WO2017197604A1 - Method for synthesizing crizotinib intermediate - Google Patents

Abstract

A method for preparing a crizotinib intermediate, the method comprising: (1) synthesizing a compound 1 and a compound 2 into a compound 3 by means of flow chemical reaction; (2) synthesizing the compound 3 obtained in step (1) and a boric acid vinegar compound 4 into a crizotinib intermediate I by means of flow chemical reaction. The preparation method results in a high yield, and can be used to greatly reduce the energy consumption and costs in the preparation process of crizotinib. The method is environmental friendly, safe and highly automated, and is suitable for large industrial production. The reaction route is as shown in (i), wherein Y is a leaving group, z is an amino protective group, and x is selected from F, Cl, Br and l.

Description

Method for synthesizing crizotinib intermediate Technical field

The invention relates to the technical field of preparation of small molecule chemical drugs, in particular to a method for synthesizing crizotinib intermediates.

Background of the invention

Crazotinib, chemical name 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl) )-1H-pyrazol-4-yl]-2-aminopyridine (CAS: 877399-52-5), a dual inhibitor of Alk and c-Met developed by Pfizer, obtained by the US FDA on August 26, 2011 Approved for listing in the US under the trade name Xalkori, subsequently listed in Korea, Japan and the European Union. It was approved by the CFDA in 2013 and is listed in China. The Chinese trade name is Seri.

Crizotinib is the first drug to be targeted to anaplastic lymphoma kinase (ALK) for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) confirmed to be ALK positive by FDA-approved testing. ALK gene variation is considered to be a key driver of cancer development such as NSCLC. ALK is more common in patients with non-squamous cell carcinoma, no smoking history, or mild smoking history, but is also found in patients with smoking and squamous cell carcinoma.

There are various methods for synthesizing crizotinib, such as:

Nitrogen compound 5 was prepared by reduction of pig liver esterase and Mitsunobu reaction with 2,6-dichloro-3-fluoroacetophenone, and bromide 7 was obtained by iron powder reduction and NBS treatment, followed by Suzuki with boric acid ester. The coupling reaction gives compound 9, which, after deprotection, gives crizotinib 1 (De Koning P D, McAndrew D, Moore R, et al. Fit-for-purpose development of the enabling route to crizotinib. Organic Process Research & Development, 2011, 15(5): 1018-1026.), the reaction route is as follows:

Among them, the preparation route of compound 15 is as follows:

The process for preparing the pinacol borate compound 15 is as follows: dissolving isopropyl magnesium chloride in tetrahydrofuran, reacting with compound 14, heating tetrahydrofuran to 20 ° C, and crystallization of compound 15 obtained from the aqueous solution of ethanol. The rate is 70-80%, and the reaction produces more three wastes, and the by-products are difficult to control.

The synthetic route of crizotinib is longer, and the yield of the intermediates in each step affects the yield of the final product crizotinib throughout the synthesis. Patent CN201210352349.2 discloses a method for synthesizing crizotinib intermediate, which is prepared by reacting 4-methanesulfonate piperidine-1-carboxylic acid tert-butyl ester with 4-nitropyrazole, and then reducing The nitridation reaction with a boronic ester gives the crizotinib intermediate, and its synthesis route is as follows:

The above synthesis method has low preparation cost and can be smoothly carried out under mild conditions, but the reaction steps are many, and the yield of the intermediate is not high.

Flow chemistry is a technique for chemically reacting reactants in a microchannel in a continuous flow. As an emerging synthetic reaction technology, it has the advantages of fast reaction, safety, controllable temperature and pressure, etc. Small, such as precipitation in the reaction may cause blockage of the entire pipeline and failure of the reaction.

Summary of the invention

In order to overcome the deficiencies of the prior art, the present invention provides a preparation method of crizotinib intermediate, and the preparation method comprises the following steps:

(1) Compound 1 and Compound 2 are chemically synthesized to form Compound 3;

(2) The compound 3 obtained in the step (1) and the boronic acid ester compound 4 are subjected to flow chemical synthesis of the crizotinib intermediate I;

The reaction route of the preparation method is as follows:

Wherein Y is a leaving group, preferably from:

F, I, Br or Cl; further preferred from: OMs, OTs, OBs, OTf; most preferably OMs;

Z is an amino protecting group, preferably from:

(tert-butoxycarbonyl, Boc),

(benzyloxycarbonyl, Cbz),

(芴methoxycarbonyl, Fmoc),

(allyloxycarbonyl, Alloc),

(trimethylsilyloxycarbonyl, Teoc),

(p-toluenesulfonyl, Ts),

(p-nitrophenylsulfonyl, Ns),

(o-nitrophenylsulfonyl, Nps),

(trityl, Trt),

(pivaloyl, Pv),

(benzoyl, Bz),

(trifluoroacetyl, Tfa),

(p-methoxybenzyl, PMB),

(2,4-dimethoxybenzyl, DMB),

(benzyl, Bn); further preferably from: Boc, Cbz, Alloc; most preferably Boc;

X is selected from the group consisting of: F, Cl, Br, I, preferably Br or I, most preferably Br;

R _{1 is} selected from the group consisting of H, a C1-C10 alkoxy group, a C1-C10 boronate ester, and a C4-C9 heterocyclic group, preferably from: H, methoxy, ethoxy, isopropoxy,

More preferably from: isopropoxy,

(2-pyridyl); most preferably isopropoxy;

R ₂ and R _{3 are} independently selected from: H, a C1-C10 alkyl group, a C6-C12 aryl group, or R ₂ and R ₃ form a heterocyclic group with a bonded oxygen atom or a boron atom; R ₂ , R _{3 is} independently preferably selected from: H, methyl, ethyl, isopropyl, substituted or unsubstituted phenyl, or R ₂ , R ₃ and the attached oxygen atom, boron atom

Further preferably, R ₂ and R _{3 are} simultaneously an ethyl group or an isopropyl group, or R ₂ and R _{3 are formed} with a linked oxygen atom or a boron atom.

Most preferably, R ₂ and R _{3 are} both isopropyl.

In one embodiment of the invention, the reaction route of the preparation method is as follows:

Preferably, in the step (1), the specific steps are:

Compound 1 was prepared as solution 1 using solvent 1, and compound 2 and base were prepared as solution 2 using solvent 2, and continuous addition of solution 1 and solution 2 was carried out to cause nucleophilic substitution reaction at a reaction temperature of 30 to 80 ° C. The time is 0.5 to 20 min. After the continuous reaction system flows out of the coil, the reaction is terminated, and the mixture is separated and concentrated to obtain a compound 3.

Preferably, the solvent 1 and the solvent 2 are independently selected from the group consisting of: tetrahydrofuran, methanol, ethanol, ethyl acetate, dichloromethane; more preferably tetrahydrofuran;

Preferably, the base is selected from the group consisting of sodium hydride, sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium t-butoxide, sodium methoxide, sodium ethoxide, preferably from potassium t-butoxide, sodium t-butoxide, and more. Preferred is potassium t-butoxide;

Preferably, the compound 1 is added in an amount of 10 to 1000 g;

Preferably, the solvent 1 is used in an amount of 1-20 mL / g of compound 1, more preferably 5-15 mL / g of compound 1, most preferably 10mL / g of compound 1;

Preferably, the solvent 2 is used in an amount of 1-30 mL / g of Compound 1, more preferably 10-20 mL / g of Compound 1, most preferably 15 mL / g of Compound 1;

Preferably, the molar ratio of the base to the compound 1 is from 1.0 to 3.0:1, more preferably from 1.0 to 2.0:1, most preferably 1.5:1;

Preferably, the molar ratio of the compound 2 to the compound 1 is from 1 to 1.5:1, more preferably 1.2:1;

Preferably, the step of terminating the reaction is to add the reaction system to the purified water;

Preferably, the step (1) further comprises extracting the aqueous phase with ethyl acetate;

In one embodiment of the invention, the reactor has a gauge of 4*6 mm and a coil length of 5-8 m.

In a preferred embodiment, in the step (1), the compound 1 is 4-methanesulfonate piperidine-1-carboxylic acid tert-butyl ester, the compound 2 is 4-bromopyrazole, and the compound 3 is 4- [4-Bromo-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester.

The step (2) is: catalytically synthesizing the crizotinib intermediate I by the flow chemistry of the compound 3 obtained in the step (1) and the borate compound 4 using an organolithium compound as a catalyst.

Preferably, the step (2) is as follows:

Compound 3 and Compound 4 were prepared as Solution 3 using Solvent 3, and organolithium compound was prepared as Solution 4 using Solvent 4, and continuous addition of Solution 3 and Solution 4 was carried out to cause low-temperature lithiation reaction at a reaction temperature of -35 to -25 °C. , the reaction residence time is 0.5 to 50 min, after the continuous reaction system flows out of the coil, the reaction is terminated, and the mixture is concentrated and concentrated to obtain crizotinib. Body I crude;

Preferably, the solvent 3 is selected from the group consisting of: tetrahydrofuran, methanol, ethanol, ethyl acetate, dichloromethane; more preferably tetrahydrofuran;

Preferably, the solvent 4 is selected from the group consisting of n-hexane, cyclohexane, n-heptane, petroleum ether, benzene, toluene, more preferably n-heptane;

Preferably, the organolithium compound is an alkyl lithium, preferably: n-butyllithium, methyllithium, phenyllithium, more preferably n-butyllithium;

Preferably, the compound 3 is added in an amount of 10 to 500 g;

Preferably, the solvent 3 is used in an amount of 1-30 mL / g of compound 3, more preferably 10-20 mL / g of compound 3, most preferably 15mL / g of compound 3;

Preferably, the concentration of the solution 4 is 2.0 to 3.0 M, more preferably 2.5 M;

Preferably, the molar ratio of the compound 4 to the compound 3 is from 1.0 to 3.0:1, more preferably from 1.0 to 2.0:1, still more preferably 1.5:1;

Preferably, the molar ratio of the lithiation reagent to the compound 3 is from 1.0 to 3.0:1, more preferably from 1.0 to 2.0:1, most preferably 1.3:1;

Preferably, the step of terminating the reaction is to add the reaction system to the purified water;

Preferably, the separating step is to adjust the pH of the system after the termination reaction with hydrochloric acid to 3 to 5, and to separate the liquid, and extract the aqueous phase with ethyl acetate;

Preferably, the step (2) further comprises a purification step: dissolving and washing the crude intermediate I with a mixture of ethyl acetate and methyl tert-butyl ether to obtain an intermediate I product;

Preferably, the mixture has a volume ratio of ethyl acetate to methyl tert-butyl ether of 1:5;

In one embodiment of the invention, the reactor has a gauge of 4*6 mm and a coil length of 6-10 m.

In a preferred embodiment, in the step (2), the compound 3 is 4-[4-bromo-1H-pyrazolyl]piperidine-1-carboxylic acid tert-butyl ester, and the compound 4 is boric acid. Triisopropyl ester, intermediate I is 1-(N-Boc-4-piperidinyl)pyrazole-4-boronic acid diisopropyl ester.

Preferably, the preparation method of the crizotinib intermediate further comprises the step (3): intermediate I and the intermediate II catalytic coupling reaction to form the intermediate III;

The reaction route of the step (3) is as follows:

Preferably, the catalyst is selected from the group consisting of a Ni catalyst, a Pd catalyst, preferably a Ni catalyst; further preferably, the Ni catalyst is a mixture of NiCl ₂ , zinc powder, tricyclohexyl phosphorus, tetrahydrofuran;

Further preferably, the molar ratio of the NiCl ₂ to the intermediate II is 0.01 to 0.10:1, more preferably 0.02 to 0.08:1;

The mass ratio of the zinc powder to the intermediate II is 0.01 to 0.5:1, more preferably 0.1 to 0.3:1;

The molar ratio of the tricyclohexylphosphine to the intermediate II is 0.01 to 0.5:1, more preferably 0.05 to 0.2:1;

The tetrahydrofuran is used in an amount of from 1 to 30 mL/g of the intermediate II, more preferably from 10 to 20 mL/g of the intermediate II.

Preferably, the zinc powder has a specification of 100 to 500 mesh, preferably 200 to 400 mesh;

In an embodiment of the present invention, the specific process of the step (3) is:

Ni catalyst was added to the reaction flask, and the system was replaced with nitrogen, and then heated to 50 to 60 ° C and stirred for 1.0 h. The system is cooled to 15~25 °C, and intermediate II, potassium bicarbonate and intermediate I are added under nitrogen protection. The system is heated to 65-85 ° C after nitrogen substitution. After the intermediate II is completely converted, the reaction system is cooled to 15-25. °C, suction filtration, the filter cake was rinsed with tetrahydrofuran, the filtrate was combined, and the silica gel pad was concentrated and concentrated to obtain the crude intermediate III;

Wherein, the molar ratio of potassium hydrogencarbonate to intermediate II is from 1.0 to 10:1, preferably from 3 to 6:1; and the molar ratio of intermediate I to intermediate II is from 1.0 to 3.0:1, preferably from 1.0 to 2.0: 1.

Preferably, the step (3) further comprises a purification step;

The purification step is that the crude intermediate III is recrystallized from a mixture of toluene and tetrahydrofuran to obtain a pure intermediate III;

Preferably, in the mixture of toluene and tetrahydrofuran, the volume ratio of toluene to tetrahydrofuran is 1:3.

In a specific embodiment of the present invention, the preparation method of the crizotinib intermediate has the following reaction route:

The intermediate II is reacted with S-1-(2,6-dichloro-3-fluorophenyl)ethanol (compound 6) and 3-hydroxy-2-nitropyridine (compound 7) to give R-3. -(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (Compound 8), which is then obtained by reduction of the nitro group at the 2-position and bromination at the 5-position;

The S-1-(2,6-dichloro-3-fluorophenyl)ethanol is obtained by enzymatic reduction of 2,6-dichloro-5-fluoro-acetophenone (compound 5);

Preferably, the enzyme is a ketoreductase having an amino acid sequence having at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 1, 2, 3 or 4, more preferably at least 90. % sequence identity, further preferably at least 95% sequence identity, in particular, at least 96%, 97%, 98%, 99% or 100% sequence identity;

More preferably, the enzyme has an amino acid sequence as shown in SEQ ID NO: 1, 2, 3 or 4;

The enzyme of the amino acid sequence shown in SEQ ID NO: 1 is APRD from Geotrichum candidum (Genebank Accession No. AB294179).

The enzyme of the amino acid sequence shown in SEQ ID NO: 2 is KRD of Zygosaccharomyces rouxii (Genebank Accession No. AF178079).

The enzyme of the amino acid sequence shown in SEQ ID NO: 3 is DADH (Genebank Accession No. BD450088) of Devosia riboflavina KNK10702.

The enzyme of the amino acid sequence shown in SEQ ID NO: 4 is adh-ht of Bacillus stearothermophilus (Genebank Accession No. Z27089).

The ketoreductase involved in the present invention can also be produced by genetically recombinantly expressing a genetically engineered bacterium containing a ketoreductase gene. Methods for recombinant expression of genes are well known to those skilled in the art. The genetically engineered bacteria containing the ketoreductase gene can be expanded and cultured by batch fermentation, fed-batch fermentation or continuous fermentation, and the cell concentration is 10% to 20% by ultrasonication or high-pressure homogenization. Crude enzyme solution. Fermentation methods and cell disruption methods for genetically engineered bacteria are well known to those skilled in the art.

Preferably, the enzyme is used in an amount of 5 to 50 mL / g of compound 5;

Preferably, the enzyme catalytic system further comprises amine formate and NAD+, wherein the molar ratio of formate to compound 5 is from 1.0 to 10.0:1, more preferably from 1.0 to 5.0:1; and the molar ratio of NAD+ to compound 5 is 0.01. ～1.0:1, more preferably 0.01 to 0.05:1;

Preferably, the enzyme catalytic reduction temperature is 20-40 ° C, preferably 25-35 ° C, pH 5.0-7.0, preferably 6.0-6.5;

In a preferred embodiment of the invention, the enzymatic reduction process is:

Add purified water and 2,6-dichloro-5-fluoro-acetophenone to the reaction flask, stir evenly, add ketone reductase solution, formic acid amine, NAD+, adjust pH=5.0-7.0, then raise the temperature to 20 ~ 30 ° C, heat 5 ~ 48h. After the reaction, the system was heated to 65-70 ° C to destroy the enzyme protein, ethyl acetate was added, the silica gel was padded, and the liquid phase was separated, and the aqueous phase was back-extracted with ethyl acetate. The organic phase was combined and concentrated to give S-1-(2, 6-Dichloro-3-fluorophenyl)ethanol (Compound 6);

Wherein the volume-mass ratio of purified water to compound 5 is 2-10 mL/g, the amount of ketoreductase solution is 5-50 mL/g compound 5, the molar ratio of formate amine to compound 5 is 1.0-10.0:1, NAD+ and The molar ratio of the compound 5 is from 0.01 to 10.0:1.

In a specific embodiment of the present invention, the preparation method of the crizotinib intermediate has the following reaction route:

The crizotinib molecule is obtained by deprotecting the intermediate III of the present invention from the N-position of the pyrazole group to form an amine group.

The method for deprotecting the amino protecting group is well known to those skilled in the art, and the invention is not limited thereto.

The compound 1 used in the preparation method of the present invention can be purchased from a commercially available product, or can be obtained by subjecting 4-hydroxypiperidine to amino-protection and hydroxy substitution or by 4-aminopiperidone after amino-protection and ketocarbonyl reduction, and the like. The present invention does not limit this.

The method for synthesizing the crizotinib intermediate provided by the invention adopts the flow chemical synthesis technology, has the characteristics of high yield, short reaction time, good safety, high degree of automation, and is suitable for industrialized scale production, and is favorable for improving Crizozin The efficiency of production and the reduction of energy consumption and cost; the use of organolithium compounds as catalysts for the preparation of intermediate I, compared with Grignard reagents, is more reactive, high yield, easy to separate products and less tendency to reduce At the same time, due to its high reactivity, the temperature in the batch reaction is generally lower (<-50 °C), and the flow chemistry technique can increase the temperature of the reaction and reduce the energy consumption, and further increase the reaction yield. In addition, the method for synthesizing the crizotinib intermediate provided by the present invention further comprises the step of preparing an S-1-(2,6-dichloro-3-fluorophenyl)ethanol by asymmetric enzyme catalytic reduction, and the reaction condition is mild. The reaction yield and the optical purity of the product are both high, which helps to simplify the preparation steps and reduce the cost of chemical resolution; the synthesis method of the crizotinib intermediate also includes the Ni catalyst to catalyze the intermediates I and II. The step of producing intermediate III has a higher reaction yield.

Mode for carrying out the invention

In the present invention, residence time = reactor volume / flow rate.

In the present invention, for the technical scheme of the boronic acid ester compound in which R _{1 is} selected from a heterocyclic group of C4-C9, unless otherwise stated, a boron atom may be bonded to any carbon atom of the heterocyclic group to form a boronic acid ester compound, such as For pyridyl, it can be 2-pyridyl

3-pyridyl

4-pyridyl

The technical solutions in the embodiments of the present invention are clearly and completely described below. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

Example 1 Synthesis of S-1-(2,6-dichloro-3-fluorophenyl)ethanol

Purified water (828 mL) and 2,6-dichloro-5-fluoro-acetophenone (1.0 mol) were added to the reaction flask, and after stirring, ketone reductase solution (9136 mL), formate (2.0 mol), NAD+ was added. (0.03 mol), adjust the system pH = 6.2 ~ 6.4, then warm the system to 27 ~ 33 ° C, keep warm for 17 ~ 24h. After the reaction, the system was heated to 65-70 ° C to destroy the enzyme protein, ethyl acetate was added, the silica gel was padded, and the liquid phase was separated, and the aqueous phase was back-extracted with ethyl acetate. The organic phase was combined and concentrated to give the product S-1-(2) , 6-Dichloro-3-fluorophenyl)ethanol, the purity is 93-98%, the reaction yield is 85-95%, and the enantiomeric excess percentage (%ee) value is greater than 98%.

^{1 H NMR (400MHz, CDCl3)} : δ: 7.32 (d, J = 7.8Hz, 1H), 7.04 (d, J = 8.0Hz, 1H), 4.89 (q, J = 7.2Hz, 1H), 1.48 (d , J = 7.6 Hz, 3H).

Example 2 Synthesis of R-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-pyridin-2-amine (Intermediate II)

Reference method (Zhang Guangyan, Li Pengcheng, Liu Difa, et al. Synthesis of crizotinib. Chinese Journal of Medicinal Chemistry, 2014, 24(6): 445-449), making S-1-(2,6 -Dichloro-3-fluorophenyl)ethanol is reacted with 2-nitro-3-hydroxypyridine to form R-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2 -nitropyridine, which is reduced to give R-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine, and then the aromatic amine compound is subjected to bromine Substitution afforded R-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-pyridin-2-amine.

Example 3 Synthesis of tert-butyl 4-(4-bromo-1H-pyrazolyl)piperidine-1-carboxylate (Compound 3)

400 g of 4-methylsulfonate piperidine-1-carboxylic acid tert-butyl ester (Compound 1) in tetrahydrofuran (4000 mL), 250.8 g of 4-bromopyrazole (Compound 2) and uncle were used in a 4*6 mm reactor. Potassium butoxide (240.9g of tetrahydrofuran solution (6000mL) was continuously fed with nucleophilic substitution reaction, the coil length was 5-8m, the reaction temperature was 50-60 °C, the reaction residence time was 1-10 min, and the continuous feed reaction yield was 80-90. %; After the continuous reaction system flows out of the coil, it is directly added to the purified water to terminate the reaction. The reaction system is directly extracted with ethyl acetate and concentrated to give the product 4-(4-bromo-1H-pyrazolyl)piperidine-1. - tert-butyl formate (compound 3), purity 93.2%, can be directly reacted to the next reaction.

^{1 H NMR (400MHz, CDCl3)} : δ: 8.37 (s, 1H), 8.05 (s, 1H), 3.89 (m, 1H), 3.12 (br, 4H), 2.01 (br, 4H), 1.40 (s, 9H).

Example 4 Synthesis of 1-(N-Boc-4-piperidinyl)-1H-pyrazole-4-boronic acid diisopropyl ester (Intermediate I)

200 g of compound 3 and isopropyl borate (with moles of compound 3) were carried out using a 4*6 mm reactor The ratio of 1.5:1) tetrahydrofuran solution (3000 mL), n-butyl lithium (molar ratio of compound 3 to 1.3:1) in n-heptane solution (2.5 M) was continuously fed with low-temperature lithiation reaction, coil length 6 ~ 10m, reaction temperature -35 ~ -25 ° C, reaction residence time 1 ~ 10min, continuous feed reaction yield of 85 ~ 95%; continuous reaction system out of the coil, directly added to the purified water to terminate the reaction, the reaction system used 600 ~1000g hydrochloric acid (2M) adjustment system pH is 3 ~ 5, after the liquid separation, the aqueous phase is directly extracted with ethyl acetate, and the organic phase is combined to obtain the product 1-(N-Boc-4-piperidinyl)-1H- The crude product of pyrazole-4-boronic acid diisopropyl ester (Intermediate I) was 93.2% pure. The crude product was washed with ethyl acetate and methyl tert-butyl ether (1:5) to give a pure intermediate I, purity 99.1%, yield 82.9%.

^{1 H NMR (400MHz, CDCl3)} : δ: 8.11 (s, 1H), 7.59 (s, 1H), 3.71 (m, 1H), 3.17 (br, 4H), 2.05 (br, 4H), 1.38 (s, 9H).

Example 5 3-[R-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(N-Boc-4-piperidyl)-1H-pyrazole Synthesis of 4-yl]-2-pyridinamine (Intermediate III)

To a 1 L four-neck reaction flask was added NiCl ₂ (molar ratio to intermediate II: 0.05:1), zinc powder (200-400 mesh, mass ratio to intermediate II of 0.2:1), and tricyclohexylphosphine ( The molar ratio to the intermediate II was 0.1:1) and the tetrahydrofuran (450 mL) system was replaced with nitrogen for 5 times and then heated to 50-60 ° C for 1.0 h. The system was cooled to 15-25 ° C, and intermediate II (prepared in Example 2), potassium hydrogencarbonate (molar ratio to intermediate II: 5.0:1) and intermediate I (prepared in Example 4, and intermediate) were added under nitrogen protection. The molar ratio of the body II is 1.5:1). After the system is replaced by nitrogen for 5 times, the temperature is raised to 65-85 ° C. After the TLC is traced to the completion of the conversion of the intermediate II, the reaction system is cooled to 15 to 25 ° C, and suction filtration is carried out. Rinse twice with tetrahydrofuran, combine the filtrate, pass through a pad of silica gel and concentrate to give 3-[R-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(N -Boc-4-piperidinyl)-1H-pyrazol-4-yl]-2-pyridinamine (Intermediate III) crude product, purity 87.3%. The crude intermediate III was recrystallized from toluene/tetrahydrofuran (1:3) to afford Intermediate III pure product, purity 99.4%, yield 82.9%.

^{1 H NMR (400MHz, DMSO-} d 6): δ: 8.11 (s, 1H), 8.05-7.95 (m, 3H), 7.31 (d, J = 7.8Hz, 1H), 7.08 (d, J = 8.0Hz , 1H), 5.17 (q, J = 7.2 Hz, 1H), 3.73 (m, 1H), 3.15 (br, 4H), 2.10 (br, 4H), 1.68 (d, J = 7.5 Hz, 3H), 1.39 (s, 9H).

The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., which are within the spirit and principles of the present invention, should be included in the scope of the present invention. within.

Claims (10)

1. A preparation method of crizotinib intermediate comprises the following steps:

   (1) Compound 1 and Compound 2 are chemically synthesized to form Compound 3;

   (2) The compound 3 obtained in the step (1) and the boronic acid ester compound 4 are subjected to flow chemical synthesis of the crizotinib intermediate I;

   The reaction route of the preparation method is as follows:

   

   among them,

   Y is a leaving group;

   Z is an amino protecting group;

   X is selected from the group consisting of: F, Cl, Br, I;

   R _{1 is} selected from the group consisting of H, a C1-C10 alkoxy group, a C1-C10 boronate ester, and a C4-C9 heterocyclic group;

   R ₂ and R _{3 are} independently selected from: H, a C1-C10 alkyl group, a C6-C12 aryl group, or R ₂ and R ₃ form a heterocyclic group with a bonded oxygen atom or a boron atom.
2. The preparation method according to claim 1, wherein said step (1) is:

   Compound 1 was prepared as solution 1 using solvent 1, and compound 2 and base were prepared as solution 2 using solvent 2, and continuous addition of solution 1 and solution 2 was carried out to cause nucleophilic substitution reaction at a reaction temperature of 30 to 80 ° C. The time is 0.5 to 20 min. After the continuous reaction system flows out of the coil, the reaction is terminated, and the mixture is separated and concentrated to obtain a compound 3.
3. The process according to claim 2, wherein the solvent 1 and the solvent 2 are independently selected from the group consisting of tetrahydrofuran, methanol, ethanol, ethyl acetate, dichloromethane; and/or

   The base is selected from the group consisting of sodium hydride, sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium t-butoxide, sodium methoxide, sodium ethoxide; and/or

   Compound 1 is added in an amount of 10 to 1000 g; and/or,

   Said solvent 1 is used in an amount of 1-20 mL / g of compound 1; and / or,

   The solvent 2 is used in an amount of 1-30 mL/g of Compound 1; and/or,

   The molar ratio of the base to the compound 1 is from 1.0 to 3.0:1; and/or,

   The molar ratio of the compound 2 to the compound 1 is from 1 to 1.5:1.
4. The preparation method according to claim 1, wherein said step (2) is:

   Compound 3 and Compound 4 were prepared as solution 3 using solvent 3, and lithiation reagent was prepared as solution 4 using solvent 4, and continuous addition of solution 3 and solution 4 was carried out to react, and the reaction temperature was -35 to -25 ° C, and the reaction was stopped. After 0.5 to 50 min, the reaction system was discharged from the coil, the reaction was terminated, and the crude phase of crizotinib intermediate I was obtained by separation and concentration.
5. The process according to claim 4, wherein the solvent 3 is selected from the group consisting of tetrahydrofuran, methanol, ethanol, ethyl acetate, dichloromethane; and/or

   The solvent 4 is selected from the group consisting of n-hexane, cyclohexane, n-heptane, petroleum ether, benzene, toluene; and/or,

   The organolithium compound is an alkyl lithium selected from the group consisting of n-butyllithium, methyllithium, phenyllithium; and/or

   Compound 3 is added in an amount of 10 to 500 g; and/or,

   The solvent 3 is used in an amount of 1-30 mL / g of the compound 3; and / or,

   The concentration of the solution 4 is 2.0 to 3.0 M; and/or,

   The molar ratio of the compound 4 to the compound 3 is from 1.0 to 3.0:1; and/or,

   Preferably, the molar ratio of the lithiation reagent to the compound 3 is from 1.0 to 3.0:1.
6. The preparation method according to claim 1, wherein the preparation method of the crizotinib intermediate further comprises the step (3): the intermediate-catalyzed coupling reaction of the intermediate I and the intermediate II to form the intermediate III; The reaction route of step (3) described is as follows:

   
7. The process according to claim 6, wherein the catalyst is selected from the group consisting of a Ni catalyst and a Pd catalyst.
8. The preparation method according to claim 7, wherein the Ni catalyst is a mixture of NiCl ₂ , zinc powder, tricyclohexyl phosphorus, tetrahydrofuran; and the molar ratio of NiCl ₂ to intermediate II in the Ni catalyst. a ratio of 0.01 to 0.10:1, and/or a mass ratio of zinc powder to intermediate II of 0.01 to 0.5:1, and/or a molar ratio of tricyclohexylphosphine to intermediate II of 0.01 to 0.5:1, and / or, the amount of tetrahydrofuran is 1 ~ 30mL / g of intermediate II.
9. The process according to claim 6, wherein the intermediate II is composed of S-1-(2,6-dichloro-3-fluorophenyl)ethanol and 3-hydroxy-2-nitropyridine. The reaction is linked to give R-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine, which is then subjected to nitro reduction at the 2-position and bromination at the 5-position. ;

   The S-1-(2,6-dichloro-3-fluorophenyl)ethanol is obtained by enzymatic reduction of 2,6-dichloro-5-fluoro-acetophenone.
10. The production method according to claim 9, wherein the enzyme has an amino acid sequence having at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 1, 2, 3 or 4; or,

    The enzyme is used in an amount of 5 to 50 mL/g 2,6-dichloro-5-fluoro-acetophenone; and/or

    The enzyme catalysis further includes amine formate and NAD+; and/or,

    The enzyme catalyzes a temperature of 20 to 40 ° C, and/or

    The enzyme catalyzes a pH of from 5.0 to 7.0.