CN116730998A - Process for preparing aryl carbon glycoside compound - Google Patents

Process for preparing aryl carbon glycoside compound Download PDF

Info

Publication number
CN116730998A
CN116730998A CN202210212952.4A CN202210212952A CN116730998A CN 116730998 A CN116730998 A CN 116730998A CN 202210212952 A CN202210212952 A CN 202210212952A CN 116730998 A CN116730998 A CN 116730998A
Authority
CN
China
Prior art keywords
compound shown
formula
alkyl
halogenated
group
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
CN202210212952.4A
Other languages
Chinese (zh)
Inventor
钮大文
张霞
张晨
左昊
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.)
West China Hospital of Sichuan University
Original Assignee
West China Hospital of Sichuan University
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 West China Hospital of Sichuan University filed Critical West China Hospital of Sichuan University
Priority to CN202210212952.4A priority Critical patent/CN116730998A/en
Publication of CN116730998A publication Critical patent/CN116730998A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Saccharide Compounds (AREA)

Abstract

The invention provides a process for preparing aryl carbon glycoside compounds, and belongs to the field of pharmacy. The method comprises the following steps: the compound shown in the formula (I) is obtained by taking the compound shown in the formula (II) and the compound shown in the formula (III) as raw materials and reacting. The method has wide applicability, can be used for preparing various aryl carbosides, not only can be used for preparing pyridine carbosides compounds, but also can be used for preparing listed-net medicines. The glycosyl donor adopted by the method has good stability, does not need protecting groups, and avoidsThe redundant protection/deprotection operation reduces the production cost and the generation amount of three wastes; the method can rapidly react at room temperature, has mild conditions, does not need n-butyllithium or a format reagent to participate, does not need to be carried out at low temperature below zero, and is safe and environment-friendly; the method has high product yield and high purity, and is suitable for industrial production.

Description

Process for preparing aryl carbon glycoside compound
Technical Field
The invention belongs to the field of pharmacy, and in particular relates to a process for preparing aryl-carbon glycoside compounds.
Background
Carbohydrate is another important living substance besides nucleic acid and protein, is an important information molecule in living body, and participates in all time and space processes of life, especially fertilization, implantation, differentiation, development, immunity, infection, transformation, aging and the like of multicellular life. Sugar plays a vital role in biological processes such as mutual recognition and interaction among cells, water and electrolyte delivery, cancer generation and metastasis, body immunity and immunosuppression, cell aggregation and the like. In recent years, there has been an increasing interest in the widespread research of chemists due to the remarkable physiological activity of saccharide compounds. Glycosides are an important form of sugar occurring in nature, which is widely present in living organisms, has a specific biological activity, and is responsible for important physiological functions. Glycoside compounds are a very important class of compounds formed by the condensation of hemiacetal hydroxyl groups of sugars with ligands to lose one molecule of water or other small molecule compounds, where the sugar moiety is called a glycosyl group and the non-sugar moiety is called an ligand. Glycoside compounds can be classified into oxy-glycoside compounds, nitrogen-glycoside compounds, thio-glycoside compounds and carbo-glycoside compounds according to the type of atom of the ligand in the molecular structure of the glycoside compound to which the carbon atom of the sugar ring is attached. Among them, the carboside compounds are a generic name of a class of compounds in which an exocyclic oxygen atom of a carboside bond is replaced by a carbon atom, and are a class of sugar-containing skeletons which exist in nature very widely and are widely found in various natural products and drug molecules, and compared with oxy-and aza-glycosides, carboside has better enzyme stability and hydrolysis resistance in organisms, so they are also an important choice for replacing natural oxy-glycoside drugs.
International patent application No. WO2021013155A1 discloses a process for preparing a carbonyl compound from an allyl sulfone glycosyl donor and a pyridinium tetrafluoroborate (synthetic route is as follows). In the method, under nitrogen atmosphere, glycosyl donor 3-1 (1.0 equiv), glycosyl acceptor tetrafluoroborate pyridine salt (2.0 equiv), photosensitizer EosinY (eosin Y,0.025 equiv.), initiator sodium trifluoromethylsulfinate (0.2 equiv.) are added into a catalytic reaction bottle, DMSO is added, and stirring is carried out for 8 hours at room temperature under the irradiation of Blue LED, thus obtaining a carboside compound C-X. However, the method can only be used for preparing pyridine-type carbostyril compounds, but cannot be used for preparing the Lijing-type medicines.
As one of hypoglycemic agents, the Liujing medicine can reduce the reabsorption of glucose by the kidney and increase the excretion of urine glucose by inhibiting SGLT-2 (sodium glucose cotransporter 2) with high selectivity, thereby reducing the blood sugar of a type II diabetes patient. Besides reducing blood sugar, the Lijing medicine can also reduce weight, reduce blood pressure, protect heart and kidney and reduce uric acid. In addition, compared with other kinds of hypoglycemic agents, the listed net drugs have no obvious side effects and do not interfere with insulin and glucagon secretion regulation pathways. The advantages make the listed drugs the first choice for treating type II diabetes. At present, 9 kinds of column-purifying medicines are marketed globally, and 4 kinds of column-purifying medicines are obtained in China and China in batch and marketed, namely dapagliflozin, canagliflozin, enggliflozin and Eagliflozin respectively. Of these, enggliflozin was marketed in 2014 and sold worldwide in 2019 for over 30 million dollars.
For the preparation method of the medicine of the Lipugliflozin class, the method for synthesizing the Lipugliflozin (also known as Engliflozin) disclosed by Dan Kejin et al (synthetic process, chemical research and application of the Lipugliflozin, 11 th year 2016, 11 th Vol. 28) is as follows: 5-bromo-2-chlorobenzoic acid is used as a raw material, and is subjected to acyl chlorination, friedel-crafts acylation reaction, nucleophilic substitution and reduction to obtain an intermediate (S) -4-bromo-1-chloro-2- (4-tetrahydrofuran-3-yloxy-benzyl) benzene, wherein the intermediate is condensed with 2,3,4, 6-tetra-O-trimethylsilyl-D-glucopyranose 1, 5-lactone, and the epoxidizing is performed to obtain the epagliflozin with the total yield of 29.8 percent and the purity of 99.13 percent. The method has low yield, and the reaction temperature of-78 ℃ is needed in the synthesis process, so that the temperature is difficult to control, and the method is not beneficial to industrial production. To increase the yield of the listed drugs, researchers improved the above process and reported an improved process for synthesizing engagliflozin (journal of the chinese medical industry, 2018, volume 49, 8): phenol (2) reacts with (R) -3-hydroxy tetrahydrofuran to obtain (S) -3-phenoxy tetrahydrofuran, and reacts with 2-chloro-5-iodobenzyl bromide through Friedel-crafts alkylation to obtain (S) -3- [4- (2-chloro-5-iodobenzyl) phenoxy ] tetrahydrofuran (6). Condensing 6 and 2,3,4, 6-tetra-O-acetyl-1-alpha-bromo-D-glucopyranose in the presence of n-butyllithium and cuprous iodide to obtain (2S, 3R,4R,5S, 6R) -2- [3- [4- [ (S) -tetrahydrofuran-3-yloxy ] benzyl ] -4-chlorophenyl ] -6-acetoxymethyl-3, 4, 5-triacetoxy-hexane (8); finally, 8 is deacetylated by lithium hydroxide to obtain the target compound 1 (i.e. Engliflozin) with a total yield of 43.0% (calculated by 2) and a product purity of 99.21%. Although this method increases the yield of the product, it has the following problems: (1) The reaction route is long, the economic cost is increased, the stability of the adopted glycosyl donor is poor, the hydroxyl on the glycosyl donor needs to be protected by a protecting group to prevent the hydroxyl from interfering with key bonding steps, and the protecting group is removed after the compound 8 is synthesized to obtain the target product, namely the enggliflozin; (2) The reaction temperature of 40 ℃ below zero is more severe, and the requirements on equipment are high; (3) the overall yield is to be further improved.
Therefore, the development of a new method for preparing aryl carbon glycoside compounds including listed net drugs has the advantages of simple reaction route, lower production cost and mild reaction conditions.
Disclosure of Invention
The invention aims to provide a process for preparing aryl carboside compounds.
The invention provides a method for preparing a compound shown as a formula (I), which comprises the following steps: taking a compound shown in a formula (II) and a compound shown in a formula (III) as raw materials, and reacting to obtain the compound shown in the formula (I);
wherein t is an integer of 0 to 5, R a Each independently selected from LOH, LOCOR 0 、C 1～4 Alkyl group,Or 2 of them a Connected into a ring;
R 0 is C 1～4 An alkyl group;
x is halogen;
the B ring is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
s is an integer of 0 to 5, R b Each independently selected from halogenated or non-halogenated C 1～4 Alkyl, halogenated or non-halogenated C 1～4 Alkoxy, COOR 5 、OCOR 5 、NHCOR 5 、CONHR 5 、COR 5 、NHR 5 、OR 5 、SR 5 Cyano, halogen, LOH, 5-6 membered saturated heterocyclic group, 5-6 membered saturated cycloalkyl group,
R 6 Is hydrogen or an amino protecting group;
R 7 is hydrogen or C 1～4 An alkyl group;
l is no or 1-4 methylene;
the ring A is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
p is an integer of 0 to 2, R 2 Independently selected from C 1～4 Alkyl, C 1～4 Alkoxy, phenyl, halogenated OR not halogenated, OR 3 ，R 3 Is 5-6 membered saturated heterocyclic group or 5-6 membered saturated cycloalkyl.
The compounds of formula (II) and (III) of the present invention are both commercially available or can be synthesized by one skilled in the art.
Further, the reaction is carried out in the presence of a Ni (I) base catalyst, a Ru (II) base photosensitizer, a Bpy-ligand complex, an initiator and a base, wherein the solvent of the reaction is an organic solvent, the temperature of the reaction is room temperature, the time is 6-18 hours, the reaction is carried out under the irradiation of an LED lamp, and the reaction is carried out under the nitrogen atmosphere;
and/or the molar ratio of the compound shown in the formula (II), the compound shown in the formula (III), the Ni (I) base catalyst, the Ru (II) base photosensitizer, the Bpy-ligand complex, the initiator and the alkali is (0.1-0.3): (0.05-0.20): (5% -15%): (0.5-1.5%): (9% -15%): (0.2-1.0): (0.1 to 0.7).
Further, the Ni (I) -based catalyst is NiBr 2 DME, the Ru (II) -based photosensitizer is Ru (bpy) 3 Cl 2 .6H 2 O, wherein the Bpy-ligand complex is diOMebpy, the initiator is sodium p-methylbenzenesulfonate, the base is tetramethyl guanidine, and the organic solvent is DMSO;
and/or the reaction time is 12 hours, and the parameters of the LED lamp are as follows: 10W, 4575 nm;
and/or the molar ratio of the compound shown in the formula (II), the compound shown in the formula (III), the Ni (I) base catalyst, the Ru (II) base photosensitizer, the Bpy-ligand complex, the initiator and the alkali is 0.15:0.1:10%:1%:12%:0.6:0.4.
further, the compound represented by the formula (II) isThe compound shown in the formula (III) isThe compound shown in the formula (I) is +.>
Wherein X is halogen;
R 1 is halogen, C 1～4 Alkyl or C 1～4 An alkoxy group;
the ring A is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
p is an integer of 0 to 2, R 2 Independently selected from C 1～4 Alkyl, C 1～4 Alkoxy, phenyl, halogenated OR not halogenated, OR 3 ，R 3 Is 5-6 membered saturated heterocyclic group or 5-6 membered saturated cycloalkyl.
Further, the compound represented by the formula (I) is one of the following compounds:
further, the compound represented by the formula (II) isThe compound shown in the formula (III) isThe compound shown in the formula (I) is +.>
Wherein X is halogen;
the B ring is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
q is an integer of 0 to 2, R 4 Independently selected from halogenated or non-halogenated C 1～4 Alkyl, halogenated or non-halogenated C 1～4 Alkoxy, COOR 5 、OCOR 5 、NHCOR 5 、CONHR 5 、COR 5 、NHR 5 、OR 5 、SR 5 Cyano, halogen, LOH,5-6 membered saturated heterocyclic group, 5-6 membered saturated cycloalkyl group,
R 5 Is hydrogen or C 1～4 Alkyl, R 6 Is hydrogen or an amino protecting group, R 7 Is hydrogen or C 1～4 Alkyl, L is no or 1-3 methylene.
Further, the method comprises the steps of,is one of the following structures:
wherein R is methoxy, methyl, tertiary butyl or OCF 3 、CF 3 Or COOMe.
Further, the compound represented by the formula (I) is one of the following compounds:
further, the compound represented by the formula (II) isThe compound shown in the formula (III) isThe compound shown in the formula (I) is +.>
Wherein X is halogen;
R 9 is hydrogen, hydroxy,OCOCH 3 、
y is an integer of 1 to 4, R 8 Independently selected from LOH, LOOCH 3 Methyl; l is no or 1-3 methylene.
Further, the compound represented by the formula (I) is one of the following compounds:
definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for terms herein apply to the terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1～4 Alkyl refers to straight or branched chain alkyl groups containing 1 to 4 carbon atoms.
In the present invention, "aryl" refers to an all-carbon monocyclic or fused-polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be a single ring or multiple rings. For example, "5-to 6-membered saturated cycloalkyl" refers to a saturated cycloalkyl group having 5 to 6 ring carbon atoms.
"fused ring alkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.
"heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carry at least one ring heteroatom (including but not limited to O, S or N). For example, "5-to 6-membered saturated heterocyclic group" means a saturated heterocyclic group having 5 to 6 ring atoms.
"heterofused ring group" refers to a polycyclic heterocyclic group having two rings sharing two adjacent carbon or heteroatom.
Halogen is fluorine, chlorine, bromine or iodine.
Compared with the prior art, the preparation method provided by the invention has the following beneficial effects:
(1) The invention provides a reaction route for preparing aryl carboside compound shown in formula (I) by taking compound shown in formula (II) and compound shown in formula (III) as raw materials for the first time. The reaction mechanism of the synthesis method is different from that in the prior art, and is a novel reaction mechanism.
(2) The method has wide applicability, can be used for preparing various aryl carbosides, not only can be used for preparing pyridine carbosides compounds, but also can be used for preparing listed-net medicines.
(3) The glycosyl donor adopted by the method has stable raw materials, does not need a protecting group, avoids redundant protecting/deprotecting operation, reduces the production cost, and reduces the generation amount of three wastes;
(4) The method adopts free radical reaction, can rapidly react at room temperature, has mild conditions, does not need to participate in n-butyllithium or a format reagent, does not need to be carried out at low temperature below zero, and is safe and environment-friendly;
(5) The method has high product yield and high purity;
(6) The reaction of the present invention is stereoselective. After the catalyst transition metal is combined with chiral ligand, the three-dimensional configuration of aryl glucoside can be regulated and controlled, so that the reaction has excellent three-dimensional selectivity.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1 is a synthetic route for enggliflozin, canagliflozin, dapagliflozin, and idagliflozin.
FIG. 2 shows the synthetic routes for compounds 10 a-10 y.
FIG. 3 shows the synthetic routes of compounds 12a to 12 k.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The glycosyl donor starting materials used in the following examples can be prepared by the methods described in International patent application No. WO2021013155A 1.
The following are examples of the preparation methods of glycosyl donors:
route one:
the glycosyl donor is synthesized according to the method of the first route, and the specific operation is as follows:
step 1: to a solution containing SI-5 (10 mmol) and 25mL CH 3 Thiourea (15 mmol,1.1 g) and BF were added sequentially to a 100ml round bottom flask of CN 3 ·Et 2 O (30 mmol,3.75 mL). The reaction solution was refluxed for 8 hours until TLC monitoring showed complete SI-5 consumption. To the resulting solution was added Et in sequence 3 N (30 mmol,5.2 mL), 3-bromo-2-methylpropene (15 mmol,1.5 mL). The resulting solution was stirred at 80 ℃ and the progress of the reaction was monitored by TLC. The resulting solution was concentrated and dissolved in CH 2 Cl 2 And washed with water. The organic layer was separated and washed with brine, dried and concentrated to give SI-6 as a mixture, which was used in the next step without further purification.
Step 2, SI-6 is dissolved in 20mLCH 2 Cl 2 And cooled at 0 c. m-CPBA (25 mmol,4.3 g) was slowly added to the reaction solution with stirring. The mixed solution was stirred at room temperature for 1 hour. The resulting mixture was filtered, and the filtrate was washed with water. The organic layer was separated with saturated Na 2 SO 3 Solution, saturated NaHCO 3 The solution was washed with brine, then dried and concentrated. The residue was flash chromatographed to give sulfone SI-7.
Step 3 SI-7 was dissolved in 20mL MeOH at 0deg.C, to which LiOH (5 mmol,120 mg) was added. And the reaction was allowed to stir at 0 ℃ for 4 hours. Silica gel was added to the mixture, which was then concentrated in vacuo. The resulting mixture was dry loaded onto a silica gel column and eluted to give the corresponding glycosyl donor.
Route two:
example 1 preparation of Engliflozin
Method according to route twoThe method for synthesizing the enggliflozin comprises the following specific operations: glycosyl donor 1 (42 mg,0.15 mmol), (3 s) -3- [4- [ (2-chloro-5-iodophenyl) methyl]Phenoxy group]Tetrahydro-furan ((3S) -3- [4- [ (2-Chloro-5-iodophenyl) methyl)]phenoxy]tetrahydro-furan，41mg，0.1mmol)、Ru(bpy) 3 Cl 2 .6H 2 O(0.8mg,1mol％),NiBr 2 .DME(3.1mg,10mol％),diOMebpy(2.6mg,12mol％),TolSO 2 Na (sodium p-methylbenzenesulfonate, 54mg,0.6 mmol), TMG (tetramethylguanidine, 25uL,0.4 mmol)) and DMSO (0.5 mL) were weighed and mixed in a screw-cap vial with a magnetic stirring bar, the vial was filled with N 2 And sealed with teflon lined covers. The mixture was stirred at room temperature under a 10W,455nm LED lamp for 12 hours, and the reaction was completed.
The reaction mixture was diluted with 10mL of ethyl acetate, and then washed with saturated brine. The organic phase was collected and the aqueous phase was extracted 3 times with 6mL ethyl acetate. The combined organic phases were concentrated under reduced pressure and the residue was chromatographed on silica gel (eluting with petroleum ether/ethyl acetate=10:7 (v/v)) to give the glycoside product engagliflozin. The single beta configuration, 26mg, yield 57% and purity more than 95%.
1 H NMR(400MHz,CD 3 OD)δ7.37–7.31(m,2H),7.27(dd,J＝8.1,2.1Hz,1H),7.13–7.06(m,2H),6.81–6.74(m,2H),4.94(ddt,J＝6.2,4.1,1.9Hz,1H),4.08(d,J＝9.7Hz,1H),4.05–3.95(m,2H),3.94–3.80(m,5H),3.71–3.64(m,1H),3.48–3.34(m,3H),3.30–3.24(m,1H),2.19(dtd,J＝13.3,8.4,6.0Hz,1H),2.10–2.02(m,1H).
Example 2 preparation of canagliflozin
With reference to the method and the molar ratio of the starting materials in example 1, only difference is that iodobenzene compound 2 is replaced by 3 s) -3- [4- [ (2-chloro-5-iodophenyl) methyl ] phenoxy ] tetrahydro-furan with 2- (4-Fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene (2- (4-fluoro-phenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene), and the volume ratio of petroleum ether/ethyl acetate in the eluent of silica gel chromatographic separation is modified to 10:5, so as to obtain the glycoside product canagliflozin. The single beta configuration, 32mg, yield 71% and purity more than 95%.
1 H NMR(400MHz,CD 3 OD)δ7.54–7.48(m,2H),7.31(d,J＝1.7Hz,1H),7.24(dd,J＝7.8,1.8Hz,1H),7.15(d,J＝7.8Hz,1H),7.08(d,J＝3.6Hz,1H),7.07–7.01(m,2H),6.68(d,J＝3.6Hz,1H),4.16–4.12(m,2H),4.11(d,J＝9.3Hz,1H),3.88(dd,J＝11.9,1.8Hz,1H),3.70(dd,J＝11.9,5.0Hz,1H),3.51–3.35(m,4H),2.29(s,3H).
Example 3 preparation of dapagliflozin
The procedure and molar ratios of starting materials were as described in reference to example 1, except that iodobenzene compound 2 was replaced with 1-Chloro-2- (4-ethoxybenzyl) -4-iodobenzene (1-Chloro-2- (4-ethoxybenzyl) -4-iodobenzene) from 3 s) -3- [4- [ (2-Chloro-5-iodophenyl) methyl ] phenoxy ] tetrahydro-furan to give the glycoside product dapagliflozin. The single beta configuration, 31mg, yield 75% and purity more than 95%.
1 H NMR(400MHz,CD 3 CN)δ7.37(d,J＝8.2Hz,1H),7.30(d,J＝2.1Hz,1H),7.24(dd,J＝8.2,2.2Hz,1H),7.12(d,J＝8.6Hz,2H),6.86–6.80(m,2H),4.08(d,J＝9.4Hz,1H),4.05–4.02(m,2H),3.99(q,J＝7.1Hz,2H),3.74(ddd,J＝11.6,5.8,2.1Hz,1H),3.63–3.56(m,1H),3.45(d,J＝3.1Hz,1H),3.36(dt,J＝7.1,3.3Hz,4H),3.24(td,J＝8.9,4.7Hz,1H),3.13(d,J＝4.8Hz,1H),2.73(t,J＝6.2Hz,1H),1.33(t,J＝7.0Hz,3H).
Example 4 preparation of Isgliflozin
/>
The procedure and molar ratios of starting materials are as described in reference to example 1, except that iodobenzene compound 2 is replaced by 3 s) -3- [4- [ (2-chloro-5-iodophenyl) methyl ] phenoxy ] tetrahydro-furan with 2- [ (5-BroMo-2-fluorophenyl) methylbenzothiophene (2- (5-BroMo-2-fluoroobenzyl) benzothiophen) to give the glycoside product, i.e., irinotecan. The single beta configuration, 27mg, yield 68% and purity more than 95%.
1 H NMR(400MHz,CD 3 OD)δ7.72(dd,J＝8.1,1.2Hz,1H),7.69–7.60(m,1H),7.43(dd,J＝7.4,2.2Hz,1H),7.35(ddd,J＝8.5,5.0,2.3Hz,1H),7.32–7.19(m,2H),7.12–7.02(m,2H),4.34–4.18(m,2H),4.11(d,J＝9.4Hz,1H),3.91–3.82(m,1H),3.73–3.63(m,1H),3.48–3.35(m,3H),3.33–3.31(m,1H).
Route three:
example 5 preparation of Compounds 10a to 10y
The method according to the route III synthesizes the compounds 10a to 10y, and the specific operation is as follows: glycosyl donor 1a (0.15 mmol), compound 2 (0.1 mmol), ru (bpy) 3 Cl 2 .6H 2 O(0.8mg,1mol％),NiBr 2 .DME(3.1mg,10mol％),diOMebpy(2.6mg,12mol％),TolSO 2 Na (54 mg,0.6 mmol), TMG (25 uL,0.4 mmol)) and DMSO (0.5 mL) were weighed and mixed in a screw cap vial with a magnetic stirring bar, the vial was filled with N 2 And sealed with teflon lined covers. The mixture was stirred at room temperature under a 10W,455nm LED lamp for 12 hours, and the reaction was completed.
The reaction mixture was diluted with 10mL of ethyl acetate, and then washed with saturated brine. The organic phase was collected and the aqueous phase was extracted 3 times with 6mL ethyl acetate. The organic phases were combined and concentrated under reduced pressure, and the residue was chromatographed on silica gel (eluting with a petroleum ether/ethyl acetate mixture) to give compounds 10a to 10y (see table 1 for specific structures), respectively.
TABLE 1 parameter control of synthetic Compounds 10 a-10 y
/>
/>
TABLE 2 characterization of the yields, purities and structures of the Compounds 10 a-10 y
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
Route four:
EXAMPLE 6 preparation of Compounds 12 a-12 k
The compounds 12a to 12k were synthesized according to the method of scheme four, which were specifically: glycosyl donor 11 (0.15 mmol), compound 2a (0.1 mmol), ru (bpy) 3 Cl 2 .6H 2 O(0.8mg,1mol％),NiBr 2 .DME(3.1mg,10mol％),diOMebpy(2.6mg,12mol％),TolSO 2 Na (54 mg,0.6 mmol), TMG (25 uL,0.4 mmol)) and DMSO (0.5 mL) were weighed and mixed in a screw cap vial with a magnetic stirring bar, the vial was filled with N 2 And sealed with teflon lined covers. The mixture was stirred at room temperature under a 10W,455nm LED lamp for 12 hours, and the reaction was completed.
The reaction mixture was diluted with 10mL of ethyl acetate, and then washed with saturated brine. The organic phase was collected and the aqueous phase was extracted 3 times with 6mL ethyl acetate. The organic phases were combined and concentrated under reduced pressure, and the residue was chromatographed on silica gel (eluting with a petroleum ether/ethyl acetate mixture) to give compounds 12a to 12k, respectively (see table 3 for specific structures).
TABLE 3 Structure of Compounds 12 a-12 k
/>
TABLE 4 yield, purity and structural characterization of Compounds 12 a-12 k
/>
/>
/>
/>
EXAMPLE 7 Synthesis of saccharide Compounds 13 a-13 j
Route five:
1. synthesis of Compound 13a
(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-methoxyphenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor a (84 mg,0.30 mmol), 4-methoxyiodobenzene (4-Iod)oanisole，47mg，0.2mmol)，Ru(bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give product 13a (single β configuration, 73mg,83% purity greater than 95%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.30–7.23(m,2H),6.90–6.82(m,2H),5.32(t,J＝9.4Hz,1H),5.23(t,J＝9.6Hz,1H),5.14(t,J＝9.6Hz,1H),4.35(d,J＝9.8Hz,1H),4.28(dd,J＝12.3,4.7Hz,1H),4.15(dd,J＝12.3,2.3Hz,1H),3.83(ddd,J＝9.9,4.6,2.2Hz,1H),3.79(s,3H),2.08(s,3H),2.06(s,3H),2.00(s,3H),1.80(s,3H).The 1 H NMR spectra coincide with theprevious report.
2. Synthesis of Compound 13b
(2R,3S,4R,5S,6S)-5-acetamido-2-(acetoxymethyl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4-diyl diacetate
According to scheme five, glycosyl donor b (97 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give product 13b (single β configuration, 44mg,50% purity greater than 95%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.30–7.25(m,2H),6.89–6.83(m,2H),5.31–5.19(m,3H),4.36(d,J＝10.2Hz,1H),4.31–4.22(m,2H),4.13(dd,J＝12.4,2.3Hz,1H),3.84–3.73(m,4H),2.08(s,3H),2.05(s,3H),2.04(s,3H),1.72(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ171.40,170.96,169.57,160.10,128.95,114.02,81.29,76.33,74.53,68.85,62.70,55.37,54.98,23.23,20.95,20.89,20.83；HRMS(DART-TOF)calculated for C 21 H 27 NNaO 9 + [M+Na] + m/z 460.1578,found 460.1570.
3. Synthesis of Compound 13c
(2S,3S,4R,5S,6S)-2-(4-methoxyphenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor c (80 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give product 13c (β/α=1:3, 53 mg, 70% purity greater than 95%) as a white solid.
α-anomer: 1 H NMR(400MHz,CDCl 3 ),δ7.46–7.38(m,2H),6.99–6.91(m,2H),5.98(t,J＝2.8Hz,1H),5.16(ddd,J＝13.9,5.9,2.3Hz,2H),5.00(d,J＝2.7Hz,1H),3.82(s,3H),3.65–3.56(m,1H),2.17(s,3H),2.05(s,3H),2.01(s,3H),1.27(d,J＝6.4Hz,3H)；β-anomer: 1 H NMR(400MHz,CDCl 3 ),δ7.26–7.24(m,2H),6.86–6.81(m,2H),5.49(dd,J＝3.0,1.3Hz,1H),5.20(dd,J＝7.4,2.5Hz,1H),5.11(d,J＝3.0Hz,1H),4.69(s,1H),3.78(s,3H),3.73–3.64(m,1H),2.08(s,3H),1.98(s,3H),1.95(s,3H),1.33(d,J＝6.1Hz,3H).The 1 H NMR spectra coincide with theprevious report.
4. Synthesis of Compound 13d
(2S,3S,4S,5R)-2-(4-methoxyphenyl)tetrahydro-2H-pyr an-3,4,5-triyl triacetate
According to scheme five, glycosyl donor d (76 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give product 13d (single β configuration, 56mg,77%, purity greater than 95%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.24(d,J＝2.0Hz,2H),6.89–6.82(m,2H),5.32(t,J＝9.5Hz,1H),5.15(dd,J＝10.2,5.6Hz,1H),5.09(t,J＝9.5Hz,1H),4.31–4.19(m,2H),3.79(s,3H),3.44(t,J＝11.0Hz,1H),2.06(s,3H),2.03(s,3H),1.80(s,3H).The 1 H NMR spectra coincide with theprevious report.
5. Synthesis of Compound 13e
(2R,3R,4S,5R)-2-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor e (76 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give product 13e (β/α=4:1, 58 mg, 79% purity greater than 95%) as a white solid.
β-anomer: 1 H NMR(400MHz,CDCl 3 )δ7.34–7.29(m,2H),6.89–6.85(m,2H),5.40(t,J＝3.6Hz,1H),5.31(dd,J＝9.7,3.1Hz,1H),4.93(dt,J＝3.9,1.9Hz,1H),4.57(d,J＝9.7Hz,1H),3.99(d,J＝1.9Hz,2H),3.79(s,3H),2.19(s,3H),2.18(s,3H),1.83(s,3H).α-anomer: 1 H NMR(400MHz,CDCl 3 )δ7.27–7.19(m,2H),6.85–6.81(m,2H),5.50(dd,J＝3.3,1.3Hz,1H),5.36–5.33(m,1H),5.22(dd,J＝10.3,3.3Hz,1H),4.62(s,1H),4.32(dd,J＝11.1,5.5Hz,1H),3.78(s,3H),3.46–3.36(m,1H),2.07(s,3H),2.00(s,3H),1.94(s,3H).The 1 H NMR spectra coincide with theprevious report.
6. Synthesis of Compound 13f
(2R,3R,4R,5R)-2-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor f (76 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give product 13f (β/α=10:1, 59 mg, 80% purity greater than 95%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.36–7.28(m,2H),6.94–6.78(m,2H),5.44–5.36(m,2H),5.17(dd,J＝10.1,3.5Hz,1H),4.23(d,J＝9.6Hz,1H),4.13(dd,J＝13.2,2.1Hz,1H),3.83–3.76(m,4H),2.21(s,3H),2.01(s,3H),1.81(s,3H).The 1 H NMR spectra coincide with theprevious report.
7. Synthesis of Compound 13g
(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5S,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor g (133 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give 13g (β/α=) of the product as a white solid10:1,118 mg, 81%, purity greater than 95%).
1 H NMR(400MHz,CDCl 3 ),δ7.25–7.19(m,2H),6.89–6.81(m,2H),5.48(d,J＝4.0Hz,1H),5.43–5.34(m,2H),5.08(t,J＝9.9Hz,1H),4.97(t,J＝9.7Hz,1H),4.89(dd,J＝10.6,4.0Hz,1H),4.48(dd,J＝12.2,2.5Hz,1H),4.38(d,J＝9.9Hz,1H),4.28(t,J＝3.9Hz,1H),4.25(t,J＝3.8Hz,1H),4.12(t,J＝9.3Hz,1H),4.07(dd,J＝12.4,2.2Hz,1H),4.00(dt,J＝10.1,3.0Hz,1H),3.84–3.75(m,4H),2.14(s,3H),2.11(s,3H),2.07(s,3H),2.03(s,3H),2.01(s,3H),1.99(s,3H),1.79(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ170.73,170.67,170.50,170.08,169.59,169.44,160.01,128.52,128.45,113.96,95.83,79.50,76.42,73.53,73.19,70.15,69.57,68.65,68.17,63.45,61.62,55.37,55.32,21.13,21.11,21.01,20.98,20.85,20.83,20.83,20.76,20.74,20.55；HRMS(DART-TOF)calculated for C 33 H 42 NaO 18 + [M+Na] + m/z 749.2263,found 749.2257.
8. Synthesis of Compound 13h
(2R,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(4-methoxyphenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor h (84 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give the product as a white solid 13h (single β configuration, 68mg,77%, purity greater than 95%).
1 H NMR(400MHz,CDCl 3 )δ7.32–7.29(m,2H),6.88–6.86(m,2H),5.52(dd,J＝3.5,1.1Hz,1H),5.35(t,J＝9.9Hz,1H),5.17(dd,J＝10.1,3.4Hz,1H),4.32(d,J＝9.7Hz,1H),4.22–4.10(m,2H),4.09–4.01(m,1H),3.79(s,3H),2.20(s,3H),2.03(s,3H),1.99(s,3H),1.81(s,3H).The 1 H NMR spectra coincide with theprevious report.
9. Synthesis of Compound 13i
(2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor i (84 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2) to give product 13i (single β configuration, 49mg,56% purity greater than 95%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.45–7.39(m,2H),7.00–6.90(m,2H),5.97(t,J＝3.1Hz,1H),5.34(t,J＝8.9Hz,1H),5.18(dd,J＝9.1,3.1Hz,1H),5.07(d,J＝3.0Hz,1H),4.37(dd,J＝12.1,6.0Hz,1H),4.12(dd,J＝12.2,2.8Hz,1H),3.83(s,3H),3.75(ddd,J＝8.8,6.0,2.8Hz,1H),2.16(s,3H),2.13(s,3H),2.06(s,3H),2.01(s,3H).The 1 H NMR spectra coincide with theprevious report.
10. Synthesis of Compound 13j
(2R,3R,4R,5R,6S)-2-(4-methoxyphenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate
According to scheme five, glycosyl donor j (80 mg,0.30 mmol), 4-methoxyiodobenzene (47 mg,0.2 mmol), ru (bpy) 3 Cl 2 .6H 2 O(1.5mg，1mol％)，NiBr 2 DME (6.2 mg, 10mol% used), diOMebpy (5.2 mg,12 mol%), tolSO 2 Na (107 mg,0.6 mmol), TMG (50 uL,0.4 mmol) and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:2),product 13j (β/α=4:1, 58 mg, 79% pure greater than 95%) was obtained as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.31(d,J＝8.6Hz,2H),6.86(d,J＝8.7Hz,2H),5.38–5.31(m,2H),5.17(dd,J＝10.1,3.4Hz,1H),4.29(d,J＝9.7Hz,1H),3.94(qd,J＝6.5,1.2Hz,1H),3.79(s,3H),2.23(s,3H),1.99(s,3H),1.80(s,3H),1.23(d,J＝6.4Hz,3H).The 1 H NMR spectra coincide with theprevious report.
The following experiments prove the beneficial effects of the invention.
Experimental example 1, reaction condition screening experiment
1. Experimental method
Route six:
the target compound in scheme six (i.e., compound 12a in example 6) was synthesized following the procedure of example 6; the reaction conditions were then changed according to table 5 to synthesize the target compounds.
The yields of the objective compounds under each condition were compared, and the results are shown in Table 5.
2. Experimental results
TABLE 5 screening results of reaction conditions
The above experimental results show that the yield of the product obtained under the reaction conditions of example 6 of the present invention is the highest.
In summary, the present invention provides a process for preparing aryl carbostyril compounds. The method has wide applicability, can be used for preparing various aryl carbosides, not only can be used for preparing pyridine carbosides compounds, but also can be used for preparing listed-net medicines. The glycosyl donor adopted by the method has good stability, does not need a protecting group, avoids redundant protecting/deprotecting operation, reduces the production cost, and reduces the generation amount of three wastes; the method can rapidly react at room temperature, has mild conditions, does not need n-butyllithium or a format reagent to participate, does not need to be carried out at low temperature below zero, and is safe and environment-friendly; the method has high product yield and high purity, and is suitable for industrial production.

Claims (10)

1. A process for preparing a compound of formula (I), characterized by: the method comprises the following steps: taking a compound shown in a formula (II) and a compound shown in a formula (III) as raw materials, and reacting to obtain the compound shown in the formula (I);
wherein t is an integer of 0 to 5, R a Each independently selected from LOH, LOCOR 0 、C 1～4 Alkyl group,Or 2 of them a Connected into a ring;
R 0 is C 1～4 An alkyl group;
x is halogen;
the B ring is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
s is an integer of 0 to 5, R b Each independently selected from halogenated or non-halogenated C 1～4 Alkyl, halogenated or non-halogenated C 1～4 Alkoxy, COOR 5 、OCOR 5 、NHCOR 5 、CONHR 5 、COR 5 、NHR 5 、OR 5 、SR 5 Cyano, halogen, LOH, 5-6 membered saturated heterocyclic group, 5-6 membered saturated cycloalkyl group,
R 6 Is hydrogen or an amino protecting group;
R 7 is hydrogen or C 1～4 An alkyl group;
l is no or 1-4 methylene;
the ring A is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
p is an integer of 0 to 2, R 2 Independently selected from C 1～4 Alkyl, C 1～4 Alkoxy, phenyl, halogenated OR not halogenated, OR 3 ，R 3 Is 5-6 membered saturated heterocyclic group or 5-6 membered saturated cycloalkyl.
2. The method according to claim 1, characterized in that: the reaction is carried out in the presence of a Ni (I) base catalyst, a Ru (II) base photosensitizer, a Bpy-ligand complex, an initiator and alkali, wherein the solvent of the reaction is an organic solvent, the temperature of the reaction is room temperature, the time is 6-18 hours, the reaction is carried out under the irradiation of an LED lamp, and the reaction is carried out under the atmosphere of nitrogen;
and/or the molar ratio of the compound shown in the formula (II), the compound shown in the formula (III), the Ni (I) base catalyst, the Ru (II) base photosensitizer, the Bpy-ligand complex, the initiator and the alkali is (0.1-0.3): (0.05-0.20): (5% -15%): (0.5-1.5%): (9% -15%): (0.2-1.0): (0.1 to 0.7).
3. The method according to claim 2, characterized in that: the Ni (I) based catalyst is NiBr 2 DME, the Ru (II) -based photosensitizer is Ru (bpy) 3 Cl 2 .6H 2 O, wherein the Bpy-ligand complex is diOMebpy, the initiator is sodium p-methylbenzenesulfonate, the base is tetramethyl guanidine, and the organic solvent is DMSO;
and/or the reaction time is 12 hours, and the parameters of the LED lamp are as follows: 10W, 4575 nm;
and/or the molar ratio of the compound shown in the formula (II), the compound shown in the formula (III), the Ni (I) base catalyst, the Ru (II) base photosensitizer, the Bpy-ligand complex, the initiator and the alkali is 0.15:0.1:10%:1%:12%:0.6:0.4.
4. a method according to any one of claims 1 to 3The method is characterized in that: the compound shown in the formula (II) isThe compound shown is +.> The compound shown is +.>
Wherein X is halogen;
R 1 is halogen, C 1～4 Alkyl or C 1～4 An alkoxy group;
the ring A is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
p is an integer of 0 to 2, R 2 Independently selected from C 1～4 Alkyl, C 1～4 Alkoxy, phenyl, halogenated OR not halogenated, OR 3 ，R 3 Is 5-6 membered saturated heterocyclic group or 5-6 membered saturated cycloalkyl.
5. The method according to claim 4, wherein: the compound shown in the formula (I) is one of the following compounds:
6. a method according to any one of claims 1-3, characterized in that: the compound shown in the formula (II) isThe compound shown is +.>The compounds shown are
Wherein X is halogen;
the B ring is 5-6 membered aryl, 5-6 membered heteroaryl, condensed ring alkyl or hetero condensed ring group;
q is an integer of 0 to 2, R 4 Independently selected from halogenated or non-halogenated C 1～4 Alkyl, halogenated or non-halogenated C 1～4 Alkoxy, COOR 5 、OCOR 5 、NHCOR 5 、CONHR 5 、COR 5 、NHR 5 、OR 5 、SR 5 Cyano, halogen, LOH, 5-6 membered saturated heterocyclic group, 5-6 membered saturated cycloalkyl group,
R 5 Is hydrogen or C 1～4 Alkyl, R 6 Is hydrogen or an amino protecting group, R 7 Is hydrogen or C 1～4 Alkyl, L is no or 1-3 methylene.
7. The method according to claim 6, wherein:is one of the following structures:
wherein R is methoxy, methyl, tertiary butyl or OCF 3 、CF 3 Or COOMe.
8. The method according to claim 7, wherein: the compound shown in the formula (I) is one of the following compounds:
9. a method according to any one of claims 1-3, characterized in that: the compound shown in the formula (II) isThe compound shown is +.>The compounds shown are
Wherein X is halogen;
R 9 is hydrogen, hydroxy or OCOCH 3 、
y is an integer of 1 to 4, R 8 Independently selected from LOH, LOOCH 3 Methyl; l is no or 1-3 methylene.
10. The method according to claim 9, wherein: the compound shown in the formula (I) is one of the following compounds:
CN202210212952.4A 2022-03-04 2022-03-04 Process for preparing aryl carbon glycoside compound Pending CN116730998A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210212952.4A CN116730998A (en) 2022-03-04 2022-03-04 Process for preparing aryl carbon glycoside compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210212952.4A CN116730998A (en) 2022-03-04 2022-03-04 Process for preparing aryl carbon glycoside compound

Publications (1)

Publication Number Publication Date
CN116730998A true CN116730998A (en) 2023-09-12

Family

ID=87904972

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210212952.4A Pending CN116730998A (en) 2022-03-04 2022-03-04 Process for preparing aryl carbon glycoside compound

Country Status (1)

Country Link
CN (1) CN116730998A (en)

Similar Documents

Publication Publication Date Title
CN114736248B (en) Sulfinate glycosyl donor and preparation method and application thereof
CN113549042B (en) Preparation method of dapagliflozin
CN110776544B (en) 2,3-unsaturated galactosucrose compounds and synthetic method thereof
CN108675976A (en) A kind of halogenated glucose carbon glycosides of 6- and its preparation method and application
WO2021013155A1 (en) Novel glycosyl donor, preparation method therefor, and use thereof
CN104327027B (en) One class novel C aryl glucoside SGLT2 inhibitor
CN109369745A (en) Acridone derivatives and its preparation method and application of the one kind containing glucose
Lichtenthaler et al. Various glycosyl donors with a ketone or oxime function next to the anomeric centre: facile preparation and evaluation of their selectivities in glycosidations
CN116730998A (en) Process for preparing aryl carbon glycoside compound
Zemlicka et al. Nucleosides. XVI. Synthesis of 2', 3'-dideoxy-3', 4'-didehydro nucleosides
CN114075255B (en) Glycosyl donor and application thereof in preparing glycoside
Jackowski et al. Formation of septanoses from hexopyranosides via 5, 6-exo-glycals
Angyal et al. 978. Cyclitols. Part XVI. Toluene-p-sulphonyl derivatives of myoinositol. Acetyl migration in anhydrous pyridine solution
CN101805339B (en) Entecavir compound preparation method
US5643885A (en) Etoposide derivatives, process for preparing them, their use as a medicinal product and their use for the preparation of a medicinal product intended for anti-cancer treatment
US4675391A (en) Glycoside derivatives
CN1978442A (en) (R,R,R,S)2,2'-[imino-di(methylen)] di-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol) nebivolo chloride
CN113372353A (en) Difluoroalkylated dihydrofuranoquinolinone derivative and preparation method thereof
Skorupa et al. Synthesis and structure of selected quaternary N-(1, 4-anhydro-5-deoxy-2, 3-O-isopropylidene-D, L-ribitol-5-yl) ammonium salts
CN100999535A (en) 15-(14-deoxy 11,12 dehydro) andrographolide carbonic side derivate and preparation process thereof
CN107235886B (en) Synthesis method of 2, 3-dihydropyrrole ring
KR950011394B1 (en) 5-fluorouracil depivatives
AU614698B2 (en) Alkoxymethylidene epipodophyllotoxin glucosides
D'Souza et al. Synthesis of carboxyl-reduced analogues related to the Chlamydia-specific Kdo trisaccharide epitope
AU2014226533A1 (en) Isohexide monotriflates and process for synthesis thereof

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