CN118047782A - Process for preparing intermediate of ponatinib - Google Patents

Abstract

The invention discloses a method for preparing a pontinib intermediate, which comprises the following steps: step 1, carrying out salt formation reaction on a raceme compound II and a compound IIIa or a compound IIIb serving as a resolving agent, and separating to obtain a compound IVa or a compound IVd respectively; and 2, treating the compound IVa or the compound IVd obtained in the step 1 with alkali to obtain a compound I, namely the intermediate of the ponifinib. By the process of the invention, compounds I with an e.e. value higher than 99.5% can be obtained. The preparation method provided by the invention has the advantages of mild reaction conditions, simple post-treatment, no need of special reagents, remarkably higher yield than the prior art method, and suitability for industrial production.

Description

Process for preparing intermediate of ponatinib

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a JAK inhibitor pontine intermediate.

Background

Poncirtinib phosphate (Ruxolitinib Phosphate), developed by Incyte, was approved by the FDA in 2011 in the united states as the first approved drug specifically for the treatment of myelofibrosis. The European and Japanese PMDA market approval was obtained in succession in 2012 and 2014, and the CFDA in 2017 was approved for market. The product is a kind of mouth IgJAKl and JAK2 tyrosine kinase inhibitor, and is used for treating middle-risk or high-risk primary myelofibrosis, myelofibrosis secondary to polycythemia vera or adult patient with myelofibrosis secondary to primary thrombocythemia. The structural formula is as follows:

The synthesis of compound 1, which has been reported to date, is as follows:

Method l: qiyan Lin et al at OL,2009,11 (9): in 1999-2002, compounds 6 and 7 are used as starting materials, asymmetric addition is carried out under the catalysis of a small molecular compound 8 to obtain a compound 9, then aldehyde groups are converted into cyano groups to obtain a compound 10, and finally SEM protecting groups are removed and salified to obtain a target product 1.

In the method 2: zhou Gucheng et al, in the patent CN105669676B, compounds 11 and 12 are used as starting materials, a protecting group is removed through coupling to obtain a compound 14, then the compound 14 is added with an alkyne compound to obtain a compound 15, then rhodium is subjected to asymmetric catalytic hydrogenation to obtain a target chiral compound 16, and finally, the compound 1 is obtained through hydrolysis and salification.

Method 3: zhu Yijun et al in patent CN113292569, using compounds 2 and 3 as starting materials, coupling, chiral resolution to obtain compound 5, and then dissociation, deprotection, salification to obtain compound 1.

The three methods are to carry out asymmetric induction and reduction by chiral micromolecules and chiral ligands to obtain the target chiral compound. However, the above methods have obvious disadvantages: in the method 1, the compound 7 is more expensive and unstable, the synthetic route of the small molecule catalyst 8 is longer, the cost is higher, and the induced chirality is lower; in the method 2, the rhodium catalyst and chiral ligand are high in price, high in production cost and not suitable for industrialized amplification; the method 3 has lower resolution yield, low optical purity after one resolution and high production cost.

Therefore, the method which is mild in condition, simple in operation and high in chemical purity and optical purity and can be successfully used for industrial production of the poncirtinib phosphate is a technical problem which needs to be solved in the field at present.

Disclosure of Invention

The invention aims to provide a method for preparing a reed-cotinib intermediate, which aims to solve the problems of high resolution cost of racemate, low e.e. value, inapplicability to industrial production and the like in the preparation of reed-cotinib in the prior art.

In order to achieve the above purpose, the invention adopts the following technical scheme:

A method for preparing a ponatinib intermediate, which comprises the following synthetic route:

Wherein Ar represents an unsubstituted or substituted C6-C14 aromatic or heteroaromatic group, said substitution being by a group selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, amide;

The synthesis steps are as follows:

Step 1, carrying out salt formation reaction on a raceme compound II and a compound IIIa or a compound IIIb serving as a resolving agent, and separating to obtain a compound IVa or a compound IVd respectively;

And 2, treating the compound IVa or the compound IVd obtained in the step 1 with alkali to obtain a compound I, namely the intermediate of the ponifinib.

Ar has a structure shown in a formula V:

Wherein R ₁、R₂、R₃、R₄、R₅ is independently hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, amido.

In another preferred embodiment, four substituents in R ₁、R₂、R₃、R₄、R₅ are hydrogen and one substituent is other than hydrogen, preferably R ₃ is other than hydrogen.

In another preferred embodiment, the amide group refers to a group having a structure selected from the group consisting of: -NHCOR, -NR 'COR, -CONHR, -CONRR', wherein each R, R 'is independently methyl, ethyl or phenyl, or N, R, R' together with the carbon atom to which it is attached form a 5-7 membered nitrogen heterocycle.

In another preferred embodiment Ar is an unsubstituted or substituted C10-C14 polycyclic aryl group, such as naphthyl, anthracenyl.

In another preferred embodiment Ar is an unsubstituted or substituted C5-C10 heteroaryl group, such as piperidinyl, piperazinyl, quinolinyl.

Ar is selected from the following groups:

Wherein represents the connection point.

In another preferred embodiment, ar is a monosubstituted benzyloxy group.

In another preferred embodiment, ar is para-substituted benzyloxy.

In another preferred example, ar is benzyl, phenyl, nitrophenyl, chlorophenyl, bromophenyl, benzyloxy, cyanophenyl.

In another preferred example, ar is benzyl, phenyl, benzyloxy.

In another preferred embodiment, ar is benzyloxy or phenyl.

In another preferred embodiment, ar is benzyl.

In said step 1, the molar ratio of compound II to compound IIIa or compound IIIb is from 1:0.3 to 1.5, preferably from 1:0.5 to 1.0, more preferably from 1:0.6.

In the step 1, the salification reaction is carried out in a single solvent or a mixed solvent of alcohols, ketones, esters, ethers, acetonitrile and water. Preferably, the salt formation reaction is carried out in methanol, ethanol, acetonitrile, water or a mixed solvent thereof. More preferably, the salification reaction is carried out in a mixed solvent of methanol and acetonitrile, wherein the volume ratio of the two solvents is 5-15:1.

In the step 1, the salification reaction is carried out at a temperature ranging from-10 ℃ to 90 ℃. Preferably 0℃to 60℃and more preferably 10-60 ℃.

In the step 1, the reaction time of the salification reaction is 2-6h, preferably 2h.

In the step1, the separation includes: the reaction system is cooled to 10 ℃, stirred for 1 to 5 hours to separate out, filtered and separated.

In another preferred example, the solid obtained by filtration separation is compound IVa or compound IVd, and the diastereoisomer recovery is carried out after the alkali treatment of compound IVb or compound IVc in the filtrate.

In the step 2, the alkali is ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or potassium phosphate.

In the step 2, the alkali treatment step is performed in water, an organic solvent or a mixed solvent of water and the organic solvent, wherein the organic solvent is selected from methyl isobutyl ketone, ethyl acetate, dichloromethane or dimethyl tetrahydrofuran or a combination thereof.

In another preferred embodiment, in step 2, the alkali treatment is performed in an aqueous alkali solution.

In another preferred embodiment, in step 2, the pH of the alkaline treatment step is 7.0-7.5.

In the step 2, in the alkali treatment step, the concentration of the resolved salt of the compound iv a or the resolved salt of the compound iv d in the solvent is 0.05=0.15 g/mL each independently; alkali treatment is carried out at the temperature of 10-35 ℃; the reaction time for the alkali treatment is 1 to 3 hours, preferably 2 hours.

The resolving agent is D-di-p-methoxybenzoyl tartaric acid VI:

。

the D-di-p-methoxyl benzoyl tartaric acid VI and a raceme compound II react in a binary solvent system of methanol/acetonitrile to obtain diastereomeric salt of a formula VII,

Subsequently, in water, the intermediate I of the lacteib is obtained by dissociating the intermediate I by using sodium hydroxide aqueous solution,

。

Based on a method for preparing the intermediate of the poncolinib, the invention provides a method for preparing the poncolinib phosphate, which comprises the following steps of:

(1) Taking a compound II as a raw material, and preparing the compound I through resolution;

(2) Salifying the compound I with phosphoric acid to obtain the poncolitinib phosphate;

The reaction formula is as follows:

The invention also provides diastereomeric salt or pharmaceutically acceptable salt thereof, which has the following structural formula:

wherein Ar represents an unsubstituted or substituted C6-C14 aromatic or heteroaromatic group, wherein said substitution is by a group selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, and amido.

The beneficial effects are that: compounds of formula I having an e.e. value of greater than 99.5% are obtainable by the process of the invention. The preparation method provided by the invention has the advantages of mild reaction conditions, simple post-treatment, no need of special reagents, remarkably higher yield than the prior art method, and suitability for industrial production.

The invention is widely and deeply researched, and discovers a method for preparing the intermediate of the ultrahigh e.e. value pontinib. In theory, since the compound II contains a basic group, the use of a carboxyl group-containing tartaric acid derivative resolving agent can generally achieve an isomer separation effect. However, the basic nitrogen atom on the pyrimidine ring in compound II is far from chiral carbon, and resolution is usually poor. Through extensive screening of resolving agents, the compound IIIa or the compound IIIb has obvious resolving effect on the compound II by taking the compound IIIa or the compound IIIb as the resolving agent, and the e.e. value can reach more than 90.0% after one-time resolution. The method has simple operation, high yield and high product purity, and is very suitable for preparing the pontinib in industrialized production.

The preparation method of the invention has the advantages that: the method has the advantages of simple reaction steps, mild reaction conditions, no need of special reagents, simple operation and suitability for industrial production; the separation of the enantiomer mixture by the tartaric acid ester can avoid the separation by a chiral phase chromatography method with high cost and low efficiency, the yield of the enantiomer mixture separated by the tartaric acid ester is more than 45 percent, the e.e. value of the intermediate is more than 99.5 percent, and the e.e. value of the final product of the poncirtinib phosphate can be more than 99.8 percent.

Detailed Description

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.

Unless otherwise indicated, all the starting materials or reagents used in the examples were either commercially available or were prepared according to conventional methods.

EXAMPLE 1 preparation of diastereomeric salt (IVa-1)

To the flask, the compound of formula II (100.0 g,326.4 mmol), compound IIIa-1 (70.2 g,195.8 mmol), methanol (500 mL), acetonitrile (500 mL) were added at room temperature (about 25 ℃), and then heated to an internal temperature of 50℃for clearing and stirring for 2h. Subsequently, the mixture was cooled to 10℃over 2h (final temperature reduced to 10 ℃) and then stirred at that temperature for 2h. Filtration and vacuum drying at 45℃gave 100.2g (92.3% of theory) of an off-white crystalline powder. Enantiomeric purity: 97.1%.

EXAMPLE 2 preparation of Compound I

The compound prepared in example 1 (100.0 g), water (1000 mL) was added to the reaction flask at room temperature (about 25 ℃). Subsequently, 20% wt aqueous sodium hydroxide solution was added over 0.5 hours, and the pH was adjusted to ph=7.2, and stirred at that temperature for 2.0 hours. Filtered and washed once with 200mL of water. Drying under reduced pressure at 50℃gives 42.0g (91.1% of theory) of a white crystalline powder. Enantiomeric purity: 97.3%.

EXAMPLE 3 preparation of diastereomeric salt (IVa-2)

To the flask, compound II (100.0 g,326.4 mmol), compound IIIa-2 (75.6 g,195.8 mmol) and acetonitrile (700 mL) were added at room temperature (about 25 ℃ C.), and then heated to an internal temperature of 50 ℃ C. To dissolve, followed by stirring for 2h. Subsequently, the mixture was cooled to 10℃over 2h (final temperature reduced to 10 ℃) and then stirred at that temperature for 2h. Filtration and vacuum drying at 45℃gave 105.3g (93.1% of theory) of an off-white crystalline powder. Enantiomeric purity: 98.2%.

EXAMPLE 4 preparation of Compounds of formula I

The compound prepared in example 3 (100.0 g), water (1000 mL) was added to the reaction flask at room temperature (about 25 ℃). Subsequently, 20% wt aqueous sodium hydroxide solution was added over 0.5 hours, and the pH was adjusted to ph=7.2, and stirred at that temperature for 2.0 hours. Filtered and washed once with 200mL of water. Drying under reduced pressure at 50℃gives 41.3g (93.4% of theory) of a white crystalline powder. Enantiomeric purity: 98.5%.

EXAMPLE 5 preparation of diastereomeric salt (IVa-3)

To the flask were added compound II (100.0 g,326.4 mmol), compound IIIa-3 (83.6 g,195.8 mmol), methanol (400 mL), acetonitrile (600 mL) at room temperature (about 25 ℃ C.), then heated to an internal temperature of 50 ℃ C. For 2h with stirring. Subsequently, the mixture was cooled to 10℃over 2h (final temperature reduced to 10 ℃) and then stirred at that temperature for 2h. Filtration and vacuum drying at 45℃gave 110.9g (92.6% of theory) of an off-white crystalline powder. Enantiomeric purity: 98.4%.

EXAMPLE 6 preparation of Compound I

The compound prepared in example 5 (100.0 g), water (1000 mL) was added to the reaction flask at room temperature (about 25 ℃). Subsequently, 20% wt aqueous sodium hydroxide solution was added over 0.5 hours, and the pH was adjusted to ph=7.2, and stirred at that temperature for 2.0 hours. Filtered and washed once with 200mL of water. Drying under reduced pressure at 50℃gives 39.2g (93.8% of theory) of a white crystalline powder. Enantiomeric purity: 98.0%.

EXAMPLE 7 preparation of diastereomeric salt (VII)

To the flask, compound II (100.0 g,326.4 mmol), compound VI (81.9 g,195.8 mmol), methanol (500 mL), acetonitrile (500 mL) were added at room temperature (about 25 ℃ C.), and then heated to an internal temperature of 50 ℃ C. For 2h with stirring. Subsequently, the mixture was cooled to 10℃over 2h (final temperature reduced to 10 ℃) and then stirred at that temperature for 2h. Filtration and vacuum drying at 45℃gave 117.6g (99.5% of theory) of an off-white crystalline powder. Enantiomeric purity: 99.8%.

EXAMPLE 8 preparation of Compound I

The compound prepared in example 7 (100.0 g), water (500 mL) was added to the reaction flask at room temperature (about 25 ℃). Subsequently, 20% wt aqueous sodium hydroxide solution was added over 0.5 hours, and the pH was adjusted to ph=7.2, and stirred at that temperature for 2.0 hours. Filtered and washed once with 200mL of water. Drying under reduced pressure at 50℃gives 41.1g (97.2% of theory) of a white crystalline powder. Enantiomeric purity: 99.8%.

EXAMPLE 9 preparation of diastereomeric salt (IVa-4)

To the flask were added compound II (100.0 g,326.4 mmol), compound IIIa-4 (87.8 g,195.8 mmol), methanol (350 mL), acetonitrile (400 mL) at room temperature (about 25 ℃ C.), then heated to an internal temperature of 50 ℃ C. For 2h with stirring. Subsequently, the mixture was cooled to 10℃over 2h (final temperature reduced to 10 ℃) and then stirred at that temperature for 2h. Filtration and vacuum drying at 45℃gave 115.7g (93.9% of theory) of an off-white crystalline powder. Enantiomeric purity: 95.1%.

EXAMPLE 10 preparation of Compound I

The compound prepared in example 9 (100.0 g), water (500 mL) was added to the reaction flask at room temperature (about 25 ℃). Subsequently, 20% wt aqueous sodium hydroxide solution was added over 0.5 hours, and the pH was adjusted to ph=7.2, and stirred at that temperature for 2.0 hours. Filtered and washed once with 200mL of water. Drying under reduced pressure at 50℃gives 38.0g (93.6% of theory) of a white crystalline powder. Enantiomeric purity: 95.0%.

EXAMPLE 11 preparation of diastereomeric salt (IVa-5)

To the flask were added compound II (100.0 g,326.4 mmol), compound IIIa-5 (101.1 g,195.8 mmol), methanol (40 mL), acetonitrile (400 mL) at room temperature (about 25 ℃ C.), then heated to an internal temperature of 50 ℃ C. For a solution, and stirred for 2h. Subsequently, the mixture was cooled to 10℃over 2h (final temperature reduced to 10 ℃) and then stirred at that temperature for 2h. Filtration and vacuum drying at 45℃gave 130.1g (96.9% of theory) of an off-white crystalline powder. Enantiomeric purity: 94.4%.

EXAMPLE 12 preparation of Compound I

The compound prepared in example 11 (100.0 g), water (500 mL) was added to the reaction flask at room temperature (about 25 ℃). Subsequently, 20% wt aqueous sodium hydroxide solution was added over 0.5 hours, and the pH was adjusted to ph=7.2, and stirred at that temperature for 2.0 hours. Filtered and washed once with 200mL of water. Drying under reduced pressure at 50℃gives 35.6g (95.4% of theory) of a white crystalline powder. Enantiomeric purity: 96.7%.

EXAMPLE 13 preparation of diastereomeric salt (IVa-6)

To the flask, compound II (100.0 g,326.4 mmol) and Compound IIIa-6 (79.9 g,195.8 mmol) in methanol (40 mL) were added at room temperature (about 25 ℃ C.) and then heated to an internal temperature of 50 ℃ C. To dissolve, followed by stirring for 2h. Subsequently, the mixture was cooled to 10℃over 2h (final temperature reduced to 10 ℃) and then stirred at that temperature for 2h. Filtration and vacuum drying at 45℃gave 99.7g (85.5% of theory) of an off-white crystalline powder. Enantiomeric purity: 97.9%.

EXAMPLE 14 preparation of Compounds of formula I

The compound prepared in example 13 (100.0 g), water (500 mL) was added to the reaction flask at room temperature (about 25 ℃). Subsequently, 20% wt aqueous sodium hydroxide solution was added over 0.5 hours, and the pH was adjusted to ph=7.2, and stirred at that temperature for 2.0 hours. Filtered and washed once with 200mL of water. Drying under reduced pressure at 50℃gives 41.8g (97.4% of theory) of a white crystalline powder. Enantiomeric purity: 97.7%.

Example 15

Consider the effect of different solvents and different solvent ratios on chiral purity.

With reference to the preparation of example 7, the corresponding substitution of the methanol/acetonitrile solvent combination is carried out, the others remaining unchanged, the purity of the product being obtained being given in the following table:

TABLE 1 influence of different solvents on the purity of the product

From the above table data, the chiral purity of the product is not too high after methanol is combined with other solvents, and can be higher than 80% only when combined with ethanol and water; after acetonitrile is combined with other solvents, the chiral purity of the product is higher, and when the product is combined with ethanol, ethyl acetate and water, the chiral purity can be higher than 80 percent.

Example 16

Consider the impact of different solvent-resolving agent equivalents on chiral purity and final product yield.

With reference to the preparation of example 7, only the equivalent of the resolving agent is adjusted, the others remain unchanged, the purity and yield of the obtained product are given in the following table:

TABLE 2 influence of different resolving agent equivalents on product purity and yield

From the above table data, it is clear that when the resolving agent equivalent is 0.6, the chiral purity and yield of the product are in the most preferable state, and other equivalent resolving agents either resolution chiral purity is high but yield is low; or the resolution yield is high, but the chiral purity is low.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. A process for preparing a ponatinib intermediate, characterized by: the synthetic route is as follows:

Wherein Ar represents an unsubstituted or substituted C6-C14 aromatic or heteroaromatic group, said substitution being by a group selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, amide;

The synthesis steps are as follows:

Step 1, carrying out salt formation reaction on a raceme compound II and a compound IIIa or a compound IIIb serving as a resolving agent, and separating to obtain a compound IVa or a compound IVd respectively;

And 2, treating the compound IVa or the compound IVd obtained in the step 1 with alkali to obtain a compound I, namely the intermediate of the ponifinib.

2. A process for preparing a pontine intermediate according to claim 1, characterized in that: ar has a structure shown in a formula V:

Wherein R ₁、R₂、R₃、R₄、R₅ is independently hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, amido.

3. A process for preparing a intermediate of poncirtinib according to claim 2, characterized in that: ar is selected from the following groups:

Wherein represents the connection point.

4. A process for preparing a pontine intermediate according to claim 1, characterized in that: in the step 1, the molar ratio of the compound II to the compound IIIa or the compound IIIb is 1:0.3-1.5.

5. A process for preparing a pontine intermediate according to claim 1, characterized in that: in the step 1, the salification reaction is carried out in a single solvent or a mixed solvent of alcohols, ketones, esters, ethers, acetonitrile and water.

6. A process for preparing a pontine intermediate according to claim 1, characterized in that: in the step 1, the salification reaction is carried out at a temperature ranging from-10 ℃ to 90 ℃.

7. A process for preparing a pontine intermediate according to claim 1, characterized in that: in the step 2, the alkali is ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or potassium phosphate.

8. A process for preparing a pontine intermediate according to claim 1, characterized in that: the resolving agent is D-di-p-methoxybenzoyl tartaric acid VI:

。

9. A process for preparing a intermediate of poncirtinib according to claim 8, characterized in that: the D-di-p-methoxyl benzoyl tartaric acid VI and a raceme compound II react in a binary solvent system of methanol/acetonitrile to obtain diastereomeric salt of a formula VII,

Subsequently, in water, the intermediate I of the lacteib is obtained by dissociating the intermediate I by using sodium hydroxide aqueous solution,

。

10. A diastereomeric salt or a pharmaceutically acceptable salt thereof, characterized in that: the structural formula is as follows:

wherein Ar represents an unsubstituted or substituted C6-C14 aromatic or heteroaromatic group, wherein said substitution is by a group selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, and amido.