Preparation method of crizotinib

Abstract

The invention provides a preparation method of crizotinib, and belongs to the technical field of medicine synthesis. 5-bromo-2-nitropyridine-3-alcohol is adopted as a raw material to prepare an intermediate 4-(4-(5-hydroxy-6-nitropyridine-3-yl) 1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester, namely a compound III, and then the compound III reacts with (S)-1-(2, 6-dichloro-3-fluorophenyl) ethanol to obtain a key intermediate (R)-4-[4-[6-nitro-5-[1-(2, 6-dichloro-3-fluorophenyl) ethyl]-4-[4-[6-nitro-5-[1-(2, 6-dichloro-3-fluorophenyl)-4-(4-(5-hydroxy-6-nitropyridine-3-yl) piperidine-1-carboxylic acid tert-butyl ester]. The preparation method comprises the following steps: carrying out catalytic reduction and deprotection reaction on a key intermediate to obtain a target product compound VII, namely crizotinib, by taking 2, 6-dichloro-3-fluorophenyl) ethyoxyl] pyridine-3-yl]-1H-pyrazol-1-yl] piperidine-1-carboxylic acid tert-butyl ester as a compound V, and carrying out catalytic reduction and deprotection reaction on the key intermediate. The crizotinib synthesis method provided by the invention is short in step, simple and easy to control, time cost and material cost are saved, and the crizotinib synthesis method has remarkable advantages and industrial practical value.

Description

A method for preparing crizotinib Technical Field

[0001] This invention relates to the field of drug synthesis technology, and in particular to a method for preparing crizotinib. Background Technology

[0002] Crizotinib, developed by Pfizer, is an ATP-competitive multi-target protein kinase inhibitor that inhibits Met / ALK / ROS. Significant clinical efficacy of crizotinib has been demonstrated in tumor patients with abnormal ALK, ROS, and Met kinase activity. The chemical name of this compound is (R)-3-[1-(2,6-dichloro-3-fluoro-benzene)-ethoxy]-5-(1-piperidin-4-alkyl-1-hydro-pyrazole-4-alkyl)-pyrimidine-2-indenhydride, and its structural formula is shown in Formula 1 below.

[0003] Formula 1

[0004] Agouron Pharmaceuticals' US patent application (US20060128724 A1) discloses the synthetic method shown in Formula 2 below. This method has a long route and requires protection of the amino group in the intermediate compound 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine during the reaction, requiring two Boc groups, which wastes raw materials. Subsequently, coupling with a borate ester and deprotecting the Boc group yields 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)-2-aminopyridine, which is then reacted with 4-(4-bromo-1 H-pyrazol-1-yl)-1-tert-butoxycarbonylpiperidine undergoes Suzuki coupling to yield 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine, which is then subjected to a Boc de-oxidation reaction to give crizotinib. This route involves eight steps with an overall yield of only about 25%, and requires two Boc de-oxidation reactions, making the process complex. Both coupling reactions in this route require purification by column chromatography, resulting in a long reaction cycle and hindering industrial production.

[0005]

[0006] Formula 2

[0007] The synthetic route disclosed in WO2006021884A2 / US7858643B2 and CN 104693184 A is shown in Equation 3. This method uses 3-hydroxy-2-nitropyridine and the chiral compound (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol as starting materials, undergoing a Mitsunobu reaction to obtain a nitro compound. This bromide is then obtained through iron powder reduction and NBS treatment, followed by a Suzuki coupling reaction with a borate ester to yield the compound. Deprotection then yields crizotinib. This method requires five steps, with an overall yield of approximately 39%. This route suffers from low yield, long reaction cycle, high time consumption, significant pollution, and harsh reaction conditions. Furthermore, the palladium-catalyzed Suzuki reaction is time-consuming and involves numerous side reactions; the palladium catalyst produced in this step requires a large amount of palladium removal reagent for adsorption. The low yield makes it difficult to scale up for production.

[0008]

[0009] Formula 3

[0010] Chinese patent CN105924431A reports a synthetic route as shown in Formula 4. This method uses a chiral intermediate (R)-1-(2,6-dichloro-3-fluorophenyl)ethanol as a starting material, reacting it sequentially with methanesulfonyl chloride and 3-hydroxy-2-nitropyridine to obtain a nitropyridine derivative. This derivative is then reduced with Raney nickel and brominated with NBS to obtain a brominated pyridine derivative. The malononitrile-containing derivative, obtained by coupling malononitrile with the brominated pyridine derivative, undergoes ammonolysis with N,N-dimethylamine hydrochloride, and finally undergoes a cyclization reaction with hydrazine to obtain crizotinib. This route involves seven steps with an overall yield of approximately 49%. This route is characterized by its long reaction time, low yield, and use of hazardous materials such as methanesulfonyl chloride and Raney nickel, requiring sophisticated equipment and making it unsuitable for large-scale production.

[0011]

[0012] Formula 4

[0013] Chinese patent CN 108341802 A reports a synthetic route as shown in Formula 5. This patent uses 2-amino-3-hydroxypyridine as the starting material. The amino group is protected by Boc, and it undergoes a photo-electrophoresis reaction with (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol. Following bromination, coupling, and deprotection by Boc, crizotinib is obtained. The synthetic strategy of this route is similar to that disclosed in WO2006021884A2 / US7858643B2 and CN 104693184 A, except that the amino group is protected by Boc before coupling, followed by deprotection by Boc.

[0014]

[0015] Formula 5 Summary of the Invention

[0016] The purpose of this invention is to provide a method for preparing crizotinib. The preparation method provided by this invention is simple, mild, and environmentally friendly.

[0017] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0018] This invention provides a method for preparing crizotinib, comprising the following steps:

[0019] (1) Compound I, first solvent, second solvent, base, catalyst and compound II are mixed and coupled to obtain compound III;

[0020] (2) After mixing the compound III obtained in step (1), the third solvent, PPh3 and compound IV, diisopropyl azodicarboxylate was added dropwise in an inert atmosphere to carry out a photo-extending reaction to obtain compound V;

[0021] (3) After mixing compound V obtained in step (2) with the fourth solvent and palladium on carbon, a catalytic reduction reaction is carried out in a hydrogen atmosphere to obtain compound VI;

[0022] (4) The compound VI obtained in step (3), dichloromethane and ethyl hydrogen chloride solution are mixed and deprotected to obtain compound VII crizotinib;

[0023] The structures of compounds I, II, III, IV, V, VI, and VII are shown in the following formulas:

[0024] ;

[0025] Wherein, X in compound I is any one of F, Cl, Br or I.

[0026] Preferably, X in compound I is Cl or Br.

[0027] Preferably, the catalyst in step (1) is at least one of Pd(dppf)Cl2·DCM and tetraphenylphosphine palladium.

[0028] Preferably, in step (1), the equivalent ratio of the catalyst to compound I is (0.010~0.20):1.

[0029] Preferably, the temperature of the coupling reaction in step (1) is 60~100℃.

[0030] Preferably, the third solvent in step (2) is at least one of toluene, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile.

[0031] Preferably, in step (2), the equivalent ratio of compound III to PPh3 is 1:(1~4).

[0032] Preferably, in step (2), the equivalent ratio of compound III to diisopropyl azodicarboxylate is 1:(1~4).

[0033] Preferably, the mass percentage of palladium in palladium on carbon in step (3) is 2% to 10%.

[0034] Preferably, in step (3), the mass ratio of compound V to palladium on carbon is 1:(0.1~0.5).

[0035] This invention provides a method for preparing crizotinib. Using 5-bromo-2-nitropyridin-3-ol as a starting material, intermediate 4-(4-(5-hydroxy-6-nitropyridin-3-yl)1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (compound III) is obtained. This tert-butyl ester is then reacted with (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol to obtain the key intermediate (R)-4-[4-[6-nitro-5-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl]-1H-pyrazole-1-yl]piperidine-1-carboxylic acid tert-butyl ester (compound V). The key intermediate is then subjected to catalytic reduction and deprotection reactions to yield the target product compound VII, which is crizotinib. The crizotinib synthesis method provided by this invention is short, simple, and easy to control, saving time and material costs, and has significant advantages and industrial practical value. Attached Figure Description

[0036] Figure 1 is a flowchart of the preparation method of crizotinib provided by the present invention;

[0037] Figure 2 shows the 1H NMR spectrum of compound III prepared in Example 1 of this invention.

[0038] Figure 3 shows the 1H NMR spectrum of compound IV prepared in Example 1 of this invention. Detailed Implementation

[0039] This invention provides a method for preparing crizotinib, comprising the following steps:

[0040] (1) Compound I, first solvent, second solvent, base, catalyst and compound II are mixed and coupled to obtain compound III;

[0041] (2) After mixing the compound III obtained in step (1), the third solvent, PPh3 and compound IV, diisopropyl azodicarboxylate was added dropwise in an inert atmosphere to carry out a photo-extending reaction to obtain compound V;

[0042] (3) After mixing compound V obtained in step (2) with the fourth solvent and palladium on carbon, a catalytic reduction reaction is carried out in a hydrogen atmosphere to obtain compound VI;

[0043] (4) Mix the compound VI obtained in step (3), dichloromethane and ethyl hydrogen chloride solution to obtain compound VII crizotinib;

[0044] The structures of compounds I, II, III, IV, V, VI, and VII are shown in the following formulas:

[0045] ;

[0046] Wherein, X in compound I is any one of F, Cl, Br or I.

[0047] Unless otherwise specified, all raw materials used in this invention are commercially available products in the art.

[0048] In this invention, X in compound I is preferably Cl or Br.

[0049] In this invention, compound I, a first solvent, a second solvent, a base, a catalyst, and compound II are mixed and coupled to obtain compound III.

[0050] In this invention, the first solvent is preferably at least one selected from 1,4-dioxane, DMF, methyltetrahydrofuran, and ethylene glycol dimethyl ether. In this invention, the second solvent is preferably purified water. In this invention, the base is preferably K₂CO₃ or Cs₂CO₃, more preferably Cs₂CO₃. In this invention, the catalyst is preferably at least one selected from Pd(dppf)Cl₂·DCM and tetraphenylphosphine palladium, more preferably Pd(dppf)Cl₂·DCM. In this invention, the equivalence ratio of the catalyst to compound I is (0.010~0.20):1. This invention controls the equivalence ratio of the catalyst to compound I within the above range to promote the coupling reaction and prepare compound III with a high yield. In this invention, the temperature of the coupling reaction is preferably 60~100℃, more preferably 80~90℃. In this invention, the time of the coupling reaction is preferably 8~13 h, more preferably 10 h. The present invention controls the temperature and time of the coupling reaction within the above-mentioned range to promote the smooth progress of the reaction and obtain compound III with a high yield.

[0051] After the coupling reaction is completed, the product of the coupling reaction is preferably extracted with ethyl acetate, concentrated, dissolved in ethyl acetate, and then stirred with n-heptane to crystallize, to obtain compound III.

[0052] This invention does not impose any particular limitation on the ethyl acetate extraction method; any well-known technical solution in the art can be used to extract and enrich compound III. This invention also does not impose any particular limitation on the ethyl acetate extraction and n-heptane crystallization methods; any well-known technical solution in the art can be used to remove the solvent.

[0053] After obtaining compound III, the present invention mixes compound III, the third solvent, PPh3 and compound IV, and then adds diisopropyl azodicarboxylate dropwise in an inert atmosphere to carry out a photoelectrophoresis reaction to obtain compound V.

[0054] In this invention, the third solvent is preferably at least one selected from toluene, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile. In this invention, the inert atmosphere is preferably a nitrogen atmosphere. In this invention, the equivalence ratio of compound III to PPh3 is preferably 1:(1~4), more preferably 1:3. In this invention, the equivalence ratio of compound III to diisopropyl azodicarboxylate (DIAD) is preferably 1:(1~4), more preferably 1:3. In this invention, the temperature of the photoelectroporation reaction is preferably room temperature; the time of the photoelectroporation reaction is preferably 3~6 hours. This invention controls the raw material ratio, the temperature of the photoelectroporation reaction, and the time within the above ranges to promote the photoelectroporation reaction and obtain compound V with a high yield.

[0055] After the photoelectrophoresis reaction is completed, the product of the photoelectrophoresis reaction is concentrated, crystallized with ethanol and n-heptane in sequence to obtain compound V.

[0056] This invention does not impose any particular limitation on the concentration method; any well-known technical solution in the art can be used to effectively separate compound V. This invention also does not impose any particular limitation on the crystallization method of ethanol and n-ane; any well-known technical solution in the art can be used to remove the solvent.

[0057] After obtaining compound V, the present invention mixes compound V, a fourth solvent, and palladium on carbon, and then carries out a catalytic reduction reaction in a hydrogen atmosphere to obtain compound VI.

[0058] In this invention, the fourth solvent is preferably at least one or a mixture of any two of methanol, ethanol, isopropanol, and n-propanol. In this invention, the mass percentage of palladium on carbon is preferably 2% to 10%, more preferably 8% to 10%. In this invention, the mass ratio of compound V to palladium on carbon is preferably 1:(0.1 to 0.5), more preferably 1:(0.125 to 0.4). In this invention, the temperature of the catalytic reduction reaction is preferably room temperature; the time of the catalytic reduction reaction is preferably 8 to 12 hours. This invention adjusts the ratio of raw materials, the temperature of the catalytic reduction reaction, and the time within the above ranges to promote the smooth progress of the catalytic reduction reaction and obtain compound VI with a high yield.

[0059] After the catalytic reduction reaction is completed, the product of the catalytic reduction reaction is first filtered to obtain a solution, which is then concentrated, dissolved in ethyl acetate, crystallized by adding n-heptane, second filtered, and dried to obtain compound VI.

[0060] This invention does not impose any particular limitation on the method of crystallization by adding n-heptane; any well-known technical solution in the art can be used to effectively separate compound VI. This invention also does not impose any particular limitation on the drying method; any well-known technical solution in the art can be used to effectively remove the solvent.

[0061] After obtaining compound VI, the present invention mixes compound VI, dichloromethane and ethyl hydrogen chloride solution, and performs a deprotection reaction to obtain compound VII crizotinib.

[0062] In this invention, the preparation method of the ethyl hydrochloride solution includes: cooling anhydrous ethanol to -10 to -5°C, adding acetyl chloride dropwise under nitrogen protection while controlling the temperature at -10 to 10°C, and after the addition is complete, slowly raising the temperature to 10°C, controlling the temperature at 10 to 20°C, and reacting for 11 to 13 hours to obtain the ethyl hydrochloride solution. In this invention, the preferred method for mixing compound VI, dichloromethane, and the ethyl hydrochloride solution is: adding a portion of dichloromethane to the ethyl hydrochloride solution, controlling the temperature at 0 to 5°C, and then dropwise adding a mixed solution formed by dissolving compound VI in the remaining dichloromethane.

[0063] In this invention, the temperature of the deprotection reaction is preferably 10-20°C, and the time of the deprotection reaction is preferably 0.5-3 hours. This invention adjusts the ratio of raw materials, the temperature of the deprotection reaction, and the time within the above ranges to promote the smooth progress of the deprotection reaction and obtain compound VI with a high yield.

[0064] After the deprotection reaction is completed, the product of the deprotection reaction is allowed to stand and separated to obtain an aqueous phase. The aqueous phase is then washed with dichloromethane, separated to obtain the aqueous phase, pH is adjusted, ethyl acetate is added for extraction, the organic phase is separated to obtain the organic phase, concentrated, dissolved in acetonitrile, crystallized by adding water, filtered and dried to obtain compound VII.

[0065] In this invention, the pH adjustment is preferably achieved by adding 20% ​​NaOH solution to adjust the pH of the aqueous phase to >10.

[0066] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0067] Unless otherwise specified, all experiments were repeated three times, and the results are expressed as averages.

[0068] Example 1

[0069] A method for preparing crizotinib, comprising the following steps:

[0070] (1) 1,4-dioxane (1000 mL), purified water (250 mL), compound I (50.0 g, 228 mmol), compound II (138 g, 366 mmol), Cs2CO3 (356 g, 1095 mmol), and Pd(dppf)Cl2·DCM (2.8 g, 3.43 mmol) were added to the reaction flask. The mixture was heated to 85 °C under nitrogen protection and carried out the coupling reaction for 10 h. After the reaction was completed, ethyl acetate was added to the product of the coupling reaction for extraction and separation. The product was concentrated and dried, and then ethyl acetate was added. Then n-heptane was added and stirred to crystallize, yielding 77.1 g of compound III, with a yield of 86%.

[0071] The equivalent ratio of the catalyst Pd(dppf)Cl2·DCM to compound I is 0.015:1;

[0072]

[0073] The relevant structural characterization data of compound III are as follows: ¹H NMR (500MHz, CDCl₃) δ7.591 (¹H, s), δ7.502 (¹H, s), δ4.311-4.250 (³H, m), δ2.906 (²H, m), δ2.162-2.141 (²H, m), δ1.971-1.899 (³H, m), δ1.487 (²H, m). The structure of compound III prepared in Example 1...1 The H NMR spectrum is shown in Figure 2;

[0074] (2) Toluene (700 mL), compound III (70 g, 180 mmol) obtained in step (1), compound IV (45.2 g, 216 mmol), and PPh3 (56.6 g, 216 mmol) were added to the reaction flask. DIAD (43.6 g, 216 mmol) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred at room temperature for 4 h to carry out the photocatalytic reaction. After the reaction was complete, water was added, the solid was washed off, and the mixture was filtered. The mother liquor was concentrated to dryness, and ethanol and n-heptane were crystallized to obtain 90 g of compound V, with a yield of 89.1%.

[0075] The equivalent ratio of compound III to PPh3 is 1:1.2; the equivalent ratio of compound III to diisopropyl azodicarboxylate (DIAD) is 1:1.2.

[0076]

[0077] The structural characterization data of compound V are as follows: ¹H NMR (500MHz, DMSO) δ8.449 (¹H, s), δ8.361-8.358 (¹H, m), δ7.918 (¹H, s), δ7.712-7.709 (¹H, m), δ7.591-7.564 (¹H, m), δ7.480-7.445 (¹H, m), δ7.591-7.564 (¹H, m), δ6.433 -6.393 (1H, m), δ4.451-4.389 (1H, m), δ4.065-4.008 (2H, m), δ2.939 (2H, m), δ2.062-2.038 (2H, m), δ1.820-1.766 (5H, m), δ1.422 (9H, m), The compound V prepared in Example 1 1 The H NMR spectrum is shown in Figure 3;

[0078] (3) Add methanol (600 mL), compound V obtained in step (3) (40 g, 0.069 mol), and 10% palladium on carbon (5 g) to the reaction flask. Carry out the catalytic reduction reaction at room temperature under hydrogen protection for 10 h. After the reaction is completed, filter the product of the catalytic reduction reaction, concentrate the solution, dissolve it in ethyl acetate, add n-heptane to crystallize, filter, and dry to obtain 35 g of compound VI, with a yield of 92%;

[0079] The mass ratio of compound V to palladium on carbon is 1:0.125;

[0080]

[0081] (4) Add anhydrous ethanol (160 mL) to the reaction flask, under nitrogen protection, cool to -10°C, and add acetyl chloride (130 mL) dropwise while maintaining the temperature at -10 to -10°C. After the addition is complete, slowly raise the temperature to 10°C, maintain the temperature at 10 to 20°C, and stir for 12 hours to form an ethyl hydrochloride solution. Then add dichloromethane (150 mL) to the ethyl hydrochloride solution, maintain the temperature at 0 to 5°C, and then add compound VI (20 mL) dissolved in dichloromethane (80 mL) dropwise. After the mixed solution of g) was added dropwise, the deprotection reaction was carried out at 10~20℃ with stirring for 1 hour. After the reaction was completed, the product of the deprotection reaction was allowed to stand and separated to obtain an aqueous phase. The aqueous phase was washed once with dichloromethane, and then separated again. The aqueous phase was then adjusted to pH>10 by adding 20% ​​NaOH solution, and extracted with ethyl acetate. The organic phase was separated, concentrated, dissolved in acetonitrile, crystallized by adding water, filtered a third time, and dried to obtain 15g of compound VII, with a yield of 91%.

[0082] The mass ratio of compound VI to acetyl chloride is 100 mg : 1.3 mL;

[0083] .

[0084] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing crizotinib, characterized in that, Includes the following steps: (1) Compound I, first solvent, second solvent, base, catalyst and compound II are mixed and coupled to obtain compound III; (2) Compound III obtained in step (1), third solvent, PPh3 and compound IV are mixed and azodicarboxylic acid diisopropyl ester is added dropwise in an inert atmosphere to carry out photo-extending reaction to obtain compound V; (3) Compound V obtained in step (2), fourth solvent and palladium on carbon are mixed and catalytic reduction reaction is carried out in a hydrogen atmosphere to obtain compound VI; (4) Compound VI obtained in step (3), dichloromethane and ethyl hydrogen chloride solution are mixed and deprotected to obtain compound VII crizotinib; The structures of compound I, compound II, compound III, compound IV, compound V, compound VI and compound VII are shown in the following formula: Wherein, X in compound I is any one of F, Cl, Br or I.

2. The preparation method according to claim 1, characterized in that, In compound I, X is either Cl or Br.

3. The preparation method according to claim 1, characterized in that, The catalyst in step (1) is at least one of Pd(dppf)Cl2·DCM and tetratriphenylphosphine palladium.

4. The preparation method according to claim 1, characterized in that, In step (1), the equivalent ratio of the catalyst to compound I is (0.010~0.20):

1.

5. The preparation method according to claim 1, characterized in that, The coupling reaction in step (1) is carried out at a temperature of 60~100℃.

6. The preparation method according to claim 1, characterized in that, The third solvent in step (2) is at least one of toluene, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile.

7. The preparation method according to claim 1, characterized in that, In step (2), the equivalent ratio of compound III to PPh3 is 1:(1~4).

8. The preparation method according to claim 1, characterized in that, In step (2), the equivalent ratio of compound III to diisopropyl azodicarboxylate is 1:(1~4).

9. The preparation method according to claim 1, characterized in that, In step (3), the mass percentage of palladium in palladium on carbon is 2% to 10%.

10. The preparation method according to claim 1, characterized in that, In step (3), the mass ratio of compound V to palladium on carbon is 1:(0.1~0.5).

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