CN118440001B - A method for synthesizing a duvelisib intermediate - Google Patents

Abstract

The invention relates to the technical field of synthesis of compounds, and particularly discloses a method for synthesizing Du Weili a siberian intermediate, which comprises the following steps: the compound 2 and dimethyl oxalate firstly undergo condensation reaction and then undergo ring closure reaction to obtain a compound 3; step (2): the compound 3 and sodium methylsulfonate undergo condensation reaction under the action of alkali to obtain a compound 4; step (3): the compound 4 and tertiary butyl sulfonamide are dehydrated after undergoing an addition reaction under the action of a catalyst to obtain a compound 5; step (4): the compound 5 and hydrogen undergo asymmetric reduction reaction under the action of a chiral catalyst to obtain a compound 6; step (5): and (3) carrying out hydrolysis reaction on the compound 6 to obtain the target compound 1. The method has the advantages that the initial raw materials and other used raw materials are low in cost and easy to obtain, the target compound 1 is prepared through five steps, and the yield of each step is high; the whole reaction process has mild condition, simple operation, low production cost, safety and environmental protection.

Description

A method for synthesizing a duvelisib intermediate

Technical Field

The present invention relates to the technical field of compound synthesis, and in particular to a method for synthesizing a duveliximab intermediate.

Background Art

Duvelisib (Formula A) is an oral kinase inhibitor targeting phosphoinositide-3-kinase (PI3K). It was developed by Verastem Pharmaceuticals in the United States. Its chemical name is 8-chloro-2-phenyl-3-[(1S)-1-(3H-purine-6-ylamino)ethyl]-1-(2H)-isoquinoline, its generic name is duvelisib, and its trade name is Copiktra. The drug is the first approved dual inhibitor of PI3Kδ and PI3Kγ. It is mainly used clinically for the treatment of adults with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory follicular lymphoma after at least two previous treatments. In March 2022, the China National Medical Products Administration also approved the marketing of duvelisib capsules, which are mainly used to treat relapsed or refractory follicular lymphoma that has undergone at least two previous systemic treatments. The structural formula of duvelisib is:

Duvelixib is synthesized by a nucleophilic substitution reaction between (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (compound 1) and 6-chloro-9-(2-tetrahydro-2H-pyran-2-yl)-9H-purine, followed by removal of the tetrahydropyran protective group. The synthetic route is:

Therefore, compound 1 is an important intermediate for the synthesis of duvelixib and is of great significance for the synthesis of duvelixib.

For the synthesis of compound 1, patent numbers US202202665637A1, WO2011146882 and CN102711767A etc. all report its synthesis method, and the synthesis route is:

The method uses L-alanine as a raw material, which is amino-protected and then reacted with Weinreb amide to obtain a Weinreb amide intermediate. The amide intermediate is condensed with 2-chloro-6-methyl-N-phenylbenzamide under the catalysis of n-butyl lithium and Grignard reagent at -78 to -50°C, and then undergoes ring closure and deprotection reactions to prepare compound 1.

The second step of the method for preparing the Weinreb amide intermediate requires the use of expensive HOBt and EDCl as condensation agents. The condensation reaction in the third step needs to be carried out at a low temperature of -78 to -50°C and under the catalysis of highly flammable n-butyl lithium and Grignard reagent. The reaction conditions are very harsh, difficult to control, and the process is unsafe. In addition, the yield of this condensation reaction is low; the stereoselectivity of the fourth step ring-closing deprotection reaction is not high, and the optical purity of the chiral amine obtained after deprotection is low (S:R=7:1), and D-tartaric acid is required for further separation. In addition, the total yield of the two-step reaction of condensation and ring-closing deprotection is low, only 9.1%. Therefore, the process for synthesizing compound 1 reported in the literature has the defects of low total yield, difficult to obtain raw materials, very harsh reaction conditions, difficult to control, unsafe process, etc., which is not conducive to industrial production.

Summary of the invention

The purpose of the present invention is to provide a method for synthesizing a duvelixibu intermediate in view of the defects of the prior art, so as to solve the problems existing in the above-mentioned background technology.

To achieve the above object, the present invention provides the following technical solution, and the specific synthesis route is as follows:

Step (1): Compound 2 and dimethyl oxalate undergo a condensation reaction and then a ring-closure reaction to obtain compound 3;

Step (2): Compound 3 reacts with sodium methanesulfinate under the action of a base to produce compound 4, wherein the base is a strong organic base;

Step (3): Compound 4 reacts with tert-butylsulfonamide in the presence of a catalyst and then undergoes dehydration to obtain Compound 5; the catalyst is a Lewis acid;

Step (4): Compound 5 undergoes an asymmetric reduction reaction with hydrogen in the presence of a chiral catalyst to obtain compound 6, wherein the chiral catalyst is a metal iridium complex;

Step (5): Compound 6 undergoes hydrolysis reaction to obtain the target compound 1.

Preferably, in step (1), in the condensation reaction, dimethyl oxalate is in excess relative to compound 2, and the reaction is refluxed in an ethanol solvent; and the base is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, sodium amide or trityl sodium.

Preferably, the reaction temperature in step (2) is 50-100° C., and the organic strong base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium amide, trityl sodium, KHMDS, NaHMDS or LiHMDS.

Preferably, in step (2), the solvent of the reaction is toluene, DMF, DMAc or ethylene glycol monomethyl ether, or a combination of the two or more thereof.

Preferably, in step (2), the molar ratio of the compound 3 to sodium methanesulfinate and the base is: compound 3: sodium methanesulfinate: base = 1.0: 1.5-3.5: 1.3-2.2.

Preferably, in step (3), the Lewis acid is selected from zinc dichloride, boron trifluoride, aluminum trichloride, and ferric chloride.

Preferably, in step (3), the reaction temperature is 60-100°C.

Preferably, in step (4), the metal iridium complex is generated in situ in the experiment by iridium acetate and a chiral ligand (R,R)-2,3-bis(tert-butylmethylphosphine)quinoxaline, and the structure of the chiral ligand is:

The amount of the chiral catalyst used is 1-5% of the amount of the compound 5.

Preferably, in step (4), the hydrogen pressure is 10 to 30 atmospheres, and the reaction temperature is 40 to 90°C.

Preferably, in step (5), the reaction temperature is 20-50°C.

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

(1) The raw materials used in this method are cheap and readily available, and the target compound 1 is prepared in five steps, with a high yield in each step;

(2) The entire reaction process is mild, simple to operate, safe and environmentally friendly;

(3) The optical purity of compound 1 prepared by this method can reach above 98%.

DETAILED DESCRIPTION

The preferred embodiments of the present invention are described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

Embodiment 1:

Synthesis of compound 3:

120mmol sodium ethoxide, 100mL ethanol and 100mmol compound 2 were added to the reaction bottle, stirred and mixed evenly, then the temperature of the reaction system was lowered to 15°C, and the reaction was stirred and kept warm for 1h. Then 110mmol dimethyl oxalate was added dropwise, and the temperature of the reaction system was raised to reflux after the addition was complete, and the reaction was stirred and kept warm for 3h. The reaction was stopped, the solvent was evaporated under reduced pressure, 100mL distilled water and 100mL ethyl acetate were added, and the mixture was allowed to stand after stirring. The water layer was separated, the water layer was washed with 60mL ethyl acetate, the organic layers were combined, and the solvent was evaporated under reduced pressure after drying to obtain a crude product.

Add 100 mL of 10M hydrochloric acid-methanol solution to the crude product, stir and dissolve, raise the temperature of the reaction system to reflux, and stir and react for 2 h. Stop the reaction, distill under reduced pressure, add 100 mL of ethyl acetate to the residue, beat at room temperature for 0.5 h, filter the precipitated solid, wash the filter cake with 100 mL of ethyl acetate three times, and dry under reduced pressure to obtain compound 3 with a yield of 85%. The structure is characterized by ¹ H NMR, ¹ HNMR (500 MHz, CDCl ₃ ) δ: 7.82 (dd, J=15.3, 14.6 Hz, 1H), 7.70-7.53 (m, 5H), 7.49-7.33 (m, 2H), 6.87 (s, 1H), 3.71 (s, 3H).

The base sodium ethoxide in the condensation reaction can be replaced by sodium methoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, sodium amide and trityl sodium.

Embodiment 2:

Synthesis of compound 4:

75mmol sodium methanesulfinate, 100mL toluene and 65mmol LiHMDS were added to a reaction flask, mixed well, and then 50mmol compound 3 was added. The temperature of the reaction system was raised to 90°C, and the reaction was stirred for 4h. The reaction was stopped, and 150mmol saturated ammonium chloride solution was added. After stirring, the water layer was separated, and the water layer was washed with 60mL toluene. The organic layers were combined, dried, and the solvent was evaporated under reduced pressure to obtain compound 4 with a yield of 67%. The compound structure was characterized by ¹ H NMR, ¹ H NMR (500MHz, CDCl ₃ )δ:7.81(t,J＝7.5Hz,1H),7.71-7.51(m,5H),7.50-7.32(m,2H),6.94(s,1H),2.19(s,3H).

Embodiment 3:

Synthesis of compound 4:

150 mmol sodium methanesulfinate, 100 mL toluene and 90 mmol LiHMDS were added to a reaction bottle, mixed evenly, and then 50 mmol compound 3 was added. The temperature of the reaction system was raised to 90° C. and stirred for 4 h. The post-treatment operation was the same as in Example 2 to obtain compound 4 with a yield of 83%.

Embodiment 4:

Synthesis of compound 4:

175 mmol sodium methanesulfinate, 100 mL toluene and 110 mmol LiHMDS were added to a reaction bottle, mixed evenly, and then 50 mmol compound 3 was added. The temperature of the reaction system was raised to 90° C. and stirred for 4 h. The post-treatment operation was the same as in Example 2 to obtain compound 4 with a yield of 84%.

On the basis of the reaction conditions of Example 3 (i.e., the molar ratio of compound 3 to sodium methanesulfinate and base is 1.0:3:1.8), the base LiHMDS in the reaction can be replaced by sodium tert-butoxide, potassium tert-butoxide, sodium amide or trityl sodium, KHMDS, NaHMDS, etc.; the temperature of the reaction system can be adjusted between 50°C and 100°C; the solvent toluene can be replaced by DMF, DMAc or ethylene glycol monomethyl ether, etc., and other reaction conditions remain unchanged. Some experimental results are shown in Table 1.

Table 1: Conditions and results for preparing compound 4 in Examples 5 to 15

Embodiment 16:

Synthesis of compound 5:

50mmol of compound 4 and 100mL of ethylene glycol monomethyl ether were added to a reaction bottle, mixed evenly, and then 55mmol of tert-butylsulfonamide and 30mmol of zinc dichloride were added. After stirring and mixing evenly, the temperature of the reaction system was raised to 100°C, and the reaction was stirred and kept warm. The reaction progress was detected by TLC. After the reaction was completed, the reaction mixture was poured into 150mL of ice water, stirred, and extracted with 200mL of ethyl acetate for 3 times. The organic layers were combined, dried, and the solvent was evaporated under reduced pressure to obtain a solid. The solid was dried under reduced pressure to obtain compound 5, with a yield of 95%. The crude solid can be directly used for the next step without purification.

Embodiment 17:

Synthesis of compound 5:

50 mmol of compound 4 and 100 mL of ethylene glycol monomethyl ether were added to a reaction bottle, mixed evenly, and then 55 mmol of tert-butylsulfonamide and 50 mmol of zinc dichloride were added. After stirring and mixing evenly, the temperature of the reaction system was raised to 100° C. and the mixture was stirred and reacted at this temperature. The reaction progress was monitored by TLC. The post-treatment operation was the same as that in Example 16 to obtain compound 5 with a yield of 96%.

On the basis of the reaction conditions of Example 16 (i.e., the molar ratio of compound 4 to tert-butylsulfonamide and Lewis acid is 1.0:1.1:0.6), the Lewis acid zinc dichloride in the reaction can be replaced by boron trifluoride, aluminum trichloride, ferric chloride, etc.; the temperature of the reaction system can be adjusted between 60°C and 100°C, and the other reaction conditions remain unchanged. Some experimental results are shown in Table 2.

Table 2: Conditions and results for preparing compound 5 in Examples 18 to 22

Embodiment 23:

Synthesis of compound 6:

Under _N2 protection, 50mmol of compound 5 and 100mL of toluene were added to the reactor, stirred and mixed evenly, and then 0.5mmol of iridium acetate and 0.5mmol of (R,R)-2,3-bis(tert-butylmethylphosphine)quinoxaline were added. After hydrogen replacement 3 times, hydrogen was introduced to 20 atmospheres, the temperature was raised to 80°C, and the mixture was stirred and reacted for 10 hours. Hydrogen was slowly released, cooled, filtered, and the filtrate was washed once with 100mL of saturated ammonium chloride and 100mL of brine, the organic phase was separated, dried, and the solvent was evaporated under reduced pressure to obtain a crude solid. 50mL of ethyl acetate and 150mL of petroleum ether were added to the crude solid for pulping, and the precipitated solid was filtered and dried to obtain compound 6 with a yield of 82% and an ee value of 92.7%. The structure of the compound was confirmed by MS and ^1H NMR. ESI-LRMS m/z: 419.3[M+H] ⁺ , ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.88-7.51 (m, 4H), 7.50-7.39 (m, 2H), 7.38-7.27 (m, 2H), 6.36 (d, J = 2.0Hz, 1H), 5.13 (dd, J = 12.1, 1. 9Hz, 1H), 4.87 (s, 1H), 1.47 (s, 9H), 1.24 (d, J = 12.2Hz, 3H).

Embodiment 24:

Synthesis of compound 6:

Under _N2 protection, 50mmol of compound 5 and 100mL of toluene were added to the reactor, stirred and mixed evenly, and then 1.5mmol of iridium acetate and 1.5mmol of (R,R)-2,3-bis(tert-butylmethylphosphine)quinoxaline were added. After hydrogen replacement for 3 times, hydrogen was introduced to 20 atmospheres, the temperature was raised to 80°C, and the reaction was stirred for 10h. The post-treatment operation was the same as that in Example 23 to obtain compound 6 with a yield of 90% and an ee value of 96.4%.

Embodiment 25:

Synthesis of compound 6:

Under _N2 protection, 50 mmol of compound 5 prepared in Example 16 and 100 mL of toluene were added to the reaction kettle, stirred and mixed evenly, and then 2.5 mmol of iridium acetate and 2.5 mmol of (R, R)-2,3-bis(tert-butylmethylphosphine)quinoxaline were added. After hydrogen replacement 3 times, hydrogen was introduced to 20 atmospheres, the temperature was raised to 80°C, and the reaction was stirred and kept warm for 10 hours. The post-treatment operation was the same as in Example 23 to obtain compound 6 with a yield of 93% and an ee value of 98.2%.

Based on the reaction conditions of Example 25 (the amount of chiral catalyst is 5% of compound 5), the temperature of the reaction system can be adjusted between 40°C and 90°C, the hydrogen pressure can be adjusted between 10 and 30 atmospheres, and other reaction conditions remain unchanged. Some experimental results are shown in Table 3.

Table 3: Conditions and results for preparing compound 6 in Examples 26 to 30

Serial number Temperature/℃ Hydrogen pressure/atmospheric pressure Yield/% ee value/% Embodiment 26 40 20 58 98.1 Embodiment 27 60 20 83 97.5 Embodiment 28 90 20 89 98.6 Embodiment 29 80 10 86 96.1 Embodiment 30 80 30 93 97.8

Embodiment 31:

Synthesis of compound 1:

Under _N2 protection, 50mmol of compound 6 prepared in Example 25 and 100mL of tetrahydrofuran were added to the reaction bottle, stirred and mixed evenly, and then 100mmol of aluminum chloride was added. The temperature of the reaction system was raised to 40°C, and the reaction was stirred and kept warm. The reaction progress was detected by TLC. After the reaction was completed, the reaction mixture was poured into 150mL of ice water, stirred, extracted with 200mL of ethyl acetate for 3 times, the organic layers were combined, ammonia water was added, the pH was adjusted to 8-9, the organic phase was separated, the aqueous phase was extracted with 50mL of ethyl acetate for 2 times, the organic layers were combined, dried, and the solvent was evaporated under reduced pressure to obtain a crude solid. 20mL of isopropanol, 30mL of ethyl acetate and 200mL of petroleum ether were added to the crude solid for pulping, the precipitated solid was filtered, and the compound 1 was obtained after drying with a yield of 93% and an ee value of 98.9%. The structure of the compound was confirmed by MS and ^1H NMR. ESI-LRMS m/z:299.1[M+H] ⁺ , ¹ H NMR (500MHz, CDCl ₃ )δ:7.79-7.52(m,4H),7.50-7.37(m,2H),7.29～7.18(m,2H),6.56(d,J＝2.0Hz,1H),4.68(q,J＝12.3,1 H), 1.95 (s, 1H), 1.61 (s, 1H), 1.24 (d, J = 12.2Hz, 3H).

Embodiment 32:

Synthesis of compound 1:

Under _N2 protection, 50 mmol of compound 6 prepared in Example 25 and 100 mL of tetrahydrofuran were added to a reaction flask. After stirring and mixing, 100 mmol of aluminum chloride was added. The temperature of the reaction system was adjusted to 20°C, and the reaction was stirred and maintained. The reaction progress was monitored by TLC. The post-treatment operation was the same as that in Example 31 to obtain compound 1 with a yield of 79% and an ee value of 98.5%.

Embodiment 33:

Synthesis of compound 1:

Under _N2 protection, 50 mmol of compound 6 prepared in Example 25 and 100 mL of tetrahydrofuran were added to a reaction flask. After stirring and mixing evenly, 100 mmol of aluminum chloride was added. The temperature of the reaction system was raised to 50°C, and the reaction was stirred and maintained. The progress of the reaction was monitored by TLC. The post-treatment operation was the same as that in Example 31 to obtain compound 1 with a yield of 92% and an ee value of 98.1%.

The above embodiments only express the implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention.

Claims (9)

1. A method for synthesizing Du Weili siberian intermediate is characterized in that: the specific synthetic route is as follows:

The method comprises the following specific steps:

Step (1): the compound 2 and dimethyl oxalate firstly undergo condensation reaction and then undergo ring closure reaction to obtain a compound 3;

Step (2): the compound 3 and sodium methylsulfinate undergo condensation reaction under the action of organic strong base, so as to obtain a compound 4, wherein the organic strong base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium amide, sodium trityl, KHMDS, naHMDS or LiHMDS;

step (3): the compound 4 and tertiary butyl sulfonamide are dehydrated after undergoing an addition reaction under the action of Lewis acid, so as to obtain a compound 5, wherein the Lewis acid is selected from zinc dichloride, boron trifluoride, aluminum trichloride or ferric trichloride;

Step (4): the compound 5 and hydrogen are subjected to asymmetric reduction reaction under the action of chiral metal iridium complex to obtain a compound 6, wherein the chiral metal iridium complex is generated in situ in experiments by iridium acetate and chiral ligand (R, R) -2, 3-bis (tert-butyl methylphosphine) quinoxaline;

Step (5): and (3) carrying out hydrolysis reaction on the compound 6 to obtain the target compound 1.

2. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein: in the step (1), in the condensation reaction, dimethyl oxalate is in excess relative to the compound 2, and the reaction is performed under reflux in an ethanol solvent; the alkali is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydride, sodium amide or sodium trityl.

3. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein:

The reaction temperature in the step (2) is 50-100 ℃.

4. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein:

in the step (2), the reaction solvent is one or a combination of more of toluene, DMF, DMAc or ethylene glycol monomethyl ether.

5. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein:

In the step (2), the ratio of the amount of the compound 3 to the sodium methylsulfinate and the organic strong base is as follows: the compound 3:sodium methylsulfinate and organic alkali=1.0:1.5-3.5:1.3-2.2.

6. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein:

in the step (3), the reaction temperature is 60-100 ℃.

7. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein:

In the step (4), the dosage of the chiral iridium complex is 1-5% of the amount of the compound 5.

8. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein:

in the step (4), the hydrogen gas pressure is 10-30 atmospheres, and the reaction temperature is 40-90 ℃.

9. The method for synthesizing Du Weili siberian intermediate according to claim 1, wherein:

in the step (5), the reaction temperature is 20-50 ℃.