Preparation method of vervorixafor

Abstract

The invention relates to a preparation method of vervorixafor. The preparation method comprises the following steps: firstly, separating an (S)-type substrate (a compound shown as a formula 3) from an initial raw material (a compound shown as a formula 1) by utilizing a chiral compound (a compound shown as a formula 2), further reacting with trifluoroacetic acid to obtain a compound shown as a formula 4, and then performing alkylation reaction with a compound shown as a formula 5 to obtain a compound shown as a formula 6. Further performing alkylation reaction on the compound as shown in the formula 6 and a compound as shown in a formula 7 to obtain a compound as shown in a formula 8, and removing an amino protecting group (Boc) from the compound as shown in the formula 8 to obtain a product, i.e., vervorixafor. According to the method disclosed by the invention, a pulping purification mode can be adopted in purification in all steps, and column chromatography is not needed for purification, so that the method has good economical efficiency.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a method for preparing mavolixafor. Background Art

[0002] Mavorixafor is an orally bioavailable CXC chemokine receptor 4 (CXCR4) antagonist that blocks the binding of the CXCR4 ligand stromal-derived factor-1α (SDF-1α) / CXC chemokine ligand 12 (CXCL12). SDF-1 / CXCR4 plays a role in the trafficking and homing of leukocytes to and from the bone marrow compartment. Gain-of-function mutations in the CXCR4 receptor gene in patients with WHIM syndrome result in increased responsiveness to CXCL12 and retention of leukocytes in the bone marrow. Mavorixafor inhibits the response to CXCL12 in both wild-type and mutant CXCR4 variants associated with WHIM syndrome. Mavorixafor treatment increases the mobilization of neutrophils and lymphocytes from the bone marrow into the peripheral circulation.

[0003] On April 26, 2024, the U.S. FDA approved X4 PHARMS's Mavolixafor Capsules for marketing (oral strength: 100MG, trade name: Xolremdi). Mavolixafor Capsules are suitable for patients aged 12 years and above with WHIM syndrome (warts, hypogammaglobulinemia, infection, and myelokathexis) to increase the number of circulating mature neutrophils and lymphocytes. The recommended dose of Mavolixafor Capsules is: 1) Weight over 50kg: 400mg, orally, once a day. 2) Weight less than or equal to 50kg: 300mg, orally, once a day. Take Xolremdi on an empty stomach after an overnight fast, and at least 30 minutes before a meal.

[0004] The chemical structure of Mavolixafor is shown in Formula I:

[0005]

[0006] Currently, the preparation method of Mavolixafor still needs to be improved. Summary of the invention

[0007] The present invention aims to solve at least one of the technical problems in the related art to a certain extent. To this end, one object of the present invention is to propose a method for preparing a compound of formula I, mavolixafor. Compared with the prior art, the method described in the present invention involves a total of 5 chemical reactions: first, the initial raw material (compound of formula 1) is separated from the (S)-type substrate (compound of formula 3) by using a chiral compound (compound of formula 2), further reacted with trifluoroacetic acid to obtain a compound of formula 4, and then alkylated with a compound of formula 5 to obtain a compound of formula 6, and the compound of formula 6 is further alkylated with a compound of formula 7 to obtain a compound of formula 8, and the compound of formula 8 is then de-amino-protecting group (Boc) to obtain the product mavolixafor.

[0008] In one aspect of the present invention, the present invention provides a method for preparing the compound mavolixafor represented by formula I. According to an embodiment of the present invention, the preparation method comprises:

[0009] (1) contacting the compound represented by Formula 1 with the compound represented by Formula 2 and NaBH(OAc)3 to obtain the compound represented by Formula 3;

[0010] (2) contacting the compound represented by Formula 3 with trifluoroacetic acid to obtain the compound represented by Formula 4;

[0011] (3) contacting the compound represented by Formula 4 with the compound represented by Formula 5 and triethylamine to obtain the compound represented by Formula 6;

[0012] (4) contacting the compound represented by Formula 6 with the compound represented by Formula 7 and triethylamine to obtain the compound represented by Formula 8;

[0013] (5) contacting the compound of formula 8 with HCl / dioxane to obtain the compound of formula I, mavolixafor,

[0014]

[0015] The inventors have found that, by using the preparation method of the present invention, using the compound represented by Formula 1 and the compound represented by Formula 2 as starting materials, a total of 5 steps of reaction can be performed to successfully synthesize and prepare the target product, Mavolixafor.

[0016] The term "contact" as used herein should be understood in a broad sense, and can be any manner that allows at least two reactants to undergo a chemical reaction, such as mixing the two reactants under appropriate conditions. If necessary, the reactants to be contacted can be mixed under stirring, and thus, the type of stirring is not particularly limited, and can be mechanical stirring, i.e. stirring under the action of mechanical force.

[0017] In this document, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0018] According to an embodiment of the present invention, the method for preparing the compound shown in Formula 3, the compound shown in Formula 4, the compound shown in Formula 6, the compound shown in Formula 8, and the compound shown in Formula I may also have at least one of the following additional technical features:

[0019] According to an embodiment of the present invention, the chemical reaction described in the present invention can be carried out according to any method known in the art. The source of the raw materials of the compound shown in Formula 3, the compound shown in Formula 4, the compound shown in Formula 6, the compound shown in Formula 8, and the compound shown in Formula I is not particularly limited, and they can be prepared by any known method or obtained commercially.

[0020] According to an embodiment of the present invention, in step (1), the contacting method of the compound represented by Formula 1, the compound represented by Formula 2, and NaBH(OAc)3 is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 1, the compound represented by Formula 2, and NaBH(OAc)3 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 3 by using this method can be further improved.

[0021] According to an embodiment of the present invention, in step (1), the following steps are included: at room temperature, NaBH(OAc)3 is placed in dichloromethane and stirred vigorously, and then the compound shown in Formula 1 and the compound shown in Formula 2 are added, the mixture is stirred and reacted at room temperature for 1 to 1.5 hours, sodium hydroxide solution is added to the reaction solution, the pH is adjusted to about 8, dichloromethane is added to the aqueous phase for extraction, saturated brine is added to the organic phase after merging, and the organic phase is dried over anhydrous sodium sulfate. The crude product obtained after the organic phase is concentrated is placed in a dichloromethane / hexane mixed solvent for pulping and purification, and dried to obtain the compound shown in Formula 3. Thus, the efficiency of the contact reaction between the compound shown in Formula 1 and the compound shown in Formula 2 and NaBH(OAc)3 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in Formula 3 by using this method can be further improved.

[0022] According to an embodiment of the present invention, in step (1), the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 and NaBH(OAc)3 is 1:(1.0-1.2):(1.5-2.0), and preferably the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 and NaBH(OAc)3 is 1:1.02:1.8. Thus, the efficiency of preparing the compound represented by Formula 3 by this method can be further improved.

[0023] According to an embodiment of the present invention, in step (1), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10.

[0024] According to an embodiment of the present invention, in step (1), the mixture is preferably stirred at room temperature for 1 hour.

[0025] According to a specific embodiment of the present invention, in step (1), the following steps are included: at room temperature, NaBH(OAc)3 (25.92 g, 122.3 mmol) is placed in dichloromethane (200 mL) and stirred vigorously, and then the compound represented by formula 1 (10.00 g, 67.95 mmol) and the compound represented by formula 2 (10.48 g, 69.31 mmol) are added, and the mixture is stirred at room temperature for 1 hour, 1M sodium hydroxide solution is added to the reaction solution, and the pH is adjusted to about 8, dichloromethane is added to the aqueous phase for extraction twice, and the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained after the organic phase is concentrated is placed in 30 mL of a dichloromethane / hexane mixed solvent (the volume ratio of dichloromethane / hexane is 1:10) for pulping and purification, and dried to obtain the compound represented by formula 3, with an amount of 12.61 g and a yield of 65.7%.

[0026] According to an embodiment of the present invention, in step (2), the contacting method of the compound represented by Formula 3 and trifluoroacetic acid is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 3 and trifluoroacetic acid can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 4 using this method can be further improved.

[0027] According to an embodiment of the present invention, in step (2), the following steps are included: adding the compound shown in Formula 3 to trifluoroacetic acid at room temperature, stirring the mixture at room temperature for 8 to 15 hours, adding methanol to quench the reaction, stirring until the mixed solution gradually becomes a clear solution, and concentrating the solution under reduced pressure to remove the solvent to obtain a solid, slurrying and purifying it in a dichloromethane / hexane mixed solvent, and drying to obtain a compound shown in Formula 4. In this way, the efficiency of the contact reaction between the compound shown in Formula 3 and trifluoroacetic acid can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in Formula 4 using this method can be further improved.

[0028] According to an embodiment of the present invention, in step (2), the molar ratio of the compound represented by Formula 3 to trifluoroacetic acid is 1:(16-50), preferably the molar ratio of the compound represented by Formula 3 to trifluoroacetic acid is 1:30. Thus, the efficiency of preparing the compound represented by Formula 4 by this method can be further improved.

[0029] According to an embodiment of the present invention, in step (2), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10.

[0030] According to an embodiment of the present invention, in step (2), the mixture is preferably stirred at room temperature for 10 hours.

[0031] According to a specific embodiment of the present invention, in step (2), the following steps are included: at room temperature, the compound represented by formula 3 (15.0 g, 53.12 mmol) is added to trifluoroacetic acid (181.7 g, 1.594 mol), the mixture is stirred at room temperature for 10 hours, methanol (20 mL) is added to quench the reaction, and the mixture is stirred until the mixed solution gradually becomes a clear solution, the solution is concentrated under reduced pressure to remove the solvent, and the solid obtained is placed in 20 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane is 1:10) for pulping and purification, and after drying, the compound represented by formula 4 is obtained, with an amount of 7.15 g and a yield of 90.8%.

[0032] According to an embodiment of the present invention, in step (3), the contacting method of the compound represented by Formula 4 with the compound represented by Formula 5 and triethylamine is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 4 and the compound represented by Formula 5 and triethylamine can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 6 by using this method can be further improved.

[0033] According to an embodiment of the present invention, in step (3), the following steps are included: at room temperature, the compound of formula 4, the compound of formula 5 and triethylamine are added to acetonitrile, the mixed solution is heated to 50-70°C, and the mixture is stirred for 9-12 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then water is added for washing, and then ethyl acetate is added for separation. The organic phase is washed with citric acid aqueous solution until the pH is 6, and then ethyl acetate is added for extraction. The organic phases are combined twice, washed with saturated brine, dried over anhydrous sodium sulfate, and the solid obtained after the filtrate is concentrated under reduced pressure to remove the solvent is placed in a dichloromethane / hexane mixed solvent for pulping and purification, filtered, and dried to obtain the compound of formula 6. Thus, the efficiency of the contact reaction between the compound of formula 4 and the compound of formula 5 and triethylamine can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 6 by using this method can be further improved.

[0034] According to an embodiment of the present invention, in step (3), the molar ratio of the compound represented by Formula 4 to the compound represented by Formula 5 and triethylamine is 1:(1.0-1.4):(1.2-2.0), and preferably the molar ratio of the compound represented by Formula 4 to the compound represented by Formula 5 and triethylamine is 1:1.2:1.5. Thus, the efficiency of preparing the compound represented by Formula 6 by this method can be further improved.

[0035] According to an embodiment of the present invention, in step (3), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10.

[0036] According to an embodiment of the present invention, in step (3), the mixed solution is preferably heated to 60° C. and stirred for 10 hours.

[0037] According to a specific embodiment of the present invention, in step (3), the following steps are included: at room temperature, the compound represented by formula 4 (6.5 g, 43.86 mmol), the compound represented by formula 5 (14.0 g, 52.62 mmol) and triethylamine (6.66 g, 65.79 mmol) are added to acetonitrile (65 mL), the mixed solution is heated to 60°C, and the mixture is stirred for 10 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and water (65 mL) is added for washing, and then ethyl acetate (50 mL) is added for separation. The organic phase is washed with 1M citric acid aqueous solution until the pH is 6, and then ethyl acetate (50 mL) is added for extraction. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to remove the solvent. The solid obtained is placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane is 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 6, with an amount of 14.71 g and a yield of 88.6%.

[0038] According to an embodiment of the present invention, in step (4), the contacting method of the compound represented by Formula 6 with the compound represented by Formula 7 and triethylamine is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 6 and the compound represented by Formula 7 and triethylamine can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 8 by using this method can be further improved.

[0039] According to an embodiment of the present invention, in step (4), the following steps are included: at room temperature, the compound of formula 6, the compound of formula 7 and triethylamine are added to acetonitrile, the mixed solution is heated to 55-75°C, and the mixture is stirred for 9-13 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then water is added for washing, and then ethyl acetate is added for separation. The organic phase is washed with citric acid aqueous solution until the pH is 6, and then ethyl acetate is added for extraction. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solid obtained after the filtrate is concentrated under reduced pressure to remove the solvent is placed in a dichloromethane / hexane mixed solvent for pulping and purification, filtered, and dried to obtain the compound of formula 8. Thus, the efficiency of the contact reaction between the compound of formula 6 and the compound of formula 7 and triethylamine can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 8 by using this method can be further improved.

[0040] According to an embodiment of the present invention, in step (4), the molar ratio of the compound represented by Formula 6 to the compound represented by Formula 7 and triethylamine is 1:(1.02-1.35):(1.2-2.0), and preferably the molar ratio of the compound represented by Formula 6 to the compound represented by Formula 7 and triethylamine is 1:1.2:1.6. Thus, the efficiency of preparing the compound represented by Formula 8 by this method can be further improved.

[0041] According to an embodiment of the present invention, in step (4), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10.

[0042] According to an embodiment of the present invention, in step (4), the mixed solution is preferably heated to 65° C. and stirred for 10 hours.

[0043] According to a specific embodiment of the present invention, in step (4), the following steps are included: at room temperature, the compound represented by formula 6 (10.0 g, 26.42 mmol), the compound represented by formula 7 (6.59 g, 31.71 mmol) and triethylamine (4.28 g, 42.27 mmol) are added to acetonitrile (120 mL), the mixed solution is heated to 65° C., and stirred for 10 hours at this temperature. After the reaction is completed, the reaction solution is cooled to room temperature, and water (100 mL) is added for washing, and then added The organic phase was separated by adding 1M citric acid aqueous solution (100 mL), and then extracted by adding ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to remove the solvent, and the solid obtained was placed in 40 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification. After filtering and drying, the compound of formula 8 was obtained, with an amount of 12.55 g and a yield of 86.4%.

[0044] According to an embodiment of the present invention, in step (5), the contacting method of the compound represented by Formula 8 and HCl / dioxane is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 8 and HCl / dioxane can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula I by using this method can be further improved.

[0045] According to an embodiment of the present invention, in step (5), the following steps are included: adding HCl / dioxane to the compound of formula 8 at 0°C, naturally heating to 25°C, and stirring at 25°C for 2 hours, and detecting the end of the reaction by TLC, concentrating the reaction solution under reduced pressure, adding dichloromethane to dissolve, and concentrating under reduced pressure again to obtain the compound of formula I, mavolixafor. In this way, the efficiency of the contact reaction between the compound of formula 8 and HCl / dioxane can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula I by using this method can be further improved.

[0046] According to an embodiment of the present invention, in step (5), the concentration of HCl / dioxane is 6M.

[0047] According to a specific embodiment of the present invention, in step (5), the following steps are included: at 0°C, 6M HCl / dioxane (40mL) is added to the compound of formula 8 (8.0g, 14.55mmol), the temperature is naturally raised to 25°C, and the mixture is kept stirred at 25°C for 2 hours. After TLC detection, the reaction is completed, the reaction solution is concentrated under reduced pressure, 10mL of dichloromethane is added to dissolve it, and then concentrated under reduced pressure again to obtain the compound of formula I, with an amount of 4.90g and a yield of 96.3%.

[0048] Compared with the prior art, the method for preparing Mavolixafor of the present invention has at least the following beneficial effects:

[0049] 1. Compared with the prior art, the method of the present invention involves a total of 5 chemical reactions: (1) the initial raw material (compound of formula 1) is first separated from the (S)-type substrate (compound of formula 3) by using a chiral compound (compound of formula 2); (2) the compound of formula 3 is reacted with trifluoroacetic acid to obtain a compound of formula 4; (3) the compound of formula 4 is subjected to an alkylation reaction with a compound of formula 5 to obtain a compound of formula 6; (4) the compound of formula 6 is further subjected to an alkylation reaction with a compound of formula 7 to obtain a compound of formula 8; (5) the compound of formula 8 is subjected to the removal of the amino protecting group (Boc) to obtain the product mavolixafor.

[0050] 2. Prior art CN 115894360A, when separating chiral amino compounds, the yield when using D-(⑴)-p-methyl dibenzoyl tartaric acid or N-acetyl-L-leucine as a resolving agent is generally less than 50%. The compound shown in Formula 2 of the present invention is not only a chiral resolving agent, but also a reaction product (converting the carbonyl group into the amino group), with a higher reaction yield (the total yield of step (1) and step (2) is as high as 59.7%); at the same time, the steps of the present invention can be reacted at room temperature, with relatively mild reaction conditions and good reaction operability. In addition, the reaction substrates in steps (3) and (4) of the present invention have a unique reaction site and a good reaction yield.

[0051] 3. The method of the present invention can be purified by pulping in all steps without column chromatography, which has good economic efficiency. In addition, the raw materials used in the present invention are easy to obtain, the operation method is simple, and the reaction rate of each step is high, which is very suitable for batch industrial production. DETAILED DESCRIPTION

[0052] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0053] Example 1 Synthesis of the compound represented by formula 3

[0054] At room temperature, NaBH(OAc)3 (25.92 g, 122.3 mmol) was placed in dichloromethane (200 mL) and stirred vigorously. Then, the compound represented by formula 1 (10.00 g, 67.95 mmol) and the compound represented by formula 2 (10.48 g, 69.31 mmol) were added. The mixture was stirred at room temperature for 1 hour. 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to about 8. Dichloromethane was added to the aqueous phase for extraction twice. After the organic phases were combined, saturated brine was added for washing and dried over anhydrous sodium sulfate. The crude product obtained after the organic phase was concentrated was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification. After drying, the compound represented by formula 3 was obtained, with an amount of 12.61 g and a yield of 65.7%.

[0055] LC-MS (APCI): m / z = 283.2 (M+1) + .

[0056] 1 H-NMR (400MHz, CDCl3) δ8.43(d,J=4.8Hz,1H),7.37(d,J=9.1Hz,2H),7.35(d,J=7.8Hz,1H),7.08(dd,J=4.8Hz,J=7.8Hz,1H),6.88(d,J=8.4 Hz,2H),4.05(q,J=6.6Hz,1H),3.85(dd,J=5.7Hz,J=7.5Hz,1H),3.82(s,3H),2.73-2.78(m,1H),2.68(dt,J=5.6Hz,J=16.8Hz,1H),2.65(br s,1H),1.82-1.87(m,1H),1.72-1.76(m,1H),1.55-1.62(m,1H),1.47-1.52(m,1H),1.46(d,J=6.6Hz,3H).

[0057] Example 2 Synthesis of the compound represented by formula 3

[0058] At room temperature, NaBH(OAc)3 (21.60 g, 101.9 mmol) was placed in dichloromethane (200 mL) and stirred vigorously. Then, the compound represented by formula 1 (10.00 g, 67.95 mmol) and the compound represented by formula 2 (10.27 g, 67.95 mmol) were added. The mixture was stirred at room temperature for 1 hour and 10 minutes. 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to about 8. Dichloromethane was added to the aqueous phase for extraction twice. After the organic phases were combined, saturated brine was added for washing and dried over anhydrous sodium sulfate. The crude product obtained after the organic phase was concentrated was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification. After drying, the compound represented by formula 3 was obtained, with an amount of 12.49 g and a yield of 65.1%.

[0059] Example 3 Synthesis of the compound represented by formula 3

[0060] At room temperature, NaBH(OAc)3 (28.80 g, 135.9 mmol) was placed in dichloromethane (250 mL) and stirred vigorously. Then, the compound represented by formula 1 (10.00 g, 67.95 mmol) and the compound represented by formula 2 (12.33 g, 81.54 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to about 8. Dichloromethane was added to the aqueous phase for extraction twice. After the organic phases were combined, saturated brine was added for washing, and the organic phases were dried over anhydrous sodium sulfate. The crude product obtained after the organic phase was concentrated was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification. After drying, the compound represented by formula 3 was obtained, with an amount of 12.57 g and a yield of 65.5%.

[0061] Comparative Example 1 Synthesis of the Compound Represented by Formula 3

[0062] At room temperature, NaBH(OAc)3 (31.68 g, 149.5 mmol) was placed in dichloromethane (250 mL) and stirred vigorously. Then, the compound represented by formula 1 (10.00 g, 67.95 mmol) and the compound represented by formula 2 (12.84 g, 84.94 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to about 8. Dichloromethane was added to the aqueous phase for extraction twice. After the organic phases were combined, saturated brine was added for washing, and the organic phases were dried over anhydrous sodium sulfate. The crude product obtained after the organic phase was concentrated was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification. After drying, the compound represented by formula 3 was obtained, with an amount of 12.47 g and a yield of 65.0%.

[0063] It can be seen that changing the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 and NaBH(OAc)3 to 1:1.25:2.2 does not further improve the yield of the compound represented by Formula 3.

[0064] Example 4 Synthesis of the compound represented by formula 4

[0065] At room temperature, the compound represented by formula 3 (15.0 g, 53.12 mmol) was added to trifluoroacetic acid (181.7 g, 1.594 mol), and the mixture was stirred at room temperature for 10 hours. Methanol (20 mL) was added to quench the reaction and stirred until the mixed solution gradually became a clear solution. The solution was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 20 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) and slurried for purification. After drying, the compound represented by formula 4 was obtained, with an amount of 7.15 g and a yield of 90.8%.

[0066] LC-MS (APCI): m / z = 149.1 (M+1) + .

[0067] [α]D20=+44.2(c=1.00in MeOH).

[0068] Example 5 Synthesis of the compound represented by formula 4

[0069] At room temperature, the compound represented by formula 3 (15.0 g, 53.12 mmol) was added to trifluoroacetic acid (96.89 g, 0.85 mol), and the mixture was stirred at room temperature for 8 hours. Methanol (20 mL) was added to quench the reaction and stirred until the mixed solution gradually became a clear solution. The solution was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 20 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) and slurried for purification. After drying, the compound represented by formula 4 was obtained, with an amount of 7.04 g and a yield of 89.4%.

[0070] Example 6 Synthesis of the compound represented by formula 4

[0071] At room temperature, the compound represented by formula 3 (15.0 g, 53.12 mmol) was added to trifluoroacetic acid (302.8 g, 2.656 mol), and the mixture was stirred at room temperature for 15 hours. Methanol (20 mL) was added to quench the reaction and stirred until the mixed solution gradually became a clear solution. The solution was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 20 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) and slurried for purification. After drying, the compound represented by formula 4 was obtained, with an amount of 7.10 g and a yield of 90.2%.

[0072] Example 7 Synthesis of the compound represented by formula 6

[0073] At room temperature, the compound represented by formula 4 (6.5 g, 43.86 mmol), the compound represented by formula 5 (14.0 g, 52.62 mmol) and triethylamine (6.66 g, 65.79 mmol) were added to acetonitrile (65 mL), and the mixture was heated to 60 ° C. and stirred for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (65 mL) was added for washing, and then ethyl acetate (50 mL) was added for separation. The organic phase was washed with 1M citric acid aqueous solution until the pH was 6, and then ethyl acetate (50 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 6, with an amount of 14.71 g and a yield of 88.6%.

[0074] LC-MS (APCI): m / z = 379.2 (M+1) + .

[0075] Example 8 Synthesis of the compound represented by formula 6

[0076] At room temperature, the compound represented by formula 4 (6.5 g, 43.86 mmol), the compound represented by formula 5 (11.70 g, 43.86 mmol) and triethylamine (5.33 g, 52.62 mmol) were added to acetonitrile (65 mL), and the mixed solution was heated to 50 ° C. and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (65 mL) was added for washing, and then ethyl acetate (50 mL) was added for separation. The organic phase was washed with 1M citric acid aqueous solution until the pH was 6, and then ethyl acetate (50 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 6, with an amount of 14.30 g and a yield of 86.2%.

[0077] Example 9 Synthesis of the compound represented by formula 6

[0078] At room temperature, the compound represented by formula 4 (6.5 g, 43.86 mmol), the compound represented by formula 5 (16.38 g, 61.404 mmol) and triethylamine (8.88 g, 87.72 mmol) were added to acetonitrile (85 mL), and the mixed solution was heated to 70 ° C. and stirred for 9 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (65 mL) was added for washing, and then ethyl acetate (50 mL) was added for separation. The organic phase was washed with 1M citric acid aqueous solution until the pH was 6, and then ethyl acetate (50 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 6, with an amount of 14.59 g and a yield of 87.9%.

[0079] Comparative Example 2 Synthesis of the Compound Represented by Formula 6

[0080] At room temperature, the compound represented by formula 4 (6.5 g, 43.86 mmol), the compound represented by formula 5 (17.55 g, 65.79 mmol) and triethylamine (11.10 g, 109.65 mmol) were added to acetonitrile (100 mL), and the mixed solution was heated to 60 ° C. and stirred for 11 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (65 mL) was added for washing, and then ethyl acetate (50 mL) was added for separation. The organic phase was washed with 1M citric acid aqueous solution until the pH was 6, and then ethyl acetate (50 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 6, with an amount of 14.33 g and a yield of 86.3%.

[0081] It can be seen that changing the molar ratio of the compound represented by Formula 4 to the compound represented by Formula 5 and triethylamine to 1:1.5:2.5 does not further improve the yield of the compound represented by Formula 6.

[0082] Example 10 Synthesis of the compound represented by formula 8

[0083] At room temperature, the compound represented by formula 6 (10.0 g, 26.42 mmol), the compound represented by formula 7 (6.59 g, 31.71 mmol) and triethylamine (4.28 g, 42.27 mmol) were added to acetonitrile (120 mL), and the mixed solution was heated to 65 ° C. and stirred for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (100 mL) was added for washing, and then ethyl acetate (100 mL) was added for separation. The organic phase was washed with 1M citric acid aqueous solution until the pH was 6, and then ethyl acetate (100 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 40 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 8, with an amount of 12.55 g and a yield of 86.4%.

[0084] LC-MS (APCI): m / z = 550.3 (M+1) + .

[0085] Example 11 Synthesis of the compound represented by formula 8

[0086] At room temperature, the compound represented by formula 6 (10.0 g, 26.42 mmol), the compound represented by formula 7 (5.60 g, 26.95 mmol) and triethylamine (3.21 g, 31.71 mmol) were added to acetonitrile (120 mL), and the mixed solution was heated to 55 ° C. and stirred for 13 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (100 mL) was added for washing, and then ethyl acetate (100 mL) was added for separation. The organic phase was washed with 1M citric acid aqueous solution until the pH was 6, and then ethyl acetate (100 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 40 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 8, with an amount of 12.34 g and a yield of 85.0%.

[0087] Example 12 Synthesis of the compound represented by formula 8

[0088] At room temperature, the compound represented by formula 6 (10.0 g, 26.42 mmol), the compound represented by formula 7 (7.41 g, 35.67 mmol) and triethylamine (5.35 g, 52.84 mmol) were added to acetonitrile (120 mL), and the mixed solution was heated to 75 ° C. and stirred for 9 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (100 mL) was added for washing, and then ethyl acetate (100 mL) was added for separation. The organic phase was washed with 1M citric acid aqueous solution until the pH was 6, and then ethyl acetate (100 mL) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The solid obtained was placed in 40 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane was 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 8, with an amount of 12.49 g and a yield of 86.0%.

[0089] Example 13 Synthesis of the compound represented by formula I

[0090] At 0°C, 6M HCl / dioxane (40 mL) was added to the compound of formula 8 (8.0 g, 14.55 mmol), and the temperature was naturally raised to 25°C, and the mixture was kept stirring at 25°C for 2 hours. The reaction was completed by TLC detection, and the reaction solution was concentrated under reduced pressure. 10 mL of dichloromethane was added to dissolve it, and then concentrated under reduced pressure again to obtain the compound of formula I. The yield was 4.90 g, and the yield was 96.3%.

[0091] LC-MS (APCI): m / z = 350.2 (M+1) + .

[0092] 1 H-NMR (600MHz, CDCl3+D2O): δ8.55-8.56(d,1H),7.56-7.59(m,2H),7.39-7.42(dd,1H),7.12-7.21(d,3H),3.96-4.08(m,3H),2.79-2.86(m ,1H),2.64-2.74(m,2H),2.45-2.54(m,3H),2.16-2.22(m,1H),1.99- 2.01(m,1H),1.84-1.95(m,1H),1.65-1.72(m,1H),1.31-1.48(m,4H).

[0093] Comparative Example 3 Synthesis of the Compound Mavolixafor Represented by Formula I

[0094] At 0°C, 6M HCl / dioxane (40 mL) was added to the compound of Formula 8 (8.0 g, 14.55 mmol), and the temperature was naturally raised to 25°C, and the mixture was kept stirred at 25°C for 3 hours. The reaction was completed by TLC detection, and the reaction solution was concentrated under reduced pressure. 10 mL of dichloromethane was added to dissolve it, and then concentrated under reduced pressure again to obtain the compound of Formula I. The yield was 4.88 g, and the yield was 96.0%.

[0095] It can be seen that extending the time of heat preservation and stirring to 3 hours does not further improve the yield of the compound represented by formula I.

[0096] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0097] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing Mavolixafor, characterized in that: include: (1) contacting the compound represented by Formula 1 with the compound represented by Formula 2 and NaBH(OAc)3 to obtain the compound represented by Formula 3; (2) contacting the compound represented by Formula 3 with trifluoroacetic acid to obtain the compound represented by Formula 4; (3) contacting the compound represented by Formula 4 with the compound represented by Formula 5 and triethylamine to obtain the compound represented by Formula 6; (4) contacting the compound represented by Formula 6 with the compound represented by Formula 7 and triethylamine to obtain the compound represented by Formula 8; (5) contacting the compound of formula 8 with HCl / dioxane to obtain the compound of formula I, mavolixafor, 2. The method according to claim 1, characterized in that In step (1), the following steps are included: at room temperature, NaBH(OAc)3 is placed in dichloromethane and stirred vigorously, and then the compound represented by formula 1 and the compound represented by formula 2 are added, the mixture is stirred and reacted at room temperature for 1 to 1.5 hours, sodium hydroxide solution is added to the reaction solution, and the pH is adjusted to about 8, dichloromethane is added to the aqueous phase for extraction, the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained after the organic phase is concentrated is placed in a dichloromethane / hexane mixed solvent for pulping and purification, and dried to obtain the compound represented by formula 3.

3. The method according to claim 2, characterized in that In step (1), the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 and NaBH(OAc)3 is 1:(1.0-1.2):(1.5-2.0), preferably the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 and NaBH(OAc)3 is 1:1.02:1.8; Optionally, in step (1), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10; Optionally, in step (1), the mixture is preferably stirred at room temperature for 1 hour.

4. The method according to claim 1, characterized in that: In step (2), the following steps are included: adding the compound represented by formula 3 to trifluoroacetic acid at room temperature, stirring the mixture at room temperature for 8 to 15 hours, adding methanol to quench the reaction, stirring until the mixed solution gradually becomes a clear solution, concentrating the solution under reduced pressure to remove the solvent, placing the solid obtained in a dichloromethane / hexane mixed solvent for pulping and purification, and drying to obtain the compound represented by formula 4; Optionally, in step (2), the molar ratio of the compound represented by formula 3 to trifluoroacetic acid is 1:(16-50), preferably the molar ratio of the compound represented by formula 3 to trifluoroacetic acid is 1:30; Optionally, in step (2), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10; Optionally, in step (2), the mixture is preferably stirred at room temperature for 10 hours.

5. The method according to claim 1, characterized in that In step (3), the following steps are included: at room temperature, adding the compound represented by formula 4, the compound represented by formula 5 and triethylamine to acetonitrile, heating the mixed solution to 50-70°C, and stirring at this temperature for 9-12 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then water is added for washing, and then ethyl acetate is added for separation. The organic phase is washed with citric acid aqueous solution until the pH is 6, and then ethyl acetate is added for extraction. The two organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solid obtained after the filtrate is concentrated under reduced pressure to remove the solvent is placed in a dichloromethane / hexane mixed solvent for pulping and purification, filtered, and dried to obtain the compound represented by formula 6.

6. The method according to claim 5, characterized in that In step (3), the molar ratio of the compound represented by formula 4 to the compound represented by formula 5 and triethylamine is 1:(1.0-1.4):(1.2-2.0), preferably the molar ratio of the compound represented by formula 4 to the compound represented by formula 5 and triethylamine is 1:1.2:1.5; Optionally, in step (3), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10; Optionally, in step (3), the mixed solution is preferably heated to 60° C. and stirred for 10 hours.

7. The method according to claim 1, characterized in that In step (4), the following steps are included: at room temperature, adding the compound represented by formula 6, the compound represented by formula 7 and triethylamine to acetonitrile, heating the mixed solution to 55-75° C., and stirring at this temperature for 9-13 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then water is added for washing, and then ethyl acetate is added for separation. The organic phase is washed with citric acid aqueous solution until the pH is 6, and then ethyl acetate is added for extraction. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solid obtained after the filtrate is concentrated under reduced pressure to remove the solvent is placed in a dichloromethane / hexane mixed solvent for pulping and purification, filtered, and dried to obtain the compound represented by formula 8.

8. The method according to claim 7, characterized in that In step (4), the molar ratio of the compound represented by Formula 6 to the compound represented by Formula 7 and triethylamine is 1:(1.02-1.35):(1.2-2.0), preferably the molar ratio of the compound represented by Formula 6 to the compound represented by Formula 7 and triethylamine is 1:1.2:1.6; Optionally, in step (4), the volume ratio of dichloromethane to hexane in the dichloromethane / hexane mixed solvent is 1:10; Optionally, in step (4), the mixed solution is preferably heated to 65° C. and stirred for 10 hours.

9. The method according to claim 1, characterized in that: In step (5), the following steps are included: adding HCl / dioxane to the compound of formula 6 at 0°C, naturally heating to 25°C, and stirring at 25°C for 2 hours. After the reaction is completed by TLC detection, the reaction solution is concentrated under reduced pressure, and dichloromethane is added to dissolve it, and then concentrated under reduced pressure again to obtain the compound of formula I, mavolixafor; Optionally, in step (5), the HCl / dioxane concentration is 6M.

10. The method according to claim 1, characterized in that In step (1), the following steps are included: at room temperature, NaBH(OAc)3 (25.92 g, 122.3 mmol) is placed in dichloromethane (200 mL) and stirred vigorously, and then the compound represented by formula 1 (10.00 g, 67.95 mmol) and the compound represented by formula 2 (10.48 g, 69.31 mmol) are added, and the mixture is stirred and reacted at room temperature for 1 hour, 1M sodium hydroxide solution is added to the reaction solution to adjust the pH to about 8, dichloromethane is added to the aqueous phase for extraction twice, the organic phases are combined and washed with saturated brine, and dried over anhydrous sodium sulfate, and the crude product obtained after the organic phase is concentrated is placed in 30 mL of a dichloromethane / hexane mixed solvent (the volume ratio of dichloromethane / hexane is 1:10) for pulping and purification, and after drying, the compound represented by formula 3 is obtained, with an amount of 12.61 g and a yield of 65.7%; In step (2), the following steps are included: at room temperature, the compound represented by formula 3 (15.0 g, 53.12 mmol) is added to trifluoroacetic acid (181.7 g, 1.594 mol), the mixture is stirred at room temperature for 10 hours, methanol (20 mL) is added to quench the reaction, and the mixture is stirred until the mixed solution gradually becomes a clear solution, the solution is concentrated under reduced pressure to remove the solvent, the solid obtained is placed in 20 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane is 1:10) for pulping and purification, and after drying, the compound represented by formula 4 is obtained, with an amount of 7.15 g and a yield of 90.8%; In step (3), the following steps are included: at room temperature, the compound represented by formula 4 (6.5 g, 43.86 mmol), the compound represented by formula 5 (14.0 g, 52.62 mmol) and triethylamine (6.66 g, 65.79 mmol) are added to acetonitrile (65 mL), the mixed solution is heated to 60°C, and the mixture is stirred for 10 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and water (65 mL) is added for washing, and ethyl acetate (50 mL) is added for separation. The organic phase is washed with 1M citric acid aqueous solution until the pH is 6, and ethyl acetate (50 mL) is added for extraction. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to remove the solvent. The solid obtained is placed in 30 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane is 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 6, with an amount of 14.71 g and a yield of 88.6%; In step (4), the following steps are included: at room temperature, the compound represented by formula 6 (10.0 g, 26.42 mmol), the compound represented by formula 7 (6.59 g, 31.71 mmol) and triethylamine (4.28 g, 42.27 mmol) are added to acetonitrile (120 mL), the mixed solution is heated to 65°C, and the mixture is stirred for 10 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then water (100 mL) is added for washing, and then ethyl acetate (100 mL) is added for separation. The organic phase is washed with 1M citric acid aqueous solution until the pH is 6, and then ethyl acetate (100 mL) is added for extraction. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to remove the solvent. The solid obtained is placed in 40 mL of a mixed solvent of dichloromethane / hexane (the volume ratio of dichloromethane / hexane is 1:10) for pulping and purification, filtered, and dried to obtain the compound represented by formula 8, with an amount of 12.55 g and a yield of 86.4%; In step (5), the following steps are included: adding 6M HCl / dioxane (40 mL) to the compound of formula 6 (8.0 g, 14.55 mmol) at 0°C, naturally heating to 25°C, and stirring at 25°C for 2 hours. After TLC detection, the reaction is complete, and the reaction solution is concentrated under reduced pressure, 10 mL of dichloromethane is added to dissolve it, and then concentrated under reduced pressure again to obtain the compound of formula I, with an amount of 4.90 g and a yield of 96.3%.

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