in detail here.

[0071] Unless otherwise specified, the mixed acid used in the following specific examples and comparative examples is prepared by the following method:

[0072] Take a 1L beaker, add 221g of ice water, slowly add 554g of 98% sulfuric acid along the wall of the beaker in an ice bath while stirring. After the sulfuric acid is added and the liquid temperature in the beaker cools to room temperature, slowly add 225g of 97% nitric acid while stirring. After cooling, you will get a mixed acid with a molar ratio of 1.6:1 between 1000g of sulfuric acid and nitric acid and a mass fraction of 70% of sulfuric acid.

[0073] Example 1

[0074] This example provides a method for preparing an erlotinib intermediate, and the synthetic route is as follows:

[0075]

[0076] The specific preparation method comprises the following steps:

[0077] (a) dissolving compound A in CH2Cl2 to prepare a solution with a concentration of compound A of 0.5 g / mL;

[0078] (b) The mixed acid is introduced into a continuous flow reactor as one stream by a plunger pump, and the solution of step (a) is introduced into a continuous flow reactor as another stream by a plunger pump. The total flow rate of the two streams is 38 mL / min, and the residence time is 65 s. At the same time, the molar ratio of nitric acid to compound A is controlled to be 4.4:1, and the reaction temperature is set to 30°C.

[0079] (c) After the reaction is completed, the reaction solution is allowed to stand for separation, and the organic phase is collected and washed with a saturated sodium carbonate aqueous solution and water. The solvent is then removed and analyzed by liquid chromatography.

[0080] Example 2

[0081] This example refers to the preparation method of Example 1, with the only difference being that in step (b), the molar ratio of nitric acid to compound A is different.

[0082] In this embodiment, the molar ratio of nitric acid to compound A is 4:1.

[0083] Example 3

[0084] This example refers to the preparation method of Example 1, with the only difference being that in step (b), the molar ratio of nitric acid to compound A is different.

[0085] In this embodiment, the molar ratio of nitric acid to compound A is 4.8:1.

[0086] Example 4

[0087] This example refers to the preparation method of Example 1, with the only difference being that in step (b), the total flow rates of the two streams of material are different.

[0088] In this embodiment, the total flow rate of the two streams of materials is 30 mL / min (the same continuous flow reactor is used, and the residence time is changed accordingly).

[0089] Example 5

[0090] This example refers to the preparation method of Example 1, with the only difference being that in step (b), the total flow rates of the two streams of material are different.

[0091] In this embodiment, the total flow rate of the two streams is 50 mL / min (the same continuous flow reactor is used, and the residence time is changed accordingly).

[0092] Example 6

[0093] This example refers to the preparation method of Example 1, with the only difference being that in step (b), the total flow rates of the two streams of material are different.

[0094] In this embodiment, the total flow rate of the two streams of materials is 36 mL / min (the same continuous flow reactor is used, and the residence time is changed accordingly).

[0095] Example 7

[0096] This example refers to the preparation method of Example 1, with the only difference being that in step (b), the total flow rates of the two streams of material are different.

[0097] In this embodiment, the total flow rate of the two streams of materials is 40 mL / min (the same continuous flow reactor is used, and the residence time is changed accordingly).

[0098] Example 8

[0099] This example refers to the preparation method of Example 1, with the only difference being that in step (a), the concentration of compound A in the prepared solution is different.

[0100] In this embodiment, the concentration of compound A in the solution prepared in step (a) is 0.4 g / mL.

[0101] Example 9

[0102] This example refers to the preparation method of Example 1, with the only difference being that in step (a), the concentration of compound A in the prepared solution is different.

[0103] In this embodiment, the concentration of compound A in the solution prepared in step (a) is 0.6 g / mL.

[0104] Example 10

[0105] This example refers to the preparation method of Example 1, with the only difference being that in step (a), the concentration of compound A in the prepared solution is different.

[0106] In this embodiment, the concentration of compound A in the solution prepared in step (a) is 0.1 g / mL.

[0107] Embodiment 11

[0108] This example refers to the preparation method of Example 1, with the only difference being that in step (a), the concentration of compound A in the prepared solution is different.

[0109] In this embodiment, the concentration of compound A in the solution prepared in step (a) is 1 g / mL.

[0110] Example 12

[0111] This example is prepared by referring to the method of Example 1, except that the composition of the mixed acid is different.

[0112] The preparation of the mixed acid in this embodiment comprises the following steps:

[0113] Take a 1L beaker, add 206g of ice water, slowly add 515g of 98% sulfuric acid along the wall of the beaker in an ice bath while stirring. After the sulfuric acid is added and the liquid temperature in the beaker cools to room temperature, slowly add 279g of 97% nitric acid while stirring. After cooling, you will get a mixed acid with a molar ratio of 1.2:1 between 1000g of sulfuric acid and nitric acid and a mass fraction of 70% sulfuric acid.

[0114] Embodiment 13

[0115] This example is prepared by referring to the preparation method of Example 1, except that the reaction temperature is different.

[0116] In this embodiment, the reaction temperature in step (b) is 40°C.

[0117] Embodiment 14

[0118] This example is prepared by referring to the preparation method of Example 1, except that the reaction temperature is different.

[0119] In this embodiment, the reaction temperature in step (b) is 50°C.

[0120] Embodiment 15

[0121] This example is prepared by referring to the preparation method of Example 1, except that the reaction temperature is different.

[0122] In this embodiment, the reaction temperature in step (b) is 60°C.

[0123] Comparative Example 1

[0124] The comparative example provides a method for preparing an erlotinib intermediate, comprising the following steps:

[0125] Compound A was dissolved in CH2Cl2 to obtain a solution with a concentration of 0.5 g / mL of compound A; the solution was placed in a kettle reactor and mixed acid (a mixed acid with a molar ratio of sulfuric acid to nitric acid of 1.6:1 and a mass fraction of sulfuric acid of 70%) was added dropwise at 30°C; the molar ratio of nitric acid to compound A in the mixed acid was 4.4:1. After the reaction was completed, the reaction solution was allowed to stand for separation, the organic phase was collected and washed with a saturated sodium carbonate aqueous solution and water, and then the solvent was removed and analyzed by liquid chromatography.

[0126] Sampling and testing were carried out at reaction times of 30min, 60min, 90min and 120min respectively.

[0127] Comparative Example 2

[0128] Comparative Example 2 refers to the preparation method of Example 1, except that in step (b), the molar ratio of nitric acid to compound A is different.

[0129] In Comparative Example 2, the molar ratio of nitric acid to compound A is 3:1.

[0130] Comparative Example 3

[0131] Comparative Example 3 refers to the preparation method of Example 1, except that in step (b), the molar ratio of nitric acid to compound A is different.

[0132] In Comparative Example 3, the molar ratio of nitric acid to compound A is 5:1.

[0133] Comparative Example 4

[0134] Comparative Example 4 refers to the preparation method of Example 1, except that the mixed acid composition is different.

[0135] The preparation of the mixed acid of Comparative Example 4 comprises the following steps:

[0136] Take a 1L beaker, add 140g of ice water, slowly add 610g of 98% sulfuric acid along the wall of the beaker in an ice bath while stirring. After the sulfuric acid is added and the liquid temperature in the beaker cools to room temperature, slowly add 250g of 97% nitric acid while stirring. After cooling, you will get a mixed acid with a molar ratio of 1.6:1 between 1000g of sulfuric acid and nitric acid and a mass fraction of 80% sulfuric acid.

[0137] Comparative Example 5

[0138] Comparative Example 5 refers to the preparation method of Example 1, except that the composition of the mixed acid is different.

[0139] The preparation of the mixed acid of Comparative Example 5 comprises the following steps:

[0140] Take a 1L beaker, add 309g of ice water, slowly add 490g of 98% sulfuric acid along the wall of the beaker in an ice bath while stirring. After the sulfuric acid is added and the liquid temperature in the beaker cools to room temperature, slowly add 201g of 97% nitric acid while stirring. After cooling, you will get 1000g of mixed acid with a molar ratio of sulfuric acid to nitric acid of 1.6:1 and a sulfuric acid mass fraction of 60%.

[0141] Experimental example

[0142] The raw material conversion rate, total yield of mononitrate and selectivity of different embodiments and comparative examples were tested and calculated, and the test results are shown in Table 1.

[0143] Table 1 Conversion rate of raw material compound A and total yield of mononitrate in different embodiments and comparative examples

[0144]

[0145] It can be seen from the above test results that the present invention improves the selectivity of mononitration of compound A to a certain extent by adopting a mixed acid with a lower sulfuric acid concentration, and at the same time adopts a higher molar ratio of nitric acid to compound A, combined with the extremely strong heat and mass transfer efficiency of the continuous flow reactor, to make up for the deficiency of weak sulfuric acid nitration capacity, while taking into account improving the mononitration selectivity of the nitration reaction, as well as the conversion rate and yield of the reaction.

[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 aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned 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 an erlotinib intermediate, characterized in that: The steps include: Compound A and mixed acid are subjected to nitration reaction in a continuous flow reactor to prepare erlotinib intermediate B; The structural formulas of the compound A and the erlotinib intermediate B are as follows: The mixed acid comprises nitric acid and sulfuric acid; in the mixed acid, the mass fraction of the sulfuric acid is 65% to 75%; The molar ratio of the nitric acid to the compound A is (4-4.8):

1.

2. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: The molar ratio of the nitric acid to the compound A is (4.2-4.6):1; And / or, in the mixed acid, the mass fraction of the sulfuric acid is 68% to 72%.

3. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: The compound A is dissolved in a solvent in advance, and then subjected to a nitration reaction with the mixed acid in a continuous flow reactor; Preferably, the solvent comprises at least one of CH2Cl2, CHCl3, DMF and DMSO.

4. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: In the continuous flow reactor, the total flow rate of the compound A and the mixed acid is 30 to 50 mL / min; Preferably, the total flow rate of the compound A and the mixed acid is 36-40 mL / min.

5. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: In the mixed acid, the molar ratio of the sulfuric acid to the nitric acid is (1.5-1.7):

1.

6. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: The mixed acid is mainly prepared from sulfuric acid with a mass fraction of 65% to 75% and nitric acid with a mass fraction of more than 97%.

7. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: The temperature of the nitration reaction is 30-50°C.

8. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: The mixing residence time of the compound A and the mixed acid in the reaction zone of the continuous flow reactor is 40 to 80 seconds.

9. The method for preparing an erlotinib intermediate according to claim 1, characterized in that: The continuous flow reactor comprises a Corning G1 continuous flow reactor; Preferably, the preparation method further comprises: standing and separating the material after the nitration reaction, and collecting the organic layer; washing the organic layer with alkali and water, removing the solvent, and collecting the solid.

10. A method for preparing erlotinib, characterized in that: The invention comprises a method for preparing the erlotinib intermediate according to any one of claims 1 to 9.

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