Key intermediate for preparing SGLTs inhibitor and preparation method thereof

Abstract

The invention relates to a key intermediate for preparing an SGLTs inhibitor and a preparation method of the key intermediate. The SGLTs inhibitor is a glucopyranosyl derivative. Specifically, the key intermediate provided by the invention is stable in property and few in impurities; the preparation method provided by the invention is low in reagent price, mild in reaction condition, simple and convenient in post-treatment, easy in purification, low in equipment requirement, low in production cost, safe and controllable in process and 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 SGLTs inhibitor and a preparation method thereof. The SGLTs inhibitor is a pyranose glucopyranose derivative. Background of the Invention

[0003] WO2015043511A1 and WO2016173425A1 disclose pyranose glucopyranose derivatives as sodium-dependent glucose transporter (SGLT) inhibitors, i.e., compounds as shown in formula (I). The compounds have good SGLTs inhibitory activity and are very potential new diabetes treatment drugs.

[0004]

[0005] WO2020143653A1 discloses a method for preparing a compound of formula (I) from a compound of formula (R-01), wherein the following reaction for preparing an intermediate compound of formula (IX) is disclosed: a compound of formula (X) and a Grignard reagent obtained by Grignard exchange of iodomethyl pivalate with isopropylmagnesium chloride and lithium chloride are subjected to an addition reaction to obtain a compound of formula (IX), which is then further reacted to obtain an intermediate compound of formula (I-04), and then reacted to obtain a compound of formula (I).

[0006] Route A:

[0007]

[0008] WO2022007838A1 also discloses a method for preparing a compound of formula (I) from a compound of formula (R-01), wherein the following reaction for preparing a compound of intermediate formula (VIIIb) is disclosed: a compound of formula (IXb) and a Grignard reagent obtained by Grignard exchange of iodomethyl pivalate with isopropylmagnesium chloride and lithium chloride are subjected to an addition reaction to obtain a compound of formula (VIIIb), and further reaction can obtain a compound of intermediate formula (I-04), and then the compound of formula (I) is obtained by reaction.

[0009] Route b:

[0010]

[0011] It can be seen from the above prior art that the compound represented by formula (IXb) prepared from the compound represented by formula (R-01) and its similar structure such as the compound represented by formula (X) can be used as a starting compound to prepare other intermediates, thereby finally obtaining the compound represented by formula (I). However, whether it is route a or route b, it is necessary to undergo a Grignard reaction, and the Grignard reagent is expensive, the reaction conditions are harsh, and the requirements for equipment are high, so the synthesis cost is high and it is not suitable for industrial production; in addition, route a or route b also has the disadvantage of having many steps, so the above method for preparing the compound represented by formula (I) is high in cost, harsh in conditions, and low in yield, and is not suitable for industrial production. Summary of the invention

[0012] In view of the problems existing in the methods for preparing the compound represented by formula (I) in the prior art, the present invention has carried out a lot of optimization exploration on the preparation method of the compound represented by formula (I), and provides a key intermediate suitable for industrial production and its preparation method, and also provides a method for using the intermediate to prepare the compound represented by formula (I-04).

[0013] On the one hand, the key intermediates of the present invention are stable in nature, have few impurities, and / or high optical purity (diastereoselectivity); on the other hand, the reagents used in the preparation method of the key intermediates of the present invention or the preparation method of the compound represented by formula (I) are cheap, the reaction conditions are mild, the post-treatment is simple, the purification is easy, the equipment requirements are low, the production cost is low, and the process is safer, controllable and simple.

[0014] The intermediate of the present invention has a structure as shown in formula (I-01), and is an important intermediate for synthesizing a compound of formula (I-04) or formula (I). Specifically, the present invention relates to a compound of formula (I-01) and a method for preparing the same, and also to a method for preparing the compound of formula (I-04), wherein the compound of formula (I-04) is reacted to obtain a compound of formula (I).

[0015] In one aspect, the present invention relates to a method for preparing a compound represented by formula (I-01), comprising the following steps: the compound represented by formula (I-00) is reacted in a solvent in the presence of a silver catalyst in the presence of CO 2 The reaction was carried out under an atmosphere to obtain a compound represented by formula (I-01).

[0016] Step B)

[0017] In some embodiments, the reaction is carried out in the presence of a base, and the base 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, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 4-dimethylaminopyridine, N,N-dimethylpropyleneurea, N-methylpyrrolidone or pyridine.

[0018] In other embodiments, the amount of the base used is 0.20-2.00, 0.20-1.00, 0.25-1.00, 0.30-1.00, 0.30-0.80, 0.30-0.70 or 0.40-0.70 times the equivalent of the compound represented by formula (I-00); optionally, the amount of the base used is 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90 or 1.00 times the equivalent of the compound represented by formula (I-00).

[0019] In some embodiments, the silver catalyst is AgOAc, AgOTf, AgNTf 2 AgNO 3 、AgPF 6 , AgBF 4 、Ag 2 CO 3 、AgF、PhCO 2 Ag, CF 3 COOAg、AgClO 4 or CF 3 SO 3 Ag.

[0020] In some embodiments, the amount of the silver catalyst used is 0.05-1.00, 0.05-0.50, 0.08-0.20 or 0.08-0.15 times the equivalent of the compound represented by formula (I-00); optionally, the amount of the silver catalyst used is 0.10 times the equivalent of the compound represented by formula (I-00).

[0021] In some embodiments, the reaction is carried out in the presence of water. Optionally, the amount of water is 0.01-10.0, 0.2-6.0, 0.25-5.5, 0.25-4.0 or 0.35-5.5 times the equivalent of the compound shown in formula (I-00); preferably, the amount of water is 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0 or 5.5 times the equivalent of the compound shown in formula (I-00).

[0022] In some embodiments, the solvent is acetonitrile.

[0023] In some embodiments, the CO 2 After being charged into the reaction system, the reaction is carried out under certain pressure conditions. 2 After being charged into the reaction system, the pressure of the reaction system is 0.50-1.50 MPa. 2 After charging into the reaction system, the pressure of the reaction system was 0.75±0.25MPa.

[0024] In some embodiments, the reaction temperature of the reaction is 30°C to 80°C, 40°C to 70°C, 45°C to 65°C, 45°C to 60°C or 50°C to 60°C; optionally, the reaction temperature is 45°C, 50°C, 52°C, 55°C or 60°C.

[0025] In some embodiments, the method for preparing the compound of formula (I-01) of the present invention also includes a method for preparing the compound of formula (I-00), which comprises the following steps: reacting the compound of formula (R-02) with an alkynyl compound in a solvent under the action of a Li catalyst to obtain the compound of formula (I-00),

[0026] Step A)

[0027] In some embodiments, the alkynyl compound is trimethylsilylacetylene.

[0028] In some embodiments, the Li catalyst is LiHMDS (lithium bis(trimethylsilyl)amide).

[0029] In some embodiments, the reaction of step A) refers to the reaction of the compound represented by formula (R-02) with trimethylsilyl acetylene in the presence of LiHMDS to obtain the compound represented by formula (I-00).

[0030] In some embodiments, the reaction of step A) 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.

[0031] In other embodiments, the amount of the additive is 0.2-1.2 times the equivalent of the compound represented by formula (R-02); preferably, the amount of the additive is 0.5-1.0 times the equivalent of the compound represented by formula (R-02); 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 (R-02).

[0032] In some embodiments, the amount of the alkynyl compound used is 1.0-2.0 or 1.1-1.6 times the equivalent of the compound represented by formula (R-02); preferably, the amount of the alkynyl compound used is 1.2-1.5 times the equivalent of the compound represented by formula (R-02); more preferably, the amount of the alkynyl compound used is 1.2 times or 1.5 times the equivalent of the compound represented by formula (R-02).

[0033] In some other embodiments, the amount of the Li catalyst used is 0.1-2.0 times the equivalent of the compound shown in formula (R-02); in some other embodiments, the amount of the Li catalyst used is 1.0-2.0 times the equivalent of the compound shown in formula (R-02); in some other embodiments, the amount of the Li catalyst used is 1.0-1.6 or 1.1-1.6 times the equivalent of the compound shown in formula (R-02); in some other embodiments, the amount of the Li catalyst used is 1.2-1.5 times the equivalent of the compound shown in formula (R-02); preferably, the amount of the Li catalyst used is 1.2 times or 1.5 times the equivalent of the compound shown in formula (R-02).

[0034] 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.

[0035] In some embodiments, in the reaction of step A), 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.

[0036] The compound represented by formula (I-01) obtained by the preparation method of the compound represented by formula (I-01) described in the present invention has high purity and high dr value. After post-treatment, the purity and dr value of the compound represented by formula (I-01) can be further improved.

[0037] The present invention also relates to a method for preparing a compound of formula (I-04) using a compound of formula (I-01). The compound of formula (I-04) can be reacted to obtain a compound of formula (I).

[0038] The preparation method of the compound represented by formula (I-04) of the present invention comprises:

[0039] Step E) The compound represented by formula (I-03) is reacted with [4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]magnesium bromide in a solvent to obtain a compound represented by formula (I-04),

[0040]

[0041] In some embodiments, the reaction solvent of step E) is tetrahydrofuran, methyltetrahydrofuran (eg, 2-methyltetrahydrofuran), methyl tert-butyl ether, toluene, dichloromethane or any combination thereof.

[0042] In some embodiments, the reaction temperature of step E) is 10°C to 40°C; preferably, the reaction temperature of step E) is 20°C to 30°C.

[0043] In some embodiments, the method for preparing the compound represented by formula (I-04) also includes the method for preparing the compound represented by formula (I-03), which comprises:

[0044] Step D) The compound represented by formula (I-02) reacts with 2,2-dimethoxypropane in a solvent to obtain a compound represented by formula (I-03),

[0045]

[0046] In some embodiments, the reaction solvent of step D) is acetone, toluene, 1,2-dichloroethane, dichloromethane, methyl tert-butyl ether, tetrahydrofuran or any combination thereof.

[0047] In some embodiments, the reaction temperature of step D) is 0°C to 40°C; in some embodiments, the reaction temperature of step D) is 10°C to 40°C; in some embodiments, the reaction temperature of step D) is 10°C to 30°C; in some embodiments, the reaction temperature of step D) is 20°C to 30°C.

[0048] In some embodiments, the reaction in step D) is carried out under the action of p-toluenesulfonic acid monohydrate. Optionally, the amount of p-toluenesulfonic acid monohydrate used is 0.50-1.50, 0.50-1.00 or 0.60-0.80 times the equivalent of the compound represented by formula (I-02).

[0049] In some embodiments, the method for preparing the compound represented by formula (I-04) or (I-03) also includes a method for preparing the compound represented by formula (I-02), which comprises:

[0050] Step C) reacting the compound represented by formula (I-01) in a solvent to obtain a compound represented by formula (I-02);

[0051]

[0052] In some embodiments, the reaction of step C) is carried out under the action of a reducing agent. Optionally, the reducing agent is sodium borohydride, lithium tri-tert-butoxyaluminum hydride or (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium (II) chloride.

[0053] In some embodiments, the reaction in step C) is carried out under hydrogen. Optionally, the pressure of the hydrogen atmosphere is 0.5 MPa-1.5 MPa, or 1.0±0.2 MPa.

[0054] In some embodiments, the reaction in step C) is carried out in the presence of a base, and optionally, the base is potassium carbonate, sodium carbonate or cesium carbonate.

[0055] In some embodiments, in step C), the solvent is methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butyl alcohol or any combination thereof.

[0056] In some embodiments, the reaction of step C) is carried out at low temperature (such as -45°C to 0°C) or under heating conditions (such as heating to 40°C to 70°C, 50°C to 70°C or 55°C to 65°C).

[0057] In some embodiments, the reaction of step C) is carried out under the action of sodium borohydride, wherein the reaction is optionally carried out in the presence of manganese chloride; wherein the reaction solvent of step C) is methyl tert-butyl ether, and the reaction temperature is -40±5°C.

[0058] In some embodiments, the reaction of step C) is carried out under the action of lithium tri-tert-butoxyaluminum hydride, wherein the reaction solvent of step C) is methyl tert-butyl ether, and the reaction temperature is 0±5°C.

[0059] In some embodiments, the reaction of step C) is carried out under the action of (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium (II) chloride, wherein the reaction is optionally carried out in the presence of a base (such as potassium carbonate, etc.), the reaction is optionally carried out under the range of hydrogen, the reaction solvent of step C) is isopropanol, and the reaction temperature is 60±5°C.

[0060] In some embodiments, the method for preparing the compound of formula (I-04), (I-03) or (I-02) also includes the method for preparing the compound of formula (I-01), and the method for preparing the compound of formula (I-01) is as described in the present invention.

[0061] Optionally, after the reaction of each step of the present invention is completed, a suitable post-treatment method can be selected according to the situation for purification; optionally, the post-treatment method includes but is not limited to methods commonly used in the art, such as filtration, washing, extraction, recrystallization and / or pulping, etc.

[0062] In one aspect, the present invention relates to a compound represented by formula (I-01),

[0063]

[0064] On the other hand, the present invention relates to the use of a compound represented by formula (I-01) in the preparation of a sodium-dependent glucose transporter (SGLT) inhibitor, wherein the sodium-dependent glucose transporter (SGLT) inhibitor is a pyranose glucopyranose derivative, preferably a compound represented by formula (I) of the present invention.

[0065] Detailed description of the invention

[0066] The present invention provides a key intermediate of a pyranose glucopyranose derivative as a sodium-dependent glucose transporter (SGLT) inhibitor and a preparation method thereof. A person skilled in the art can refer to the contents of this invention and appropriately improve the process parameters to achieve the above. It should be particularly noted that all similar substitutions and modifications are obvious to a person skilled in the art and are considered to be included in the present invention.

[0067] Definitions and general terms

[0068] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0069] 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 present invention as defined in the claims. It should be appreciated by those skilled in the art 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.

[0070] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0071] 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.

[0072] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent 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 can 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.

[0073] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that 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., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0074] The term "equivalent" or "eq." or "eq" number used in the present invention refers to the equivalent amount of other raw materials required based on the equivalent relationship of the chemical reaction, with the basic raw material used in each step as the benchmark (1 equivalent).

[0075] The term "dr" or "dr value" used in the present invention refers to the ratio of the content of one diastereomer to the content of another 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 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, then dr = diastereomer A / diastereomer B.

[0076] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0077] 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.

[0078] In the context of the present invention, all numbers disclosed herein are approximate. The value of each number may differ 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 explicitly disclosed, where "+ / -" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, are disclosed in a numerical range, any value within the disclosed range is explicitly disclosed.

[0079] All the reaction steps described in the present invention are subjected to post-treatment after the reaction reaches a certain degree, such as when the raw material consumption is about greater than 70%, greater than 80%, greater than 90%, greater than 95%, or after the reaction raw material is detected to have been completely consumed, such as cooling, collecting, extracting, filtering, separating, purifying or a combination thereof. The degree of reaction can be detected by conventional methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) and the like. The reaction solution can be post-treated by conventional methods, for example, after vacuum evaporation or conventional distillation of the reaction solvent, the crude product is collected and directly put into the next step of reaction; or the crude product is directly filtered to obtain the crude product and directly put into the next step of reaction; or after standing, the supernatant is poured out to obtain the crude product and directly put into the next step of reaction; or an appropriate organic solvent or a combination thereof is selected to perform extraction, distillation, crystallization, column chromatography, rinsing, beating and other purification steps.

[0080] The solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent replacements, or solvents, solvent combinations, and different proportions of solvent combinations equivalent to those described in the present invention in the art are considered to be included in the scope of the present invention. The present invention provides preferred solvents used in each reaction step.

[0081] 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 regarded as 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.

[0082] General synthesis and detection methods

[0083] In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure shall prevail.

[0084] Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many compounds similar to the compounds described herein. Those skilled in the art can also implement the present invention by modifying methods, such as appropriate protecting groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions, and these conventional preparation method modifications should also be considered to be within the scope of the present invention. In addition, the reactions disclosed in the present invention or known reaction conditions are also recognized to be applicable to the preparation of other compounds similar to the compounds described herein.

[0085] Generally, the method described in the present invention can prepare any compound described in the present invention, such as the compound represented by formula (I-01). The following examples are used to further illustrate the content of the present invention.

[0086] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR). 1 H-NMR, 13C-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvent used was deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) or deuterated DMSO (DMSO-d 6 ), using TMS (0 ppm) or deuterated chloroform (7.26 ppm) as the reference standard. When multiple peaks appear, 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 doublet of doublets), ddt (doublet of doublet of triplets), td (triplet of doublets), brs (broadened singlet). Coupling constants, J, are expressed in Hertz (Hz).

[0087] MS was determined using an Agilen-6120 Quadrupole LC / MS mass spectrometer;

[0088] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate.

[0089] 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.

[0090] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0091] Nitrogen atmosphere or nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon or steel kettle with a volume of about 1L.

[0092] Hydrogen atmosphere or 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.

[0093] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0094] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0095] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent was adjusted according to the polarity of the compound.

[0096] HPLC refers to high performance liquid chromatography.

[0097] Agilent 1200 high pressure liquid chromatograph (Zorbax Eclipse Plus C18 150×4.6 mm column) was used for HPLC determination.

[0098] HPLC test conditions: Run time: 30min Column temperature: 35°C PDA: 210nm, 254nm

[0099] Mobile phase: Phase A: H 2 OB phase: acetonitrile flow rate: 1.0 mL / min

[0100] Synthesis scheme

[0101]

[0102] The compound shown in formula (I) can be prepared according to the above synthesis scheme, wherein the oxidation reaction in the first step and the reduction ring-closing reaction in the last step can refer to the method recorded in the prior art (such as mentioned in the present invention); each step from step A to step E can be reacted according to the method or conditions described in the present invention. The method of the synthesis scheme can prepare the compound shown in formula (I) with high yield and high purity, and the reaction conditions of each step are mild and the operation is simple, which is suitable for industrial production. Among them, the preparation method of the intermediate used, such as the compound shown in formula (I-00), (I-01), (I-02) and / or (I-03), is simple, low-cost, and easy to operate. The intermediate has advantages in terms of purity and yield, and can be used to efficiently prepare the compound shown in formula (I). DETAILED DESCRIPTION

[0103] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0104] The embodiments of the present invention disclose a method for preparing an optically pure compound of formula (I-01). 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 particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the scope of the present invention. The method of the present invention has been described by way of example, 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.

[0105] In order to further understand the present invention, the present invention is described in detail below in conjunction with embodiments.

[0106] Example

[0107] 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 (I-00))

[0108]

[0109] Step 1 Synthesis of (3R, 4S, 5R, 6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one

[0110]

[0111] The compound 2,3,4,6-tetra-O-benzyl-D-pyranose (50.0 g, 92.5 mmol) was dissolved in dichloromethane (450 mL), and a solution of sodium bicarbonate (46.6 g, 555 mmol) in water (450 mL) was added, cooled to 0°C, potassium bromide (6.6 g, 55 mmol) and TEMPO (2.19 g, 13.9 mmol) were added, and after stirring for 2 minutes, a NaClO solution (120 g, 270 mmol, effective chlorine 4.0 mass%) was added, and the mixture was stirred for 1 hour. The mixture was separated, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil (48.6 g, 90.2 mmol, yield: 97.6%).

[0112] Step 2 tert-Butyl 4-[(2R,3S,4R,5R)-2,3,4,6-tetrabenzyloxy-5-hydroxy-hexanoyl]piperazine-1-carboxylate ester( Compound represented by formula (R-01) )

[0113]

[0114] 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 protection at room temperature. The temperature was maintained and the reaction was stirred for 12 hours. After the reaction is completed, water (500 mL) is added to the reaction system and stirred for 10 minutes. The mixture is allowed to stand for separation. The upper organic phase is washed once with a saturated aqueous sodium chloride solution (800 mL). The system becomes turbid after adding n-heptane (3.0 L) dropwise. The mixture is stirred at room temperature for 4-5 hours to precipitate a large amount of white solid. The mixture is cooled to 10°C and stirred for 3 hours. The mixture is filtered with suction. The wet product is added to toluene (600 mL) and stirred to dissolve. N-hexane (1.6 L) is added and stirred for crystallization for 12 hours to precipitate an off-white solid. The solid is filtered with suction and rinsed with a small amount of n-heptane (150 mL). The solid is collected and dried in vacuo at 40°C to obtain the title compound as an off-white solid (153.2 g, 211.36 mmol, yield: 56.8%).

[0115] Step 3 4-[(2 R ,3 S ,4 S tert-Butyl 2,3,4,6-tetrabenzyloxy-5-oxohexanoyl]piperazine-1-carboxylate Synthesis of the compound represented by formula (R-02)

[0116]

[0117] 4-[(2R,3S,4R,5R)-2,3,4,6-tetrabenzyloxy-5-hydroxy-hexanoyl]piperazine-1-carboxylic acid tert-butyl ester (500.0 g, 689.8 mmol) was dissolved in toluene (1.5 L), DMSO (900 mL) and DIPEA (800 mL, 4828.4 mmol) were added, and the mixture was cooled to 0°C under a nitrogen atmosphere. Sulfur trioxide pyridine (384.2 g, 2415.2 mmol) was added in batches at 0-5°C. After the addition was completed, the mixture was stirred at 0-5°C for 2 hours and the reaction was tracked by TLC. It was found that a small amount of the raw material was not completely reacted. Sulfur trioxide pyridine (100 g) was added and the reaction was continued to be stirred. 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 liquids were 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, then filtered and 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%). Step 4: tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynoyl Synthesis of 1-piperazine-1-carboxylate (compound represented by formula (I-00))

[0118]

[0119] 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, 4-[(2R,3S,4S)-2,3,4,6-tetrabenzyloxy-5-oxohexanoyl] dissolved in THF (1.0 L) was slowly added dropwise. ] Piperazine-1-carboxylic acid tert-butyl ester (compound represented by formula (R-02)) (470.0 g, 650.2 mmol) solution was reacted at -78°C for 2 h, then ethyl acetate (1.0 L) was added for dilution, and the reaction was quenched with saturated aqueous ammonium chloride solution (1.0 L). The upper organic phase was washed with 10% citric acid aqueous solution (2.0 L) until the aqueous phase was weakly acidic (pH was about 3 to 5), and then washed with saturated brine (500 mL). The organic phase was concentrated under reduced pressure to near dryness, and MeOH (800 mL) and K were added at 0°C. 2 CO 3 (100g) was added to the concentrated oil, and after adding, the mixture was returned to room temperature and stirred. The reaction was monitored by TLC. The reaction was completed in about 0.5 to 2 hours. The filtrate was filtered and concentrated to near dryness to obtain the title compound as a red oil (480g, HPLC purity: 80.8%, dr value 86:14). Isopropyl ether (960mL) was added to the red oil, and it was heated at 60°C to completely dissolve it, and then returned to room temperature. The product seed was added and stirred for 2-4 hours, then moved to 0°C and stirred for another 1 hour, and then filtered and washed with isopropyl ether (50.0mL×2) at 0°C to obtain a white powder solid, i.e., the compound represented by formula (I-00) (233.0g, 311.11mmol, yield: 48.0%, HPLC purity: 98.42%, dr value>99:1).

[0120] (1) LC-MS: calculation for C 45 H 53 N 2 O 8 + [M+H] + :749.4;found:749.3;

[0121] (2) 1 H NMR (400 MHz, CDCl 3)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);

[0122] 13 C NMR (100 MHz, CDCl 3 )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.

[0123] Example 2 Synthesis of tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxy-6-oxoheptanoyl)piperazine-1-carboxylate (compound represented by formula (I-01))

[0124]

[0125] Example 1:

[0126] Add 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 (I-00), 50 g, 66.76 mmol, purity: 98.70%), acetonitrile (592.50 g), silver acetate (1.11 g, 6.68 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.08 g, 33.38 mmol) and drinking water (0.60 g, 33.38 mmol) into the bottle. After the addition is complete, replace N 2 After three times of gas, CO 2When the pressure reaches 0.75±0.25MPa, the temperature is raised to 50°C and the reaction is stirred for 11h. After the reaction is completed, the temperature is lowered to 10°C, and an aqueous citric acid solution (10.5 g) is added to the reaction solution, and the mixture is concentrated under reduced pressure. The concentrate is dissolved with ethyl acetate (180.00 g), washed with water (100 g×2), and concentrated under reduced pressure. The concentrate is dissolved with ethanol (98.50 g) at 60°C. After the solution becomes clear, n-heptane (85.50 g) is added, the temperature is lowered to 0°C, stirred for 2 h, filtered under reduced pressure, and the filtrate is concentrated under reduced pressure. The concentrate is dissolved with isopropyl ether (109.00 g), the temperature is lowered to 0°C, stirred for 2 h, filtered under reduced pressure, and the filter cake is washed with ice isopropyl ether (36.30 g). The wet product is dried under vacuum at 25±5°C to obtain the title compound as an off-white solid (39.80 g, 52.00 mmol, product content: 99.94%, yield: 77.73%).

[0127] Identification of the compound represented by formula (I-01):

[0128] LC-MS: calculated value C 45 H 53 N 2 O 8 + [M+H] + :749.4; Measured value:749.3;

[0129] 1 H NMR (400MHz, CD 3 Cl)δ(ppm)7.37–7.28(m,16H),7.26–7.20(m,4H),4.71(td,J=15.4,13.8,8.9Hz,5H),4.55–4.39(m,5H),4.22(t,J=6 .3Hz,1H),4.12(d,J=6.2Hz,1H),3.75–3.60(m,2H),3.47–3.20(m,4H),3.15–2.93(m,4H),2.07(s,3H),1.47(s,9H);

[0130] 13 C NMR (151 MHz, CD 3Cl)δ(ppm)209.58,168.79,154.46,137.60,137.46,137.33,128.53,128.46,128.42,128.38,128.32,128.23,128.22,128 .03,127.96,127.85,127.81,127.77,83.55,80.06,78.84,77.68,74.99,74.41,73.79,73.62,72.55,44.88,41.85,28.40.

[0131] Example 2-37:

[0132] Referring to the method of Example 1, the dosage of catalyst, alkali and water as well as the reaction temperature were studied. The experimental operation and results are shown below.

[0133] To a 25 mL bottle, tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5-hydroxyhept-6-ynyl)piperazine-1-carboxylate (the compound represented by formula (I-00)), MeCN (10 mL / g), DBU, a catalyst (0.1 eq), and water were added in sequence. After stirring for 10 min, the mixture was placed in an autoclave and heated to 40 ℃ for 10 min. 2 Replace 3 times and fill with CO 2 (1.0MPa), stir the reaction at a certain temperature overnight, and take samples for HPLC inspection.

[0134] The catalyst type, DBU dosage, temperature, water dosage and experimental results used in each example are shown in Table 5.

[0135] Table 5

[0136]

[0137]

[0138]

[0139] In the above table, the product content refers to the content of the target product in the reaction system calculated based on the HPLC test results after the reaction is completed.

[0140] Example 3 Synthesis of tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-5-((benzyloxy)methyl)-5,6-dihydroxyheptanoyl)piperazine-1-carboxylate (compound represented by formula (I-02))

[0141]

[0142] Example 1:

[0143] Add 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) into a bottle, cool to 0°C, add lithium tri-tert-butoxyaluminum hydride (9.95 g, 39.12 mmol), and react with stirring for 2 h after the addition. Add water (10 g), stir for 10 min, filter under reduced pressure, wash the filter cake with methyl tert-butyl ether (30 g), collect the filtrate, wash with 1M HCl solution (200 g), and concentrate under reduced pressure to obtain the title compound as a yellow oil (10.03 g, 13.00 mmol, product content: 92.81%, yield: 100%).

[0144] Example 2:

[0145] Under nitrogen atmosphere, 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%), isopropanol (79 g), potassium carbonate (0.18 g, 1.30 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium (II) chloride (0.17 g, 0.26 mmol) were added to the bottle to replace H 2 After the gas is filled three times, H 2 When the pressure is 1.0±0.2MPa, the temperature is raised to 60°C, and the reaction is stirred for 24h. After the reaction is completed, the temperature is lowered to 15°C, and citric acid aqueous solution (1mL) is added to the reaction solution, and it is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate (27.06g), washed with water (30g), and concentrated under reduced pressure to obtain the title compound as a yellow-brown oil (10.03g, 0.013mmol, product content: 92.79%, yield: 100%). The method of this example can effectively control the generation of isomers, and obtain the target product with high yield and high purity.

[0146] Example 4 Synthesis of tert-butyl-4-((2R,3S,4S,5S)-2,3,4-tribenzyloxy-4-((4R,5R)-4-(benzyloxymethyl)-2,2,5-trimethyl-1,3-dioxolane-4-yl)butanoyl)piperazine-1-carboxylate (compound represented by formula (I-03))

[0147]

[0148] Tert-butyl-4-((2R,3S,4S,5S)-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 stirred for 1 h. After the reaction was completed, saturated sodium bicarbonate solution (1 mL) was added, stirred for 10 min, and concentrated under reduced pressure. 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: calcd.For C 48 H 61 N 2 O 9 + [M+H] + :809.5;found:809.5.

[0149] Example 5 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 (compound represented by formula (I-04))

[0150]

[0151] Tert-butyl-4-((2R,3S,4S,5S)-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 method was added dropwise for about 30 minutes. After the addition was completed, the mixture was stirred at -20°C for 20 minutes and then moved to room temperature for 2 hours. After the reaction was completed, a 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, and the organic phase was washed with saturated brine (1.65 L) and concentrated under reduced pressure to obtain the title compound as a yellow oily product (484.18 g, product content: 82.48%, yield: 100%). HRMS: calcd.for C 54 H 61 ClNO 8 + [M+NH 4 ] + :886.4;found:886.4.

[0152] 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.

[0153] 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 a compound represented by formula (I-01), comprising the following steps: The compound represented by formula (I-00) is reacted in a solvent in the presence of a silver catalyst under a CO2 atmosphere to obtain a compound represented by formula (I-01).

2. The preparation method according to claim 1, wherein the reaction is carried out in the presence of a base; wherein The base 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, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 4-dimethylaminopyridine, N,N-dimethylpropyleneurea, N-methylpyrrolidone or pyridine.

3. The preparation method according to claim 2, wherein The amount of the base used is 0.20-2.00, 0.20-1.00, 0.25-1.00, 0.30-1.00, 0.30-0.80, 0.30-0.70 or 0.40-0.70 times the equivalent of the compound represented by formula (I-00); optionally, the amount of the base used is 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90 or 1.00 times the equivalent of the compound represented by formula (I-00).

4. The preparation method according to any one of claims 1 to 3, wherein: The silver catalyst is AgOAc, AgOTf, AgNTf2, AgNO3, AgPF6, AgBF4, Ag2CO3, AgF, PhCO2Ag, CF3COOAg, AgClO4 or CF3SO3Ag.

5. The preparation method according to any one of claims 1 to 4, wherein: The amount of the silver catalyst used is 0.05-1.00, 0.05-0.50, 0.08-0.20 or 0.08-0.15 times the equivalent of the compound represented by formula (I-00); optionally, the amount of the silver catalyst used is 0.10 times the equivalent of the compound represented by formula (I-00).

6. The preparation method according to any one of claims 1 to 5, wherein: The reaction is carried out in the presence of water.

7. The preparation method according to claim 6, wherein: The amount of water used is 0.01-10.0, 0.2-6.0, 0.25-5.5, 0.25-4.0 or 0.35-5.5 times the equivalent of the compound represented by formula (I-00); preferably, the amount of water used is 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0 or 5.5 times the equivalent of the compound represented by formula (I-00).

8. The preparation method according to any one of claims 1 to 7, wherein: The solvent is acetonitrile.

9. The preparation method according to any one of claims 1 to 8, wherein: After the CO2 is charged into the reaction system, the pressure of the reaction system is 0.50-1.50 MPa.

10. The preparation method according to any one of claims 1 to 9, wherein: The reaction temperature of the reaction is 30°C to 80°C, 40°C to 70°C, 45°C to 65°C, 45°C to 60°C or 50°C to 60°C.

11. The compound represented by formula (I-01),

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