CN112920185A - Synthetic method of heterocyclic intermediate applied to JAK inhibitor drugs - Google Patents

Abstract

The present application provides a process for the preparation of a compound of formula II. The compound in the formula II can be applied to synthesis of JAK inhibitor medicines such as the lapatinib, and the like.

Description

Synthetic method of heterocyclic intermediate applied to JAK inhibitor drugs

Technical Field

The application relates to the field of drug synthesis, in particular to a preparation method of a heterocyclic synthesis JAK inhibitor intermediate.

Background

The specific pathogenesis of Rheumatoid Arthritis (RA) and psoriatic arthritis (PsA) is unknown, and the medical practice conjectures that the specific pathogenesis has an important relationship with partial defects of the immune function of patients. Rheumatoid arthritis has a long course of disease, and patients often die due to cardiovascular, infection and renal function impairment and other complications because of immune dysfunction.

JAK inhibitors are currently one of the means to effectively treat such immune system diseases. Among them, the Upadacitinib (upaactinib) is an experimental new drug for ibervin treatment of rheumatoid arthritis and psoriatic arthritis, and by means of a novel target JAK1 inhibitor, JAK1 is a kinase playing a key role in the pathophysiological processes of various inflammatory diseases, including Rheumatoid Arthritis (RA), Crohn's Disease (CD), Ulcerative Colitis (UC), psoriatic arthritis (PsA), and the like. Empowermet is also currently evaluating the potential of ipatinib for the treatment of other immune diseases, including PsA, UC and AS, and atopic dermatitis. Empatinib has been approved for marketing in the united states on 8/16 in 2019.

So far, related patent reports at home and abroad are few, and the main reported patent synthetic route is the synthetic route of original grinding albervia company (WO 2017066775):

wherein, the compound A3 is synthesized by a noble metal catalyst Pd (OAc)₂And ligand XantPhos (4, 5-bis diphenylphosphine-9, 9-dimethyl xanthene) through catalytic coupling reaction, wherein the using amount of the catalyst is about 1%, the using amount of the ligand is about 2%, and the yield is 83%.

In addition, the synthesis of the analogous compound A9 is also disclosed in CN108218873A, example 56, step 3, page 158 [1709 ]:

，

wherein, the compound A9 is synthesized by a noble metal catalyst Pd (OAc)₂And ligand XantPhos (4, 5-bis diphenylphosphine-9, 9-dimethyl xanthene) through catalytic coupling reaction, wherein the using amount of the catalyst is about 1%, the using amount of the ligand is about 2%, and the yield is 75%.

Therefore, optimizing the coupling reaction conditions and designing a route that can accomplish the reaction efficiently with low cost reagents would have positive practical significance.

Disclosure of Invention

The purpose of the application is to provide a preparation method of a compound shown in a formula II.

It is a further object of the present application to provide the use of compounds of general formula II for the synthesis of JAK inhibitor intermediates.

In one aspect, the present application provides a synthetic method for preparing a compound of formula II, compound II is prepared by a Pd-catalyzed reaction of compound I with ethyl carbamate in an organic solvent, the method comprising the steps of:

，

wherein the Pd catalyst is palladium acetate; the organic solvent is toluene.

Among them, it is emphasized that phenylsulfonyl, although a relatively inexpensive amino-protecting group, is not commonly used for p-toluenesulfonyl (Ts), p-bromophenylsulfonyl (Bs), p-nitrobenzenesulfonyl (Ns) and o-nitrobenzenesulfonyl (Nps) in the reaction. However, through the screening of sulfonyl protecting groups, the applicant unexpectedly found that the benzenesulfonyl group probably affects the electrical property of the compound I more positively due to the coordination with the triazacycle in the compound I, so that the compound I has better reactivity compared with the compounds A3 and A9 in the background introduction, and the separation yield of the product II is higher than that in the prior art.

In another aspect, the present application provides a process for preparing a compound of formula I, said process comprising the step of preparing a compound of formula I from a compound of formula III:

，

in yet another aspect, the present application provides a synthetic method for preparing a compound of formula VI, said method comprising the steps of:

firstly, synthesizing a compound V by a substitution reaction of a compound of a formula II and a compound of a formula IV:

；

II, synthesizing a compound VI by a cyclization reaction of a compound of formula V:

。

the compound VI is a JAK inhibitor sepiolite key intermediate, and can be applied to synthesis of sepiolite.

Compared with the prior art, the method for synthesizing the intermediate of the lapatinib has the following advantages:

1. the yield of the reaction is improved by 7 to 15% compared with the conventional method;

2. the preparation method is simple to operate, the process is easy for industrial scale-up production, and the phenyl sulfonyl chloride used for preparing the compound I is liquid, so that large-scale feeding is easier to complete compared with solid raw materials such as p-toluene sulfonyl chloride.

Detailed Description

Embodiments of the present application are described below by way of examples, and it should be appreciated by those skilled in the art that these specific examples merely illustrate selected embodiments for achieving the purposes of the present application and are not intended to limit the technical solutions. Modifications of the technical solutions of the present application in combination with the prior art are obvious from the teachings of the present application and fall within the protection scope of the present application.

The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.

Among them, the chemical agents used in the following examples are all commercially available chemical agents.

In the exemplary embodiments of the present invention, a person skilled in the art may also make changes to the synthetic route, such as changing specific reaction conditions or making adjustments to the synthetic route of one or more steps, etc., as needed, and such changes are within the scope of the present application without departing from the spirit of the present invention.

Example 1:

adding 5 g of the compound 1 into a 250 mL three-neck flask, adding 100 mL of THF, stirring, cooling to 0-10 ℃, adding 1.21 g of NaOH, stirring for 20-30 min, dropwise adding 5.35 g of phenylsulfonyl chloride into the three-neck flask, and continuing to react for 1 h after dropwise adding. After the reaction is finished, controlling the temperature to be 0-10 ℃, dropwise adding acetic acid to adjust the pH =7, adding 25 mL of NaCl solution, heating to 20-30 ℃, stirring, separating, collecting an organic phase, and spin-drying the organic phase at 40 ℃ to obtain a light yellow solid (compound 2).

Compound 2 nuclear magnetic data are as follows:

¹H NMR (400 MHz, DMSO): δ 8.59(s, 1H), 8.39~8.40 (d, 1 H), 8.11~8.13(d, 2 H), 7.74~7.78(t, 1H), 7.63~7.67(t, 2H), 7.03~7.04(d, 1H).

mass spectral data for compound 2: [ M + H ]]⁺ 338.1

Example 2:

to a 100 mL three-necked jacketed bottle was added 20 mL of toluene, N₂Bubbling degassing for 1.5 h, adding 2 g of compound 2, 1.06 g of ethyl carbamate, 2.45 g K₂CO₃，14 mg Pd(OAc)₂70 mg of XantPhos, system replacement of N₂And thirdly, heating to 90 ℃ for reaction for 6 hours, completely reacting, cooling to room temperature, adding 50 mL of dichloromethane, stirring at room temperature, filtering, concentrating the filtrate under reduced pressure to remove dichloromethane to obtain a crude product of the compound 3, and passing through a column to obtain 2.1 g of the compound 3 with the yield of 90%.

Compound 3 nuclear magnetic data are as follows:

¹H NMR (400 MHz, DMSO) δ 10.45(s, 1H), 8.84(s, 1H), 8.22~8.21(d, 1H), 8.11~8.10(d, 2H), 7.75~7.71(m, 1H), 7.65~7.61(m, 2H), 6.88~6.87(d, 1H), 4.18~4.13(m, 2H), 1.25~1.21(t, 3H).

mass spectral data for compound 3: [ M + H ]]⁺347.1.

Example 3:

to a 100 mL three-necked jacketed flask was added 8 mL of DMA, 1.6 g of Compound 3. Cooling to 5 ℃, adding 375 mg of lithium tert-butoxide, further cooling to below-10 ℃, dropwise adding 1.5 g of DMA solution of the compound 4, reacting at-10 to-20 ℃ for 1 h, completely reacting, adding acetic acid to quench the reaction, raising the temperature to 15 ℃, adding water, adding isopropyl acetate to extract, separating, and sequentially adding NaHCO into the organic phase₃The solution was washed twice and once. The organic phase was concentrated under reduced pressure to remove isopropyl acetate to give crude compound 5, which was passed through a column to give compound 5 in 83% yield.

Compound 5 nuclear magnetic data are as follows:

¹H NMR (400 MHz, DMSO) δ 8.82(s, 1H), δ 8.26~8.23(m, 1H), 8.14~8.12(d, 2H), 7.75~7.71(m, 1H), 7.65~7.62(m, 2H), 7.33~7.25(m, 5H), 6.82~6.71(dd, 1H), 5.07~5.02(m, 2H), 4.83(s, 2H), 4.19~4.13(m, 2H), 3.63~3.57(m, 1H), 3.51~3.38 (m, 3H), 3.20~3.16(t, 1H), 2.42(s, 1H), 1.46~1.40(m, 1H), 1.27~1.23(m, 1H), 1.19~1.16(d, 3H), 0.89~0.84(d, 3H).

mass spectral data for compound 5: [ M + H ]]⁺620.30.

Example 4:

into a 25 mL single-neck flask was added acetonitrile 5 mL, 1.6 g Compound 6, 0.35 g pyridine, 1.3 g trifluoroacetic acid dry, N₂Protecting, heating to 75 ℃, and reacting for 4 h to complete the reaction. Cooling to 50 ℃, concentrating under reduced pressure to remove acetonitrile, adding 7 mL of 2-methyltetrahydrofuran and 7 g of NaOH aqueous solution, reacting for 3.5 h at 55 ℃, reacting completely, cooling to room temperature, separating to obtain an organic phase, concentrating under reduced pressure to remove a solvent to obtain a crude product of the compound 6, and passing through a column to obtain the compound 6 with a yield of 79%.

Compound 6 nuclear magnetic data is as follows:

¹H NMR (400 MHz, DMSO) δ 12.29(s, 1H), 8.58(s, 1H), 7.58~7.57(d, 1H), 7.45~7.44(t, 1H), 7.41~7.31(m, 5H), 6.99~6.97(m, 1H), 5.76(s, 1H), 5.18~5.10(m, 2H), 4.39~4.34(m, 1H), 3.93~3.71(m, 3H), 3.36~3.29(m, 1H), 2.57~ 2.55(m, 1H), 1.09~1.03(m, 1H), 0.91~0.83(m, 1H), 0.63~0.58(m, 3H)。

mass spectral data for compound 6: [ M + H ]]⁺390.2。

Example 5:

adding 5 g of the compound 1 into a 250 mL three-neck flask, adding 100 mL of THF, stirring, cooling to 0-10 ℃, adding 1.21 g of NaOH into the three-neck flask, stirring for 20-30 min, controlling the temperature to be 0-10 ℃, dropwise adding 6.20 g of p-ethylsulfonyl chloride into the three-neck flask, and reacting for 1 h at 0-10 ℃. After the reaction is finished, controlling the temperature to be 0-10 ℃, dropwise adding acetic acid to adjust the pH =7, adding 25 ml of NaCl solution, heating to 20-30 ℃, stirring for 20 min, separating liquid, collecting an organic phase, and spin-drying the organic phase at 40 ℃ to obtain a light yellow solid (compound 7).

Compound 7 nuclear magnetic data is as follows:

¹H NMR (400 MHz, DMSO) δ 8.58(s, 1H), 8.37~8.38(d, 1H), 8.01~8.03(d, 2H), 7.45~7.47(d, 2H), 7.01~7.02(d, 1H), 2.60~2.65(q, 2H), 1.08~1.12(t, 3H).

mass spectral data for compound 7: [ M + H ]]⁺366.0。

Example 6:

to a 100 mL three-necked jacketed bottle was added 20 mL of toluene, N₂Bubbling and degassing for 1.5 h, N₂2 g of Compound 7, 1.0 g of ethyl carbamate, 2.3 g K are added with protection₂CO₃，13 mg Pd(OAc)₂63 mg XantPhos, system arrangementChange N₂And thirdly, heating to 90 ℃ for reaction for 6 hours, completely reacting, cooling to room temperature, adding 50 mL of dichloromethane, stirring at room temperature, filtering, concentrating the filtrate under reduced pressure to remove dichloromethane to obtain a crude product of the compound 8, and passing through a column to obtain 1.8 g of the compound 8 with the yield of 84%.

Compound 8 nuclear magnetic data is as follows:

¹H NMR (400 MHz, DMSO) δ 10.44(s, 1H), 8.86(s, 1H), 8.21~8.19(d, 1H), 8.01~7.99(d, 2H), 7.46~7.44(d, 2H), 6.90~6.85(d, 1H), 4.17~4.13(m, 2H), 2.65~2.59(m, 2H), 1.25~1.22(t, 3H), 1.12~1.08(t, 3H).

mass spectral data for compound 8: [ M + H ]]⁺375.1.

Example 7:

adding 8 mL of DMA (direct memory access) and 1.7 g of compound 8 into a 100 mL three-opening jacketed bottle, cooling to 5 ℃, adding 375 mg of lithium tert-butoxide, further cooling to below-10 ℃, dropwise adding 1.5 g of DMA solution of compound 4, reacting for 1 h at-10 to-20 ℃, completely reacting, adding acetic acid to quench the reaction, raising the temperature to 15 ℃, adding water, adding isopropyl acetate to extract, and sequentially adding 7.5 mL of 4% NaHCO into an organic phase₃The organic phase was washed twice and once with water. The organic phase was concentrated under reduced pressure to remove isopropyl acetate to give crude compound 9, which was passed through a column to give compound 9 in 89% yield.

Compound 9 nuclear magnetic data are as follows:

¹H NMR (400 MHz, DMSO) δ 8.79(s, 1H), 8.24~8.21(m, 1H), 8.03~8.01(d, 2H), 7.48~7.45(d, 2H), 7.33~7.31(t, 4H), 7.29~7.25(m, 1H), 6.81~6.70(dd, 1H), 5.08~5.01(m, 2H), 4.82(s, 2H), 4.19~4.13(m, 2H), 3.61~3.54(m, 1H), 3.52~3.39(m, 3H), 3.18~3.14(t, 1H), 2.66~2.60(m, 2H), 2.41~2.38(m, 1H), 1.45~1.39(m, 1H), 1.27~1.22(m, 1H), 1.20~1.0(m, 6H).

example 8:

a25 mL single neck flask was charged with acetonitrile 5 mL, 1 g Compound 9, 0.33 g pyridine, 1.3 g trifluoroacetic acid dry, N₂Protecting, heating to 75 ℃, and reacting for 4 h to complete the reaction. Cooling to 50 ℃, concentrating under reduced pressure to remove acetonitrile, adding 7 mL of 2-methyltetrahydrofuran and 7 g of NaOH aqueous solution, reacting for 3.5 h at 55 ℃, reacting completely, cooling to room temperature, separating to obtain an organic phase, concentrating under reduced pressure to remove a solvent to obtain a crude product of the compound 6, and passing through a column to obtain the compound 6 with the yield of 81%.

Mass spectral data for compound 6: [ M + H ]]⁺390.2。

Example 9:

300mL of toluene and N are added into a 500 mL three-mouth jacket bottle₂Bubbling and degassing for 1.5 h, N₂30 g of Compound 1, 15.8 g of urethane, 36.8 g of 36.8 g K were added under protection₂CO₃，199 mg Pd(OAc)₂1.03 g of XantPhos, system replacement of N₂And thirdly, heating to 90 ℃ for reaction for 6 hours, completely reacting, cooling to room temperature, adding 600 mL of dichloromethane, stirring at room temperature, filtering, leaching a filter cake with 450 mL of dichloromethane, concentrating the filtrate under reduced pressure to remove dichloromethane to obtain a crude product of the compound 2, and passing through a column to obtain 28.3 g of the compound 2 with the yield of 92%.

Compound 2 nuclear magnetic data are as follows:

¹H NMR (400 MHz, DMSO) δ 10.45(s, 1H), 8.84(s, 1H), 8.22~8.21(d, 1H), 8.11~8.10(d, 2H), 7.75~7.71(m, 1H), 7.65~7.61(m, 2H), 6.88~6.87(d, 1H), 4.18~4.13(q, 2H), 1.25~1.21(t, 3H)。

mass spectral data for compound 2: [ M + H ]]⁺347.1。

Example 10:

500 200 mL of toluene and N are added into a mL three-mouth jacket bottle₂Bubbling and degassing for 1.5 h, N₂20 g of compound 10, 10.1 g of ethyl carbamate, 23.6 g K were added under protection₂CO₃，127 mg Pd(OAc)₂657 mg XantPhos, system replacement of N₂And thirdly, heating to 90 ℃ for reaction for 6 hours, completely reacting, cooling to 50 ℃, adding 200 mL of tetrahydrofuran, stirring, filtering, leaching a filter cake with 400 mL of tetrahydrofuran, concentrating the filtrate under reduced pressure to remove the tetrahydrofuran to obtain a crude product of the compound 11, and passing through a column to obtain 17.2 g of the compound 11 with the yield of 84%.

Compound 11 nuclear magnetic data are as follows:

¹H NMR (400 MHz, DMSO) δ 10.42(s, 1H), 8.85(s, 1H), 8.20~8.19(d, 1H), 7.99~7.97(d, 2H), 7.44~7.42(d, 2H), 6.86~6.85(d, 1H), 4.20~4.14(q, 2H), 2.33(s,3H), 1.26~1.23(t, 3H)。

this application is intended to cover any variations, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.

Claims (6)

1. A synthetic process for the preparation of a compound of formula II, compound II being prepared by the Pd-catalyst catalyzed reaction of compound I with ethyl carbamate in an organic solvent, said process comprising the steps of:

。

2. the Pd catalyst as in claim 1, which is palladium acetate.

3. The organic solvent according to claim 1, which is toluene.

4. A synthetic method for preparing a compound of formula VI, compound VI being prepared from a compound II and a compound IV via a substitution and cyclization reaction, said method comprising the steps of:

。

5. a compound of formula II, said compound comprising the structure:

。

6. the use of the compounds of formula II and their related reactions as described in claims 1-5 for the synthesis of uppertib or its corresponding salts and other JAK inhibitors containing such structures.