阅读说明：本技术 一种制备杜韦利西布中间体的方法 (Method for preparing Duvirucisib intermediate ) 是由 宋敬威 余斌 杨成武 王河清 李硕梁 高强 郑保富 于 2021-09-10 设计创作，主要内容包括：本发明提供了一种制备杜韦利西布中间体的方法,包括以下步骤：(1)、在适合溶剂中,以2-氯-6-甲基苯胺化合物1为原料,制备得到2-氯-6-甲基苯胺化合物1的氯化氢盐,与硝化试剂水溶液混合后进行重氮化反应,得到2-氯-6-甲基苯胺的重氮盐；再与碘代试剂经桑德迈尔反应制备得到3-氯-2-碘甲苯化合物2；(2)、化合物2与反应物氰基物反应经过取代反应,得到2-氯-6-碘苯甲腈化合物3；(3)、化合物3经过水解反应,得到2-氯-6-甲基苯甲酸化合物4,反应方程式如下：本方法所用原料廉价易得,巧妙经过碘代物,反应转化率高,简单快捷,反应条件温和可控,成本优势明显,所得产品收率高、分离纯化容易,纯度高,易于工业化大生产。(The invention provides a method for preparing a Duvirusb intermediate, which comprises the following steps: (1) in a proper solvent, 2-chloro-6-methylaniline compound 1 is taken as a raw material to prepare hydrogen chloride of the 2-chloro-6-methylaniline compound 1, and the hydrogen chloride is mixed with a nitration reagent aqueous solution and then subjected to diazotization reaction to obtain diazonium salt of the 2-chloro-6-methylaniline; then the 3-chloro-2-iodotoluene compound is prepared by the sandmeyer reaction with an iodo reagent 2; (2) compound 2 and reactantsThe cyano-compound reacts and is substituted to obtain a 2-chloro-6-iodobenzonitrile compound 3; (3) and the compound 3 is subjected to hydrolysis reaction to obtain a 2-chloro-6-methylbenzoic acid compound 4, and the reaction equation is as follows:)

1. A method for preparing a duvirucisib intermediate, comprising the steps of:

(1) in a proper solvent, 2-chloro-6-methylaniline compound 1 is taken as a raw material to prepare hydrogen chloride of the 2-chloro-6-methylaniline compound 1, and the hydrogen chloride is mixed with a nitration reagent aqueous solution and then subjected to diazotization reaction to obtain diazonium salt of the 2-chloro-6-methylaniline;

then the 3-chloro-2-iodotoluene compound is prepared by the sandmeyer reaction with an iodo reagent 2;

(2) reacting the compound 2 with a reactant cyano-group substance to obtain a 2-chloro-6-iodobenzonitrile compound 3 through a substitution reaction;

(3) and the compound 3 is subjected to hydrolysis reaction to obtain a 2-chloro-6-methylbenzoic acid compound 4, and the reaction equation is as follows:

2. the method of claim 1, wherein: in the step (1), the sandmeyer reaction is carried out in the following reaction solvent, wherein the reaction solvent is one or the combination of water, ethyl acetate or toluene;

the iodination reagent in the step (1) is selected from one or any combination of copper iodide, potassium iodide and sodium iodide, and potassium iodide is preferred.

3. The method according to claim 1 or 2, characterized in that: in the step (1), in the sandmeyer reaction, the molar amount of the iodo reagent is (1-2) times, preferably (1.1-1.3) times that of the raw material of the 2-chloro-6-methylaniline compound 1; the temperature of the Sandmeyer reaction is-10-15 ℃, and preferably 0-10 ℃; the reaction time of the sandmeyer reaction is 20 to 120 minutes, preferably 20 to 60 minutes.

4. The method according to claim 1 or 2, characterized in that: the step (1), the suitable solvent is selected from one or any combination of water, THF or acetonitrile, preferably water;

the nitrating reagent in the step (1) is selected from sodium nitrite NaNO₂Or nitrites selected from n-butyl nitrite, isoamyl nitrite or tert-butyl nitrite, preferably sodium nitrite NaNO₂The molar ratio of the nitrating reagent to the compound 2-chloro-6-methylaniline in the formula 1 is (1-2) to 1, preferably (1.05-1.2) to 1;

the mass concentration of the nitration reagent aqueous solution in the step (1) is preferably 18-40%, more preferably 18-32%, and most preferably 20-30%.

5. The method according to claim 1 or 2, characterized in that: the preparation process of the hydrogen chloride salt of the 2-chloro-6-methylaniline compound 1 in the step (1) comprises the following steps: mixing the aqueous solution of hydrogen chloride and the 2-chloro-6-methylaniline compound 1 at the temperature of-5-25 ℃ to separate out white solid to obtain suspension; the mass concentration of the aqueous hydrogen chloride solution is 30-60%, more preferably 35-55%, and most preferably 40-45%.

6. The method according to claim 1 or 2, characterized in that: the reaction temperature of the diazotization reaction in the step (1) is-10-35 ℃, preferably-10-15 ℃, and more preferably-5-0 ℃; the diazotization reaction time is preferably 10-120 minutes, more preferably 15-100 minutes, and most preferably 20-60 minutes.

7. The method according to claim 1 or 2, characterized in that: the substitution reaction of the step (2) is carried out in a reaction solvent selected from N, N-dimethylformamide DMF, N-dimethylacetamide DMAC, N-methylpyrrolidone NMP, DMSO, acetonitrile or toluene, preferably N, N-dimethylformamide DMF; the mass-to-gram ratio of the input amount/ml of the reaction solvent to the compound 2 is (2-20) to 1, preferably (3-10) to 1;

in the substitution reaction in the step (2), the cyano-compound is one or any combination of CuCN, NaCN, KCN or potassium ferricyanide, preferably CuCN; the reaction temperature of the substitution reaction is selected from 75-150 ℃, and preferably 90-130 ℃;

in the step (2), in the substitution reaction, the molar ratio of the reactant cyano compound to the compound 2 is (1-2) to 1, preferably (1.1-1.3) to 1;

the reaction time of the substitution reaction is 8 to 24 hours, preferably 10 to 18 hours.

8. The method according to claim 1 or 2, characterized in that: the hydrolysis reaction of the step (3) comprises the following steps of hydrolyzing a compound 3 serving as a raw material in a suitable reaction solvent in the presence of a nitration reagent and an acid to obtain a compound 4;

the suitable reaction solvent is selected from one or any combination of AcOH or water, preferably AcOH;

the nitrating reagent is selected from sodium nitrite NaNO₂NitriteIsoamyl acid or tert-butyl nitrite, preferably sodium nitrite NaNO₂(ii) a The acid is selected from sulfuric acid and hydrochloric acid, and is preferably concentrated sulfuric acid.

9. The method of claim 3, wherein: after the completion of the sandmeyer reaction, it is preferable to conduct a post-treatment using sodium thiosulfate, sodium bisulfite or sodium sulfite.

10. The method of claim 8, wherein: in the hydrolysis reaction of the step (3), the molar ratio of the acid to the compound 3 is (1-10) to 1, preferably (2-7) to 1;

the mass ratio of the suitable reaction solvent to the compound 3 is (1-5) to 1, preferably (1-3) to 1, further preferably (1-2) to 1, and more preferably (1.2-1.5) to 1; the reaction temperature of the hydrolysis reaction in the step (3) is 100-130 ℃, and preferably 110-125 ℃;

the molar ratio of the nitrating agent to the compound 3 is (1-4):1, preferably (1.05-3):1, wherein the nitrating agent can be added in batches or at one time, wherein the molar ratio of the nitrating agent added in batches to the compound 3 is (1-2):1, preferably (1.05-1.5): 1.

Technical Field

The invention relates to the field of organic chemical synthesis, in particular to a synthetic method of a Duvirusib intermediate 2-chloro-6-methylbenzoic acid.

Background

Duvirisib capsule (Invitrogen name: Duvelisib trade name: COPIKTRA), a novel PI3K delta inhibitory anticancer drug developed by Verastem corporation. Duvirisib, also known as IPI-145 and INK-1197, is the first approved dual inhibitor of PI3K-delta and PI3K-gamma, which is effective as a small molecule inhibitor of phosphoinositide-3 kinase in blocking PI3K-delta and PI3K-gamma kinase proteins. These two enzymes play a key role in the growth and survival of malignant B and T cells: its signaling pathway causes the proliferation of malignant B and T cells, and may also play a role in the formation and maintenance of the tumor microenvironment.

Duvirisib has been FDA approved for marketing 24/09/2018 for the treatment of relapsed/refractory Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) adult patients who have received at least two prior therapies. EMA approved duvelisib for marketing as monotherapy for treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior treatments and relapsed or refractory Follicular Lymphoma (FL) after at least two prior systemic treatments at month 5 2021; at present, China is used for treating recurrent and refractory follicular lymphoma in the clinical phase 2 trial stage.

2-chloro-6-methylbenzoic acid (structure shown below) is used as a key intermediate for synthesizing Duvelisib.

The synthesis routes of 2-chloro-6-methylbenzoic acid have been published and reported mainly in the following categories:

1) chem. soc.,1921, vol.119,1460 and Helvetica Chimica Acta,1960, vol.43,104-113 all used the route of cyano hydrolysis, the reaction scheme is as follows:

the yield of the route is low, and the intermediate cyano compound is not an easily obtained compound, is expensive and is not suitable for industrial production;

2) journal fur praktische Chemie (leipizing 1954),1939, vol. <2>153,200,213, etc. reported a route using 2-amino-6-methylbenzoic acid as a starting material, isoamyl nitrite and CuCl to produce 2-chloro-6-methylbenzoic acid by sandmeyer reaction, the reaction formula is as follows:

the raw materials of the route are expensive, the cost is high, and the yield is only 49%;

3) J.chem.Soc.Perkin I,1995,10, 1265-:

the reaction condition of the route needs low temperature, and flammable sec-butyl lithium is used, so that huge potential safety hazard exists, and the danger coefficient of industrial production and operation is high;

4) patent US20030181759a1 discloses a preparation route for chlorination on benzene ring by using o-methylbenzoic acid as a raw material and palladium acetate as a catalyst, and the reaction formula is as follows:

the route needs to use a noble metal catalyst, so the cost is high;

5) org. Process. Res. Dev.2005, vol.9,6,1003-1008 et al report a route to 2-chloro-6-methylbenzoic acid by oxidation of 2-chloro-6-methylbenzaldehyde with sodium chlorite, DMSO, the reaction scheme is as follows:

the method has expensive and not easily available raw materials. Meanwhile, the oxidation reaction has certain potential safety hazards;

6) beilstein J. org. chem.2016, vol.12,1503-1511 reports that 1-chloro-2-iodo-3-toluene is adopted as a raw material and is subjected to one-step carbonyl insertion reaction under the catalysis of palladium acetate to obtain a product, namely 2-chloro-6-methylbenzoic acid, wherein the reaction formula is as follows:

the route needs to be catalyzed by noble metals, and the cost is high; the highly toxic gas carbon monoxide is used in the raw materials, the yield is only 12 percent, and the method is not suitable for industrialization;

in addition, routes for synthesizing 2-chloro-6-methylbenzoic acid by taking cyano compounds as raw materials are reported in J.org.chem.2013, vol.78,6,2786-2791 and J.chem.Soc.1921, vol.119,1460, but the two use expensive metal catalysts and highly toxic products respectively, which are not suitable for industrial scale amplification;

the existing synthetic route of 2-chloro-6-methylbenzoic acid mainly has the following defects: 1) expensive catalysts or starting materials are used, so that the cost is high; 2) the overall yield of the reaction is low; 3) dangerous reagents such as sec-butyl lithium and the like are used, ultralow temperature-90 ℃ reaction conditions are required, the operation difficulty is high, and great potential safety hazards exist; these factors make the above-described scheme difficult to industrially produce on a large scale.

Therefore, the development of a green, environment-friendly, high-yield, low-cost and efficient 2-chloro-6-methylbenzoic acid process route and process has urgent needs and broad prospects.

Disclosure of Invention

The invention aims to provide a method for preparing a Duvirusib intermediate 2-chloro-6-methylbenzoic acid, and the process route has the advantages of easily available raw materials, simplicity and convenience in operation, environmental friendliness, high product yield and high purity, and is easy for industrial production.

The invention relates to a synthesis process of a Duvirusib intermediate 2-chloro-6-methylbenzoic acid, which comprises the following steps:

(1) in a proper solvent, 2-chloro-6-methylaniline (compound 1) is taken as a raw material to prepare hydrogen chloride of the 2-chloro-6-methylaniline (compound 1), and the hydrogen chloride is mixed with a nitration reagent aqueous solution and then subjected to diazotization reaction to obtain diazonium salt of the 2-chloro-6-methylaniline;

then the product is reacted with iodo reagent by Sandmeyer reaction to prepare 3-chloro-2-iodotoluene (compound 2);

(2) carrying out substitution reaction on the compound 2 and a reactant cyano to prepare 2-chloro-6-iodobenzonitrile (compound 3);

(3) and the compound 3 is subjected to hydrolysis reaction to obtain 2-chloro-6-methylbenzoic acid (compound 4), and the reaction equation is as follows:

step (1) of the present invention, wherein the suitable solvent is selected from one or any combination of water, THF or acetonitrile, preferably water;

in the invention, the nitrating reagent in the step (1) is selected from sodium nitrite NaNO₂Nitrites (n-butyl nitrite, isoamyl nitrite or tert-butyl nitrite)) Preferably sodium nitrite NaNO₂The nitrating agent (for example: sodium nitrite NaNO)₂) The molar ratio of the compound to the compound 2-chloro-6-methylaniline in the formula 1 is (1-2) to 1, preferably (1.05-1.2) to 1;

in the invention, the mass concentration of the nitration reagent aqueous solution in the step (1) is preferably 18-40%, more preferably 18-32%, and most preferably 20-30%;

further, the temperature of the diazotization reaction in the step (1) is preferably-10-35 ℃, more preferably-10-15 ℃, and most preferably-5-0 ℃; the diazotization reaction time is preferably 10-120 minutes, more preferably 15-100 minutes, and most preferably 20-60 minutes. In the present invention, the time of the diazotization reaction is measured after all raw materials are mixed, and does not include the time of dropping the sodium nitrite aqueous solution. In the invention, the preferable temperature for dropwise adding/slowly adding the sodium nitrite aqueous solution in the step (1) is-10 ℃.

In the present invention, the preferred technical scheme is to prepare the hydrogen chloride salt of the 2-chloro-6-methylaniline (compound 1) by using the 2-chloro-6-methylaniline (compound 1) as a raw material, and the method comprises the following steps: mixing a hydrogen chloride water solution (a mixture of concentrated hydrochloric acid and water) and 2-chloro-6-methylaniline (a compound 1) at-5-25 ℃ (preferably-5-15 ℃) to precipitate a white solid to obtain a suspension;

further, according to the preferable technical scheme of the invention, the hydrogen chloride salt solution of the obtained 2-chloro-6-methylaniline (compound 1) is cooled to-5-0 ℃, and is mixed with the aqueous solution of the nitrating reagent to obtain the diazonium salt of the 2-chloro-6-methylaniline; it is preferable to add 2-chloro-6-methylaniline dropwise or slowly to the aqueous solution containing hydrogen chloride to prevent the reaction rate from being excessively fast;

in the present invention, the mass concentration of the aqueous hydrogen chloride solution in the step (1) is preferably 30 to 60%, more preferably 35 to 55%, and most preferably 40 to 45%. In the course of the diazotization reaction according to the invention, sodium nitrite is used as the diazotizing agent to react with the hydrogen chloride salt of 2-chloro-6-methylaniline to form a diazonium salt, which is of the formula:

after the diazotization reaction is finished, the product system is not required to be purified and processed, and the product system is directly participated in the next reaction without being processed;

in the step (1), the sandmeyer reaction is carried out in the following reaction solvent, wherein the reaction solvent is one or the combination of water, ethyl acetate or toluene;

the diazo salt of the obtained 2-chloro-6-methylaniline is mixed with an iodinating reagent and then subjected to a sandmeyer reaction to obtain 3-chloro-2-iodotoluene (compound 2). In the present invention, it is preferable that an iodinating reagent and a reaction solvent (for example, water, ethyl acetate, or toluene) are mixed to obtain a mixed solution, and then a diazotization reaction solution obtained by the diazotization reaction is added dropwise to the mixed solution; because nitrogen is generated and released in the sandmeyer reaction process, the nitrogen can be well controlled to be uniformly released in a dropwise adding and feeding manner, and the flushing is avoided;

in the step (1), in the sandmeyer reaction, the iodinated reagent is selected from one or any combination of copper iodide, potassium iodide and sodium iodide, preferably potassium iodide;

further, in the sandmeyer reaction, the molar amount of the iodo reagent is (1-2) times, preferably (1.1-1.3) times that of the raw material of the 2-chloro-6-methylaniline (compound 1); the temperature of the Sandmeyer reaction is-10-15 ℃, and preferably 0-10 ℃; the sandmeyer reaction time is 20-120 minutes, preferably 20-60 minutes.

After the sandmeyer reaction is finished, the invention preferably performs purification treatment on the obtained product system to obtain a 3-chloro-2-iodotoluene (compound 2) product, and the post-treatment preferably comprises the following steps:

in the step (1), after the sandmeyer reaction is finished, sodium thiosulfate, sodium bisulfite or sodium sulfite is preferably used for post-treatment;

adding ethyl acetate and water into the product obtained by the Sandmeyer reaction, washing an ethyl acetate layer by using 5 wt% -10% of sodium thiosulfate, sodium bisulfite or sodium sulfite and the like, optionally washing by using saturated saline solution, concentrating an organic phase, and directly carrying out the next step of reaction.

In the present invention, the substitution reaction of step (2) is represented by the following reaction formula:

in the present invention, the substitution reaction of step (2) is carried out in a reaction solvent selected from the group consisting of N, N-dimethylformamide DMF, N-dimethylacetamide DMAC, N-methylpyrrolidone NMP, DMSO, acetonitrile or toluene, preferably N, N-dimethylformamide DMF; the mass ratio (g/g) of the feeding amount (mL/mL) of the reaction solvent to the compound 2 is (2-20) to 1, preferably (3-10) to 1;

in the present invention, the cyano reactant in the substitution reaction of step (2) is selected from CuCN, NaCN, KCN, potassium ferricyanide, etc., preferably CuCN; the reaction temperature of the substitution reaction is selected from 75-150 ℃, and preferably 90-130 ℃;

in the step (2), in the substitution reaction, the molar ratio of the reactant cyano compound to the compound 2 is (1-2) to 1, preferably (1.1-1.3) to 1;

the reaction time of the substitution reaction is 8 to 24 hours, preferably 10 to 18 hours.

In the present invention, the hydrolysis reaction of step (3) has the following reaction formula:

in the present invention, the hydrolysis reaction of step (3) comprises the following steps:

hydrolyzing the compound 3 serving as a raw material in a proper reaction solvent in the presence of a nitration reagent and acid to obtain a compound 4.

In the present invention, the reaction solvent of the hydrolysis reaction of step (3) is selected from one or any combination of AcOH and water, preferably AcOH; the mass ratio of the reaction solvent to the compound 3 is (1-5) to 1, preferably (1-3) to 1, more preferably (1-2) to 1, and even more preferably (1.2-1.5) to 1;

in the present invention, in the hydrolysis reaction of step (3), the acid is selected from sulfuric acid, hydrochloric acid, preferably concentrated sulfuric acid; the molar ratio of the acid to the compound 3 is (1-10) to 1, preferably (2-7) to 1;

in the invention, the reaction temperature of the hydrolysis reaction in the step (3) is 100-130 ℃, preferably 110-125 ℃;

in the invention, the nitrating reagent in the step (3) is selected from sodium nitrite NaNO₂Isoamyl nitrite or tert-butyl nitrite, preferably sodium nitrite NaNO₂The molar ratio of the nitrating reagent to the compound 3 is (1-4):1, preferably (1.05-3):1, wherein the nitrating reagent can be added in batches or at one time; if the addition is carried out in portions, the molar ratio of the nitrating agent to compound 3 added first is preferably (1-2):1, preferably (1.05-1.5): 1.

Compared with the prior art, the invention has the following beneficial technical effects:

the diazotization method avoids the use of sulfuric acid, phosphoric acid and the like, avoids the occurrence of a plurality of side reactions by using hydrochloric acid, avoids hydrolysis reaction, coupling reaction and tar phenomenon, obtains diazotized salt without purification treatment in water, tetrahydrofuran or acetonitrile solution, and directly prepares the 3-chloro-2-iodotoluene (compound 2) through Sandmeyer reaction, wherein the yield reaches more than 95 percent, and more preferably 97.2 percent; in the salification reaction process, the aqueous hydrogen chloride solution can maintain the acidity of a reaction system and can form hydrogen chloride salt with 2-chloro-6-methylaniline (compound 1), so that the salification reaction is thorough, and the generation of subsequent azo byproducts is avoided; the classical sandmeyer reaction has high reaction selectivity, few byproducts and high product quality;

the present inventors tried reaction-2-chloro-6-methylaniline (compound 1) directly to the cyanide and tried less toxic CuCN, but failed the reaction, this route is not available and the results show: the reaction product in this step is very miscellaneous, and only a very small amount of product is obtained; when the reaction of di, 2-chloro-6-methylaniline (compound 1) is tried to be brominated or chlorinated, the same problem of low product yield can occur;

according to the invention, through the iodide reaction skillfully, KI iodide is adopted according to the activity of 2-chloro-6-methylaniline (compound 1), so that the reaction effect is good, the separation is simple and the yield is high; the iodide with higher activity and the CuCN with lower toxicity are used for reaction, the reaction yield is high, and the purification is simple; avoiding the use of KCN and the like;

in addition, the invention solves the problems of difficult hydrolysis reaction and easy sublimation of raw materials in the third step through screening and optimizing the solvent, particularly, the acetic acid or the mixed solvent of the acetic acid and the water is used, and the polarity of the reaction system and the viscosity of the solvent are very suitable for the hydrolysis reaction environment of the compound 3; the inventor tries different complex solvents and proportions, and finally uses the solvent containing AcOH to effectively prevent the product from sublimating, does not influence the reaction conversion rate (the yield is about 90 percent and is higher than 91 percent), and has very simple and convenient post-treatment.

The route adopted by the invention is as follows:

finally, the route adopts cheap and easily-obtained starting materials, an expensive metal catalyst is not used in the whole reaction process, the use of high-toxicity and inflammable reagents and gas is avoided, the reagents are easily obtained without using any catalyst, and particularly, the utilization rate of iodine is improved by adopting a method of iodination in the Sandmeyer reaction; the three-step reaction has the advantages of high reaction yield, good purity, simplicity, rapidness, mild and controllable reaction conditions, obvious cost advantage, high product yield, easiness in separation and purification, high purity and easiness in industrial production.

Detailed Description

The technical solution of the present invention will be described in detail below with reference to specific examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention thereto.

Example 1

Preparation method of compound 2:

adding 20L of water and 13.4L of concentrated hydrochloric acid into a 100L reaction kettle (R1), cooling a reaction system to 0-15 ℃, and slowly adding 4000g of 2-chloro-6-methylaniline to separate out white solids; cooling the reaction system to-5-0 ℃, and slowly dripping NaNO into the reaction kettle₂An aqueous solution (2.144kg of sodium nitrite dissolved in 7.5L of water) is dripped to a solid disappearance solution for clarification, and the reaction is carried out for 20 minutes under the condition of heat preservation;

adding 8L of water, 5.6kg of potassium iodide and 16L of ethyl acetate into another 100L of reaction kettle (R2), cooling to 0-10 ℃, slowly dropwise adding the solution in the reaction kettle R1 into the reaction kettle R2, and stirring for 30 minutes. After the reaction was completed, 26L of ethyl acetate was added to R2, the mixture was separated into layers, and 13L of ethyl acetate was added to the aqueous phase for extraction, and the organic layers were combined, washed successively with 40L of 5 wt% sodium thiosulfate and 16L of saturated brine, separated into layers, and concentrated to dryness to give 7kg of compound 2 with a yield of 97.8%, which was used directly in the next reaction as a yellow liquid.

Example 2

Preparation method II of compound 2:

adding 24mL of water and 16.8mL of concentrated hydrochloric acid into a 100mL three-necked flask (R1), cooling to-5-0 ℃, adding 5.0g of 2-chloro-6-methylaniline, separating out a white solid, and slowly dropwise adding NaNO into R1 at-5-0 DEG C₂Dropwise adding an aqueous solution (2.7g of sodium nitrite is dissolved in 10mL of water) until the solid solution disappears, clarifying, and stirring for 20mins for later use;

adding 10mL of water and 7.03g of KI into another 100mL three-necked bottle (R2), and cooling to 0-10 ℃; slowly dripping the solution in the R1 into the R2, and stirring for 30 minutes to 1 hour; after the reaction, 25mL of ethyl acetate was added to R2, the mixture was separated into layers, 50mL of ethyl acetate was added to the aqueous phase for extraction, the organic phases were combined, washed sequentially with 50mL of 5 wt% sodium thiosulfate and 50mL of Brine, the layers were separated, the organic phase was concentrated to dryness, and petroleum ether was chromatographed to give 7.96g of Compound 2, 89.6% yield, as a yellow liquid, which was used directly in the next reaction.

Example 3

Preparation method of compound 3:

adding 139.0g of compound 2 into 556mL of DMF, and replacing nitrogen for two times, wherein the reaction temperature is 20-25 ℃; under the protection of nitrogen, adding 59.6g of CuCN, heating to 95-100 ℃, and reacting for 16 hours; after the raw materials are completely reacted, cooling to 30-40 ℃, adding 250mL of MTBE, dropwise adding 750mL of water, adding 20g of diatomite after the dropwise adding is finished, filtering solids, washing a filter cake by using 100mL of MTBE, layering a mother solution, adding 250mL of MTBE into a water phase, extracting, combining organic phases, concentrating to dryness, and obtaining 79g of a compound 3 which is a white-like solid with the yield of 94.9%.

Example 4

Preparation method II of compound 3:

adding 7.0kg of compound 2 into 28L of DMF in a 100L reaction kettle, and replacing with nitrogen twice, wherein the reaction temperature is 20-25 ℃; adding CuCN 2.994kg under the protection of nitrogen, heating to 95-100 ℃ and reacting for 16 hours; after the raw materials are completely reacted, cooling to 30-40 ℃, adding 14L of MTBE, dropwise adding 37.5L of water, after dropwise adding, adding 500g of diatomite, filtering solids, flushing a filter cake with 40L of MTBE, layering a mother solution, adding 15L of MTBE into a water phase, extracting, concentrating an organic phase to obtain a white solid, and performing vacuum drying at 35-40 ℃ for 16 hours to obtain 4.0kg of compound 3, wherein the yield is 95.5%;

example 5

Synthesis of Compound 4:

adding 60g of ice into a 500mL three-necked bottle, adding 150g of concentrated sulfuric acid, 60g of AcOH and 50g of compound 3 under stirring, heating to 120-125 ℃, and stirring for 4 hours. Cooling to 30-40 ℃, and dropwise adding NaNO₂The aqueous solution (34.1g sodium nitrite in 70mL water) was exothermic and a large amount of gas was formed. Stirring overnight, and supplementing NaNO₂The aqueous solution (16g sodium nitrite in 32mL water) continues to react; after the reaction was completed, 100mL of water was added, filtered, and the filter cake was washed with water and dried to obtain 50g of Compound 4 as white crystals with a yield of 89% and an HPLC purity of 99.04%.

Example 6

Synthesis of Compound 4:

80g of ice was added to a 500mL three-necked flask, and 150g of concentrated sulfuric acid, 70g of AcOH and 50g of Compound 3 were added with stirring, and the mixture was heated to reflux and stirred for 4 hours. Cooling to 20-30 ℃, and dropwise adding NaNO₂Aqueous solution (68.3g sodium nitrite in 125mL water), exothermic and large amount of gas generatedAnd (4) obtaining. Stirring overnight, after the reaction was complete as monitored by HPLC; 100mL of water was added, filtered, and the filter cake was washed with water and dried to give 51.2g of Compound 4 as white crystals in 91% yield and 99.10% HPLC purity.

It should be noted that, in each step, other auxiliary steps for collecting the product, increasing the yield, increasing the product purity, removing impurities, etc. may be adopted, such as common auxiliary means of filtration, washing, extraction, purification, drying, etc.

While the invention has been described with reference to specific preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims,

the above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.