Synthesis method of toxyanib phosphate

Abstract

The invention relates to the field of medicine synthesis and preparation, in particular to a synthesis method of toxyanib phosphate. The use amount of acetic acid is greatly reduced in the preparation process, so that excessive acid does not need to be neutralized in the post-treatment process, and a large amount of wastewater is not generated; in addition, the use amount of sodium nitrite is reduced, and the environment and health are facilitated; the enamine reduction reaction does not use acetic acid as a solvent and a hydrogenation reaction catalyzed by heavy metal palladium, so that the safety of the reaction is improved, and the purity of the product is also improved; a decarboxylation reaction and a Vilsmeier-Haack reaction are carried out by a one-pot method, so that the reaction steps are reduced, and the product purity is improved; when aldol reaction is carried out in side chain splicing, side reaction and generation of isomer impurities are reduced. The method is short in route, mild in reaction condition, low in equipment requirement and convenient to operate, industrial production is easy to achieve, and a complex purification method is not needed.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical synthesis and preparation, and in particular to a method for synthesizing tocinib phosphate. Background Art

[0002] Toceranib phosphate is the world's first pet cancer tumor targeted drug. It is a highly selective multi-target tyrosine kinase receptor inhibitor that can inhibit multiple tyrosine kinase receptors. It produces anti-angiogenic and anti-tumor effects by blocking the blood and nutrient supply for tumor cell growth. In addition, it can also directly injure or kill tumor cells. Toceranib phosphate has many targets and is a broad-spectrum tumor targeted drug. It can be used for pet dogs and cats at the same time, and it has good tolerance and no toxic side effects caused by conventional chemotherapy. The compound was developed by Zoetis and the overseas marketed drug name is (RTK) Palladia.

[0003] However, the synthesis route of tocinib phosphate announced by Zoetis is relatively complicated. Acetic acid is used as a solvent in the key reaction step, and the hydrogenation reaction is catalyzed by heavy metal palladium. The disadvantages are that the post-processing of acetic acid is troublesome and a large amount of organic waste acid will be generated; the product is not easy to purify and often contains more isomer impurities; high temperature and acidic hydrogenation have high requirements on equipment. Summary of the invention

[0004] In order to solve the technical problems that the acetic acid produced in the synthesis process of tocinib phosphate in the background technology is troublesome to post-treat, a large amount of organic waste acid is generated, the product is difficult to purify, and the high temperature and acidic hydrogenation have high requirements on equipment, the present invention provides a new synthesis method of tocinib phosphate.

[0005] The synthesis method of tocinib phosphate provided by the present invention comprises the following steps: S1, reacting diketene and 1-(2-aminoethyl)pyrrolidine in an aprotic solvent to generate compound 1; S2, reacting tert-butyl acetoacetate with sodium nitrite and acetic acid in tetrahydrofuran to generate compound II; in this step, tert-butyl acetoacetate is used as a starting material, and when reacting with sodium nitrite to prepare enamine, the amount of acetic acid used is greatly reduced, so there is no need to neutralize excess acid in post-treatment, no large amount of wastewater is generated, and the amount of sodium nitrite used is also reduced, which is beneficial to the environment and health.

[0006] S3. Compound 1 and Compound 2 are subjected to a reduction reaction using zinc powder and ammonium chloride as reducing agents to generate Compound 3. The reduction reaction in this step does not use acetic acid as a solvent, nor does it use a heavy metal palladium-catalyzed hydrogenation reaction, which not only improves the purity of the product, but also improves the safety of the reaction.

[0007] S4. Using trifluoroacetic acid as a solvent and catalyst, the tert-butoxycarbonyl group of compound three is removed. After the reaction is complete, triester of orthoformate is added to carry out decarboxylation reaction and Vilsmeier-Haack reaction in one pot to obtain compound four. In this step, trifluoroacetic acid is used to remove the intermediate of the tert-butoxycarbonyl group, and no separation or purification is required. In addition, the decarboxylation reaction and Vilsmeier-Haack reaction are carried out in one pot to introduce an aldehyde functional group, reduce the reaction steps, and improve the product purity.

[0008] S5. Compound 4 is subjected to an aldol reaction with 5-fluoroindol-2-one in a highly polar solvent under the action of a catalyst to obtain compound 5. In this step, when the aldol reaction is carried out by side chain splicing, the use of a catalyst reduces the side reaction and the formation of isomeric impurities, thereby simplifying the purification step.

[0009] S6, reacting compound 5 and phosphoric acid in an ethanol solvent to generate tocinib phosphate; Wherein, the structural formula of the compound 1 is: ; The structural formula of the compound 2 is: ; The structural formula of the compound three is: ; The structural formula of the compound four is: ; The structural formula of the compound five is: ; The structural formula of the tocinib phosphate is: .

[0010] Furthermore, the reaction temperature in S1 is -10 to 35° C.; and the aprotic organic solvent is dichloromethane or methyl tert-butyl ether.

[0011] Furthermore, in the S1, the reaction molar ratio of diketene to 1-(2-aminoethyl)pyrrolidine is 1:1 to 1.1.

[0012] Furthermore, the molar ratio of tert-butyl acetoacetate, sodium nitrite and acetic acid in S2 is 1:1-2:1-2, and the reaction temperature is -10-45°C.

[0013] Preferably, the molar ratio of tert-butyl acetoacetate, sodium nitrite and acetic acid is 1:1.2:1.5, and the reaction temperature is 30-40°C.

[0014] Furthermore, the molar ratio of compound 1, compound 2, zinc powder and ammonium chloride in S3 is 1:1-2:2-8:2-8, and the reaction temperature is 65-75°C.

[0015] Preferably, the molar ratio of compound 1, compound 2, zinc powder and ammonium chloride is 1:1.2:5:5.

[0016] Furthermore, the molar ratio of compound three to the orthoformate triester in S4 is 1:1-3; the orthoformate triester is trimethyl orthoformate or triethyl orthoformate.

[0017] Preferably, the molar ratio of compound three to orthoformate triester is 1:1.5.

[0018] Preferably, the orthoformate triester is triethyl orthoformate.

[0019] Furthermore, the reaction concentration of compound three in S4 is 0.15-0.5 mol / L.

[0020] Preferably, the reaction concentration of compound three is 0.3 mol / L.

[0021] Furthermore, the catalyst in S5 is one of lithium hydroxide, sodium hydroxide or potassium hydroxide; the amount of the catalyst used is 1% to 20% of the mass of compound four.

[0022] Furthermore, the highly polar solvent in S5 is one of alcohols, tetrahydrofuran or amides.

[0023] Preferably, the highly polar solvent is an alcohol solvent.

[0024] More preferably, the alcohol solvent is ethanol.

[0025] Furthermore, the reaction molar ratio of compound four and 5-fluoroindol-2-one in S5 is 1:1-1.2; the reaction concentration of compound four and 5-fluoroindol-2-one is 0.15-0.5 mol / L.

[0026] Preferably, the reaction molar ratio of compound tetrakis and 5-fluoroindol-2-one is 1:1.01.

[0027] Preferably, the reaction concentration of the compound tetrakis and 5-fluoroindol-2-one is 0.45 mol / L.

[0028] Specifically, the preparation method of tocinib phosphate of the present invention is as follows:

[0029] The process route of the invention uses diketene as a raw material, reacts with 1-(2-aminoethyl)pyrrolidine in a non-protonic solvent to generate an intermediate compound one; tert-butyl acetoacetate reacts with sodium nitrite and acetic acid in tetrahydrofuran to generate an intermediate compound two; zinc powder and ammonium chloride are used as reducing agents to react the two intermediate compounds one with compound two to generate compound three; thereafter, trifluoroacetic acid is used as a solvent and a catalyst to remove the tert-butyloxycarbonyl group of compound three, and after the reaction is complete, orthoformate is added to obtain compound four by a one-pot method; compound four reacts with 5-fluoroindol-2-one under the action of a catalyst to obtain tocinib free base; and finally reacts with phosphoric acid to generate a target product.

[0030] Compared with the prior art, the method for synthesizing tocinib phosphate provided by the present invention has the following beneficial effects: the present invention greatly reduces the amount of acetic acid used in the preparation process, so there is no need to neutralize excess acid in the post-treatment process, and a large amount of wastewater will not be generated, simplifying the treatment steps; in addition, the amount of sodium nitrite used is reduced, which is beneficial to the environment and health; the enamine reduction reaction no longer uses acetic acid as a solvent, and no heavy metal palladium-catalyzed hydrogenation reaction is used, which not only improves the safety of the reaction, but also improves the purity of the product; the decarboxylation reaction and the Vilsmeier-Haack reaction are carried out in one pot, and the aldehyde functional group is introduced, the reaction steps are reduced, and the purity of the product is improved; when the side chain splicing is carried out for the aldehyde reaction, the side reaction and the generation of isomer impurities are reduced, and the purification step is simplified. The route of the present invention is short, the reaction conditions are mild, the equipment requirements are low, the operation is convenient, and it is easy to realize industrial production without the need for a complex purification method. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the 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 creative work.

[0032] Figure 1 The target product tocinib phosphate in Example 1 provided by the present invention 1 H-NMR spectrum; Figure 2 The target product tocinib phosphate in Example 1 provided by the present invention 13 C-NMR spectrum; Figure 3 The mass spectrum of tocinib phosphate, the target product in Example 1 provided by the present invention; Figure 4 This is an infrared spectrum of the target product tocinib phosphate in Example 1 provided by the present invention; Figure 5 This is a high performance liquid chromatogram of the target product tocinib phosphate in Example 1 provided by the present invention. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] Taking into account the technical problems that a large amount of organic waste acid is generated in the existing synthesis process of tocinib phosphate, the product is difficult to purify, and the high temperature and acidic hydrogenation have high requirements on equipment, the present invention provides a method for synthesizing tocinib phosphate.

[0035] The present invention provides the following embodiments: Embodiment 1: Provides such as Figure 1-5 The synthesis method of tocinib phosphate shown in Example 1 is as follows: S1: Add diketene (100 g, 1.19 mol, 1 eq) and 1 L of dichloromethane to a 3 L three-necked flask equipped with a constant pressure dropping funnel, a thermometer and a mechanical stirrer, start stirring and cool the system to -10°C. Then slowly add 1-(2-aminoethyl)pyrrolidine (136 g, 1.19 mol, 1 eq) dropwise to the reaction system, and then naturally warm up overnight after the addition. After the reaction is completed, concentrate under reduced pressure to obtain compound 1 (225 g, yield 95%).

[0036] S2: In a 3 L reactor equipped with a thermometer, mechanical stirring and a dropping funnel, add tert-butyl acetoacetate (100 g, 0.63 mol, 1 eq), 1 L of tetrahydrofuran and acetic acid (56.7 g, 0.95 mol, 1.5 eq), and start stirring. Sodium nitrite (52.4 g, 0.76 mol, 1.2 eq) is prepared into a 30% aqueous solution, the reaction temperature is controlled at 30℃~40℃, and it is slowly added dropwise to the reaction system. After the addition is completed, the reaction is continued at a constant temperature for 2 hours. After the reaction is completed by TLC detection, the organic phase is allowed to stand and the stratification is carried out. The organic phase is washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, washed, and concentrated to obtain compound II (110 g, yield 93%).

[0037] S3: In a 3 L reactor equipped with a thermometer and mechanical stirring, add compound 1 (100 g, 0.5 mol, 1 eq), compound 2 (112.2 g, 0.6 mol, 1.2 eq), 1 L of tetrahydrofuran and ammonium chloride (132.5 g, 2.5 mol, 5 eq), and start stirring. Add zinc powder (162.5 g, 2.5 mol, 5 eq) to the reaction system in batches, keeping tetrahydrofuran in a slightly boiling state (65-75°C). After adding, heat and reflux for 5 hours. After the reaction is completed by TLC detection, cool and filter, and wash the filter cake with ethyl acetate. Combine the organic phases, wash once with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, wash, and concentrate to obtain compound 3 (130.6 g, yield 78%).

[0038] S4: In a 3 L reactor equipped with a thermometer, mechanical stirring and a dropping funnel, add 1 L of trifluoroacetic acid, slowly add compound three (100 g, 0.3 mol, 1 eq) in batches at room temperature, react at room temperature for 2 hours after addition, and slowly add triethyl orthoformate (66.6 g, 0.45 mol, 1.5 eq) after the reaction is complete by TLC detection, and react at room temperature overnight. After the reaction is completed, concentrate and recover trifluoroacetic acid, pour the concentrated solution into 2 L of ice water, neutralize with sodium hydroxide to pH>12, crystallize, filter, and wash the filter cake with ice water. Vacuum drying to obtain compound four (67.1 g, yield 85%).

[0039] S5: In a 3 L reactor equipped with a thermometer and mechanical stirring, add 1 L of ethanol, compound 4 (100 g, 0.38 mol, 1 eq), 5-fluoroindole-2-one (58.0 g, 0.384 mol, 1.01 eq), add potassium hydroxide (5 g, 5%) at room temperature, and react at room temperature for 3 hours. After the reaction is completed, filter, wash twice with water and ethanol respectively, and vacuum dry to obtain compound 5 (140 g, yield 93%).

[0040] S6: In a 3 L reactor equipped with a thermometer and mechanical stirring, add 1 L of ethanol and compound 5 (100 g, 0.25 mol, 1 eq) and mix and stir evenly. Then add 85% phosphoric acid (30 g, 0.26 mol, 1.05 eq) dropwise to the above reaction system and react at room temperature for 2 hours. Filter, wash the filter cake with water and ethanol twice each, and vacuum dry to obtain tocinib phosphate (117 g, yield 54.4%).

[0041] The nuclear magnetic resonance characterization results of the tocinib phosphate are as follows Figure 1-2 The specific data are as follows: 1H-NMR(500 MHz, d6-DMSO)δ:13.72 (s, 1H), 10.92 (s, 1H), 7.98-8.02 (m,1H), 7.71-7.77 (m, 1H), 6.83-6.95 (m, 2H), 3.20-3.25 (m, 8H), 2.45-2.47 (m,6H), 1.90-1.94 (m, 4H); 13 C-NMR (125 MHz, d6-DMSO) δ: 170.0, 165.7, 159.7, 157.6, 137.4, 135.0,126.3, 125.3, 120.4, 115.3, 112.7, 110.1, 106.5, 56.5, 54.0, 53.8, 36.1,23.1, 19.0, 14.0, 11.2.

[0042] The mass spectrometry results of the tocinib phosphate are as follows Figure 3 The specific data are as follows: [M+H]+ = 397.

[0043] The infrared spectrum results of the tocinib phosphate are as follows Figure 4 The specific data are as follows: IR (KBr) cm-1: 3400, 3299, 2907, 2873, 2773, 1677, 1588, 1542, 1479,1334, 1191, 860, 798, 778, 668, 585.

[0044] The HPLC results of the tocinib phosphate are as follows Figure 5 As shown: As can be seen from the figure, the purity of the toceranib phosphate is 99.15%.

[0045] For the reaction conditions in the above-mentioned Example 1, such as the specific amount of solvent, constant temperature time, type of extraction solvent, etc., those skilled in the art can make appropriate adjustments in the design concept of the present invention.

[0046] Embodiment 2: Based on Example 1, in this example, the dichloromethane in S1 is replaced with methyl tert-butyl ether for reaction, and other conditions remain unchanged, then the yield of compound 1 is 93%, the reaction conditions of other S2-S6 remain unchanged, and the yields of other steps of S2-S6 remain unchanged. The total yield of toceranib phosphate is 54.4%.

[0047] Embodiment 3: Based on Example 2, in this Example S1, after stirring is started, the system does not need to be cooled to -10°C, and then 1-(2-aminoethyl)pyrrolidine is slowly added dropwise to the reaction system and the temperature is slowly raised to 50°C. Other conditions remain unchanged, and the yield of compound 1 is 82%. The reaction conditions of other S2-S6 remain unchanged, and the yields of other steps of S2-S6 remain unchanged. The total yield of toceranib phosphate is 48.5%.

[0048] Embodiment 4: Based on Example 1, in this example, the sodium nitrite content in S2 is replaced with: 43.5 g, 0.63 mol, 1 eq for reaction, and other conditions remain unchanged, then the yield of compound 2 is 75%, the reaction conditions of other S1 and S3-S6 remain unchanged, and the yields of other steps of S1 and S3-S6 remain unchanged. The total yield of toceranib phosphate is 54.4%.

[0049] Embodiment 5: Based on Example 1, in this example, the content of compound II in S3 is replaced by: 93.5 g, 0.5 mol, 1 eq; the content of ammonium chloride is replaced by: 53 g, 1.0 mol, 2 eq; the content of zinc powder is replaced by: 65 g, 1.0 mol, 2 eq; the heating reflux reaction time is 12 hours, and other conditions remain unchanged, then the yield of compound III is 65%, and the other reaction conditions of S1-S2 and S4-S6 remain unchanged, and the yields of each step of S1-S2 and S4-S6 remain unchanged. The total yield of toceranib phosphate is 45.3%.

[0050] Embodiment 6: Based on Example 1, in this example, the content of triethyl orthoformate in S4 is replaced by: 44.4 g, 0.3 mol, 1 eq; other conditions remain unchanged, the yield of compound 4 is 75%, the reaction conditions of other S1-S3 and S5-S6 remain unchanged, and the yields of other steps of S1-S3 and S5-S6 remain unchanged. The total yield of toceranib phosphate is 48.0%.

[0051] Embodiment 7: Based on Example 1, in this example, the content of trifluoroacetic acid in S4 is replaced with 500 mL, the reaction time at room temperature is 5 hours, and other conditions remain unchanged. The yield of compound 4 is 80%, the reaction conditions of other S1-S3 and S5-S6 remain unchanged, and the yields of other steps of S1-S3 and S5-S6 remain unchanged. The total yield of toceranib phosphate is 51.2%.

[0052] Embodiment 8: Based on Example 1, in this example, potassium hydroxide in S5 is replaced by 1 g, 1%, and the reaction time at room temperature is extended to 12 hours, and other conditions remain unchanged. The yield of compound 5 is 90%, and the reaction conditions of other S1-S4 and S6 remain unchanged, and the yields of other steps of S1-S4 and S6 remain unchanged. The total yield of toceranib phosphate is 52.6%.

[0053] Embodiment 9: Based on Example 1, in this example, 1 L of ethanol in S5 is replaced with 1 L of N,N-dimethylformamide, and the reaction time at room temperature is shortened to 2 hours, and other conditions remain unchanged. The yield of compound 5 is 80%, and the reaction conditions of other S1-S4 and S6 remain unchanged, and the yields of other steps of S1-S4 and S6 remain unchanged. The total yield of toceranib phosphate is 46.8%.

[0054] In summary, the test results of the embodiment are summarized as shown in Table 1 below: Table 1

[0055] The invention greatly reduces the amount of acetic acid used in the preparation process, so there is no need to neutralize excess acid in the post-treatment process, and a large amount of waste water is not generated, thereby simplifying the treatment steps; in addition, the amount of sodium nitrite used is reduced, which is beneficial to the environment and health; the enamine reduction reaction no longer uses acetic acid as a solvent, and the heavy metal palladium-catalyzed hydrogenation reaction is not used, which not only improves the safety of the reaction but also improves the purity of the product; the decarboxylation reaction and the Vilsmeier-Haack reaction are carried out in a one-pot method, an aldehyde functional group is introduced, the reaction steps are reduced, and the product purity is improved; when the side chain splicing is carried out for the aldol reaction, the side reaction and the generation of isomer impurities are reduced, and the purification step is simplified.

[0056] The invention has a short route, mild reaction conditions, low equipment requirements, convenient operation, and easy industrial production without the need for complex purification methods.

[0057] Although the terms such as toceranib phosphate, tetrahydrofuran and acetic acid are used more frequently in this article, the possibility of using other terms is not excluded. The use of these terms is only for more convenient description and explanation of the essence of the present invention; interpreting them as any additional limitation is contrary to the spirit of the present invention.

[0058] 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 synthesizing tocinib phosphate, characterized in that: The steps include: S1, reacting diketene and 1-(2-aminoethyl)pyrrolidine in an aprotic solvent to generate compound 1; S2, reacting tert-butyl acetoacetate with sodium nitrite and acetic acid in tetrahydrofuran to generate compound 2; S3, using zinc powder and ammonium chloride as reducing agents to reduce compound 1 and compound 2 to generate compound 3; S4, using trifluoroacetic acid as a solvent and a catalyst to remove the tert-butyloxycarbonyl group of compound three, after the reaction is complete, adding orthoformate triester, and performing a decarboxylation reaction and a Vilsmeier-Haack reaction in one pot to obtain compound four; S5, subjecting compound 4 to an aldol reaction with 5-fluoroindol-2-one in a highly polar solvent in the presence of a catalyst to obtain compound 5; S6, reacting compound 5 and phosphoric acid in an ethanol solvent to generate tocinib phosphate; Wherein, the structural formula of the compound 1 is: ; The structural formula of the compound 2 is: ; The structural formula of the compound three is: ; The structural formula of the compound four is: ; The structural formula of the compound five is: ; The structural formula of the tocinib phosphate is: .

2. The method for synthesizing tocinib phosphate according to claim 1, characterized in that: The reaction temperature in S1 is -10 to 35°C; the aprotic organic solvent is dichloromethane or methyl tert-butyl ether.

3. The method for synthesizing tocinib phosphate according to claim 1, characterized in that: The reaction molar ratio of diketene to 1-(2-aminoethyl)pyrrolidine in S1 is 1:1 to 1.

1.

4. The method for synthesizing tocinib phosphate according to claim 1, characterized in that: The molar ratio of tert-butyl acetoacetate, sodium nitrite and acetic acid in S2 is 1:1-2:1-2, and the reaction temperature is -10-45°C.

5. The method for synthesizing tocinib phosphate according to claim 1, characterized in that: The molar ratio of compound 1, compound 2, zinc powder and ammonium chloride in S3 is 1:1-2:2-8:2-8, and the reaction temperature is 65-75°C.

6. The method for synthesizing tocinib phosphate according to claim 1, characterized in that: The molar ratio of compound three to the orthoformate triester in S4 is 1:1-3; the orthoformate triester is trimethyl orthoformate or triethyl orthoformate.

7. The method for synthesizing toceranib phosphate according to claim 1, characterized in that: The reaction concentration of compound 3 in S4 is 0.15-0.5 mol / L.

8. The method for synthesizing tocinib phosphate according to claim 1, characterized in that: The catalyst in S5 is one of lithium hydroxide, sodium hydroxide or potassium hydroxide; the amount of the catalyst used is 1% to 20% of the mass of compound four.

9. The method for synthesizing toceranib phosphate according to claim 1, characterized in that: The highly polar solvent in S5 is one of alcohols, tetrahydrofuran or amides.

10. The method for synthesizing toceranib phosphate according to claim 1, characterized in that: The reaction molar ratio of compound four and 5-fluoroindol-2-one in S5 is 1:1-1.2; the reaction concentration of compound four and 5-fluoroindol-2-one is 0.15-0.5 mol / L.

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