Preparation method of XZ426

Abstract

The invention belongs to the technical field of compound synthesis, and discloses a preparation method of a compound XZ426, which comprises the following steps: step (8): in an organic solvent, carrying out hydrogenation reaction on a compound shown in a formula 12 under the action of a catalyst to obtain a compound shown in a formula 13; (9) under the action of an acid reagent, performing deprotection on the compound shown in the formula 13 to obtain XZ426; the reaction formula is shown as follows: # imgabs 0 #, and R is selected from 2, 3-dimethoxy benzyl, 2, 4-dimethoxy benzyl, 2, 5-dimethoxy benzyl, 2, 6-dimethoxy benzyl, 3, 4-dimethoxy benzyl, 3, 5-dimethoxy benzyl or 4-methoxy benzyl, preferably 2, 4-dimethoxy benzyl or 4-methoxy benzyl. The synthesis method provided by the invention is mild in reaction condition, simple and convenient to operate, environment-friendly, high in reaction yield, high in purity and suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of compound synthesis, and in particular to a method for preparing XZ426, an effective integrase strand transfer inhibitor with anti-HIV activity. Background Art

[0002] XZ426 is a potent integrase strand transfer inhibitor with anti-HIV activity, and its chemical structure is shown below;

[0003]

[0004] The prior art WO2014186398A1 discloses a method for preparing XZ426, which uses microwave reaction and is not suitable for large-scale production; the coupling reaction uses a sealed tube, which is dangerous and difficult to detect; the last two steps use the method of first deprotecting the group and then hydrogenating, and the parent nucleus has a serious problem of over-reduction.

[0005] In view of the above problems, the present invention optimizes and improves the experimental reaction device in the synthesis route, eliminates the use of sealed tube reaction, and improves the safety of the experiment; in the optimization and improvement of the post-reaction treatment, the yield is effectively improved, the various energy consumptions such as solvents are reduced, and the reaction scale is increased; for the situation where the hydrogenation reaction leads to excessive reduction of the parent nucleus, the method of first hydrogenation and then deprotection is creatively adopted to reduce the generation of impurities and improve the reaction yield. The synthesis method has the advantages of simple operation, avoidance of complex separation and purification, high yield, low energy consumption, etc. Summary of the invention

[0006] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing XZ426 with mild reaction conditions, high yield, environmental protection and high purity.

[0007] The first aspect of the present invention provides a method for preparing XZ426, which comprises the following steps:

[0008] Step (8): In an organic solvent, the compound of formula 12 undergoes a hydrogenation reaction in the presence of a catalyst to obtain a compound of formula 13;

[0009] Step (9): deprotecting the compound of formula 13 in the presence of an acid reagent to obtain XZ426;

[0010] The reaction formula is as follows:

[0011]

[0012] Wherein, the R is selected from 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl or 4-methoxybenzyl, preferably 2,4-dimethoxybenzyl or 4-methoxybenzyl.

[0013] In some embodiments of the present invention, the mass ratio of the compound of formula 12 in step (8) to the catalyst is (10-3):1, for example, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1.

[0014] In some embodiments of the present invention, the catalyst in step (8) is selected from Pd / C or Pd(OH) 2 / C.

[0015] In some embodiments of the present invention, the organic solvent in step (8) is selected from one or more of alcohols, esters, ethers or sulfoxides.

[0016] In some embodiments of the present invention, the organic solvent in step (8) is a mixed solvent, and the mixed solvent is alcohols and esters, alcohols and ethers, or alcohols and sulfoxides.

[0017] In some embodiments of the present invention, the alcohol in step (8) is selected from methanol and ethanol, the ester is selected from ethyl acetate, the ether is selected from tetrahydrofuran, and the sulfoxide is selected from DMSO.

[0018] In some embodiments of the present invention, the organic solvent in step (8) is a mixed solvent of alcohols and esters; preferably, the volume ratio of the alcohols and esters is (10-2):1, and more preferably, the alcohol is selected from methanol, and the ester is selected from ethyl acetate, and the volume ratio is 3:1.

[0019] In some embodiments of the present invention, the reaction temperature of step (8) is 10-50°C, preferably 10-35°C, such as 20-35°C.

[0020] In some embodiments of the present invention, the reaction time of step (8) is 1 to 10 hours, preferably 2 to 6 hours.

[0021] In some embodiments of the present invention, the acid reagent in step (9) is selected from trifluoroacetic acid or hydrochloric acid.

[0022] In some embodiments of the present invention, the mass volume ratio g:mL of the compound of formula 13 in step (9) to the acid reagent is 1:(1-5), preferably 1:(1-3), and more preferably 1:1.6.

[0023] In some embodiments of the present invention, the step (9) is further performed in the presence of an organic solvent to further deprotect the XZ426; the organic solvent is selected from one or more of alcohols, esters, ethers, halogenated alkanes or sulfoxides; preferably one or more of methanol, ethyl ester, ethanol, ethyl acetate, DMSO or dichloromethane; more preferably dichloromethane or methanol.

[0024] In some embodiments of the present invention, the mass volume ratio g:mL of the compound of formula 13 to the organic solvent in step (9) is 1:(5-50), preferably 1:(15-35).

[0025] In some embodiments of the present invention, a base is added in step (9) to maintain alkalinity, and the base is an organic base or an inorganic base, such as triethylamine, K 2 CO 3 Or Na 2 CO 3 .

[0026] In some embodiments of the present invention, the reaction temperature of step (9) is 10-30°C, preferably 10-25°C.

[0027] In some embodiments of the present invention, the reaction time of step (9) is 1 to 10 hours, preferably 2 to 5 hours.

[0028] In some embodiments of the present invention, the step (9) optionally includes a post-processing purification step, such as filtration, concentration, reverse phase preparation, etc.

[0029] In other embodiments of the present invention, the preparation method of the compound of formula 12 can be prepared by referring to the similar method disclosed in WO2014186398A1, and the reaction formula thereof is shown below:

[0030]

[0031] Wherein, the R is selected from 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl or 4-methoxybenzyl, preferably 2,4-dimethoxybenzyl or 4-methoxybenzyl.

[0032] In some other embodiments of the present invention, in step (1), the compound of formula 1 and the compound of formula 2 are reacted in the presence of an organic solvent to obtain compound 3; the organic solvent is selected from one or more of 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, acetonitrile and toluene; preferably, the organic solvent is 1,4-dioxane.

[0033] In other embodiments of the present invention, the reaction temperature of step (1) is 100°C-130°C; for example, the reaction temperature is 105°C, 110°C, 115°C, 120°C, 125°C, etc.

[0034] In other embodiments of the present invention, the reaction time of step (1) is 10 h-20 h; preferably, the reaction time is 12 h, 14 h, 16 h, 18 h, etc.

[0035] In some other embodiments of the present invention, in step (2), the compound of formula 3 and the compound of formula 4 react in the presence of an organic solvent to obtain a compound of formula 5; the organic solvent is selected from one or more of chloroform, tetrahydrofuran, and dichloromethane; preferably, the organic solvent is dichloromethane.

[0036] In other embodiments of the present invention, the concentration of the reaction solution in step (2) is 0.1-1 mol / L; preferably, the concentration of the reaction solution is 0.4-0.8 mol / L.

[0037] In other embodiments of the present invention, the reaction time of step (2) is 10 h-20 h; preferably, the reaction time is 10 h-16 h.

[0038] The second aspect of the present invention provides a compound of formula 13, the structure of which is shown below:

[0039]

[0040] Wherein, the R is selected from 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl or 4-methoxybenzyl, preferably 2,4-dimethoxybenzyl or 4-methoxybenzyl.

[0041] Furthermore, the compound of formula 13 is preferably of the following structure:

[0042]

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) The final compound was synthesized through nine steps, and the total yield was increased from 5.83% in the prior art to 8.67%, which increased production capacity and reduced energy consumption.

[0045] (2) By changing and optimizing the experimental conditions, the reaction can be scaled up, which greatly reduces the time cost and lowers the risk factor.

[0046] (3) The existing method of deprotection followed by hydrogenation has serious over-reduction, with the product content of 36.56% and the impurity content of 30.95% monitored by the reaction. The present invention unexpectedly discovered through a large number of experiments that the selection of hydrogenation followed by deprotection reduces the occurrence of by-products. In particular, the use of trifluoroacetic acid, potassium carbonate, and methanol conditions during the deamino protecting group of the present invention can remove by-products and increase the conversion rate to products. The product content of the reaction monitoring is 83.25%, the impurity content is 16.75%, and the product content of the final product is more than 99%.

[0047] (4) While ensuring high yield and high purity, the raw materials are easily available and cheap, the reaction conditions are milder, and the cost is effectively reduced, making it suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is the LCMS spectrum of the reaction solution of Example 9.

[0049] Figure 2 The HPLC spectrum of the final product of Example 9 is shown in FIG.

[0050] Figure 3 For the final product of Example 9 1 H NMR spectrum.

[0051] Figure 4 For the final product of Example 9 19 F NMR spectrum.

[0052] Figure 5 This is the LCMS spectrum of the reaction solution in Comparative Example 3. DETAILED DESCRIPTION

[0053] The following examples further illustrate some features of the present invention, but the content and scope of the present invention are not limited to the following examples.

[0054] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0055] Example 1 Preparation of Compound 3

[0056]

[0057] In a 1L three-necked flask, compound 1 (100g, 399.24mmol) and compound 2 (245.84g, 2mol) were added to 200mL of 1,4-dioxane, and the resulting mixture was heated to 120°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate, and the organic phase was then rinsed with dilute hydrochloric acid aqueous solution. The combined organic phases were rinsed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column (cyclohexane / ethyl acetate = 100 / 0 ~ 90 / 10 ~ 80 / 20) to obtain compound 3 as a light brown oil (112g, yield 83.2%).

[0058] Example 2 Preparation of Compound 5

[0059]

[0060] In a 1L three-necked flask, compound 3 (140g, 415.22mmol) was added to 500mL of dichloromethane, and then TEA (84.03g, 830.42mmol) was added. The resulting mixture was placed in an ice bath, and compound 4 (113.38g, 830.44mmol) was slowly added. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. The reaction solution was poured into 1L of water for quenching, extracted with dichloromethane (1L*2), and the combined organic phases were rinsed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column (cyclohexane / ethyl acetate = 100 / 0 ~ 90 / 10 ~ 80 / 20) to obtain compound 5 as a light brown oil (140g, crude product, yield 77%).

[0061] Example 3 Preparation of Compound 6

[0062]

[0063] In a 3L three-necked flask, compound 5 (140g, 320.19mmol) was dissolved in 2L methanol, and MeONa (51.89g, 960.40mmol) was added in batches. The resulting mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 4-5 with 1M dilute hydrochloric acid while stirring, and then stirred for 0.5h. Most of the solid dissolved, filtered, the filter cake was rinsed with water, collected and dried to obtain compound 6 as a white solid (90g, yield 69.3%).

[0064] Example 4 Preparation of Compound 8

[0065]

[0066] In a 1L three-necked flask, compound 6 (90g, 222.11mmol) was dissolved in 0.3L DMF, and compound 7 (158.96g, 1.11mol) was added, and the resulting mixture was stirred overnight at 120°C. The reaction solution was cooled to room temperature and poured into water, and a large amount of solid precipitated. After filtration, the filter cake was rinsed with water and methanol, and compound 8 was collected and dried to obtain a white solid (110g, yield 96%).

[0067] Example 5 Preparation of Compound 9

[0068]

[0069] In a 3L three-necked flask, compound 8 (110g, 213.05mmol) was dissolved in 0.9L DCM and 0.6L ACN, TEA (129.36g, 1.28mol) was added, TsCl (121.85g, 639.13mmol) was added in batches at 0°C, and the resulting mixture was stirred overnight at room temperature. The reaction solution was poured into water, and a large amount of solid precipitated. After filtration, the filter cake was rinsed with water and methanol, and the compound 9 was collected and dried to obtain about 80g. The filtrate was purified by column to obtain 45g of product. The white solid compound 9 was combined to obtain a total of 125g (yield 87.5%).

[0070] Example 6 Preparation of Compound 10-1

[0071]

[0072] In a 2L three-necked flask, compound 9 (125 g, 186.43 mmol) was dissolved in 0.5L DMF, DIEA (240.96 g, 1.86 mol) was added, and then DMBNH 2 (153.87 g, 920.22 mmol), the resulting mixture was stirred at 50°C for 2 h. The reaction solution was cooled to room temperature and poured into water, a large amount of solid precipitated, filtered, the filter cake was rinsed with water and ethyl acetate, collected and dried to obtain compound 10-1 as a nearly white solid (110 g, yield 88.6%).

[0073] Example 7 Preparation of Compound 12-1

[0074]

[0075] In a 1L three-necked flask, compound 10-1 (50 g, 75.13 mmol) and compound 11 (11.06 g, 112.7 mmol) were dissolved in 300 mL DMF, and DIEA (9.71 g, 75.13 mmol), (PhP 3 ) 2 PdCl2 (2.64 g, 3.76 mmol), CuI (1.43 g, 7.51 mmol), the resulting mixture was replaced with nitrogen three times and stirred at 80°C for 6 h. The reaction solution was diluted with 1000 mL EA, washed twice with 500 mL water, and once with saturated brine, dried over anhydrous sodium sulfate, and mixed with a silica gel column with DCM:EtOAc=1:1, and dried to obtain compound 12-1 as a nearly white solid (40 g, yield 78%).

[0076] Example 8 Preparation of Compound 13-1

[0077]

[0078] Compound 12-1 (40 g, 58.59 mmol) was dissolved in 900 mL MeOH and 300 mL EtOAc, and Pd / C (8 g, 20% by mass) was added, and hydrogen was replaced three times, and stirred at room temperature for 6 h. The reaction solution was filtered and concentrated to obtain compound 13-1 as a light brown solid (31.3 g, yield 89.5%).

[0079] Example 9 Preparation of Compound XZ426

[0080]

[0081] Compound 13-1 (31.3 g, 52.46 mmol) was dissolved in 500 mL of DCM, and TFA (50 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to obtain a crude product, which was then redissolved in methanol (500 mL), and K was added. 2 CO 3 (21.75 g, 157.38 mmol), continued to stir at room temperature for 2 h, monitored the reaction solution by LCMS, the over-reduction impurities were significantly reduced, the product content was 83.25%, and the impurity content was 16.75% (LCMS spectrum see Figure 1 The reaction mixture was filtered, concentrated, and the crude product was prepared by reverse phase (0.5% FA aqueous solution / acetonitrile) to obtain XZ426 as a white solid (9.8 g, yield 42%; purity 99.76%, HPLC as Figure 2 As shown, 1 H NMR spectrum Figure 3 As shown, 19 F NMR spectrum Figure 4 shown).

[0082] Comparative Example 1 Preparation of Compound 3

[0083]

[0084] Compound 1 (10 g, 39.92 mmol) and compound 2 (24.58 g, 200 mmol) were added to a 1L three-necked flask. After nitrogen replacement three times, the reaction mixture was heated to 120°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate. The organic phase was then rinsed with dilute hydrochloric acid aqueous solution. The combined organic phases were rinsed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column to obtain compound 3 as a light brown oil (5 g, yield 37.2%).

[0085] Comparative Example 2 Preparation of Compound 5

[0086]

[0087] In a 1L three-necked flask, compound 3 (15.3 g, 45.38 mmol) was dissolved in 300 mL of dichloromethane, and TEA (9.18 g, 90.75 mmol) was added. Compound 4 (12.39 g, 90.75 mmol) was slowly added dropwise to the resulting mixture under an ice bath. After the addition was complete and the mixture was stirred for 2 h, there was basically no reaction; it was stirred at room temperature overnight with no obvious change.

[0088] Comparative Example 3 Preparation of Compound 14

[0089]

[0090] Compound 15 (9 g, 12.4 mmol) and 5-hexynol (4.86 g, 49.52 mmol) were dissolved in 150 mL of TEA, and then (PhP) 2 PdCl 2 (1.74 g, 2.48 mmol), CuI (470 mg, 2.48 mmol) were added, and stirred at 110°C for 2 h. Post-treatment: The reaction solution was diluted with 200 mL EA, washed twice with 200 mL water, and once with saturated brine, dried over anhydrous sodium sulfate, and mixed with the sample and passed through a silica gel column, DCM: MeOH = 20:1, and dried to obtain 6 g of white solid compound 15, yield: 64%.

[0091] Compound 16 (2.9 g, 3.9 mmol) was placed in a 100 mL single-mouth bottle, 10 mL of dioxane was added to dissolve, and then 20 mL of 4N hydrochloric acid dioxane was added and stirred at room temperature overnight. The reaction solution was spin-dried and slurried with tertiary methyl ether to obtain 1.5 g of yellow solid compound 17, and the crude product was not counted in yield.

[0092] Compound 17 (1.5 g, 3.38 mmol) was placed in a 50 mL three-necked flask, and 30 mL of a mixed solvent of MeOH:EA = 3:1 was added to dissolve the mixture. Then, 600 mg of Pd / C, 0.2 mL of pyridine, and H2 , stirred at room temperature for 3 days, and the reaction solution was monitored by LCMS, which contained a large amount of over-reduced impurities, with a product content of 36.56% and an impurity content of 30.95% (LCMS spectrum see Figure 5 Post-treatment: The reaction solution was filtered to remove Pd / C, the mother liquor was spin-dried and directly sent to reverse phase preparation, and finally lyophilized to obtain 100 mg of light yellow final product, with a yield of 1%.

Claims

1. A method for preparing XZ426, characterized in that: The steps include: Step (8): In an organic solvent, the compound of formula 12 undergoes a hydrogenation reaction in the presence of a catalyst to obtain a compound of formula 13; Step (9): Deprotecting the compound of formula 13 in the presence of an acid reagent to obtain XZ426; The reaction formula is as follows: Wherein, the R is selected from 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl or 4-methoxybenzyl.

2. The preparation method according to claim 1, characterized in that: The mass ratio of the compound of formula 12 in step (8) to the catalyst is (10-3):

1.

3. The preparation method according to any one of claims 1 to 2, characterized in that: The catalyst in step (8) is selected from Pd / C or Pd(OH)2 / C.

4. The preparation method according to claim 3, characterized in that: The step (8) further comprises any of the following conditions: i. The organic solvent is selected from one or more of alcohols, esters, ethers or sulfoxides; ii. The organic solvent is a mixed solvent, and the mixed solvent is alcohols and esters, alcohols and ethers, or alcohols and sulfoxides.

5. The preparation method according to claim 4, characterized in that: The step (8) further includes at least one of the following conditions: i. The alcohol is selected from methanol and ethanol, the ester is selected from ethyl acetate, the ether is selected from tetrahydrofuran, and the sulfoxide is selected from DMSO; ii. The organic solvent is a mixed solvent of alcohols and esters; preferably, the volume ratio of the alcohols and esters is (10-2):1, more preferably, the alcohol is selected from methanol, the ester is selected from ethyl acetate, and the volume ratio is 3:1; iii. The reaction temperature is 10 to 50°C, preferably 10 to 35°C; iv. The reaction time is 1 to 10 hours, preferably 2 to 6 hours.

6. The preparation method according to claim 1, characterized in that: The acid reagent in step (9) is selected from trifluoroacetic acid or hydrochloric acid.

7. The preparation method according to claim 1, characterized in that: The mass volume ratio g:mL of the compound of formula 13 in step (9) to the acid reagent is 1:(1-5), preferably 1:(1-3).

8. The preparation method according to any one of claims 6 to 7, characterized in that: The step (9) further comprises at least one of the following conditions: i. In step (9), the protecting group is further removed in the presence of an organic solvent to obtain XZ426; the organic solvent is selected from one or more of alcohols, esters, ethers, halogenated alkanes or sulfoxides; preferably one or more of methanol, ethyl ester, ethanol, ethyl acetate, DMSO or dichloromethane; more preferably dichloromethane or methanol; ii. The mass volume ratio of the compound of formula 13 to the organic solvent is g:mL 1:(5 to 50), preferably 1:(15 to 35); iii. The base in step (9) is an organic base or an inorganic base, preferably triethylamine, K2CO3 or Na2CO3; iv. the reaction temperature is 10 to 30°C, preferably 10 to 25°C; v. The reaction time is 1 to 10 hours, preferably 2 to 5 hours; vi. Optionally include post-processing purification steps: filtration, concentration, reverse phase preparation.

9. The preparation method according to claim 1, characterized in that: The preparation of the compound of formula 12 comprises the following steps: wherein R is selected from 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl or 4-methoxybenzyl; And / or, in step (1), the compound of formula 1 and the compound of formula 2 are reacted in the presence of an organic solvent to obtain compound 3; the organic solvent is selected from one or more of 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, acetonitrile and toluene; Preferably, the organic solvent is 1,4-dioxane; And / or, the reaction temperature of step (1) is 100°C-130°C; And / or, the reaction time of step (1) is 10h-20h; And / or, in step (2), the compound of formula 3 and the compound of formula 4 are reacted in the presence of an organic solvent to obtain a compound of formula 5; the organic solvent is selected from one or more of chloroform, tetrahydrofuran, and dichloromethane; preferably, the organic solvent is dichloromethane; And / or, the concentration of the reaction solution in step (2) is 0.1-1 mol / L; preferably, the concentration of the reaction solution is 0.4-0.8 mol / L; And / or, the reaction time of step (2) is 10h-20h; preferably, the reaction time is 10h-16h.

10. A compound of formula 13, whose structure is shown below: in, The R is selected from 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl or 4-methoxybenzyl; Preferably, the compound of formula 13 is preferably of the following structure:

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