CN117430571A - Key intermediate for preparing glucopyranosyl derivative and preparation method thereof - Google Patents

Key intermediate for preparing glucopyranosyl derivative and preparation method thereof Download PDF

Info

Publication number
CN117430571A
CN117430571A CN202310868761.8A CN202310868761A CN117430571A CN 117430571 A CN117430571 A CN 117430571A CN 202310868761 A CN202310868761 A CN 202310868761A CN 117430571 A CN117430571 A CN 117430571A
Authority
CN
China
Prior art keywords
formula
compound
reaction
equivalent
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310868761.8A
Other languages
Chinese (zh)
Inventor
阮赛
彭飞
袁炜辉
李峥
张宗远
伍武勇
廖俊旭
顾峥
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yichang Hec Changjiang Pharmaceutical Co ltd
Original Assignee
Yichang Hec Changjiang Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yichang Hec Changjiang Pharmaceutical Co ltd filed Critical Yichang Hec Changjiang Pharmaceutical Co ltd
Publication of CN117430571A publication Critical patent/CN117430571A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a key intermediate for preparing a glucopyranosyl derivative and a preparation method thereof, wherein the glucopyranosyl derivative is a sodium-dependent glucose transporter (SGLT) inhibitor. Specifically, the key intermediate provided by the invention has stable property, less impurities and high optical purity (diastereoselectivity); the preparation method provided by the invention has the advantages of low price of the used reagent, mild reaction conditions, no need of silica gel column chromatography purification, simple and convenient post-treatment, easy purification, low requirement on equipment, low production cost, safe and controllable process and suitability for industrial production.

Description

Key intermediate for preparing glucopyranosyl derivative and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a key intermediate for preparing a glucopyranosyl derivative and a preparation method thereof, wherein the glucopyranosyl derivative is a sodium-dependent glucose transporter (SGLT) inhibitor.
Background
It has been found that glucose transporters are a class of carrier proteins that intercalate on the cell membrane to transport glucose, which must pass through the lipid bilayer structure of the cell membrane via the glucose transporter. Glucose transporters fall into two broad categories, one being sodium-dependent glucose transporters (sodium-dependent glucose transporters, SGLTs); another class is the glucose transporters (glucose transporters, GLUTs). Two major family members of SGLTs are SGLT-1 and SGLT-2.SGLT-1 is distributed mainly in the small intestine, kidney, heart and trachea, expressed mainly in the brush border of the small intestine and S3 segment of the proximal tubular of the kidney, expressed in small amounts in the heart and trachea, and transports glucose and galactose in a sodium-glucose 2:1 ratio. Whereas SGLT-2 is predominantly distributed in the kidney, expressed predominantly in the S1 and S2 segments of the proximal tubular of the kidney, transporting glucose at a sodium-glucose 1:1 ratio. In organisms, SGLTs transport glucose against concentration gradients in an active manner while consuming energy, whereas GLUTs transport glucose along concentration gradients in an facilitated diffusion manner without consuming energy. Studies have shown that plasma glucose is usually filtered in the glomeruli of the kidney and 90% of the glucose is actively transported by SGLT-2 into the epithelial cells at the proximal S1 and S2 segments of the tubule, 10% of the glucose is actively transported by SGLT-1 into the epithelial cells at the Guan Yuanduan S3 segment of the kidney, and is transported by GLUT on the basal membrane side of the epithelial cells into the surrounding capillary network, completing the reabsorption of glucose by the tubules. Therefore, SGLTs are the first gateway for regulating cell carbohydrate metabolism and are ideal targets for effectively treating diabetes. It was found that patients with SGLT-2 deficiency have a large urinary sugar excretion, which provides a basis for the reduction of glucose uptake by inhibition of SGLT-2 activity and thus for the treatment of diabetes. Therefore, the SGLTs transporter activity is inhibited, the reabsorption of glucose by the kidney tubules can be blocked, and the excretion of glucose in urine is increased, so that the concentration of glucose in blood plasma is normalized, and the conditions of diabetes and diabetic complications are controlled. Inhibition of SGLTs does not affect normal glucose counterregulatory mechanisms, creating a risk of hypoglycemia; and simultaneously, the excretion of the kidney glucose is increased to reduce the blood sugar, so that the weight of an obese patient can be reduced. It has also been found that SGLTs inhibitors act independently of the degree of dysfunction of islet β -cells or insulin resistance, and therefore their effect does not decline with β -cell failure or severe insulin resistance. It can be used alone or in combination with other hypoglycemic agents. Therefore, SGLTs inhibitors are ideal novel hypoglycemic agents.
In addition, it has been found that SGLTs inhibitors can be used in the treatment of diabetes related complications. Such as retinopathy, neuropathy, nephropathy, insulin resistance caused by glucose metabolism disorder, hyperinsulinemia, hyperlipidemia, obesity, etc. Meanwhile, the SGLTs inhibitor can be used in combination with the existing therapeutic drugs, such as sulfonamide, thiazolidinedione, metformin, insulin and the like, and the dosage is reduced under the condition that the drug effect is not affected, so that adverse reactions are avoided or reduced, and the compliance of patients to treatment is improved.
The applicant has made an effort to develop glucopyranosyl derivatives as inhibitors of sodium-dependent glucose transporter (SGLT), and has disclosed in WO2015043511A1 and WO2016173425A1 that compounds of formula (I) have good SGLTs inhibitory activity.
The compound is in clinical III phase at present, and is a novel diabetes therapeutic drug with great potential.
Subsequently, the applicant disclosed in WO2020143653A1 a process for the preparation of a compound of formula (I), wherein the following reaction for the preparation of intermediates is disclosed in the synthetic route: the compound represented by formula (X) and Grignard reagent obtained by Grignard exchange of iodomethyl pivalate and lithium isopropyl chloride are subjected to addition reaction to obtain the compound represented by formula (IX) (see, for details, step 4 of description example 1 thereof).
Step a:
the applicant also discloses in WO2022007838A1 a process for the preparation of a compound of formula (I), wherein the following reaction for the preparation of intermediates is disclosed in the synthetic route: the compound represented by the formula (IXb) and the grignard reagent obtained by grignard exchange of iodomethyl pivalate with lithium isopropylmagnesium chloride are subjected to an addition reaction to obtain the compound represented by the formula (VIIIb) (see, for details, step 4 of example 1 of the specification thereof).
Step b:
as can be seen from the above reaction for preparing intermediates, the compound of formula (IXb), which is the same as the compound of formula (II-a) of the present invention, and the compound of similar structure as shown in formula (X) can be used as a starting compound to prepare additional intermediates, thereby finally obtaining the compound of formula (I). However, in both the step a and the step b, the Grignard reaction is required, and the Grignard reagent has high price, severe reaction conditions, high requirements on equipment and high synthesis cost, and is not suitable for industrial production.
Disclosure of Invention
Aiming at the problems of preparing an intermediate in a synthetic route for preparing a compound shown in a formula (I) in the prior art, the invention provides a key intermediate suitable for industrial production and a preparation method thereof through a great amount of optimization and search on the intermediate and the preparation method thereof in the synthetic route for preparing the compound shown in the formula (I). On the one hand, the key intermediate has stable property, less impurities and high optical purity (diastereoselectivity); on the other hand, the preparation method has the advantages of low price of the used reagent, mild reaction conditions, no need of silica gel column chromatography purification, simple and convenient post-treatment, easy purification, low requirement on equipment, low production cost, safer and controllable process and simplicity.
The intermediate has a structure shown in the formula (I-a), and is an important intermediate for synthesizing the compound shown in the formula (I). Specifically, the invention relates to a preparation method of a compound shown in a formula (I-a), the compound shown in the formula (I-a) and a crystal form A thereof.
In one aspect, the present invention relates to a process for the preparation of a compound of formula (I-a), comprising the steps of: the compound shown in the formula (II-a) is subjected to addition reaction with trimethylsilyl acetylene in a solvent in the presence of LiHMDS to obtain the compound shown in the formula (I-a),
in some embodiments, the addition reaction is performed in the presence of an additive that is 2,4, 6-trimethylpyridine, piperidine, triethylenediamine, pyrrole, tetramethylethylenediamine, tetramethyltartaric acid amide, hexamethylphosphoric triamide, (-) -cytidine, triethylamine, propylenediamine, ethylenediamine, dimethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine, N-dimethylpropylurea, N-methylpyrrolidone, or pyridine; preferably, the additive is tetramethyl ethylenediamine or (-) -cytisine; more preferably, the additive is tetramethyl ethylenediamine.
In other embodiments, the additive is used in an amount of 0.2 to 1.2 equivalents of the compound of formula (II-a); preferably, the additive is used in an amount of 0.5 to 1.0 times equivalent to the compound of formula (II-a); more preferably, the additive is used in an amount of 0.2 times, 0.5 times or 1.0 times equivalent to the compound represented by the formula (II-a).
In some embodiments, the trimethylsilylacetylene is used in an amount of 1.0 to 2.0 times the equivalent of the compound of formula (II-a); preferably, the amount of the trimethylsilylacetylene is 1.2 to 1.5 times the equivalent of the compound shown in the formula (II-a); more preferably, the trimethylsilylacetylene is used in an amount of 1.2 times or 1.5 times the equivalent of the compound of formula (II-a).
In still other embodiments, the LiHMDS is used in an amount of 1.0 to 2.0 times the equivalent of the compound of formula (II-a); preferably, the LiHMDS is used in an amount of 1.2 to 1.5 times the equivalent of the compound represented by the formula (II-a); more preferably, the LiHMDS is used in an amount of 1.2 times or 1.5 times the equivalent of the compound of formula (II-a).
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.
In still other embodiments, the reaction temperature in the reaction of the compound of formula (II-a) with trimethylsilylacetylene is from-40℃to-80 ℃; preferably, the reaction temperature is-50 ℃ to-80 ℃; preferably, the reaction temperature is-60 ℃ to-80 ℃; more preferably, the reaction temperature is-78 ℃.
According to the preparation method of the compound shown in the formula (I-a), disclosed by the invention, the trimethylsilyl acetylene is used for carrying out an asymmetric addition reaction on a ketone group on the compound shown in the formula (II-a), a new chiral center is introduced, and the compound shown in the formula (I-a) with high purity and high dr value can be obtained by optimizing the selection of the additive. In addition, the type and amount of additives will not affect the reaction. When the additive is tetramethyl ethylenediamine and the dosage of the tetramethyl ethylenediamine is 0.5 times of the equivalent of the compound shown in the formula (II-a), the reaction is complete, and the purity of the product is high and the dr value is high; when the additive is (-) -cytisine and the amount of (-) -cytisine is 1.0 times the equivalent of the compound of formula (II-a), the reaction is complete, and the purity of the product is high and the dr value is high.
The compound shown in the formula (I-a) obtained by the preparation method of the compound shown in the formula (I-a) has high purity and high dr value, and the purity and dr value of the compound shown in the formula (I-a) can be further improved through recrystallization, wherein the dr value after recrystallization can be more than 99:1.
The 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 form, i.e. a compound represented by formula (I-a) and its crystalline form. The crystal forms provided by the invention can be identified and distinguished from other crystal forms by means of their characteristic X-ray single crystal diffraction patterns, X-ray powder diffraction (XRPD) patterns, differential Scanning Calorimetric (DSC) curves and Thermogravimetric (TGA) analysis patterns.
In one aspect, the present invention relates to compounds of formula (I-a),
in another aspect, the present invention relates to crystalline form A of a compound of formula (I-a),
in some embodiments, the differential scanning calorimetry pattern of form a of the compound of formula (I-a) comprises a maximum endothermic peak at 93.12 ℃ ± 3 ℃.
In some embodiments, form a of the compound of formula (I-a) has a differential scanning calorimeter substantially as shown in fig. 1.
In some embodiments, form a of the compound of formula (I-a) has the following unit cell parameters:
unit cell specification:α＝90°、β＝97.3928°、γ＝90°；
space group: p2 1 ；
Unit cell volume:
number of asymmetric units in unit cell Z:2.
in some embodiments, the X-ray powder diffraction pattern of form a of the compound of formula (I-a) 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 °, 19.86 ° ± 0.2 °.
In still other embodiments, the X-ray powder diffraction pattern of form a of the compound of formula (I-a) 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 °, 23.82 ° ± 0.2 °.
In other embodiments, the X-ray powder diffraction pattern of form a of the compound of formula (I-a) 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 °, 17.76 ° ± 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 ° ± 0.26.40 ° ± 0.26 ° ± 62 ° ± 0.84 ° ± 0.2 °, 52 ° ± 0.42 ° ± 0.82 °, 52 ° ± 0.32 ° ± 0.2 °, and/62 ° ± 0.32 ° ± 0.2.32 ° ± 0.2 °.
In still other embodiments, form a of the compound of formula (I-a) has an X-ray powder diffraction pattern substantially as shown in figure 4.
In some embodiments, form a of the compound of formula (I-a) loses 0.1199% weight when heated to 150.09 ℃, the loss in weight ratio being within a margin of error of ± 0.1%.
In some embodiments, form a of the compound of formula (I-a) has a thermogravimetric analysis substantially as shown in figure 2.
Detailed description of the invention
The invention provides a key intermediate of a glucopyranosyl derivative serving as a sodium-dependent glucose transporter (SGLT) inhibitor and a preparation method thereof, and a person skilled in the art can properly improve the technological parameters by referring to the content of the text. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention.
Definitions and general terms
Unless otherwise indicated, the terms used in the specification and claims of the present invention have the following definitions.
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato: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.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The terms "equivalent" or "eq" as used herein are equivalent amounts of other starting materials required based on the basic raw materials used in each step (1 eq) in terms of equivalent relationship of the chemical reaction.
The term "dr" or "dr value" as used herein refers to the ratio of the content of one diastereomer to another, the higher the dr value, the higher the diastereoselectivity. For example, the 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 of formula (I-a), of the present invention is diastereomer A, and the tert-butyl-4- ((2R, 3S,4S, 5R) -2,3, 4-tribenzyloxy-5- ((benzyloxy) methyl) -5-hydroxyhept-6-ynyl) piperazine-1-carboxylate is diastereomer B. Dr = diastereomer a/diastereomer B.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
The term "room temperature" refers to 10 ℃ to 40 ℃, in some embodiments, "room temperature" refers to 10 ℃ to 30 ℃; in some embodiments, "room temperature" refers to 20 ℃ to 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and so forth.
In the context of the present invention, all numbers disclosed herein are approximations. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, or 10%. Whenever a number is disclosed having a value of N, any number within the values of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, of a range of values is disclosed, any value falling within the disclosed range is explicitly disclosed.
All of the reaction steps described herein are reacted to an extent such as greater than about 70% raw material consumption, greater than 80%, greater than 90%, greater than 95%, or post-treatment such as cooling, collecting, extracting, filtering, separating, purifying, or a combination thereof, after detecting that the raw materials have been consumed. The degree of reaction can be detected by conventional methods such as Thin Layer Chromatography (TLC), high Performance Liquid Chromatography (HPLC), gas Chromatography (GC), etc. The reaction solution may be subjected to post-treatment by a conventional method, for example, by evaporating under reduced pressure or conventionally distilling the reaction solvent, and then collecting the crude product, and directly put into the next reaction; or directly filtering to obtain a crude product, and directly putting the crude product into the next reaction; or standing, pouring out supernatant to obtain crude product, and directly adding into the next reaction; or selecting proper organic solvent or combination thereof for extraction, distillation, crystallization, column chromatography, rinsing, pulping and other purification steps.
The solvent used in each of the reaction steps described in the present invention is not particularly limited, and any solvent which dissolves the starting materials to some extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention. The present invention gives the preferred solvents to be used in each reaction step.
The content of moisture in the solvent according to the present invention is not particularly limited, that is, the content of moisture in the solvent does not affect the occurrence of the reaction according to the present invention. Any solvent containing a certain amount of moisture that can be used in the present invention to some extent is considered a solvent according to the present invention. Such as a moisture content of less than about 0.05%, less than about 0.1%, less than about 0.2%, less than about 0.5%, less than about 5%, less than about 10%, less than about 25%, less than about 30%, or about 0%. In some embodiments, the solvent has a moisture content within a range that is more conducive to the reaction; for example, in the step of using ethanol as a reaction solvent, anhydrous ethanol is used, and the reaction is more advantageously carried out. In some embodiments, the moisture content of the solvent is outside a certain range, which may affect the progress of the reaction (e.g., affect the yield of the reaction), but not the occurrence of the reaction.
The crystalline forms may be identified by a variety of techniques such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, 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, and the like.
The X-ray powder diffraction (XRPD) can detect the information of crystal form change, crystallinity, crystal structure state and the like, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns are largely dependent on the structure of the crystalline form, relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the invention. Meanwhile, the measure of 2θ of the XRPD pattern may have experimental errors, and the measure of 2θ of the XRPD pattern may slightly differ from instrument to instrument and sample to sample, so the value of 2θ cannot be regarded as absolute. Depending on the instrument conditions used in this test, diffraction peaks have a margin of error of + -0.2 deg..
Differential Scanning Calorimeter (DSC) is a method for measuring the temperature of a sample and an inert reference substance (commonly used alpha-Al) by continuously heating or cooling under the control of a program 2 O 3 ) A technique in which the energy difference between them varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relative to realityThe assay details are relatively insensitive. Thus, in some embodiments, the crystalline forms of the invention are characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profile provided in the accompanying figures of the invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so that the peak position or the value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrument conditions used in this test, there is an error margin of + -3deg.C for the endothermic peak.
Thermogravimetric analysis (TGA) is a technique for measuring the mass of a substance as a function of temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can be used to infer the presence of water of crystallization or a crystallization solvent in the crystal. The quality change exhibited by the TGA profile depends on many factors such as sample preparation and instrumentation; the quality of TGA detection varies slightly from instrument to instrument and from sample to sample. Depending on the instrument conditions used in this test, there was a margin of error of + -0.1% for the mass change.
In the context of the present invention, the 2 theta values in the X-ray powder diffraction pattern are all in degrees (°).
The term "substantially as shown in the figures" 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 DSC pattern or raman spectrum or infrared spectrum are shown in the figures.
When referring to a spectrogram or/and data appearing in the graph, a "peak" refers to a feature that one skilled in the art can recognize that is not attributable to background noise.
The present invention relates to the crystalline form of said 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 of formula (I-a) which is present in substantially pure crystalline form.
By "substantially pure" is meant that one form is substantially free of the other form or forms, i.e., the purity of the 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 form contains 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% of the total volume or total weight of the forms.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline forms 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%.
"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first intensity peak to the intensity of the first intensity peak of all diffraction peaks of the X-ray powder diffraction pattern, taken as 100%.
General synthetic and detection methods
In this specification, if there is any difference between a chemical name and a chemical structure, the structure is subject to.
Those skilled in the art will recognize that: the chemical reactions described herein can be used to suitably prepare a number of compounds similar to those described herein. The person skilled in the art can carry out the invention by modifying, for example by suitable protecting groups, other known reagents in addition to those described in the invention or by making some conventional modifications of the reaction conditions, which conventional modifications of the preparation method are also considered to be within the scope of the invention. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds similar to those described herein.
In general, the methods described herein can be used to prepare the compounds of the invention as shown in formula (I-a). The following examples serve to further illustrate the context of the present invention.
The structure of the compound is that nuclear magnetic resonance is adopted 1 H-NMR、 13 C-NMR). 1 H-NMR、 13 The C-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR、 13 The C-NMR was performed using Bruker Ultrashield-400 NMR spectrometer and Bruker Avance III HD 600 NMR spectrometer, with deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD) or deuterated DMSO (DMSO-d) 6 ) TMS (0 ppm) or deuterated chloroform (7.26 ppm) was used as a reference standard. When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, multiplet), m (multiplet ), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet), ddd (doublet of doubletof doublets, doublet), ddt (doublet of doublet of triplets, doublet), td (triplet of doublets, triplet), brs (broadened singlet, broad doublet). Coupling constant J, expressed in hertz (Hz).
The MS was determined using an Agilen-6120 Quadragole LC/MS mass spectrometer;
The thin layer chromatography silica gel plate uses a tobacco stand yellow sea HSGF254 silica gel plate.
The starting materials for the present invention are known and commercially available from Shanghai Shaosha Company (Shanghai Accela Company), an Naiji Company (Energy Company), barbary Company (J & K), chengdu Altai Company (Chengdu Aiertai Company), tianjin A Fabricius Company (Alfa Company), etc., or synthesized according to methods known in the art.
The reactions were carried out under nitrogen atmosphere without any particular explanation in the examples.
The nitrogen atmosphere means that the reactor flask is connected to a nitrogen balloon or steel kettle of about 1L volume.
The hydrogen atmosphere means that the reactor is connected with a hydrogen balloon with the volume of about 1L or a stainless steel high-pressure reactor with the volume of about 1L.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature was room temperature, unless otherwise specified in the examples.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following developing reagent systems: the volume ratio of the methylene chloride to the methanol system, the methylene chloride to the ethyl acetate system, the petroleum ether to the ethyl acetate system and the solvent is adjusted according to the polarity of the compound.
HPLC refers to high performance liquid chromatography.
HPLC was performed using Agilent 1200 high pressure liquid chromatograph (Zorbax Eclipse Plus C18 150X 4.6mm column).
HPLC test conditions: run time: column temperature for 30 min: PDA at 35 ℃): 210nm,254nm
Mobile phase: phase A: h 2 O B phase: acetonitrile flow rate: 1.0mL/min
The following abbreviations are used throughout the present invention:
drawings
FIG. 1 is a Differential Scanning Calorimeter (DSC) of form A of a compound of formula (I-a) according to the present invention.
FIG. 2 is a thermogravimetric analysis (TGA) of form A of the compound of formula (I-a) according to the present invention.
FIG. 3 is a unit cell diagram of form A of the compound of formula (I-a) according to the present invention.
FIG. 4 is an X-ray powder diffraction (XRPD) pattern of form A of the compound of formula (I-a) according to the invention.
Synthetic scheme
The compounds of formula (I) can be prepared according to the above-described synthetic schemes, wherein the last step of the reductive cyclization reaction can be performed by reference to the methods described in the prior art (as referred to in the present invention); the compound shown in the formula (I-a) can be prepared by the method disclosed by the invention. In the synthesis scheme, the compound shown in the formula (I) is prepared by taking the compound shown in the formula (II-a) or (I-a) as a starting raw material in high yield and high purity, and the reaction conditions of each step are mild, the operation is simple, and the method is suitable for industrial production. Wherein, the compound shown in the formula (I-a) is an important intermediate, and can be used for preparing the compound shown in the formula (I) with high yield and high purity; methods for preparing the compound of formula (I) using the compound of formula (I-a) include, but are not limited to, those described in the examples of the present invention.
Detailed Description
The invention is further illustrated by way of examples which are not intended to limit the scope of the invention.
The X-ray powder diffraction analysis method used in the invention comprises the following steps: an Empyrean diffractometer was used to obtain X-ray powder diffraction patterns using Cu-K alpha radiation (45 KV,40 mA). The powdered sample was prepared as a thin layer on a monocrystalline silicon sample holder, placed on a rotating sample stage and analyzed in steps of 0.0167 ° in the range of 3 ° -40 ° or 3 ° -60 °. Data was collected using Data Collector software, highScore Plus software processed the Data, and Data Viewer software read the Data.
The Differential Scanning Calorimeter (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimeter was performed using a TA Q2000 module with a thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid, and sample analysis was performed from room temperature to about 300 ℃ using a linear heating device of 10 ℃/min. During use, the DSC cell was purged with dry nitrogen.
The thermal weight loss (TGA) analysis method used in the invention comprises the following steps: thermogravimetric analysis was performed using a TA Q500 module with a thermogravimetric analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 10-30mg of the sample was placed in a platinum crucible and the sample analysis was performed from room temperature to about 300 c using a linear heating device at 10 c/min. During use, the TGA cell was purged with dry nitrogen.
The present examples disclose a process for the preparation of optically pure tert-butyl-4- ((2R, 3S,4S, 5S) -2,3, 4-tribenzyloxy-5- ((benzyloxy) methyl) -5-hydroxyhept-6-ynyl) piperazine-1-carboxylate, a compound of formula (I-a). Those skilled in the art can practice the teachings of the present invention with reference to the present disclosure or with appropriate modification of the process parameters. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the scope of the present invention. While the methods of the present invention have been described by way of example, it will be apparent to those skilled in the relevant art that variations and suitable modifications and combinations of the methods described herein can be made to practice and use the techniques of the present invention without departing from the spirit or scope of the invention.
The present invention will be described in detail with reference to examples.
Examples
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 (a compound shown as formula (I-a))
Step 1 Synthesis of (3R, 4S,5R, 6R) -3,4, 5-Tribenzyloxy-6- (benzyloxymethyl) tetrahydropyran-2-one
Compound 2,3,4, 6-tetra-O-benzyl-D-glucopyranose (50.0 g,92.5 mmol) is dissolved in dichloromethane (450 mL), a solution of sodium bicarbonate (46.6 g,555 mmol) in water (450 mL) is added, cooled to 0 ℃, potassium bromide (6.6 g,55 mmol) and TEMPO (2.19 g,13.9 mmol) are added, after stirring for 2 minutes, naClO solution (120 g,270mmol, available chlorine 4.0 mass%) is added and the mixture stirred for a further 1 hour. The mixture was separated, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (48.6 g,90.2mmol, yield: 97.6%).
Step 24- [ (2R, 3S,4R, 5R) -2,3,4, 6-tetrabenzyloxy-5-)Hydroxy-hexanoyl]Piperazine-1-carboxylic acid tert-butyl ester Synthesis of esters
(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) at room temperature, and 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, and the temperature was maintained and the reaction was stirred for 12 hours. After the reaction, water (500 mL) was added to the reaction system and stirred for 10 minutes, the mixture was left to stand for liquid separation, the upper organic phase was washed once with a saturated aqueous sodium chloride solution (800 mL), the system was made turbid by dropwise addition of n-heptane (3.0L), stirring at room temperature was carried out for 4-5 hours, a large amount of white solid was precipitated, cooling to 10℃and continuing stirring for 3 hours, suction filtration was carried out, the wet product was added to toluene (600 mL) and stirred for dissolution, n-hexane (1.6L) was added, stirring was carried out for 12 hours, off-white solid was precipitated, suction filtration was carried out, the solid was rinsed with a small amount of n-heptane (150 mL), and the solid was collected and dried under vacuum at 40℃to give the title compound as off-white solid (153.2 g,211.36mmol, yield: 56.8%).
Step 34- [ (2R, 3S, 4S) -2,3,4, 6-tetrabenzyloxy-5-oxohexanoyl]Piperazine-1-carboxylic acid tert-butyl ester (type Synthesis of Compound (II-a)
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 (1.5L), DMSO (900 mL) and DIPEA (800 mL,4828.4 mmol) were added, the mixture was cooled to 0℃under nitrogen atmosphere, and pyrithione (384.2 g,2415.2 mmol) was added in portions at 0-5℃and after the addition was complete, the reaction was followed by TLC after stirring the mixture at 0-5℃for 2 hours and a small amount of unreacted starting material was found to be complete, the reaction was continued with stirring, and TLC plate monitoring found to be complete. Tap water (2.5L) was added to the reaction system to wash, the solution was separated, the upper organic phase was further washed with saturated brine (500 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in THF (2000 mL), silica gel (100 g) and activated carbon (50 g) were added and stirred for 20 minutes, and after filtration, the filtrate was concentrated under reduced pressure to give the title compound as a red oil (470.0 g,650.2mmol, yield: 94.2%).
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-carboxylic acid ester (Compound of formula (I-a)
Example 1:
dissolving trimethylsilylacetylene (110.2 mL,780.2 mmol) in THF (1.0L) under nitrogen protection, cooling to-78deg.C, slowly adding TMEDA (48.7 mL,325.1 mmol), stirring for 10min, slowly adding LiHMDS (780.2 mL,1 mol/L), stirring for 30min, slowly adding THF (1.0L) to dissolve 4- [ (2R, 3S, 4S) -2,3,4, 6-tetrabenzyloxy-5-oxohexanoyl) ]A solution of piperazine-1-carboxylic acid tert-butyl ester (compound of formula (II-a)) (470.0 g,650.2 mmol), after 2h reaction at-78deg.C, ethyl acetate (1.0L) was added to dilute the solution, the reaction was quenched with saturated aqueous ammonium chloride (1.0L), the solution was separated, the upper organic phase was washed with 10% aqueous citric acid (2.0L) until the aqueous phase was weakly acidic (pH of about 3-5), saturated brine (500 mL) was washed, the organic phase was concentrated to near dryness under reduced pressure, meOH (800 mL) and K were added at 0deg.C 2 CO 3 (100g) To the concentrated oil, the reaction was monitored by stirring TLC after completion of addition and returning to room temperature, and the reaction was completed for about 0.5 to 2 hours. The filtrate obtained was concentrated to near dryness by suction filtration to give the title compound as a red oil (480 g, HPLC purity: 80.8%, dr value 86:14). Adding isopropyl ether (960 mL) into the red oily substance, heating at 60deg.C to dissolve completely, recovering to room temperature, adding seed crystal, stirring for 2-4 hr, transferring to 0deg.C, stirring for 1 hr, vacuum filtering, and washing with isopropyl ether (50.0 mL×2) at 0deg.C to obtain white powdery solid (i.e. formula (I-a))Crystal form A of the compound (233.0 g,311.11mmol, yield: 48.0%, HPLC purity: 98.42%, dr value)>99:1)。
Identification of form a of the compound of formula (I-a):
(1)LC-MS:calcd.for C 45 H 53 N 2 O 8 + [M+H] + :749.4；found:749.3；
(2)
1 H NMR(400MHz,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)；
13 C NMR(100MHz,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.
(3) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scan rate was 10 c/min, including an endothermic peak at 93.12 c, with an error margin of ± 3 c.
(4) Identification by TA Q500 for Thermogravimetric (TGA) analysis: the temperature rise rate was 10 ℃/min, and when heated to 150.09 ℃, the weight loss was 0.1199%, with a margin of error of + -0.1%.
(5) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ: an error margin of ±0.2° exists for 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 °.
Examples 2-15:
adding trimethylsilanylethylene, additive and THF (2.0 mL) into 10mL reaction tube, cooling to a certain reaction temperature, stirring for 10min, adding LiHMDS, maintaining the temperature, and stirring for 15-After 30min, 4- [ (2R, 3S, 4S) -2,3,4, 6-tetrabenzyloxy-5-oxohexanoyl was added]The piperazine-1-carboxylic acid tert-butyl ester, namely a solution of the compound (0.72 g,1.0 mmol) shown in the formula (II-a) in THF (2.0 mL), is stirred at a constant temperature for 1-2 h, and then the reaction is monitored to be complete by a dot plate. Post-treatment: diluting the reaction solution with ethyl acetate (10 mL), quenching with 1M hydrochloric acid aqueous solution (pH is adjusted to 3-5), separating, concentrating the upper organic phase under reduced pressure to near dryness, adding MeOH (2.0 mL) and K at 0deg.C 2 CO 3 (0.2 g) was added to the concentrated oil, and the reaction was monitored by stirring TLC at room temperature after completion of the addition, and was completed for about 0.5 to 2 hours. After substantially complete removal of the TMS groups, insoluble material was filtered off and the organic phase was diluted in small amounts for HPLC analysis. The additives used in examples 2 to 15 and the amounts thereof, the amounts of trimethylsilylacethylene, the amounts of LiHMDS, the reaction temperatures and the experimental results are shown in Table 1.
Table 1:
note that: "-indicates no addition or no presence.
Examples 16-17:
into a 10mL reaction tube were added trimethylsilylacetylene (0.15 mL,1.1 eq.) and THF (2.0 mL), with or without TMEDA (165.0. Mu.L, 1.1 eq.) added, cooled to-78 ℃, stirred for 10min, then added with n-BuLi (1.1 mL,1.0 mol/L), stirred for 15-30min at a constant temperature, and then added with 4- [ (2R, 3S, 4S) -2,3,4, 6-tetrabenzyloxy-5-oxohexanoyl)]The piperazine-1-carboxylic acid tert-butyl ester, namely a solution of the compound (0.72 g,1.0 mmol) shown in the formula (II-a) in THF (2.0 mL), is stirred at a constant temperature for 1-2 h, and then the reaction is monitored to be complete by a dot plate. Post-treatment: diluting the reaction solution with ethyl acetate (10 mL), quenching with 1M hydrochloric acid aqueous solution (pH is adjusted to 3-5), separating, concentrating the upper organic phase under reduced pressure to near dryness, adding MeOH (2.0 mL) and K at 0deg.C 2 CO 3 (0.2 g) to the concentrated oil, add After completion, the reaction is recovered to room temperature and monitored by stirring TLC, and the reaction is completed for about 0.5-2 hours. After substantially complete removal of the TMS groups, insoluble material was filtered off and the organic phase was diluted in small amounts for HPLC analysis. The experimental results are shown in table 2.
Table 2:
note that: "-indicates no addition or no presence.
Experimental results show that when trimethyl silylacetylene and n-BuLi are used for reaction, TMEDA is added or not added, the effect on dr value is small, but HPLC purity is affected, and TMEDA is added, so that the HPLC purity is lower; when the reaction is carried out by using the trimethylsilylacethylene and the LiHMDS, as shown in the experimental results of examples 2-15, the HPLC purity and dr value of the obtained product are higher, and the effect is obviously better than that of the product without TMEDA (example 4), and the HPLC purity and dr value are improved by about 10%. As can be seen, the organolithium reagent was different, with and without TMEDA, and the reaction results were different. In addition, n-BuLi is dangerous, inflammable and explosive, has the risk of ignition, and is not suitable for industrial scale-up.
Example 18:
to a 10mL reaction tube was added tert-butyl 4- [ (2R, 3S, 4S) -2,3,4, 6-tetrabenzyloxy-5-oxohexanoyl ] piperazine-1-carboxylate, which is a solution of the compound of formula (II-a) (0.72 g,1.0 mmol) in THF (3.0 mL), cooled to-20℃and stirred for 30min, then ethynylmagnesium bromide (5.0 mL,0.5 mol/L) was added, and after stirring with heat preservation, the reaction was monitored by a spot plate for 1-2 h. Post-treatment: the reaction solution was diluted with ethyl acetate (10 mL), quenched with 1M aqueous hydrochloric acid (pH 3-5), separated, and the upper organic phase diluted and analyzed by HPLC. The experimental results are shown in table 3.
Table 3:
note that: "-indicates no addition or no presence.
Experimental results show that when the Grignard reagent ethynyl magnesium bromide is used for reaction, the diastereoselectivity of the obtained product is low, and the dr value is 53.4:46.6; when the reaction is carried out by using the trimethylsilylacethylene and the LiHMDS, the diastereoselectivity of the obtained product is obviously higher as shown in the experimental results shown in examples 2-15, and the dr value is more than or equal to 74:26. In addition, ethynyl magnesium bromide is expensive, the quality is difficult to ensure, and the method is not suitable for industrial scale-up.
Examples 19-21:
into a 10mL reaction tube, trimethylsilylacetylene (0.17 mL,1.2 eq.) was added, the metal salt (M), chiral ligand (L), additive and THF (2.0 mL) were cooled to-78deg.C, stirred for 10min, then LiHMDS (1.2 mL,1.0 mol/L) was added, stirred for 15-30min with heat preservation, then 4- [ (2R, 3S, 4S) -2,3,4, 6-tetrabenzyloxy-5-oxohexanoyl was added]The piperazine-1-carboxylic acid tert-butyl ester, namely a solution of the compound (0.72 g,1.0 mmol) shown in the formula (II-a) in THF (2.0 mL), is stirred at a constant temperature for 1-2 h, and then the reaction is monitored to be complete by a dot plate. Post-treatment: diluting the reaction solution with ethyl acetate (10 mL), quenching with 1M hydrochloric acid aqueous solution (pH is adjusted to 3-5), separating, concentrating the upper organic phase under reduced pressure to near dryness, adding MeOH (2.0 mL) and K at 0deg.C 2 CO 3 (0.2 g) was added to the concentrated oil, and the reaction was monitored by stirring TLC at room temperature after completion of the addition, and was completed for about 0.5 to 2 hours. After substantially complete removal of the TMS groups, insoluble material was filtered off and the organic phase was diluted in small amounts for HPLC analysis. The metal salt (M), chiral ligand (L), additive and amounts thereof, reaction temperatures and experimental results used in examples 19 to 21 are shown in Table 4.
Table 4:
note that: "-means not added or not present; "NR" means unreacted.
ExperimentThe results indicate that when Zn (OTf) is used 2 With Salen ligand or high-activity diethyl zinc and R- (+) -BINOL ligand as Lewis acid activated carbonyl to control chiral environment, thereby improving reaction diastereoselectivity, and not obtaining better results; when the reaction is carried out using TMEDA, which is a common additive, as shown in examples 2 to 15, high diastereoselectivity control can be achieved and the purity of the obtained product is high. In addition, the metal salt (M) and the chiral ligand (L) are expensive and have high cost.
Example 22:
lithium bis (trimethylsilyl) amide (81.5 g,94.77mmol,1mol/L in tetrahydrofuran), N, N' -tetramethyl ethylenediamine (11.09 g,95.45 mmol) were cooled to-78℃under nitrogen, trimethylsilylacetylene (9.51 g,96.84 mmol) was added, the reaction was continued for 120min after the addition, and a dropwise addition of a solution of 4- [ (2R, 3S, 4S) -2,3,4, 6-tetrabenzyloxy-5-oxohexanoyl ] piperazine-1-carboxylic acid tert-butyl ester (50.00 g,69.17mmol, purity: 98.72%) in tetrahydrofuran (70 g) was started, the temperature was controlled at-78℃after the dropwise addition, and the reaction was stirred for 30min. Methanol (79 g) was added, the reaction was stirred at room temperature for 0.5h, concentrated under reduced pressure, the concentrate was added with isopropyl ether (109 g) and dissolved in a solution of citric acid (25 g) in water (100 g), the solution was separated, concentrated under reduced pressure, the concentrate was added with isopropyl ether (109 g) and dissolved at 60℃and cooled to 20℃to 30℃and stirred for 5h, cooled to 0℃and stirred for 1h, crystallized, centrifuged, the cake was washed with isopropyl ether (36 g) at 0℃and the cake was collected and dried under vacuum at 45℃for 6 h to give the title compound as a white solid (37.07 g,49.5mmol, product content: 99.47% and yield: 71.56%).
EXAMPLE 2 Single Crystal growth of Crystal form A of Compound of formula (I-a)
The tert-butyl-4- ((2R, 3S,4S, 5S) -2,3, 4-tribenzyloxy-5- ((benzyloxy) methyl) -5-hydroxyhept-6-ynyl) piperazine-1-carboxylate obtained in example 1, i.e. crystalline form A (30 mg,0.040 mmol) of the compound of formula (I-a) was weighed into a 5.0mL round bottom flask, ethyl acetate (0.5 mL) was added, slightly warmed and dissolved, n-heptane (2.5 mL) was slowly added, and the mixture was left standing in a refrigerator at 4℃for 10 days to precipitate a single crystal.
EXAMPLE 3X-ray Single Crystal diffraction study of Single Crystal of Crystal form A of Compound of formula (I-a)
Cu K alpha radiation on Agilent Technologies Gemini AUltra diffractometerData were collected, measured intensity data were indexed and processed using the Crysalis PRO program, cell parameters were determined by pre-experiments, and data collection strategies were formulated based on the cell parameters for data collection.
Structural analysis and refinement were performed using the SHELX-97 (Sheldrick, G.M. SHELXTL-97,Program for Crystal Structure Solution and Refinement;University of Gottingen:Gottingen,Germany,1997) procedure, and analysis was performed by direct method. The derived atomic parameters (coordinates and temperature factors) are corrected by the full matrix least squares method. Function sigma minimized in correction w (|F o |-|F c |) 2 . R is defined as Sigma I F o |-|F c ||/∑|F o I, 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. The difference map is checked at all stages of correction. The positions of the remaining hydrogen atoms were obtained by theoretical calculation except that the positions of the hydrogen atoms H1N and H2N were determined using a difference fourier map. The simulated X-ray powder diffraction pattern was calculated using Mercury software.
Single crystals of a suitable size (single crystals of form A of the compound of formula (I-a) prepared in example 2) were selected for single crystal diffraction analysis. Selected crystals were fixed to fine glass fibers with a small amount of petrolatum and mounted on a Agilent Technologies Gemini A Ultra diffractometer and measured at a temperature of about 150K to give the unit cell parameter characterization listed in table 5 and fractional atomic coordinates as shown in table 6.
TABLE 5 unit cell parameters of single crystals of form A of the compound of formula (I-a)
TABLE 6 fractional atomic coordinates of single crystals of form A of the compound of formula (I-a)
/>
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
To the flask was added tert-butyl-4- ((2R, 3S,4S, 5S) -2,3, 4-tribenzyloxy-5- ((benzyloxy) methyl) -5-hydroxyhept-6-ynyl) piperazine-1-carboxylate (749 mg,1.00mmol, 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), after addition, N was replaced 2 After three times of gas charging CO 2 The temperature is raised to 60 ℃ until the pressure is 1MPa, and the reaction is stirred for 18h. After the completion of the reaction, the temperature was lowered to 10℃and an aqueous solution of citric acid (1.0 mL) was added to the reaction mixture, which was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (5 mL), washed with water (5 mL. Times.2) and concentrated under reduced pressure to give the title compound as a yellow oil (770 mg,1.00mmol, product content: 66.44%, yield: 100%). MS (ESI, pos.ion) m/z 767.4[ M+H ]] + 。
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
To the flask was added tert-butyl-4- ((2R, 3S,4S, 5S) -2,3, 4-tribenzyloxy-5- ((benzyloxy) methyl) -5-hydroxy-6-oxoheptanoyl) piperazine-1-carboxylate (10 g,13.04mmol, purity: 98.26%) and methyl tert-butyl ether (296 g), cooled to 0 ℃, lithium aluminum tri-tert-butoxide (9.95 g,39.12 mmol) was added, the reaction was stirred for 2h after the addition was completed, water (10 g) was added, stirred for 10min, suction filtration under reduced pressure, the filter cake was washed with methyl tert-butyl ether (30 g) and the filtrate was collected, washed with 1M HCl solution (200 g) and concentrated under reduced pressure to give the title compound as a yellow oil (10.03 g,13.00mmol, product content: 92.81%, yield: 100%).
EXAMPLE 5 Synthesis of tert-butyl-4- ((2R, 3S, 4S) -2,3, 4-tribenzyloxy-4- ((4R, 5R) -4- (benzyloxymethyl) -2, 5-trimethyl-1, 3-dioxolan-4-yl) butanoyl) piperazine-1-carboxylate
Tert-butyl-4- ((2R, 3S,4S,5R, 6R) -2,3, 4-tribenzyloxy-5- ((benzyloxy) methyl) -5, 6-dihydroxyheptanoyl) piperazine-1-carboxylate (3.4 g,4.42mmol, content: 92.81%) was dissolved in acetone (26.86 g), 2-dimethoxypropane (1.38 g,13.26 mmol) and p-toluenesulfonic acid monohydrate (63 mg,0.33 mmol) were added and stirred for 1h. After the completion of the reaction, saturated sodium hydrogencarbonate solution (1 mL) was added, stirred for 10min, concentrated under reduced pressure, and the concentrate was dissolved with ethyl acetate (9.2 g), washed with water (9.2 g) and concentrated under reduced pressure to give the title compound as a pale 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。
EXAMPLE 6 Synthesis of (2R, 3S, 4S) -2,3, 4-tribenzyloxy-4- ((4R, 5R) -4- ((benzyloxymethyl) -2, 5-trimethyl-1, 3-dioxolan-4-yl) -1- (4-chloro-3- (4-ethoxyphenyl) methyl) phenyl) butan-1-one
Tert-butyl-4- ((2R, 3S, 4S) -2,3, 4-tribenzyloxy)1-methyl-4- ((4R, 5R) -4- (benzyloxymethyl) -2, 5-trimethyl-1, 3-dioxolan-4-yl) butyryl) piperazine-carboxylate (450.50 g,556.86mol, purity of product: 90.47%) in anhydrous tetrahydrofuran (1.21 kg) and cooled to-20℃under nitrogen, and [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] prepared according to the prior art method was added dropwise ]Phenyl group]A solution of magnesium bromide (891.30 mmol, purity: 95.00%) in tetrahydrofuran was added dropwise over a period of about 30 minutes, after which the mixture was stirred for 20 minutes at-20℃and then allowed to stir at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by addition of a dilute hydrochloric acid solution (1.25L, 1 mol/L) at 0 ℃. To the mixed solution was added n-heptane (1.27 kg) for extraction, and the organic phase was washed with saturated brine (1.65L) and concentrated under reduced pressure to give 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。
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (11)

1. A process for the preparation of a compound of formula (I-a), comprising the steps of:
the compound shown in the formula (II-a) is subjected to addition reaction with trimethylsilyl acetylene in a solvent in the presence of LiHMDS to obtain the compound shown in the formula (I-a),
2. the production process 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, tetramethyl ethylenediamine, tetramethyl tartaric acid amide, hexamethylphosphoric triamide, (-) -cytisine, triethylamine, propylene diamine, ethylenediamine, dimethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine, N-dimethylpropylurea, N-methylpyrrolidone or pyridine.
3. The production process according to claim 2, wherein the additive is used in an amount of 0.2 to 1.2 times equivalent to the compound represented by the formula (II-a); preferably, the additive is used in an amount of 0.5 to 1.0 times equivalent to the compound of formula (II-a); more preferably, the additive is used in an amount of 0.2 times, 0.5 times or 1.0 times equivalent to the compound represented by the formula (II-a).
4. The production process according to any one of claims 1 to 3, wherein the trimethylsilylacetylene is used in an amount of 1.0 to 2.0 times equivalent to the compound of formula (II-a); preferably, the amount of the trimethylsilylacetylene is 1.2 to 1.5 times the equivalent of the compound shown in the formula (II-a); more preferably, the trimethylsilylacetylene is used in an amount of 1.2 times or 1.5 times the equivalent of the compound of formula (II-a).
5. The production process according to any one of claims 1 to 4, wherein the LiHMDS is used in an amount of 1.0 to 2.0 times equivalent to the compound represented by the formula (II-a); preferably, the LiHMDS is used in an amount of 1.2 to 1.5 times the equivalent of the compound represented by the formula (II-a); more preferably, the LiHMDS is used in an amount of 1.2 times or 1.5 times the equivalent of the compound of formula (II-a).
6. The production process according to any one of claims 1 to 5, wherein the solvent is tetrahydrofuran, dichloromethane, toluene, diethyl ether, 2-methyl-tetrahydrofuran, n-hexane, cyclohexane or n-heptane.
7. The production process according to any one of claims 1 to 6, wherein, in the reaction of the compound represented by the formula (II-a) with trimethylsilylacetylene, the reaction temperature is from-40 ℃ to-80 ℃; preferably, the reaction temperature is-50 ℃ to-80 ℃; preferably, the reaction temperature is-60 ℃ to-80 ℃; more preferably, the reaction temperature is-78 ℃.
8. A compound represented by the formula (I-a),
9. a crystalline form A of a compound of formula (I-a),
has at least one of the following features:
1) The differential scanning calorimeter diagram comprises a maximum endothermic peak at 93.12 +/-3 ℃; or (b)
2) It has the following unit cell parameters:
unit cell specification:α＝90°、β＝97.3928°、γ＝90°；
space group: p2 1 ；
Unit cell volume:
number of asymmetric units in unit cell Z:2; or (b)
3) The X-ray powder diffraction pattern thereof 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 °, 19.86 ° ± 0.2 °.
10. Form a of claim 9 having a differential scanning calorimeter substantially as shown in figure 1.
11. Form a of claim 9 or 10, having an X-ray powder diffraction pattern with 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 °, 23.82 ° ± 0.2 °; or (b)
The X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the following 2 theta 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 °, 17.76 ° ± 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 °, 25.75 ° ± 0.2 °, 26.40 ° ± 0.26 ° ± 0.93 ° ± 62.2 °, 52 ° ± 0.83 ° ± 0.2 °, 52.42 ° ± 0.32 ° ± 0.2); or (b)
Form a having an X-ray powder diffraction pattern substantially as shown in figure 4.
CN202310868761.8A 2022-07-15 2023-07-14 Key intermediate for preparing glucopyranosyl derivative and preparation method thereof Pending CN117430571A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022108355711 2022-07-15
CN202210835571 2022-07-15

Publications (1)

Publication Number Publication Date
CN117430571A true CN117430571A (en) 2024-01-23

Family

ID=89535655

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310868761.8A Pending CN117430571A (en) 2022-07-15 2023-07-14 Key intermediate for preparing glucopyranosyl derivative and preparation method thereof

Country Status (2)

Country Link
CN (1) CN117430571A (en)
WO (1) WO2024012568A1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2968375B1 (en) * 2013-03-14 2019-06-12 MSD International GmbH Methods for preparing sglt2 inhibitors
CN104513283B (en) * 2013-09-27 2018-01-16 广东东阳光药业有限公司 Glucopyranosyl derivatives and its application in medicine
WO2020143653A1 (en) * 2019-01-08 2020-07-16 广东东阳光药业有限公司 Preparation method for glucopyranosyl derivative and intermediate thereof
CN113912567B (en) * 2020-07-08 2024-01-16 宜昌东阳光长江药业股份有限公司 Process for preparing glucopyranosyl derivatives and intermediates therefor

Also Published As

Publication number Publication date
WO2024012568A1 (en) 2024-01-18

Similar Documents

Publication Publication Date Title
JP6937322B2 (en) Salt of substituted piperidine compound
JP7371006B2 (en) Method for preparing modulators of P300 and/or CBP
EP3190102A1 (en) Crystal of pyrrole derivative and method for producing the same
CN113195510B (en) Process for producing glucopyranosyl derivative and intermediate therefor
CA2553345C (en) Novel crystalline forms of an inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1
CN101790531A (en) Process for the preparation of pyrido [2, 1-a] isoquinoline derivatives and polymorphic froms thereof
CN110627801A (en) HDAC inhibitor and application thereof
KR20150001802A (en) Solid state forms of fidaxomycin and processes for preparation thereof
CN107286220B (en) 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof
EP2205580A1 (en) Crystalline forms of dmxaa sodium salt
WO2013027227A1 (en) Novel polymorphic form i of rifaximin
US10703750B2 (en) Crystalline valbenazine free base
CN117430571A (en) Key intermediate for preparing glucopyranosyl derivative and preparation method thereof
CN113912567B (en) Process for preparing glucopyranosyl derivatives and intermediates therefor
CN115772159A (en) KIF18A inhibitors
US11053261B2 (en) Solid state forms of ixazomib citrate
CN113321673A (en) Preparation method and application of neobynine boric acid compound
CN113045554A (en) Fexotinib crystal form and preparation method thereof
KR20120053027A (en) Crystalline forms of fesoterodine fumarate and fesoterodine base
EP3831834A1 (en) Borate of azetidine derivative
JP2020189856A (en) Crystalline form of sofpironium bromide and preparation method thereof
CN112480129A (en) Polycyclic spiroindoline compound containing guanidyl structural unit and preparation method and application thereof
CN112830919B (en) Benzopiperidine derivatives as pharmaceutical agents and process for preparing them
AU2021407012B2 (en) CRYSTAL FORM OF CASEIN KINASE 1ε INHIBITOR, AND PREPARATION METHOD THEREFOR AND USE THEREOF
CN111393416B (en) Preparation method and application of pyrazole compound containing 1-methylpyridine-3- (4-chlorphenyl) pyrazole unit

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination