A key intermediate for preparing pyranose glucopyranosyl derivatives and preparation method thereof

Abstract

The present invention relates to a key intermediate for preparing a glucopyranosyl derivative, which is a sodium-dependent glucose transporter (SGLT) inhibitor, and a preparation method thereof. Specifically, the key intermediate provided by the present invention has stable properties, few impurities, and high optical purity (diastereoselectivity). The preparation method provided by the present invention utilizes inexpensive reagents, mild reaction conditions, does not require silica gel column chromatography purification, is simple to post-process, is easy to purify, has low equipment requirements, low production costs, and a safe and controllable process, making it suitable for industrial production.

Description

Field of the Invention

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a key intermediate for preparing a pyranose glucopyranose derivative and a preparation method thereof. The pyranose glucopyranose derivative is a sodium-dependent glucose transporter (SGLT) inhibitor. Background of the Invention

[0002] Research has discovered that glucose transporters are a class of carrier proteins embedded in cell membranes that transport glucose. Glucose must rely on glucose transporters to cross the lipid bilayer of the cell membrane. Glucose transporters are divided into two major categories: sodium-dependent glucose transporters (SGLTs) and glucose transporters (GLUTs). The two main members of the SGLT family are SGLT-1 and SGLT-2. SGLT-1 is primarily distributed in the small intestine, kidneys, heart, and trachea, expressed primarily in the small intestinal brush border and the S3 segment of the renal proximal convoluted tubule, with smaller amounts expressed in the heart and trachea. It transports glucose and galactose at a sodium-to-glucose ratio of 2:1. SGLT-2, on the other hand, is primarily distributed in the kidneys, expressed primarily in the S1 and S2 segments of the renal proximal convoluted tubule, transporting glucose at a sodium-to-glucose ratio of 1:1. In vivo, SGLTs actively transport glucose against a concentration gradient, consuming energy, while GLUTs transport glucose along a concentration gradient by facilitated diffusion, a process that does not consume energy. Studies have shown that plasma glucose is normally filtered in the glomeruli of the kidney, with 90% of glucose actively transported into epithelial cells by SGLT-2 in the proximal S1 and S2 segments of the renal tubules. 10% of glucose is actively transported into epithelial cells in the distal S3 segment of the renal tubules by SGLT-1. This glucose is then transported by GLUTs on the basement membrane of the epithelial cells to the surrounding capillary network, completing renal tubular reabsorption of glucose. Therefore, SGLTs are the first checkpoint in regulating cellular glucose metabolism and represent an ideal target for the effective treatment of diabetes. Studies have shown that patients with SGLT-2 deficiency excrete significant amounts of glucose in their urine, providing evidence for the therapeutic potential of diabetes by inhibiting SGLT-2 activity to reduce glucose absorption. Therefore, inhibiting the activity of SGLTs transporters can block the reabsorption of glucose by the renal tubules and increase the excretion of glucose in the urine, thereby normalizing the plasma glucose concentration and controlling the condition of diabetes and diabetic complications. Inhibiting SGLTs will not affect the normal glucose counter-regulatory mechanism and cause the risk of hypoglycemia; at the same time, by increasing the excretion of glucose in the kidneys to lower blood sugar, it can promote weight loss in obese patients. Studies have also found that the mechanism of action of SGLTs inhibitors does not depend on the degree of abnormal pancreatic β-cell function or insulin resistance. Therefore, its effect will not decrease with β-cell failure or severe insulin resistance. It can be used alone or in combination with other hypoglycemic drugs. Therefore, SGLTs inhibitors are ideal new hypoglycemic drugs.

[0003] Furthermore, research has shown that SGLT inhibitors can be used to treat diabetes-related complications, such as retinopathy, neuropathy, nephropathy, and insulin resistance, hyperinsulinemia, hyperlipidemia, and obesity caused by impaired glucose metabolism. SGLT inhibitors can also be used in combination with existing therapeutic agents, such as sulfonamides, thiazolidinediones, metformin, and insulin, to reduce dosage without compromising efficacy, thereby avoiding or mitigating adverse reactions and improving patient compliance with treatment.

[0004] After diligent research, the applicant has developed pyranose glucopyranose derivatives as sodium-dependent glucose transporter (SGLT) inhibitors, and disclosed in WO2015043511A1 and WO2016173425A1 that the compound represented by formula (I) has good SGLTs inhibitory activity.

[0005] This compound is currently in Phase III clinical trials and is a very promising new diabetes treatment drug.

[0006]

[0007] Subsequently, the applicant disclosed a method for preparing the compound represented by formula (I) in WO2020143653A1, wherein the synthesis route disclosed the following reaction for preparing the intermediate: a compound represented by formula (X) is subjected to an addition reaction with a Grignard reagent obtained by Grignard exchange of iodomethyl pivalate and isopropylmagnesium chloride and lithium chloride to obtain a compound represented by formula (IX) (see step 4 of Example 1 in its specification for details).

[0008] Step a:

[0009]

[0010] The applicant also disclosed a method for preparing a compound represented by formula (I) in WO2022007838A1, wherein the synthesis route discloses the following reaction for preparing an intermediate: a compound represented by formula (IXb) is reacted with a Grignard reagent obtained by Grignard exchange of iodomethyl pivalate and isopropylmagnesium chloride and lithium chloride to obtain a compound represented by formula (VIIIb) (see step 4 of Example 1 in its specification for details).

[0011] Step b:

[0012]

[0013] As can be seen from the above reactions for preparing intermediates, the compound represented by formula (IXb) (the compound represented by formula (IXb) is identical to the compound represented by formula (II-a) of the present invention) and compounds with similar structures, such as the compound represented by formula (X), can be used as starting compounds to prepare other intermediates, thereby ultimately obtaining the compound represented by formula (I). However, both step a and step b require a Grignard reaction, which is expensive, has harsh reaction conditions, high equipment requirements, and high synthesis costs, making it unsuitable for industrial production. Summary of the Invention

[0014] In response to the problems existing in the preparation of intermediates in the synthetic routes for preparing the compound represented by formula (I) in the prior art, the present invention has conducted extensive optimization and exploration of the intermediates in the synthetic routes of the compound represented by formula (I) and their preparation methods, and provides a key intermediate suitable for industrial production and its preparation method. On the one hand, the key intermediate has stable properties, few impurities, and high optical purity (diastereoselectivity); on the other hand, the preparation method uses inexpensive reagents, mild reaction conditions, does not require silica gel column chromatography purification, is simple to post-process, is easy to purify, has low equipment requirements, low production costs, and a safer, more controllable, and simple process.

[0015] The intermediate of the present invention has a structure as shown in formula (Ia) and is an important intermediate for synthesizing the compound of formula (I). Specifically, the present invention relates to a method for preparing the compound of formula (Ia), the compound of formula (Ia) and its crystalline form A.

[0016] On the one hand, the present invention relates to a method for preparing a compound represented by formula (Ia), comprising the following steps: reacting a compound represented by formula (II-a) with trimethylsilyl acetylene in a solvent in the presence of LiHMDS to obtain a compound represented by formula (Ia).

[0017]

[0018] In some embodiments, the addition reaction is carried out in the presence of an additive, and the additive is 2,4,6-trimethylpyridine, piperidine, triethylenediamine, pyrrole, tetramethylethylenediamine, tetramethyltartrate, hexamethylphosphoric triamide, (-)-cytisine, triethylamine, propylenediamine, ethylenediamine, dimethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N-dimethylpropyleneurea, N-methylpyrrolidone or pyridine; preferably, the additive is tetramethylethylenediamine or (-)-cytisine; more preferably, the additive is tetramethylethylenediamine.

[0019] In other embodiments, the amount of the additive is 0.2-1.2 times the equivalent of the compound represented by formula (II-a); preferably, the amount of the additive is 0.5-1.0 times the equivalent of the compound represented by formula (II-a); more preferably, the amount of the additive is 0.2 times, 0.5 times or 1.0 times the equivalent of the compound represented by formula (II-a).

[0020] In some embodiments, the amount of trimethylsilyl acetylene used is 1.0-2.0 times the equivalent of the compound represented by formula (II-a); preferably, the amount of trimethylsilyl acetylene used is 1.2-1.5 times the equivalent of the compound represented by formula (II-a); more preferably, the amount of trimethylsilyl acetylene used is 1.2 times or 1.5 times the equivalent of the compound represented by formula (II-a).

[0021] In some further embodiments, the amount of LiHMDS used is 1.0-2.0 times the equivalent of the compound represented by formula (II-a); preferably, the amount of LiHMDS used is 1.2-1.5 times the equivalent of the compound represented by formula (II-a); more preferably, the amount of LiHMDS used is 1.2 times or 1.5 times the equivalent of the compound represented by formula (II-a).

[0022] In some embodiments, the solvent is tetrahydrofuran, dichloromethane, toluene, diethyl ether, 2-methyl-tetrahydrofuran, n-hexane, cyclohexane or n-heptane; preferably, the solvent is tetrahydrofuran.

[0023] In some other embodiments, in the reaction of the compound represented by formula (II-a) with trimethylsilyl acetylene, the reaction temperature is -40°C to -80°C; preferably, the reaction temperature is -50°C to -80°C; preferably, the reaction temperature is -60°C to -80°C; more preferably, the reaction temperature is -78°C.

[0024] As described in the present invention, the preparation method of the compound represented by formula (Ia) of the present invention is to carry out an asymmetric addition reaction on the ketone group on the compound represented by formula (II-a) by trimethylsilyl acetylene to introduce a new chiral center. This reaction can obtain a compound represented by formula (Ia) with high purity and high dr value by optimizing the selection of additives. In addition, the type and amount of additives have different effects on the reaction. When the additive is tetramethylethylenediamine and the amount of tetramethylethylenediamine is 0.5 times the equivalent of the compound represented by formula (II-a), the reaction is complete, and the product has high purity and high dr value; when the additive is (-)-cytisine and the amount of (-)-cytisine is 1.0 times the equivalent of the compound represented by formula (II-a), the reaction is complete, and the product has high purity and high dr value.

[0025] The compound represented by formula (Ia) obtained by the preparation method of the compound represented by formula (Ia) described in the present invention has high purity and high dr value. After recrystallization, the purity and dr value of the compound represented by formula (Ia) can be further improved, wherein the dr value after recrystallization can be >99:1.

[0026] The present invention also relates to tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate and its crystalline forms, namely, the compound represented by formula (Ia) and its crystalline forms. The crystalline forms provided by the present invention can be identified and distinguished from other crystalline forms by means of their characteristic single crystal X-ray diffraction patterns, X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) curves, and thermogravimetric (TGA) analysis patterns.

[0027] In one aspect, the present invention relates to a compound represented by formula (Ia),

[0028]

[0029] On the other hand, the present invention relates to a crystalline form A of the compound represented by formula (Ia),

[0030]

[0031] In some embodiments, the differential scanning calorimetry chart of Form A of the compound represented by Formula (Ia) comprises a maximum endothermic peak at 93.12°C ± 3°C.

[0032] In some embodiments, the crystalline form A of the compound represented by formula (Ia) has substantially Figure 1 Differential scanning calorimetry diagram shown.

[0033] In some embodiments, the crystalline form A of the compound represented by formula (Ia) has the following unit cell parameters:

[0034] Unit cell specifications: α=90°, β=97.3928°, γ=90°;

[0035] Space group: P21;

[0036] Unit cell volume:

[0037] The number of asymmetric units Z in the unit cell is 2.

[0038] In some embodiments, the X-ray powder diffraction pattern of Form A of the compound represented by formula (Ia) has diffraction peaks at the following 2θ angles: 5.92°±0.2°, 8.62°±0.2°, 11.32°±0.2°, 12.97°±0.2°, 17.76°±0.2°, and 19.86°±0.2°.

[0039] In some further embodiments, the X-ray powder diffraction pattern of Form A of the compound represented by formula (Ia) has diffraction peaks at the following 2θ angles: 5.72°±0.2°, 5.92°±0.2°, 8.62°±0.2°, 11.32°±0.2°, 12.97°±0.2°, 13.35°±0.2°, 14.91°±0.2°, 15.29°±0.2°, 15.57°±0.2°, 16.51°±0.2°, 17.02°±0.2°, 17.76°±0.2°, 19.40°±0.2°, 19.86°±0.2°, 20.26°±0.2°, 22.52°±0.2°, and 23.82°±0.2°.

[0040] In other embodiments, the X-ray powder diffraction pattern of the crystalline form A of the compound represented by formula (Ia) has diffraction peaks at the following 2θ angles: 5.72°±0.2°, 5.92°±0.2°, 8.62°±0.2°, 11.32°±0.2°, 11.82°±0.2°, 12.38°±0.2°, 12.97°±0.2°, 13.35°±0.2°, 14.91°±0.2°, 15.29°±0.2°, 15.57°±0.2°, 16.51°±0.2°, 17.02°±0.2°, 17.33°±0.2°, 1 .2°, 7.76°±0.2°, 19.40°±0.2°, 19.86°±0.2°, 20.26°±0.2°, 20.93°±0.2°, 21.59°±0.2°, 22.22°±0.2°, 22.52°±0.2°, 23.85°±0.2°, 25.21°±0.2°, 25.75°±0.2°, 26.40°±0.2°, 26.93°±0.2°, 29.84°±0.2°, 30.32°±0.2°, 32.57°±0.2°, 37.05°±0.2°, and 38.44°±0.2°.

[0041] In some other embodiments, the crystalline form A of the compound represented by formula (Ia) has substantially Figure 4 The X-ray powder diffraction pattern is shown.

[0042] In some embodiments, when the crystalline form A of the compound represented by formula (Ia) is heated to 150.09° C., it loses 0.1199% of its weight, and the weight loss ratio has an error tolerance of ±0.1%.

[0043] In some embodiments, the crystalline form A of the compound represented by formula (Ia) has substantially Figure 2 Thermogravimetric analysis diagram shown.

[0044] Detailed description of the invention

[0045] The present invention provides a key intermediate of a glucopyranosyl derivative that serves as a sodium-dependent glucose transporter (SGLT) inhibitor and a method for its preparation. Those skilled in the art can refer to the disclosure herein and appropriately modify the process parameters to achieve the desired results. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

[0046] Definitions and General Terms

[0047] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0048] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0049] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0050] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0051] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, the chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0052] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0053] The term "equivalent" or "eq." as used in the present invention refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0054] As used herein, the term "dr" or "dr value" refers to the ratio of the content of one diastereomer to the content of the other diastereomer. The higher the dr value, the higher the diastereoselectivity. For example, tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate of the present invention, i.e., the compound represented by formula (Ia), is diastereomer A, and tert-butyl-4-((2R,3S,4S,5R)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate is diastereomer B. Thus, dr = diastereomer A / diastereomer B.

[0055] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0056] The term "room temperature" refers to 10°C to 40°C. In some embodiments, "room temperature" refers to 10°C to 30°C; in some embodiments, "room temperature" refers to 20°C to 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0057] In the context of the present invention, all numerical values ​​disclosed herein are approximate. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, or 10%. Whenever a number having a value of N is disclosed, any number within the value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is expressly disclosed, where "+ / -" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, are disclosed within a numerical range, any value within the disclosed range is expressly disclosed.

[0058] All reaction steps described in the present invention are subjected to post-processing, such as cooling, collection, extraction, filtration, separation, purification, or a combination thereof, after the reaction reaches a certain level, such as when the raw material consumption is greater than 70%, greater than 80%, greater than 90%, or greater than 95%, or after detection that the raw material has been completely consumed. The reaction level can be detected by conventional methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), etc. The reaction solution can be post-processed using conventional methods, for example, by evaporating the reaction solvent under reduced pressure or conventional distillation, collecting the crude product, and directly feeding it into the next reaction; or directly filtering the crude product, and directly feeding it into the next reaction; or standing it, decanting the supernatant to obtain the crude product, and directly feeding it into the next reaction; or selecting an appropriate organic solvent or a combination thereof for purification steps such as extraction, distillation, crystallization, column chromatography, rinsing, and beating.

[0059] The solvents used in each reaction step described in the present invention are not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents equivalent to those described in the present invention, solvent combinations, and different ratios of solvent combinations in the art are considered to be within the scope of the present invention. The present invention provides preferred solvents for use in each reaction step.

[0060] The content of water in the solvent of the present invention is not particularly limited, that is, the content of water in the solvent does not affect the occurrence of the reaction of the present invention. Any solvent containing a certain amount of water that can be used in the present invention to a certain extent is considered to be the solvent of the present invention. For example, the content of water in the solvent is approximately less than 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, less than 5%, less than 10%, less than 25%, less than 30%, or 0%. In some embodiments, the water content of the solvent is within a certain range, which is more conducive to the reaction; for example, in the step of using ethanol as the reaction solvent, using anhydrous ethanol is more conducive to the reaction. In some embodiments, the water content of the solvent exceeds a certain range, which may affect the reaction (for example, affecting the yield of the reaction), but does not affect the occurrence of the reaction.

[0061] The crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0062] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the numerical value of the 2θ cannot be considered absolute. According to the instrument conditions used in this experiment, there is an error tolerance of ±0.2° for the diffraction peak.

[0063] Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling the sample under program control. The height of the endothermic peak of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline form of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values ​​of the DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. According to the instrument conditions used in this experiment, the endothermic peak has an error tolerance of ±3°C.

[0064] Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation or decomposition of a sample, and can infer the presence of water of crystallization or solvent in the crystals. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and samples. Due to the instrumentation used in this test, the mass change has an error tolerance of ±0.1%.

[0065] In the context of the present invention, the 2θ values ​​in the X-ray powder diffraction pattern are all in degrees (°).

[0066] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, or the DSC pattern, or the Raman spectrum pattern, or the infrared spectrum pattern are shown in the pattern.

[0067] When referring to a spectrum and / or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and is not attributable to background noise.

[0068] The present invention relates to the crystalline form of tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate, i.e., the compound represented by formula (Ia), which exists in a substantially pure crystalline form.

[0069] "Substantially pure" means that one crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystalline form contains other crystalline forms, and the percentage of the other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0070] "Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0071] The "relative intensity" (or "relative peak height") in the XRPD pattern refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in the X-ray powder diffraction pattern when the intensity of the first strongest peak is 100%.

[0072] General synthesis and detection methods

[0073] In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure shall prevail.

[0074] Those skilled in the art will recognize that the chemical reactions described herein can be suitably used to prepare a wide variety of compounds similar to those described herein. Those skilled in the art can also implement the present invention by modifying the reactions, such as by using appropriate protecting groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions, and such conventional modifications are considered within the scope of the present invention. Furthermore, the reactions disclosed herein and known reaction conditions are also generally applicable to the preparation of other compounds similar to those described herein.

[0075] Generally, the methods described herein can produce the compounds of formula (Ia). The following examples are provided to further illustrate the present invention.

[0076] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR). 1 H-NMR, 13 C-NMR chemical shifts (δ) are given in parts per million (ppm). 1H-NMR, 13 C-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvents used were deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or deuterated DMSO (DMSO-d6), with TMS (0 ppm) or deuterated chloroform (7.26 ppm) as the reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doubletofdoublets), ddt (doublet of doublet of triplets), td (triplet of doublets), brs (broadened singlet). Coupling constants, J, are expressed in Hertz (Hz).

[0077] MS was determined using an Agilen-6120 Quadrupole LC / MS mass spectrometer;

[0078] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate.

[0079] The starting materials of the present invention are known and can be purchased on the market from companies such as Shanghai Accela Company, Energy Company, J&K, Chengdu Aiertai Company, and Tianjin Alfa Company, or can be synthesized according to methods known in the art.

[0080] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0081] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon or steel autoclave with a capacity of about 1L.

[0082] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L or a stainless steel high-pressure reactor with a volume of about 1L.

[0083] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0084] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0085] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions included: dichloromethane and methanol system, dichloromethane and ethyl acetate system, and petroleum ether and ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0086] HPLC refers to high performance liquid chromatography.

[0087] HPLC analysis was performed using an Agilent 1200 high pressure liquid chromatograph (Zorbax Eclipse Plus C18 150×4.6 mm column).

[0088] HPLC test conditions: Run time: 30 min Column temperature: 35°C PDA: 210 nm, 254 nm

[0089] Mobile phase: Phase A: H2O Phase B: Acetonitrile Flow rate: 1.0 mL / min

[0090] The following abbreviations are used throughout this disclosure:

[0091] BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1 This is a differential scanning calorimetry (DSC) diagram of Form A of the compound represented by formula (Ia) of the present invention.

[0093] Figure 2 This is a thermogravimetric analysis (TGA) diagram of Form A of the compound represented by formula (Ia) of the present invention.

[0094] Figure 3 1 is a unit cell diagram of the crystalline form A of the compound represented by formula (Ia) of the present invention.

[0095] Figure 4 This is the X-ray powder diffraction (XRPD) pattern of Form A of the compound represented by formula (Ia) of the present invention.

[0096] Synthesis scheme

[0097]

[0098] The compound represented by formula (I) can be prepared according to the above-mentioned synthesis scheme, wherein the reduction ring-closure reaction in the last step can refer to the method described in the prior art (such as mentioned in the present invention); the compound represented by formula (Ia) can be prepared according to the method described in the present invention. In the synthesis scheme, the compound represented by formula (II-a) or (Ia) is used as the starting material to prepare the compound represented by formula (I) in high yield and high purity. The reaction conditions of each step are mild and the operation is simple, which is suitable for industrial production. Among them, the compound represented by formula (Ia) is an important intermediate and can be used to prepare the compound represented by formula (I) in high yield and high purity; the method for preparing the compound represented by formula (I) using the compound represented by formula (Ia) includes but is not limited to the method described in the embodiments of the present invention. DETAILED DESCRIPTION

[0099] The present invention is further described below by way of examples, which do not limit the present invention to the scope of the examples.

[0100] The X-ray powder diffraction analysis method used in this invention is to obtain X-ray powder diffraction patterns using an Empyrean diffractometer using Cu-Kα radiation (45 kV, 40 mA). A thin layer of powdered sample was prepared on a single crystal silicon sample holder and placed on a rotating sample stage. Analysis was performed within the range of 3°-40° or 3°-60° with a step size of 0.0167°. Data were collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0101] The differential scanning calorimetry (DSC) analysis method used in this invention is performed using a TA Q2000 module with a thermal analysis controller. Data are collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample is accurately weighed into a custom aluminum crucible with a lid. Samples are analyzed from room temperature to approximately 300°C using a linear heating device at 10°C / min. During use, the DSC cell is purged with dry nitrogen.

[0102] Thermogravimetric analysis (TGA) was performed using a TA Instruments Q500 thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10-30 mg of sample was placed in a platinum crucible and analyzed using a linear heating device at 10°C / min from room temperature to approximately 300°C. The TGA chamber was purged with dry nitrogen during use.

[0103] The embodiments of the present invention disclose a method for preparing optically pure tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate, i.e., a compound represented by formula (Ia). Those skilled in the art can refer to the contents of this article or appropriately improve the process parameters to implement the contents of the present invention. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the scope of the present invention. The method of the present invention has been described through examples, and relevant personnel can obviously modify or appropriately change and combine the methods described herein without departing from the content and scope of the present invention to implement and apply the technology of the present invention.

[0104] In order to further understand the present invention, the present invention is described in detail below with reference to the embodiments.

[0105] Example

[0106] Example 1 Synthesis of tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate (compound represented by formula (Ia))

[0107]

[0108] Step 1 Synthesis of (3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one

[0109]

[0110] Dissolve 2,3,4,6-tetra-O-benzyl-D-glucopyranose (50.0 g, 92.5 mmol) in dichloromethane (450 mL). Add sodium bicarbonate (46.6 g, 555 mmol) in water (450 mL). Cool to 0°C, add potassium bromide (6.6 g, 55 mmol) and TEMPO (2.19 g, 13.9 mmol). Stir for 2 minutes, then add NaClO solution (120 g, 270 mmol, 4.0 mass% available chlorine). Stir the mixture for 1 hour. Separate the liquid, wash with water (50 mL), then with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a yellow oil (48.6 g, 90.2 mmol, yield: 97.6%).

[0111] Step 2 tert-Butyl 4-[(2R,3S,4R,5R)-2,3,4,6-tetrabenzyloxy-5-hydroxy-hexanoyl]piperazine-1-carboxylate Synthesis of esters

[0112]

[0113] At room temperature, (3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one (199.0 g, 396.5 mmol) was dissolved in toluene (600 mL). A solution of N-Boc piperazine acetate (227.5 g, 923.7 mmol) in toluene (400 mL) was slowly added dropwise under nitrogen at room temperature. The temperature was maintained and the reaction was stirred for 12 hours. After the reaction was completed, water (500 mL) was added to the reaction system and stirred for 10 minutes. The mixture was allowed to stand for separation. The upper organic phase was washed once with saturated aqueous sodium chloride solution (800 mL). n-heptane (3.0 L) was added dropwise until the system became turbid. The mixture was stirred at room temperature for 4-5 hours to precipitate a large amount of white solid. The temperature was lowered to 10°C and stirring was continued for 3 hours. The mixture was filtered with suction. The wet product was added to toluene (600 mL) and stirred to dissolve. n-hexane (1.6 L) was added and stirred for crystallization for 12 hours to precipitate an off-white solid. The solid was filtered with suction and rinsed with a small amount of n-heptane (150 mL). The collected solid was dried in vacuo at 40°C to give the title compound as an off-white solid (153.2 g, 211.36 mmol, yield: 56.8%).

[0114] Step 3 tert-Butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate (Formula Synthesis of the compound (II-a)

[0115]

[0116] tert-Butyl 4-[(2R,3S,4R,5R)-2,3,4,6-tetrabenzyloxy-5-hydroxy-hexanoyl]piperazine-1-carboxylate (500.0 g, 689.8 mmol) was dissolved in toluene (1.5 L), and DMSO (900 mL) and DIPEA (800 mL, 4828.4 mmol) were added. The mixture was cooled to 0°C under a nitrogen atmosphere, and sulfur trioxide pyridine (384.2 g, 2415.2 mmol) was added portionwise at 0-5°C. After the addition was complete, the mixture was stirred at 0-5°C for 2 hours and the reaction was monitored by TLC. It was found that a small amount of the starting material had not reacted completely, so sulfur trioxide pyridine (100 g) was added and the reaction was continued with stirring. The reaction was found to be complete by TLC spot plate monitoring. Tap water (2.5 L) was added to the reaction system for washing, and the liquid was separated. The upper organic phase was washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2000 mL), and silica gel (100 g) and activated carbon (50 g) were added and stirred for 20 minutes. After filtering, the filtrate was concentrated under reduced pressure to near dryness to give the title compound as a red oil (470.0 g, 650.2 mmol, yield: 94.2%).

[0117] Step 4: tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxy Synthesis of hept-6-ynyl)piperazine-1-carboxylate (compound represented by formula (Ia))

[0118]

[0119] Example 1:

[0120] Under nitrogen protection, trimethylsilyl acetylene (110.2 mL, 780.2 mmol) was dissolved in THF (1.0 L) and cooled to -78 °C. TMEDA (48.7 mL, 325.1 mmol) was slowly added. After stirring for 10 min, LiHMDS (780.2 mL, 1 mol / L) was slowly added dropwise. After stirring for 30 min, tert-butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate (compound represented by formula (II-a)) dissolved in THF (1.0 L) was slowly added dropwise. A solution of 470.0 g (650.2 mmol) was reacted at -78°C for 2 h, then diluted with ethyl acetate (1.0 L) and quenched with saturated aqueous ammonium chloride (1.0 L). The upper organic phase was washed with 10% aqueous citric acid (2.0 L) until the aqueous phase became slightly acidic (pH approximately 3-5), then washed with saturated brine (500 mL). The organic phase was concentrated to near dryness under reduced pressure. MeOH (800 mL) and K2CO3 (100 g) were added to the concentrated oil at 0°C. After addition, the oil was returned to room temperature with stirring and monitored by TLC. The reaction was complete in approximately 0.5-2 h. The filtrate was filtered and concentrated to near dryness to afford the title compound as a red oil (480 g, HPLC purity: 80.8%, dr value: 86:14). Isopropyl ether (960 mL) was added to the red oil, and the mixture was heated at 60°C to completely dissolve it. The temperature was then restored to room temperature, seed crystals were added, and the mixture was stirred for 2-4 h. The mixture was moved to 0°C and stirred for another 1 h. The mixture was filtered and washed with isopropyl ether (50.0 mL×2) at 0°C to obtain a white powdery solid, i.e., Form A of the compound represented by formula (Ia) (233.0 g, 311.11 mmol, yield: 48.0%, HPLC purity: 98.42%, dr value >99:1).

[0121] Identification of Form A of the compound represented by formula (Ia):

[0122] (1)LC-MS:calcd.for C 45 H 53 N2O8 + [M+H] + :749.4;found:749.3; (2)

[0124] 1H NMR (400MHz, CDCl3) δ7.39–7.23(m,20H),4.91(dd,J=11.6,6.4Hz,2H),4.74(dd,J=20.8,10.8Hz,2H),4.68–4.47(m, 6H),4.05(d,J=3.6Hz,1H),3.84(s,1H),3.65(s,2H),3.59–3.36(m,4H),3.36–2.94(m,4H),2.54(s,1H),1.48(s,9H);

[0125] 13 C NMR (100MHz, CDCl3) δ168.4,154.5,138.2,137.8,137.7,137.0,128.7,128.5,128.4,128.4,128.3,128.2,128.1,128.0,127 .9,127.8,127.8,127.6,84.6,80.2,79.1,78.2,77.3,77.0,76.8,75.1,74.7,74.6,73.7,73.2,73.0,72.7,45.0,42.3,28.4.

[0126] (3) TA Q2000 differential scanning calorimetry (DSC) analysis was performed at a scanning speed of 10°C / min, including an endothermic peak at 93.12°C, with an error margin of ±3°C.

[0127] (4) Thermogravimetric analysis (TGA) was performed by TA Q500: when the temperature was increased at a rate of 10°C / min and heated to 150.09°C, the weight loss was 0.1199%, with an error margin of ±0.1%.

[0128] (5) X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following peaks expressed in degrees 2θ: 5.72°, 5.92°, 8.62°, 11.32°, 11.82°, 12.38°, 12.97°, 13.35°, 14.91°, 15.29°, 15.57°, 16.51°, 17.02°, 17.33°, 17.76°, 19.40°, 19.86°, 20.26°, 20.93°, 21.59°, 22.22°, 22.52°, 23.85°, 25.21°, 25.75°, 26.40°, 26.93°, 29.84°, 30.32°, 32.57°, 37.05°, 38.44°, with an error tolerance of ±0.2°.

[0129] Example 2-15:

[0130] Trimethylsilylacetylene, additives and THF (2.0 mL) were added to a 10 mL reaction tube, cooled to a certain reaction temperature, stirred for 10 min, and then LiHMDS was added. After stirring at this temperature for 15-30 min, 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylic acid tert-butyl ester, i.e., a solution of the compound represented by formula (II-a) (0.72 g, 1.0 mmol) in THF (2.0 mL) was added. After stirring at this temperature for 1-2 h, the reaction was monitored by a plate to see if it was complete. Post-treatment: The reaction solution was diluted with ethyl acetate (10 mL), and then quenched with 1 M aqueous hydrochloric acid solution (adjusting the pH range to 3-5), and then separated. The upper organic phase was concentrated under reduced pressure to near dryness, and MeOH (2.0 mL) and K2CO3 (0.2 g) were added to the concentrated oil at 0°C. After the addition was complete, the mixture was returned to room temperature and stirred. TLC was used to monitor the reaction. The reaction was complete in about 0.5-2 hours. After the TMS group was basically completely removed, the insoluble matter was filtered out, and a small amount of the organic phase was diluted and sent for HPLC analysis. The additives used in Examples 2-15 and their amounts, the amount of trimethylsilyl acetylene, the amount of LiHMDS, the reaction temperature, and the experimental results are shown in Table 1.

[0131] Table 1:

[0132]

[0133]

[0134] Note: “─” means not added or does not exist.

[0135] Example 16-17:

[0136] To a 10 mL reaction tube, trimethylsilylacetylene (0.15 mL, 1.1 eq.) and THF (2.0 mL) were added, with or without TMEDA (165.0 μL, 1.1 eq.). The temperature was lowered to -78°C, and after stirring for 10 min, n-BuLi (1.1 mL, 1.0 mol / L) was added. After stirring at this temperature for 15-30 min, a solution of tert-butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate, i.e., the compound represented by formula (II-a) (0.72 g, 1.0 mmol) in THF (2.0 mL) was added. After stirring at this temperature for 1-2 h, the reaction was monitored by a plate. Post-treatment: The reaction mixture was diluted with ethyl acetate (10 mL) and quenched with 1 M aqueous hydrochloric acid (adjusted to pH 3-5). The upper organic phase was separated and concentrated to near dryness under reduced pressure. MeOH (2.0 mL) and K2CO3 (0.2 g) were added to the concentrated oil at 0°C. After complete addition, the mixture was returned to room temperature and stirred. The reaction was monitored by TLC. The reaction was complete in approximately 0.5-2 h. After the TMS group was essentially removed, the insoluble material was filtered and a small amount of the organic phase was diluted and analyzed by HPLC. The results are shown in Table 2.

[0137] Table 2:

[0138]

[0139] Note: “─” means not added or does not exist.

[0140] The experimental results show that when trimethylsilyl acetylene and n-BuLi are used for the reaction, adding or not adding TMEDA has little effect on the dr value, but it will affect the HPLC purity. Adding TMEDA will make the HPLC purity even lower. When trimethylsilyl acetylene and LiHMDS are used for the reaction, as shown in the experimental results of Examples 2-15, the HPLC purity and dr value of the obtained product are both high, and adding TMEDA (Example 4) is significantly better than not adding TMEDA (Example 5), and the HPLC purity and dr value are increased by about 10%. It can be seen that different organolithium reagents have different effects on the reaction results with or without TMEDA. In addition, n-BuLi is more dangerous, flammable and explosive, has a fire risk, and is not suitable for industrial amplification.

[0141] Example 18:

[0142] A solution of tert-butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate (Formula (II-a)) (0.72 g, 1.0 mmol) in THF (3.0 mL) was added to a 10 mL reaction tube. The mixture was cooled to -20°C and stirred for 30 minutes. Afterwards, ethynylmagnesium bromide (5.0 mL, 0.5 mol / L) was added. The mixture was stirred and allowed to react for 1-2 hours. The reaction was monitored for completion by a flow cytometer. Post-treatment: The reaction mixture was diluted with ethyl acetate (10 mL) and quenched with 1 M aqueous hydrochloric acid (pH adjusted to 3-5). The mixture was separated, and the upper organic phase was diluted and analyzed by HPLC. The results are shown in Table 3.

[0143] Table 3:

[0144]

[0145]

[0146] Note: “─” means not added or does not exist.

[0147] Experimental results show that when the Grignard reagent ethynylmagnesium bromide is used for the reaction, the resulting product has a low diastereoselectivity, with a dr value of 53.4:46.6. However, when trimethylsilylacetylene and LiHMDS are used for the reaction, as shown in the experimental results of Example 2-15, the resulting product has a significantly higher diastereoselectivity, with a dr value of ≥74:26. ​​Furthermore, ethynylmagnesium bromide is not only expensive but also difficult to guarantee in quality, making it unsuitable for industrial scale-up.

[0148] Example 19-21:

[0149] To a 10 mL reaction tube, trimethylsilylacetylene (0.17 mL, 1.2 eq.), metal salt (M), chiral ligand (L), additives, and THF (2.0 mL) were added. The temperature was lowered to -78°C, and the mixture was stirred for 10 min. LiHMDS (1.2 mL, 1.0 mol / L) was added. The mixture was stirred at this temperature for 15-30 min, and then a solution of tert-butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate, i.e., the compound represented by formula (II-a) (0.72 g, 1.0 mmol) in THF (2.0 mL) was added. The mixture was stirred at this temperature for 1-2 h, and the reaction was monitored by a plate. Post-treatment: The reaction solution was diluted with ethyl acetate (10 mL), and then quenched with 1 M aqueous hydrochloric acid solution (adjusting the pH range to 3-5). The upper organic phase was concentrated under reduced pressure to near dryness. MeOH (2.0 mL) and K2CO3 (0.2 g) were added to the concentrated oil at 0°C. After addition, the mixture was returned to room temperature and stirred. The reaction was monitored by TLC. The reaction was complete in about 0.5-2 hours. After the TMS group was basically completely removed, the insoluble matter was filtered out, and a small amount of the organic phase was diluted and sent for HPLC analysis. The metal salt (M), chiral ligand (L), additives and their amounts, reaction temperature and experimental results used in Examples 19-21 are shown in Table 4.

[0150] Table 4:

[0151]

[0152] Note: “─” indicates not added or not present; “NR” indicates no reaction.

[0153] Experimental results show that using Zn(OTf)2 with a Salen ligand, or highly active diethylzinc with an R-(+)-BINOL ligand, as Lewis acids to activate the carbonyl group to control the chiral environment and thereby improve the diastereoselectivity of the reaction, did not yield good results. However, using the common additive TMEDA for the reaction, as shown in the experimental results of Example 2-15, achieved high diastereoselectivity and a high-purity product. Furthermore, the metal salt (M) and chiral ligand (L) are relatively expensive and costly.

[0154] Example 22:

[0155] Lithium bis(trimethylsilyl)amide (81.5 g, 94.77 mmol, 1 mol / L tetrahydrofuran solution) and N,N,N,N′-tetramethylethylenediamine (11.09 g, 95.45 mmol) were cooled to -78 ° C under a nitrogen atmosphere, and trimethylsilyl acetylene (9.51 g, 96.84 mmol) was added. After the addition, the mixture was stirred for 120 minutes. Then, a solution of tert-butyl 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate (50.00 g, 69.17 mmol, purity: 98.72%) in tetrahydrofuran (70 g) was added dropwise. After the addition was completed, the temperature was controlled at -78 ° C and the reaction was stirred for 30 minutes. Methanol (79 g) was added, and the reaction was stirred at room temperature for 0.5 h, and the mixture was concentrated under reduced pressure. Isopropyl ether (109 g) was added to the concentrate, and the mixture was stirred to dissolve. The mixture was washed with a solution of citric acid (25 g) in water (100 g), and the layers were separated and concentrated under reduced pressure. Isopropyl ether (109 g) was added to the concentrate and the mixture was dissolved at 60°C, then the temperature was reduced to 20°C-30°C, and the mixture was stirred for 5 h, then reduced to 0°C, and stirred for 1 h. The mixture was crystallized and centrifuged. The filter cake was washed with 0°C isopropyl ether (36 g), and the filter cake was collected and dried in vacuo at 45°C for 6 hours to give the title compound as a white solid (37.07 g, 49.5 mmol, product content: 99.47%, yield: 71.56%).

[0156] Example 2 Single Crystal Cultivation of Form A of the Compound Represented by Formula (Ia)

[0157] Tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate prepared in Example 1, i.e., Form A of the compound represented by Formula (Ia) (30 mg, 0.040 mmol) was weighed into a 5.0 mL round-bottom flask, and ethyl acetate (0.5 mL) was added. After slight heating to dissolve, n-heptane (2.5 mL) was slowly added, and the mixture was allowed to stand in a refrigerator at 4°C for 10 days. Single crystals precipitated after 10 days.

[0158] Example 3 X-ray single crystal diffraction study of the single crystal of Form A of the compound represented by formula (Ia)

[0159] The diffractometer was operated on an Agilent Technologies Gemini AUltra using Cu Kα radiation. The data were collected, indexed and processed using the CrysAlis PRO program. The unit cell parameters were determined through preliminary experiments and a data collection strategy was developed based on the unit cell parameters.

[0160] The structure was solved and refined using the SHELX-97 (Sheldrick, GMSHELXTL-97, Program for Crystal Structure Solution and Refinement; University of Gottingen: Gottingen, Germany, 1997) program. The solution was performed by direct methods. The derived atomic parameters (coordinates and temperature factors) were refined by complete matrix least squares. The function ∑ w (|F o |-|F c |) 2 . R is defined as ∑||F o |-|F c || / ∑|F o |, and R w =[∑ w (|F o |-|F c |) 2 / ∑ w |F o |2] 1 / 2 , where w is a suitable weighting function based on the error in the observed intensity. Difference maps were examined at all stages of the correction. With the exception of hydrogen atoms H1N and H2N, whose positions were determined using difference Fourier maps, the positions of the remaining hydrogen atoms were obtained by theoretical calculations. Simulated X-ray powder diffraction patterns were calculated using Mercury software.

[0161] Single crystals of appropriate size (single crystals of Form A of the compound represented by Formula (Ia) prepared in Example 2) were selected for single crystal diffraction analysis. The selected crystals were secured to a thin glass fiber with a small amount of vaseline and mounted on an Agilent Technologies Gemini A Ultra diffractometer. Measurements were performed at approximately 150 K, yielding the unit cell parameters listed in Table 5 and the fractional atomic coordinates shown in Table 6.

[0162] Table 5 Unit cell parameters of single crystal of Form A of the compound represented by formula (Ia)

[0163]

[0164] Table 6 Fractional atomic coordinates of single crystal of Form A of the compound represented by formula (Ia)

[0165]

[0166]

[0167] Example 3 Synthesis of tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxy-6-oxoheptanoyl)piperazine-1-carboxylate

[0168]

[0169] To the bottle, tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate (749 mg, 1.00 mmol, purity: 98.42%), acetonitrile (1.58 g), cuprous oxide (29 mg, 0.20 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (76 mg, 0.50 mmol) and drinking water (36 mg, 2.00 mmol) were added. After the addition, the N2 gas was replaced three times, and then CO2 was introduced to a pressure of 1 MPa. The temperature was raised to 60°C and the reaction was stirred for 18 hours. After the reaction was completed, the temperature was lowered to 10°C, and an aqueous solution of citric acid (1.0 mL) was added to the reaction solution. The solution was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (5 mL), washed with water (5 mL x 2), and concentrated under reduced pressure to obtain the title compound as a yellow oil (770 mg, 1.00 mmol, product content: 66.44%, yield: 100%). MS (ESI, pos. ion) m / z: 767.4 [M+H] + .

[0170] Example 4 Synthesis of tert-butyl-4-((2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5,6-dihydroxyheptanoyl)piperazine-1-carboxylate

[0171]

[0172] To the bottle, tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxy-6-oxoheptanoyl)piperazine-1-carboxylate (10 g, 13.04 mmol, purity: 98.26%) and methyl tert-butyl ether (296 g) were added, and the temperature was lowered to 0°C. Lithium tri-tert-butoxyaluminum hydride (9.95 g, 39.12 mmol) was added. After the addition, the mixture was stirred for 2 h. Water (10 g) was added and stirred for 10 min. The mixture was filtered under reduced pressure. The filter cake was rinsed with methyl tert-butyl ether (30 g). The filtrate was collected, washed with 1 M HCl solution (200 g), and concentrated under reduced pressure to give the title compound as a yellow oil (10.03 g, 13.00 mmol, product content: 92.81%, yield: 100%).

[0173] Example 5 Synthesis of tert-butyl-4-((2R,3S,4S)-2,3,4-tribenzyloxy-4-((4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)butanoyl)piperazine-1-carboxylate

[0174]

[0175] Tert-butyl-4-((2R,3S,4S,5R,6R)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5,6-dihydroxyheptanoyl)piperazine-1-carboxylate (3.4 g, 4.42 mmol, content: 92.81%) was dissolved in acetone (26.86 g), 2,2-dimethoxypropane (1.38 g, 13.26 mmol) and p-toluenesulfonic acid monohydrate (63 mg, 0.33 mmol) were added, and the mixture was stirred for 1 hour. After the reaction, saturated sodium bicarbonate solution (1 mL) was added, and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (9.2 g), washed with water (9.2 g), and concentrated under reduced pressure to obtain the title compound as a light yellow oil (3.58 g, HPLC purity: 96.01%, yield: 100%). LC-MS: calculated. For C 48 H 61 N2O9 + [M+H] + :809.5;found:809.5.

[0176] Example 6 Synthesis of (2R,3S,4S)-2,3,4-tribenzyloxy-4-((4R,5R)-4-((benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)-1-(4-chloro-3-(4-ethoxyphenyl)methyl)phenyl)butan-1-one

[0177]

[0178] Tert-butyl-4-((2R,3S,4S)-2,3,4-tribenzyloxy-4-((4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)butanoyl)piperazine-1-carboxylate (450.50 g, 556.86 mol, product purity: 90.47%) was dissolved in anhydrous tetrahydrofuran (1.21 kg) and cooled to -20°C under a nitrogen atmosphere. A tetrahydrofuran solution of [4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]magnesium bromide (891.30 mmol, purity: 95.00%) prepared according to the prior art was added dropwise over a period of about 30 minutes. After completion of the addition, the mixture was stirred at -20°C for 20 minutes and then moved to room temperature and stirred for 2 hours. After the reaction was completed, dilute hydrochloric acid solution (1.25 L, 1 mol / L) was added at 0°C to quench the reaction. n-Heptane (1.27 kg) was added to the mixed solution for extraction. The organic phase was washed with saturated brine (1.65 L) and concentrated under reduced pressure to obtain the title compound as a yellow oil (484.18 g, product content: 82.48%, yield: 100%). HRMS: calcd. for C 54 H 61 ClNO8 + [M+NH4] + :886.4;found:886.4.

[0179] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean 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 can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0180] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a compound represented by formula (Ia), comprising the following steps: The compound represented by formula (II-a) undergoes an addition reaction with trimethylsilyl acetylene in a solvent in the presence of LiHMDS to obtain a compound represented by formula (Ia).

2. The preparation method according to claim 1, wherein the addition reaction is carried out in the presence of an additive; wherein The additive is 2,4,6-trimethylpyridine, piperidine, triethylenediamine, pyrrole, tetramethylethylenediamine, tetramethyltartrate, hexamethylphosphoramide, (-)-cytisine, triethylamine, propylenediamine, ethylenediamine, dimethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N-dimethylpropyleneurea, N-methylpyrrolidone or pyridine.

3. The preparation method according to claim 2, wherein The amount of the additive used is 0.2-1.2 times the equivalent of the compound represented by formula (II-a).

4. The preparation method according to claim 2, wherein The amount of the additive used is 0.5-1.0 times the equivalent of the compound represented by formula (II-a).

5. The preparation method according to claim 2, wherein The dosage of the additive is 0.2 times, 0.5 times or 1.0 times the equivalent of the compound represented by formula (II-a).

6. The preparation method according to claim 1, wherein The amount of trimethylsilyl acetylene used is 1.0-2.0 times the equivalent of the compound represented by formula (II-a).

7. The preparation method according to claim 1, wherein The amount of trimethylsilyl acetylene used is 1.2-1.5 times the equivalent of the compound represented by formula (II-a).

8. The preparation method according to claim 1, wherein The amount of trimethylsilyl acetylene used is 1.2 times or 1.5 times the equivalent of the compound represented by formula (II-a).

9. The preparation method according to claim 1, wherein The amount of LiHMDS used is 1.0-2.0 times the equivalent of the compound represented by formula (II-a).

10. The preparation method according to claim 1, wherein The amount of LiHMDS used is 1.2-1.5 times the equivalent of the compound represented by formula (II-a).

11. The preparation method according to claim 1, wherein The amount of LiHMDS used is 1.2 times or 1.5 times the equivalent of the compound represented by formula (II-a).

12. The preparation method according to claim 1, wherein The solvent is tetrahydrofuran, dichloromethane, toluene, ether, 2-methyl-tetrahydrofuran, n-hexane, cyclohexane or n-heptane.

13. The preparation method according to claim 1, wherein In the reaction of the compound represented by formula (II-a) and trimethylsilyl acetylene, the reaction temperature is -40°C to -80°C.

14. The preparation method according to claim 13, wherein The reaction temperature is -50°C to -80°C.

15. The preparation method according to claim 13, wherein The reaction temperature is -60°C to -80°C.

16. The preparation method according to claim 13, wherein The reaction temperature was -78°C.

17. A compound represented by formula (Ia), 18. Crystalline Form A of the compound represented by formula (Ia), It has the following characteristics: It has the following unit cell parameters: Unit cell specifications: α=90°, β=97.3928°, γ=90°; Space group: P21; Unit cell volume: The number of asymmetric units Z in the unit cell is 2.

19. The crystalline form A according to claim 18, which has the following characteristics: its differential scanning calorimetry diagram comprises a maximum endothermic peak at 93.12°C ± 3°C.

20. The crystalline form A according to claim 18, having the following characteristics: its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.92°±0.2°, 8.62°±0.2°, 11.32°±0.2°, 12.97°±0.2°, 17.76°±0.2°, and 19.86°±0.2°.

21. The crystalline form A according to claim 18 or 19, which has a differential scanning calorimetry diagram as shown in Figure 1.

22. The crystalline form A according to claim 18 or 20, wherein the X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.72°±0.2°, 5.92°±0.2°, 8.62°±0.2°, 11.32°±0.2°, 12.97°±0.2°, 13.35°±0.2°, 14.91°±0.2°, 15.29°±0.2°, 15.57°±0.2°, 16.51°±0.2°, 17.02°±0.2°, 17.76°±0.2°, 19.40°±0.2°, 19.86°±0.2°, 20.26°±0.2°, 22.52°±0.2°, and 23.82°±0.2°.

23. The crystalline form A according to claim 18 or 20, wherein the X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.72°±0.2°, 5.92°±0.2°, 8.62°±0.2°, 11.32°±0.2°, 11.82°±0.2°, 12.38°±0.2°, 12.97°±0.2°, 13.35°±0.2°, 14.91°±0.2°, 15.29°±0.2°, 15.57°±0.2°, 16.51°±0.2°, 17.02°±0.2°, 17.33°±0.2°, 17. .2°, 76°±0.2°, 19.40°±0.2°, 19.86°±0.2°, 20.26°±0.2°, 20.93°±0.2°, 21.59°±0.2°, 22.22°±0.2°, 22.52°±0.2°, 23.85°±0.2°, 25.21°±0.2°, 25.75°±0.2°, 26.40°±0.2°, 26.93°±0.2°, 29.84°±0.2°, 30.32°±0.2°, 32.57°±0.2°, 37.05°±0.2°, and 38.44°±0.2°.

24. The crystalline form A according to claim 18 or 20, which has an X-ray powder diffraction pattern as shown in Figure 4.

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