You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


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The present invention relates to the technical field of medicine and
organic synthesis, particularly to a method for preparing crizotinib. The
method comprises the compound of formula b and the compound of formula e
undergoing Suzuki coupling reaction to produce the compound of formula a
which then was subjected to deprotection to afford (.+-.) crizotinib.
##STR00001##

1. A method for preparing the compound of formula a, comprising Suzuki coupling reaction of the compound of formula b with the compound of formula e to produce the
compound of formula a, ##STR00014## Wherein, R is a protecting group, the protecting group is Boc or Cbz; both R.sub.1 and R.sub.2 are hydrogen or methyl, or are incorporated into the group having the following formula M: ##STR00015##

2. The method according to claim 1, the agent employed in Suzuki coupling reaction is palladium catalyst and base.

3. The method according to claim 2, the palladium catalyst is Pd(OAc).sub.2, Ph(Ph.sub.3P).sub.4, Pd(Ph.sub.3P).sub.2Cl.sub.2, Pd(dppf)Cl.sub.2 or Pd/C; the base is sodium carbonate, potassium carbonate or cesium carbonate.

4. The method according to claim 1, further comprising the reaction of deprotection of the compound of formula a to afford (.+-.) crizotinib.

5. The method according to claim 4, the agent employed in the reaction of deprotection is hydrochloric acid-alcohol solution when the protecting group is Boc, the agent is Pd/C when the protecting group is Cbz.

6. The method according to claim 1, further comprising Mitsunobu reaction of the compound of formula c with the compound of formula f to produce the compound of formula b, ##STR00016##

7. The method according to claim 6, further comprising the step of protection of the amino-group of the compound of formula d to produce the compound of formula c, ##STR00017##

8. The method according to claim 7, the protecting agent is di-tert-butyl dicarbonate or benzyloxycarbonyl chloride.

9. The method according to claim 1, the compound of formula a having the structure represented by formula a, ##STR00018## Wherein, R is as defined in claim 1.

10. The method according to claim 9, further comprising the step of converting the compound of formula f' to the compound of formula a', ##STR00019##

Description

This application claims the
priority of China Patent Application No. 201310051483.3, filed with the Patent Office of China on Feb. 16, 2013, titled "Crizotinib Preparation Method", the contents of which are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the technical field of medicine and organic synthesis, particularly to a method for preparing crizotinib.

BACKGROUND OF THE INVENTION

Crizotinib, a new drug developed by Pfizer to treat lung cancer, is one of the first targeted therapy in the treatment of anaplastic lymphoma kinase (ALK), active in ALK-positive locally advanced or metastaticnon-small cell lung cancer and it is
described chemically as 3-(R)-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-py- razol-4-yl]pyridin-2-amine.

##STR00002##

Currently, the commonly used methods for preparing crizotinib are, for example, as described in America patent application of Pfizer with publication no. US20060128724.

Method 1:

##STR00003## ##STR00004##

Many steps in the method were included and reagent was wasted for two Boc groups were introduced into the intermediate compound 5-bromo-3-(1-(6-dichloro-3-fluorophenyl) ethoxyl)-2-amino-pyridine which was then coupled with the borate, followed
by the deprotection of the two Boc groups to produce 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxyl-5-(4,4,5,5-tetramethyl-1,3,2-di- oxaborolan-2-yl)-2-amino-pyridine. This product was subjected to Suzuki coupling reaction with
4-(4-bromo-1H-pyrazol-4-yl)pyridin-2-amine, followed by removal of the Boc group to finally generate crizotinib. The deprotection of Boc group being repeated twice results intedious steps. In addition, both the coupling products were purified on silica
gel column chromatography, these led to longer reaction cycle and the limit of industrial production.

Method 2:

##STR00005##

Sodium hydride is difficult to handle and may cause explosion easily in this method.

Method 3:

##STR00006##

More byproducts were generated in this method, for the free amino group of 5-bromo-3-(2,6-dichloro-3-fluorophenyl)ethoxy)2-amino-pydine wasn't protected. The product was produced in a low yield of 61% after purification on silica gel column
chromatography.

SUMMARY OF THE INVENTION

To solve the above-mentioned problems, such as multi-steps, low yield etc., the following methods for preparing crizotinib were provided in the present invention:

A method for preparing the compound of formula a comprises Suzuki coupling reaction of the compound of formula b and the compound of formula e to produce the compound of formula a,

##STR00007##

Wherein R is an amino-protecting group, particularly is Boc or Cbz.

Both R.sub.1 and R.sub.2 are hydrogen or methyl, or are incorporated into the group having the following formula M:

##STR00008##

The preferred coupling agent employed in the Suzuki coupling reaction is palladium catalyst and base, the palladium catalyst can be Pd(OAc).sub.2, Ph(Ph.sub.3P).sub.4, Pd(Ph.sub.3P).sub.2Cl.sub.2, Pd(dppf)Cl.sub.2 or Pd/C and the preferred base
can be sodium carbonate, potassium carbonate or cesium carbonate. A skill person in the art can select suitable reaction temperature in accordance with the solvent employed. For example, the temperature is 40-100.degree. C. when the solvent is
dimethylformamide.

Further, the compound of formula a was subjected to deprotection of Boc to afford (.+-.) crizotinib. The agent employed in the deprotection is hydrochloric acid-alcohol solution, preferably, is hydrochloric acid-methanol solution or
hydrochloric acid-ethanol solution.

The compound of formula b can be obtained by the Mitsunobu reaction of the compound of formula b and the compound of formula f to generate the compound of formula b,

##STR00009##

Wherein, R is protecting group, preferably, is Boc or Cbz.

The agent employed can be diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) or azodicarbonyldipiperidine (ADDP) and triphenylphosphine or tri-n-butylphosphine. A skill person in the art can select suitable reaction temperature
in accordance with the solvent employed. For example the temperature is 0-40.degree. C. when the solvent is tetrahydrofuran.

The compound of formula c is generated by protecting the amino-group of the compound of formula d,

##STR00010##

The preferred protecting agent employed is di-tert-butyl dicarbonate (Boc.sub.2O) or benzyloxycarbonyl chloride (CbzCl). A skill person in the art can select suitable reaction temperature in accordance with the solvent employed. For example
the reaction can be carried out at room temperature when the solvent is dichloromethane.

Further, the preferred compound of formula a has the following formula a',

##STR00011##

The said compound further undergoes the deprotection to afford crizotinib.

The compound of formula a' can be produced from the compound of formula f',

##STR00012##

The present invention provides a method for preparing crizotinib, which has the following advantages: the reaction route is short. Only one amino protecting group was introduced into the compound of formula d, thus saving the agents and benefit
to environment protection. After the completion of the Mitsunobu reaction, the product can be produced in desired purify by utilizing ethanol recrystallization instead of the silica gel column chromatography purification. After the completion of the
Suzuki coupling reaction, the yield is over 90% without the purification on silica gel column chromatography, which was increased at least by 25% as compared with that of 65% in the prior art. The deprotection step was only once performed in the last
step of all the processes. Thus, the reaction processes are shortened and the deprotection step was carried out in the presence of hydrochloric acid-alcohol solution, which can increase the purity of crizotinib.

The following abbreviations have been used in the present invention:

Boc: t-butyloxycarboryl;

Cbz: carbobenzyloxy;

DEAD: diethyl azodicarboxylate;

DMAP: 4-diMethylaMinopyridine;

Mitsunobu reaction: the Mitsunobu reaction is a type of bimolecular nucleophilicsubstitution (S.sub.N2 reaction).

Suzuki coupling reaction: is also referred to as the "Suzuki Coupling, which is Palladium-catalyzed cross-coupling reaction of arylboronic acid, alkenylboronic acid or esters thereof with aryl halides or alkene, wherein, halide is selected from
chloride, bromide, iodide.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is HPLC spectrogram of reaction mixture produced in comparison example 1.

FIG. 2 is HPLC spectrogram of reaction mixture produced in example 3.

DETAILED EMBODIMENTS

In order to better understand the present invention, it is illustrated in detail by the following examples. However, it should be understood that these descriptions are not to limit the claims of the present invention.

Comparison Example 1

The preparation of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonyl-p- iperid-4-yl)-1H-pyrazol-4-yl)-2-amino-pyridine

The following step was performed according to the method described in US20060128724 (see page 70 paragraph[0433]).

##STR00013##

After completion of the reaction, 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonyl-p- iperid-4-yl)-1H-pyrazol-4-y)-2-amino-pyridine was found to be produced in 79.36% yield by HPLC analysis of the reaction mixture. The
data analyzed by HPLC was presented in table 1.

The preparation of 5-bromo-3-hydroxy-2-tert-butyloxycarbonylamino pyridine

To a solution of 2-amino-3-hydroxy-5-bromopyridine (10.0 g, 53.0 mmol) and Et.sub.3N (10 mL, 71.8 mmol) in dichloromethane (100 mL) was added Boc.sub.2O (12.7 g, 58.4 mmol). The mixture was stirred at room temperature for 18 h and continued to
stir for 30 min after the addition of 150 ml water. The reaction mixture was filtrated off through celite. The organic layer was separated and the aqueous layer was extracted with 150 dichloromethane. The combined organic layers were washed with
saturated NaCl aqueous solution (2.times.100 mL) and then dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed under reduced pressure and the obtained residue was triturated in hexane (100 mL), filtrated, and dried under vacuum to afford 15.0
g 5-bromo-3-hydroxy-2-tert-butyloxycarbonylamino pyridine as a white solid, with a yield of 98.0%.

The preparation of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butyloxycarbonyl- amino pyridine

1-(2,6-dichloro-3-fluorophenyl)ethanol (1.0 g, 4.78 mmol), 5-bromo-3-hydroxy-2-tert-butyloxycarbonyl amino pyridine (1.4 g, 4.78 mmol) and triphenylphosphine (1.6 g, 6.2 mmol) were dissolved in 20 ml of anhydrous THF under N.sub.2atmosphere.
The reaction mixture was cooled to below 0.degree. C. and then diisopropylazodiformate (1.25 g, 6.2 mmol) was added to the mixture at below 5.degree. C. The mixture was stirred at room temperature for 6 h, and then was filtrated. The solvent was
evaporated under reduced pressure to afford product as an oil, which was then recrystallized by ethanol to produce 2.13 g of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butyloxycarbonyl- amino pyridine as a white solid with a yield of 93.0%.

The preparation of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonylam- inopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine

5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)-ethoxy)-2-tert-butyloxycarbony- lamino-pyridine (0.24 g, 0.5 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-1-ter- t-butyloxycarbonyl pyridine (0.19 g, 0.5 mmol) were
dissolved in 5 ml of DMF, and then an aqueous solution of Na.sub.2CO.sub.3 (0.16 g, 1.5 mmol) in 1 ml water and Pd(Ph.sub.3P).sub.2Cl.sub.2 (8.8 mg, 0.0125 mmol) were added successively. After being heated to 60.degree. C. with stirring for 6 h under
N.sub.2atmosphere, the mixture was cooled to room temperature, filtrated to remove undissolved solid, and extracted with methyl tert-butyl ether (3.times.5 mL). Combined organic layers were washed with saturated NaCl aqueous solution (2.times.5 mL),
dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated up to dryness under reduced pressure to afford 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonylam-
inopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine as a white solid, with a yield of 92.3%.

3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonylam- inopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine (162.6 mg, 0.25 mmol) was dissolved in 2 ml dichloromethane and then the mixture was cooled to
below 0.degree. C. After the addition of 0.4 ml hydrochloric acid-ethanol solution, the mixture was stirred at room temperature for 12 h, quenched with 1 ml water, adjusted to pH>9 with 2N NaOH aqueous solution, and then was extracted with
dichloromethane (2.times.10 mL). The combined organic layer was washed with 10 ml saturated NaCl aqueous solution, dried over anhydrous Na.sub.2SO.sub.4 and then evaporated to produce 0.11 g of crizotinib as an off-white solid, with a yield of 97.8%.

Example 5

The preparation of (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butyloxycarb- onylamino-pyridine

(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (1.0 g, 4.78 mmol, ee 99.9%), 5-bromo-3-bromo-3-hydroxyl-tert-butyloxycarbonylamino pyridine (1.4 g, 4.78 mmol) and triphenylphosphine (1.6 g, 6.2 mmol) were dissolved in 20 ml of anhydrous THF under
N.sub.2atmosphere, cooled to below 0.degree. C. and then diisopropylazodiformate (1.25 g, 6.2 mmol) was added to the mixture at below 5.degree. C. The mixture was stirred at room temperature for 6 h and then filtered. The solvent was evaporated under
reduced pressure to afford product as oil which was recrystallized by ethanol to produce 2.16 g of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butyloxycarbonyl- amino pyridine as a white solid with a yield of 94.3%, ee 99.9%.

Example 6

The preparation of (R)-3-(1-(2,6-dichloro-3-flurophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbony- laminopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine

(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)-ethoxy)-2-tert-butyloxycar- bonylamino-pyridine (0.24 g, 0.5 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-1-ter- t-butyloxycarbonyl pyridine (0.19 g, 0.5 mmol) were
dissolved in 5 ml of DMF, then an aqueous solution of Na.sub.2CO.sub.3 (0.16 g, 1.5 mmol) in 1 ml water and Pd(Ph.sub.3P).sub.2Cl.sub.2 (8.8 mg, 0.0125 mmol) were added successively. After being heated to 60.degree. C. with stirring for 6 h under
N.sub.2atmosphere, the mixture was cooled to room temperature and filtrated to remove undissolved solid. The filtrate was extracted with methyl tert-butyl ether (3.times.5 mL). The combined organic layer was washed with saturated NaCl aqueous solution
(2.times.5 mL), dried over anhydrous Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to afford 0.31 g of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonylam-
inopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine as a white solid, with a yield of 95.4%, ee 99.9%.

Example 7

The Preparation of Crizotinib

(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbon- ylamino piperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridi- ne (162.6 mg, 0.25 mmol) was dissolved in 2 ml dichloromethane and then the mixture was cooled
to below 0.degree. C. after the addition of 0.4 ml hydrochloric acid-ethanol solution, the mixture was stirred at room temperature for 12 h, quenched with 1 ml water, adjusted to pH>9 with 2N NaOH aqueous solution, and then was extracted with
dichloromethane (2.times.10 mL). The combined organic layer was washed with 10 ml saturated NaCl aqueous solution, dried over anhydrous Na.sub.2SO.sub.4 and then concentrated to produce 0.112 g of crizotinib as an off-white solid, with a yield of 99.6%,
ee 99.9%.

Example 8

The preparation of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butyloxycarbonyl- amino pyridine

1-(2,6-dichloro-3-fluorophenyl)ethanol (1.0 g, 4.78 mmol), 5-bromo-3-hydroxy-2-tert-butyloxycarbonyl amino pyridine (1.4 g, 4.78 mmol) and triphenylphosphine (1.6 g, 6.2 mmol) were dissolved in 20 ml of anhydrous THF under N.sub.2atmosphere,
cooled to below 0.degree. C. and then diisopropylazodiformate (1.08 g, 6.2 mmol) was added to the mixture at below 5.degree. C. The mixture was stirred at room temperature for 6 h, and then was allowed to filtrate. The solvent was removed under
reduced pressure to afford product as oil which was recrystallized by ethanol to produce 2.14 g of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butyloxy carbonylamino pyridine as a white solid with a yield of 93.3%.

Example 9

The preparation of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-benzyloxycarbonyl amino pyridine

1-(2,6-dichloro-3-fluorophenyl)ethanol (1.0 g, 4.78 mmol), 5-bromo-3-hydroxy-2-benzyloxy carbonyl amino pyridine (1.54 g, 4.78 mmol) and triphenylphosphine (1.6 g, 6.2 mmol) were dissolved in 20 ml of anhydrous THF under N.sub.2atmosphere,
cooled to below 0.degree. C. and then diisopropylazodiformate (1.25 g, 6.2 mmol) was added to the mixture at below 5.degree. C. The mixture was stirred at room temperature for 6 h, and then was allowed to filtrate. The solvent was removed under
reduced pressure to afford product as oil which was recrystallized from ethanol to produce 2.25 g of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-tert-butyloxycarbonyl- amino pyridine as a white solid with a yield of 91.5%.

Example 10

The preparation of (R)-3-(1-(2,6-dichloro-3-flurophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbony- laminopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine

5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)-ethoxy)-2-tert-butyloxycarbony- lamino-pyridine (0.24 g, 0.5 mmol) and 1-(1-tert-butyloxycarbonylamino piperid-4-yl)-1H-pyrazol-4-yl boric acid (0.19 g, 0.5 mmol) were dissolved in 5 ml of DMF, then an
aqueous solution of Na.sub.2CO.sub.3 (0.16 g, 1.5 mmol) in 1 ml water and Ph(Ph.sub.3P).sub.4 (14.4 mg, 0.0125 mmol) were added successively. After being heated to 60.degree. C. with stirring for 6 h under N.sub.2atmosphere, the mixture was cooled to
room temperature, filtrated to remove undissolved solid, extracted with methyl tert-butyl ether (3.times.5 mL). Combined organic layers were washed with saturated NaCl aqueous solution (2.times.5 mL), dried over anhydrous Na.sub.2SO.sub.4 and the
solvent was removed under reduced pressure to afford 0.30 g of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonylam- inopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine as a white solid, with a yield of 90.1%.

Example 11

The preparation of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonylam- inopiperid-4-yl)-1H-pyrazol-4-yl)-2-benzyloxycarbonyl amino-pyridine

To a solution of 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)-ethoxy)-2-benzyloxycarbonyl amino-pyridine (0.24 g, 0.5 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-1-ter- t-butyloxycarbonyl pyridine (0.19 g, 0.5
mmol) in 5 ml of DMF was added an aqueous solution of Na.sub.2CO.sub.3 (0.16 g, 1.5 mmol) in 1 ml water and Pd(Ph.sub.3P).sub.2Cl.sub.2 (8.8 mg, 0.0125 mmol) successively. After being heated to 60.degree. C. with stirring for 6 h under
N.sub.2atmosphere, the mixture was cooled to room temperature, filtrated to remove undissolved solid, extracted with methyl tert-butyl ether (3.times.5 mL). Combined organic layers were washed with saturated NaCl aqueous solution (2.times.5 mL), dried
over anhydrous Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to afford 0.29 g of 3-(1-(2,6-dichloro-3-fluorophenyl) ethoxy)-5-(1-(1-tert-butyloxycarbonylaminopiperid-4-yl)-1H-pyrazol-4-yl)-- 2-benzyloxycarbonyl amino-pyridine as a
white solid, with a yield of 91.8%.

Example 12

The Preparation of (.+-.) Crizotinib

To a solution of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-tert-butyloxycarbonyl aminopiperid-4-yl)-1H-pyrazol-4-yl)-2-tert-butyloxycarbonylamino-pyridine (171 mg, 0.25 mmol) in 2 ml ethanol was added 0.1 g Pd/C and then was stirred at
room temperature for 3 h. after completion of the reaction, the reaction mixture was filtrated through celite. The filtrate was concentrated and was extracted with dichloromethane (2.times.10 mL). The combined organic layer was washed with 10 ml
saturated NaCl aqueous solution, dried over anhydrous Na.sub.2SO.sub.4 and then concentrated to produce 0.112 g of crizotinib as an off-white solid, with a yield of 99.6%.