Preparation method of Lenapavir intermediate

Abstract

The invention provides a preparation method of a Lenapavir intermediate and a preparation method of the Lenapavir intermediate. Specifically, the invention provides a preparation method of a compound as shown in a formula I. The preparation method comprises the following steps: in a first solvent, in the presence of a metal reagent, a compound as shown in a formula II and a compound as shown in a formula III react to obtain a reaction solution containing the compound I, acid is added to adjust the pH value to 2-6, an organic phase is separated and concentrated to obtain a crude product of the compound as shown in the formula I. The metal reagent is selected from LiX, CuX, CuX2, MgX2 or a combination of LiX, CuX, CuX2 and MgX2, and each X is independently selected from Cl or Br. Experiments prove that the method disclosed by the invention can effectively reduce the content of the isomer, so that the yield is improved, and the cost is reduced. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical synthesis, and specifically relates to a method for preparing a Lenacapavir intermediate (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfenamide. Background Art

[0002] Lenacapavir is a long-acting HIV capsid inhibitor developed by Gilead. It has been approved for marketing in the European Union and the United States in 2022 for use in combination with other antiretroviral drugs (ARV) to treat adult patients infected with multidrug-resistant (MDR) human immunodeficiency virus (HIV). Lenacapavir has a multi-stage mechanism of action that distinguishes it from other currently approved classes of antiviral drugs, and has shown no known cross-resistance with other existing drug classes in vitro. It is the world's only approved long-acting HIV treatment regimen that only requires twice-yearly dosing, bringing hope to the goal of "ending the AIDS epidemic."

[0003] (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (compound of formula I) is an intermediate of Lenacapavir, which is prepared by nucleophilic addition reaction of compound II and compound III. Compound I is desulfinylated under acidic conditions to further obtain (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl-1-amine (compound of formula IV), an important intermediate of Lenacapavir.

[0004]

[0005] In WO2018035359A1, a THF solution of compound III is added dropwise to compound II at a temperature of 8°C to obtain a mixture of compound I and its isomers, which is directly used in the next step, and the isomers are separated by column chromatography in the subsequent step.

[0006] In patent EP2943481B1, a THF solution of compound III is added dropwise to a dichloromethane solution of compound II and Cu(OTf)2 at 0°C. After the reaction, two isomers are obtained in a ratio of 1:3. Compound I with a single configuration is obtained by purification by column chromatography.

[0007] The isomer content of compound I obtained by the existing process is high. The ratio of compound I and its isomers obtained by the WO2018035359A1 process is 1.3:1, and the ratio of compound I and its isomers obtained by the patent EP2943481B1 process is 3:1. The excessively high isomer content not only causes waste of materials and reduces the yield, but also increases the burden of post-processing. In addition, the current processes are all purified by column chromatography, which is not suitable for industrial production.

[0008] In view of the shortcomings of the current process, it is necessary to study and develop a synthesis process for the compound of formula I with high stereoselectivity and simple purification method. Summary of the invention

[0009] The invention aims to provide a method for preparing a Lenacapavir intermediate (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfenamide (compound of formula I) which has high reaction stereoselectivity, simple post-treatment, high reaction yield and high product purity.

[0010] In a first aspect, the present invention provides a method for preparing a compound of formula I, comprising the steps of: reacting a compound of formula II with a compound of formula III in a first solvent in the presence of a metal reagent to obtain a reaction solution containing compound I, adding an acid to adjust the pH to 2 to 6, separating and concentrating the organic phase to obtain a crude product of the compound of formula I.

[0011]

[0012] Wherein, the metal reagent is selected from LiX, CuX, CuX2, MgX2, or a combination thereof, wherein each X is independently selected from Cl or Br.

[0013] In another preferred embodiment, the metal reagent is selected from CuCl, CuCl2, LiCl, LiBr, MgCl2, LiOAc, or a combination thereof, preferably CuCl, CuCl2 or LiCl.

[0014] In another preferred embodiment, the molar ratio of compound II to compound III is 1:(1-2), preferably 1:(1.3-1.6), and more preferably 1:1.5.

[0015] In another preferred embodiment, the molar ratio of the metal reagent to compound II is (0.1-3):1, preferably (1.5-2.5):1, and more preferably 2:1.

[0016] In another preferred embodiment, the compound of formula III is added to the reaction system by dropwise addition (such as dissolving in THF).

[0017] In another preferred embodiment, the first solvent is selected from: tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, C2-C8 ether solvents, C1-C6 alkane solvents, or a combination thereof.

[0018] In another preferred embodiment, the first solvent is selected from the following group: tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, or a combination thereof.

[0019] In another preferred embodiment, the first solvent is a mixed solvent of N,N-dimethylformamide and tetrahydrofuran.

[0020] In another preferred embodiment, the above reaction is carried out at -10 to 20°C, preferably 0 to 15°C, more preferably 4 to 10°C.

[0021] In another preferred embodiment, the method is carried out under the protection of an inert gas.

[0022] In another preferred embodiment, the acid is added in the form of an aqueous solution.

[0023] In another preferred embodiment, the acid is selected from AcOH, NH4Cl, HCl, HBr, HI or H2SO4.

[0024] In another preferred embodiment, the pH is adjusted to 3-5.

[0025] In another preferred embodiment, in the crude product of the compound of formula I, the enantiomeric excess ee% of the compound of formula I is ≥75%, preferably ≥78% or ≥80%.

[0026] In another preferred embodiment, in the crude product of the compound of formula I, the molar ratio of the compound of formula I to its chiral isomer is greater than 6:1, such as (7-11):1, preferably, (8-10):1.

[0027] The second aspect of the present invention provides a method for preparing a key intermediate compound of Lenacapavir, formula IV, comprising the following steps:

[0028] (S1) in a first solvent, in the presence of a metal reagent, reacting a compound of formula II with a compound of formula III to obtain a reaction solution containing compound I, adding an acid to adjust the pH to 2-6, separating and concentrating the organic phase to obtain a crude product of compound I, wherein the metal reagent is selected from LiX, CuX, CuX2, MgX2, or a combination thereof, wherein each X is independently selected from Cl or Br;

[0029] (S2) adding the crude product of the compound of formula I obtained in step (S1) to a second solvent, adding an acid to react to obtain a reaction solution containing compound IV, and filtering to obtain a crude product of compound IV; and

[0030] (S3) Adding the crude product of compound IV obtained in (S2) above to a third solvent, adding a chiral acid and crystallizing to obtain an acid addition salt of compound IV

[0031]

[0032] In another preferred embodiment, the metal reagent in (S1) is selected from CuCl, CuCl2, LiCl, LiBr, MgCl2, LiOAc, preferably CuCl, CuCl2, LiCl.

[0033] In another preferred embodiment, the molar ratio of compound II to compound III in (S1) is 1:(1-2), preferably 1:(1.3-1.6), and more preferably 1:1.5.

[0034] In another preferred embodiment, the molar ratio of the metal reagent to compound II in (S1) is (0.1-3):1, preferably (1.5-2.5):1, and more preferably 2:1.

[0035] In another preferred embodiment, the compound of formula III in (S1) is added to the reaction system by dropwise addition (such as dissolved in THF).

[0036] In another preferred embodiment, the first solvent in (S1) is selected from: tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, C2-C8 ether solvents, C1-C6 alkane solvents, or a combination thereof.

[0037] In another preferred embodiment, the first solvent in (S1) is selected from the following group: tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, or a combination thereof.

[0038] In another preferred embodiment, the first solvent in (S1) is a mixed solvent of N,N-dimethylformamide and tetrahydrofuran.

[0039] In another preferred embodiment, the reaction in (S1) is carried out at -10 to 20°C, preferably 0 to 15°C, more preferably 4 to 10°C.

[0040] In another preferred embodiment, the method described in (S1) is carried out under the protection of an inert gas.

[0041] In another preferred embodiment, the acid in (S1) is added in the form of an aqueous solution.

[0042] In another preferred embodiment, the acid in (S1) is selected from AcOH, NH4Cl, HCl, HBr, HI, H2SO4.

[0043] In another preferred embodiment, the pH in (S1) is adjusted to 3-5.

[0044] In another preferred embodiment, in the crude product of the compound of formula I, the enantiomeric excess ee% of the compound of formula I is ≥75%, preferably ≥78% or ≥80%.

[0045] In another preferred embodiment, in the crude product of the compound of formula I, the molar ratio of the compound of formula I to its chiral isomer is greater than 6:1, such as (7-11):1, preferably, (8-10):1.

[0046] In another preferred embodiment, the second solvent in (S2) is selected from C2-C8 ether solvents, C1-C6 alcohol solvents, acetonitrile, or a combination thereof.

[0047] In another preferred embodiment, the C2-C8 ether solvent is selected from the following group: methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, preferably, methyl tert-butyl ether.

[0048] In another preferred embodiment, the C1-C6 alcohol solvent is selected from methanol, ethanol and isopropanol.

[0049] In another preferred embodiment, the acid in (S2) is selected from HCl, HBr, HI, H2SO4; preferably, HCl.

[0050] In another preferred embodiment, the third solvent in (S3) is selected from C2-C8 ether solvents, C1-C6 alkane solvents, C6-C 10 Aromatic hydrocarbon solvents, or combinations thereof.

[0051] In another preferred embodiment, the C2-C8 ether solvent is selected from the following group: methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, preferably, methyl tert-butyl ether.

[0052] In another preferred embodiment, the C6-C 10 The aromatic hydrocarbon solvent is toluene.

[0053] In another preferred embodiment, the chiral acid in (S3) is selected from mandelic acid, mandelic acid derivatives, tartaric acid, malic acid, camphoric acid, preferably R-mandelic acid.

[0054] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1The high performance liquid chromatogram (HPLC) of the reaction solution of compound I prepared in Example 1 is shown.

[0056] Figure 2 The high performance liquid chromatography (HPLC) of compound IV prepared in Example 1 is shown.

[0057] Figure 3 The high performance liquid chromatography (HPLC) of isomer detection of compound IV prepared in Example 1 is shown.

[0058] Figure 4 The high performance liquid chromatogram (HPLC) of the reaction solution of compound I prepared in Example 2 is shown.

[0059] Figure 5 The high performance liquid chromatogram (HPLC) of the reaction solution of compound I prepared in the comparative example is shown.

[0060] Figure 6 The high performance liquid chromatography (HPLC) of isomer detection of compound IV prepared in the comparative example is shown. DETAILED DESCRIPTION

[0061] The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, provided a method for preparing a key intermediate of Lenacapavir, in which the stereoselectivity of the reaction is unexpectedly improved by carrying out the reaction in the presence of a specific metal salt reagent (such as CuCl, CuCl2, LiCl, LiBr, etc.), thereby greatly reducing the content of isomeric impurities. The present invention was completed on this basis.

[0062] the term

[0063] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0064] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0065] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0066] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0067] The main advantages of the present invention include:

[0068] (1) The method of the present invention can effectively reduce the content of isomers, and the ratio of compound I to its isomers is increased from the original 1.3:1 to about 10:1, and the yield of compound IV is increased from the original 35.6% to 81.84% (based on compound II), thereby further improving production efficiency and reducing costs.

[0069] (2) The product of the present invention can be purified by chiral acid to obtain compound IV, which is more industrially advantageous than column chromatography in the original process.

[0070] The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0071]

[0072] Example 1

[0073] Preparation of compound III:

[0074] In a 25mL four-necked bottle, add 0.36g zinc powder, replace the argon atmosphere three times, add 2mL THF and a small amount of iodine, stir,

[0075] Add 0.04 g 3,5-difluorobenzyl bromide, then heat up to initiate the reaction; after initiation, dropwise add 0.80 g 3,5-difluorobenzyl bromide dissolved in 6 mL THF; after the dropwise addition, heat up to 45-50° C. for reaction, and cool down after the reaction is completed for later use.

[0076] Preparation of Compound I:

[0077] In a 25mL four-necked bottle, 0.14g LiCl and 1.00g compound II were added, and 4mL DMF was added. The argon gas was replaced three times, and the temperature was lowered to 8°C. The compound III prepared above was added dropwise. After the addition was completed, the reaction was carried out at 7-9°C. After the reaction was completed, HPLC detection showed that the content of compound I was 79.78%, and the content of its isomer was 8.77%. Its HPLC spectrum is shown as follows Figure 1 shown.

[0078] 10 mL of 5% AcOH aqueous solution was added dropwise to the reaction solution at 7-9°C, and then 5 mL of cyclopentyl methyl ether was added for separation. The organic phase was washed with 5 mL of 5% AcOH aqueous solution, 5 mL of 0.5 M NaOH aqueous solution, and 5 mL of 20% NaCl in sequence, dried over anhydrous sodium sulfate, and the organic phase was directly used in the next reaction after being spin-dried.

[0079] Preparation of compound IV:

[0080] To the crude product of compound I obtained in the previous step, add 7 mL of cyclopentyl methyl ether and 3 mL of acetonitrile, and then dropwise add concentrated HCl (37%, 0.2 mL). After the dropwise addition, stir for 0.5 h and filter to obtain a crude product of compound IV.

[0081] Add 3 mL of toluene and 7 mL of methyl tert-butyl ether to the above crude product, heat to 50-55°C to dissolve, add 0.43 g of R-mandelic acid, slowly cool to crystallize after 0.5 h, filter at low temperature to obtain 1.21 g of R-mandelate salt of compound IV, with a yield of 81.84% (based on compound II). HPLC detection showed that its purity was 99.77% and the isomer content was ND. Its HPLC spectrum is as follows Figure 2 As shown, the HPLC spectrum of its isomer detection is as follows Figure 3 shown.

[0082] Example 2

[0083] Preparation of compound III:

[0084] In a 25mL four-necked bottle, add 0.36g zinc powder, replace the argon atmosphere three times, add 2mL THF and a small amount of iodine, stir,

[0085] Add 0.04 g of 3,5-difluorobenzyl bromide, then heat up to initiate the reaction; after initiation, dropwise add 0.80 g of 3,5-difluorobenzyl bromide dissolved in 6 mL of THF; after the addition, heat up to 45-50° C. for reaction, and cool down after the reaction is completed for later use.

[0086] Preparation of Compound I:

[0087] In a 25mL four-necked bottle, 0.41g CuCl and 1.00g compound II were added, and 4mL DMF was added. The argon gas was replaced three times, and the temperature was lowered to 0°C. The compound III prepared above was added dropwise. After the addition was completed, the reaction was carried out at -1 to 1°C. After the reaction was completed, HPLC detection showed that the content of compound I was 81.08%, and the content of its isomer was 9.44%. Its HPLC spectrum is shown as follows Figure 4 shown.

[0088] Comparative Example:

[0089] Preparation of compound III:

[0090] In a 25mL four-necked bottle, add 0.36g zinc powder, replace the argon atmosphere three times, add 2mL THF and a small amount of iodine, stir,

[0091] Add 0.04 g 3,5-difluorobenzyl bromide, then heat up to initiate the reaction; after initiation, dropwise add 0.80 g 3,5-difluorobenzyl bromide dissolved in 6 mL THF; after the dropwise addition, heat up to 45-50° C. for reaction, and cool down after the reaction is completed for later use.

[0092] Preparation of Compound I:

[0093] In a 25mL four-necked bottle, 1.00g of compound II and 4mL of DMF were added, the argon gas was replaced three times, the temperature was lowered to 8°C, and the compound III prepared above was added dropwise. After the addition was completed, the reaction was carried out at 0-10°C. After the reaction was completed, HPLC detection showed that the content of compound I was 42.56%, and the content of its isomer was 31.89%. Its HPLC spectrum is shown as follows Figure 5 shown.

[0094] 10 mL of 5% AcOH aqueous solution was added dropwise to the reaction solution at 7-9°C, and then 5 mL of cyclopentyl methyl ether was added for separation. The organic phase was washed with 5 mL of 5% AcOH aqueous solution, 5 mL of 0.5 M NaOH aqueous solution, and 5 mL of 20% NaCl in sequence, dried over anhydrous sodium sulfate, and the organic phase was directly used in the next reaction after being spin-dried.

[0095] Preparation of compound IV:

[0096] To the crude product of compound I obtained in the previous step, add 7 mL of cyclopentyl methyl ether and 3 mL of acetonitrile, and then dropwise add concentrated HCl (37%, 0.2 mL). After the dropwise addition, stir for 0.5 h and filter to obtain a crude product of compound IV.

[0097] 3 mL of toluene and 7 mL of methyl tert-butyl ether were added to the crude product, the temperature was raised to 50-55°C to dissolve, 0.43 g of R-mandelic acid was added, the temperature was slowly lowered to crystallize after 0.5 h, and 0.53 g of R-mandelic acid salt of compound IV was obtained by low temperature filtration, with a yield of 35.6% (based on compound II). The isomer content was 29.01% as determined by HPLC, and the HPLC spectrum of the isomer detection was as follows: Figure 6 shown.

[0098] It can be seen from the above that the method of the present invention can significantly improve the stereoselectivity of the reaction and is very suitable for large-scale preparation of compound I and compound IV.

[0099] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a compound of formula I, characterized in that: The method comprises the following steps: reacting a compound of formula II with a compound of formula III in a first solvent in the presence of a metal reagent to obtain a reaction solution containing compound I, adding an acid to adjust the pH to 2 to 6, separating and concentrating the organic phase to obtain a crude product of compound I; Wherein, the metal reagent is selected from LiX, CuX, CuX2, MgX2, or a combination thereof, wherein each X is independently selected from Cl or Br.

2. The method according to claim 1, characterized in that The metal reagent is selected from CuCl, CuCl2, LiCl, LiBr, MgCl2, LiOAc, or a combination thereof, preferably CuCl, CuCl2 or LiCl.

3. The method according to claim 1, characterized in that The method has one or more technical features selected from the following group: The molar ratio of compound II to compound III is 1:(1-2), preferably 1:(1.3-1.6), more preferably 1:1.5; The molar ratio of the metal reagent to compound II is (0.1-3):1, preferably (1.5-2.5):1, more preferably 2:1; The compound of formula III is added to the reaction system by dropwise addition; The first solvent is selected from tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, C2-C8 ether solvents, C1-C6 alkane solvents, or a combination thereof; The reaction is carried out at -10 to 20°C, preferably 0 to 15°C, more preferably 4 to 10°C; The reaction is carried out under the protection of an inert gas; The acid is added in the form of an aqueous solution; The acid is selected from AcOH, NH4Cl, HCl, HBr, HI or H2SO4; Adjust pH to 3-5; and / or The molar ratio of the compound of formula I to its chiral isomer is greater than 6:1, such as (7-11):1, preferably, (8-10):

1.

4. The method according to claim 1, characterized in that The first solvent is selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, or a combination thereof.

5. The method according to claim 1, characterized in that The first solvent is a mixed solvent of N,N-dimethylformamide and tetrahydrofuran.

6. A method for preparing a key intermediate compound of formula IV of Lenacapavir, comprising the following steps: (S1) in a first solvent, in the presence of a metal reagent, reacting a compound of formula II with a compound of formula III to obtain a reaction solution containing compound I, adding an acid to adjust the pH to 2 to 6, separating and concentrating the organic phase to obtain a crude product of the compound of formula I, wherein the metal reagent is selected from LiX, CuX, CuX2, MgX2, or a combination thereof, wherein each X is independently selected from Cl or Br; (S2) adding the crude product of the compound of formula I obtained in step (S1) to a second solvent, adding an acid to react to obtain a reaction solution containing compound IV, and filtering to obtain a crude product of compound IV; and (S3) Adding the crude product of compound IV obtained in (S2) above to a third solvent, adding a chiral acid and crystallizing to obtain an acid addition salt of compound IV 7. The method according to claim 6, characterized in that The metal reagent in (S1) is selected from CuCl, CuCl2, LiCl, LiBr, MgCl2, LiOAc, preferably CuCl, CuCl2, LiCl.

8. The method according to claim 6, characterized in that Step (S1) has one or more technical features selected from the following group: The molar ratio of compound II to compound III in (S1) is 1:(1-2), preferably 1:(1.3-1.6), more preferably 1:1.5; The molar ratio of the metal reagent to compound II in (S1) is (0.1-3):1, preferably (1.5-2.5):1, more preferably 2:1; The compound of formula III described in (S1) is added dropwise into the reaction system; (S1) wherein the first solvent is selected from tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, C2-C8 ether solvents, C1-C6 alkane solvents, or a combination thereof; The reaction in (S1) is carried out at -10 to 20°C, preferably 0 to 15°C, more preferably 4 to 10°C; The method described in (S1) is carried out under the protection of an inert gas; (S1) wherein the acid is added in the form of an aqueous solution; The acid in (S1) is selected from AcOH, NH4Cl, HCl, HBr, HI, H2SO4; (S1) adjusting the pH to 3-5; and / or The molar ratio of the compound of formula I to its chiral isomer is greater than 6:1, such as (7-11):1, preferably, (8-10):

1.

9. The method according to claim 6, characterized in that Step (S2) has one or more technical features selected from the following group: (S2) wherein the second solvent is selected from a C2-C8 ether solvent, a C1-C6 alcohol solvent, acetonitrile, or a combination thereof; The acid in (S2) is selected from HCl, HBr, HI, H2SO4; preferably, HCl.

10. The method according to claim 6, characterized in that Step (S3) has one or more technical features selected from the group consisting of: The third solvent in (S3) is selected from C2-C8 ether solvents, C1-C6 alkane solvents, C6-C 10 Aromatic hydrocarbon solvents, or combinations thereof; The chiral acid in (S3) is selected from mandelic acid, mandelic acid derivatives, tartaric acid, malic acid, camphoric acid, preferably R-mandelic acid.

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