[go: up one dir, main page]

CN106349201B - The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls - Google Patents

The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls Download PDF

Info

Publication number
CN106349201B
CN106349201B CN201610635305.9A CN201610635305A CN106349201B CN 106349201 B CN106349201 B CN 106349201B CN 201610635305 A CN201610635305 A CN 201610635305A CN 106349201 B CN106349201 B CN 106349201B
Authority
CN
China
Prior art keywords
formula
chlorphenyls
added
preparation
hexane
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.)
Active
Application number
CN201610635305.9A
Other languages
Chinese (zh)
Other versions
CN106349201A (en
Inventor
吴永谦
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.)
Jilin Huisheng Biopharmaceutical Co ltd
Beijing Huizhiheng Biological Technology Co Ltd
Original Assignee
Shandong Xuanzhu Pharma 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 Shandong Xuanzhu Pharma Co Ltd filed Critical Shandong Xuanzhu Pharma Co Ltd
Priority to CN201610635305.9A priority Critical patent/CN106349201B/en
Publication of CN106349201A publication Critical patent/CN106349201A/en
Application granted granted Critical
Publication of CN106349201B publication Critical patent/CN106349201B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)

Abstract

The invention belongs to pharmaceutical technology fields, more particularly to the C glycosides derivatives of 4 chlorphenyl of optically pure benzyl shown in formula (II) and formula (III), prepare these compounds and its method of intermediate, pharmaceutical preparation containing these compounds and pharmaceutical composition, and the C glycosides derivatives of 4 chlorphenyl of optically pure benzyl of the present invention are preparing treatment and/or are preventing the diabetes of insulin-dependent as sodium glucose cotransporter (SGLT) inhibitor, Non-Insulin Dependent Diabetes Mellitus, application in the drug of the various diabetes such as insulin resistance disease or obesity and its relevant disease.

Description

The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls
The application be the applying date be on January 3rd, 2014, application No. is 201410004395.2, entitled " optical voidnesses Benzyl -4- chlorphenyls C- glycosides derivatives " application divisional application.
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the C- glycosides derivatives of optically pure benzyl -4- chlorphenyls or Its medicinal acceptable salt, prepares these compounds and its method of intermediate, the pharmaceutical preparation containing these compounds and medicine Compositions, and the C- glycosides derivatives of the optically pure benzyl -4- chlorphenyls of the present invention or its medicinal acceptable salt are made For white (SGLT) inhibitor of sodium glucose co-transporter 2 prepare treatment and/or prevent various diabetes (including insulin according to Rely type diabetes and Non-Insulin Dependent Diabetes Mellitus) or various diabetes related diseases (including insulin resistance disease and It is fat) drug in application.
Background technology
The whole world about 100,000,000 people suffer from type-2 diabetes mellitus, it is characterised in that because excessive hepatic glucose generates and periphery pancreas Hyperglycemia caused by the element resistance of island.Hyperglycemia is considered as forming the Major Risk Factors of diabetic complication, and may be with The impaired insulin secretion of late Type II diabetes is directly related.It is therefore contemplated that the normalization of insulin can improve II types The blood glucose of diabetic.Most of current existing diabetes medicament is Insulin-secreting agent or insulin sensitizer, such as Sulfonylurea, meglitinide, thiazolidinediones and melbine etc. have potential side effect, such as easily weight are caused to increase Add, hypoglycemia, lactic acidosis etc., therefore, there is an urgent need for developmental function mechanism novel, safe and effective antidiabetic medicine.
In kidney, glucose can be freely from glomerular filtration (about 180g/ days), but almost actively turn in proximal convoluted tubule It transports and reabsorption.Two of which sodium-glucose transporter has played important function to the reabsorption of glucose, i.e. SGLT-1 and SGLT-2, and the effect of SGLT-2 is especially prominent.SGLT-2 is the specifically expressed transmembrane protein of S1 sections only in proximal tubule, One of most important physiological action is to absorb to flow through sugared part in renal tubule blood, account for 90%, SGLT-2 of reabsorption with Sodium-glucose 1：1 ratio is transported through, and SGLT-2 inhibitor can inhibit blood glucose in the absorption of renal tubule, make sugared part from urine A large amount of discharges.And SGLT-1 is mainly expressed in distal convoluted tubule, accounts for the 10% of reabsorption, SGLT-1 is with sodium-glucose 2：1 Ratio transhipment.In addition SGLT-1 is had also discovered in enteron aisle and its hetero-organization.These transporters are pumped by Na+/ATP enzymes and are played Effect, and be transferred back in blood by glucose transporter 2 (GLUT2).This shows most possibly to develop into drug target Point is SGLT-2 transporters, is on the one hand its absolute reabsorption to glucose, is on the other hand that it is only expressed in kidney It is dirty.In the research to familial form nephrosis glucose in urine, the feasibility of the approach is also demonstrated.Familial nephrosis glucose in urine is mainly shown as not Quantitative glucose in urine (about 10-120g/ days), but patient's general status is good, does not find the long term negative effect unfavorable to health. For this benign glucose in urine mainly caused by SGLT-2 transporter genes are mutated, this shows the selectively pharmacology suppression to SGLT-2 System not will produce adverse consequences other than inducing glycosuria.It has been demonstrated that an important clinical advantage of SGLT-2 inhibitor It is to be not easy to cause hypoglycemia.And inhibit SGLT-1 that can cause sugar-gala carbohydrate malabsorption syndrome, it can cause to be dehydrated, and Evidence suggests SGLT-1 inhibitor will delay the absorption of carbohydrate, and individual can be caused to be difficult to the gastrointestinal symptom being resistant to, And select high SGLT-2 inhibitor that SGLT-1 will not be blocked to absorb the effect of glucose in intestinal transport, therefore be not easy to cause stomach Bowel symptoms.In addition, SGLT-1 is equally highly expressed in human body cardiac muscular tissue, cardiac function will likely can be caused after being blocked to it New or organic disease.Therefore, exploitation there is highly selective compound to have to the drug of research treatment diabetes SGLT-2 It is significant.
SGLT-2 inhibitor inhibits the reabsorption of kidney sugar to treat hyperglycemia by acting on SGLT-2 transporters, is glycosuria The treatment of disease provides new approach.Although this approach can not directly act on the Pathological Physiology of type-2 diabetes mellitus, It is to reduce blood glucose by increasing the excretion of renal glucose sugar, the deficiency of net energy can be caused, promote weight loss and changes indirectly Kind obesity symptom.Research finds that these drugs and existing hypoglycemic medicine or insulin share, and the risk that hypoglycemia occurs is lower, And there is potential losing weight.Function and insulin resistance of such drug independent of beta cell, therefore SGLT-2 inhibits Agent is in the case that effective to general diabetic, while to the sugar of biguanides, the failure of DPP-4 inhibitor class drug therapies Urine patient also has fine curative effect.Therefore, such drug in the future can also be with the antidiabetic drugs such as biguanides, DPP-4 inhibitor classes Use in conjunction.
Wherein, the patent documents such as WO0127128, US2005209166 disclose a series of changes as SGLT-2 inhibitor Close object.
The applicant also discloses a series of C- glycosides SGLT-2 inhibitor chemical combination in patent WO2013/000275A1 Object, wherein compound 4 have good inhibiting effect to SGLT-2 and preferably selectivity, structural formula are
The compound is the mixture of stereoisomer, and with asymmetric center, there are multiple optical isomers.Consider Exist to many chiral mixture drugs in the prior art and is also easy to produce unknown toxic side effect, reduces drug effect and quality control difficulties Equal potential problems, can greatly increase R＆D risk, and optically pure stereoisomer relative to chiral mixture have it is safer, Generate toxic side effect probability is relatively low, stability is more preferable and the easier advantage of quality control, and optically pure stereoisomer Also there is the potential improved characteristic in terms of pharmacodynamics, pharmacokinetics and toxicology, therefore, exploitation has height to SGLT-2 The good single stereoisomers of selective, rapid-action, efficient, safe and stability, to medicine after subsequent medicament research and development and listing Quality control in object production is of great significance.
Invention content
Technical scheme is as follows：
1. the stereoisomeric compounds of compound shown in formula (I) or its medicinal acceptable salt, selected from formula (II), (III), (IV) and (V)：
Its entitled (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) Benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols,
Its entitled (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) Benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols,
Its entitled (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) Benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols,
Its entitled (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) Benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols.
2. further requirement of the present invention protects the preparation method of formula (II) compound described in above-mentioned 1, the preparation method Reaction route is：
Wherein, X represents fluorine, chlorine, bromine or iodine,
G represents hydroxyl protection base, selected from trimethylsilyl, triethyl silyl, benzyl, to methoxy-benzyl, to nitre Base benzyl, pivaloyl group, allyl, methoxyl methyl, benzyloxymethyl or trimethylsilyl ethyl etc., preferably trimethyl silane Base.
Preparation process：
By formula b, i.e. it is (described to have to be dissolved in organic solvent for (1R, 3r, 5S)-two ring [3.1.0] hexane -3- base methanesulfonates Solvent can be selected from N-Methyl pyrrolidone, n,N-Dimethylformamide, tetrahydrofuran, dioxane and acetonitrile, preferably N- Methyl pyrrolidone) in, formula a is added, control temperature is reacted under the conditions of 0 DEG C to 70 DEG C, is prepared formula c, formula c withFormula d-1 is obtained by the reaction, formula d-1 is deprotected to obtain formula d-2, by formula d-2 in -78 DEG C to 30 DEG C models of temperature Production e is reacted under the conditions of enclosing, formula e obtains formula (II) compound by purifying.
Above-mentioned formula e, which purifies to obtain formula (II) compound, may be used following purification process, but be not limited only to following methods.
Purification process：Formula e is subjected to hydroxyl protection and reacts production f, formula f carries out deprotection reaction production (II) chemical combination Object.
Wherein, G ' represents hydroxyl protection base, selected from acetyl group, trimethylsilyl, triethyl silyl, benzyl, to first Oxy-benzyl, to nitrobenzyl, pivaloyl group, allyl, methoxyl methyl, benzyloxymethyl, trimethylsilyl ethyl, propionyl Base, isobutyryl or benzoyl etc., preferably acetyl group, pivaloyl group, propiono, isobutyryl or benzoyl.
Method and/or those of ordinary skill in the art described in above-mentioned flow may be used in formula (II) compound Known other technologies synthesize, but are not limited only to the above method.
3. further requirement of the present invention protects the preparation method of formula (III) compound described in above-mentioned 1, the preparation method Reaction route is：
Wherein, X represents fluorine, chlorine, bromine or iodine,
G represents hydroxyl protection base, selected from trimethylsilyl, triethyl silyl, benzyl, to methoxy-benzyl, to nitre Base benzyl, pivaloyl group, allyl, methoxyl methyl, benzyloxymethyl or trimethylsilyl ethyl etc., preferably trimethyl silane Base.
Preparation process：
By formula a be dissolved in organic solvent (organic solvent can be selected from toluene, N,N-dimethylformamide, tetrahydrofuran, Dioxane and acetonitrile, preferably toluene) in, formula b is added, control temperature is reacted under the conditions of 0 DEG C to 70 DEG C, and formula is prepared C ', formula c ' withFormula d ' -1 is obtained by the reaction, formula d ' -1 is deprotected to obtain formula d ' -2, by formula d ' -2 in temperature - Production e ' is reacted under 78 DEG C to 30 DEG C range of condition, formula e ' obtains formula (III) compound by purifying.
Above-mentioned formula e ' purifying obtains formula (III) compound and following purification process may be used, but is not limited only to following methods.
Purification process：Formula e ' carry out hydroxyl protections are reacted into production f ', formula f ' carry out deprotection reaction productions (III) Compound.
Wherein, G ' represents hydroxyl protection base, selected from acetyl group, trimethylsilyl, triethyl silyl, benzyl, to first Oxy-benzyl, to nitrobenzyl, pivaloyl group, allyl, methoxyl methyl, benzyloxymethyl, trimethylsilyl ethyl, propionyl Base, isobutyryl or benzoyl etc., preferably acetyl group, pivaloyl group, propiono, isobutyryl or benzoyl.
Method and/or those of ordinary skill in the art described in above-mentioned flow may be used in formula (III) compound Known other technologies synthesize, but are not limited only to the above method.
4. further requirement of the present invention protects the intermediate of formula as follows (II) compound,
5. further requirement of the present invention protects the intermediate of formula as follows (II) compound,
Wherein, X represents bromine or iodine.
6. further requirement of the present invention protects the intermediate of formula as follows (III) compound,
7. further requirement of the present invention protects the intermediate of formula as follows (III) compound,
Wherein, X represents bromine or iodine.
" the medicinal acceptable salt " includes alkali metal salt, such as sodium salt, sylvite, lithium salts；Alkali salt, such as calcium Salt, magnesium salts etc.；Other metal salts, such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt；Inorganic base salts, such as ammonium salt；Organic base Salt, such as t-octyl amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N- methyl Glucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N'- dibenzyl ethylenediamine salts, chloroprocanine Salt, procaine salt, diethanolamine salt, N- benzyls-phenethyl amine salt, piperazine salt, tetramethyl amine salt, three (methylol) amido first Alkane salt etc.；Halogen acid salt, such as hydrofluoride, hydrochloride, hydrobromate, hydriodate；Inorganic acid salt, such as nitrate, high chlorine Hydrochlorate, sulfate, phosphate etc.；Rudimentary alkyl sulfonate, such as mesylate, fluoroform sulphonate, esilate；Aryl sulfonic acid Salt, such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt；Acylate, such as acetate, malate, fumarate, succinate, lemon Hydrochlorate, tartrate, oxalates, maleate etc.；Amino-acid salt, as glycinate, trimethylglycine salt, arginine salt, Ornithine salt, glutamate, aspartate etc..
The present invention is also claimed including formula (II) and/or formula (III) compound of the invention or its medicinal acceptable salt With the pharmaceutical composition of one or more pharmaceutical carriers and/or diluent, pharmaceutically acceptable any dosage form can be made.With The modes such as oral, parenteral, rectum or transpulmonary administration, which are applied to, needs its patient.When for being administered orally, routine can be made into Solid pharmaceutical preparation, such as tablet, capsule, pill, granule；Oral liquid is may be made as, such as oral solution takes orally Suspension, syrup etc..When oral preparation is made, suitable filler, adhesive, disintegrant, lubricant etc. can be added.With When parenteral administration, injection, including injection, injection sterile powder and concentrated solution for injection can be made into.Injection is made When agent, the conventional method production that can be used in existing pharmaceutical field can be added without additives when preparing injection, also can root Suitable additives are added according to the property of drug.When for rectally, suppository etc. can be made into.When for transpulmonary administration, it can make At inhalant or spray etc..In per unit preparation extremely containing physiology a effective amount of formula (I) compound represented 0.005g 10g, can be 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g etc..
The formula (II) and/or formula (III) compound of the further requirement protection present invention of the present invention or its medicinal acceptable salt With the pharmaceutical composition of other medicinal active ingredients, other medicinal active ingredients can be one or more hypoglycemic medicines, The hypoglycemic medicine be selected from hypoglycemic medicine be selected from phosphoric acid Xi Gelieting, vildagliptin, saxagliptin, alogliptin benzoate, Li Gelieting, for Ge Lieting, Jimmy Ge Lieting, melbine, insoral, Yi Xina peptides or Liraglutide etc..
The present invention is also claimed to exist including formula (II) and/formula (III) compound of the invention or its medicinal acceptable salt Prepare the application in the drug for treating and/or preventing various diabetes or various diabetes related diseases.The diabetes include The diabetes (type-1 diabetes mellitus) and Non-Insulin Dependent Diabetes Mellitus (type-2 diabetes mellitus) of insulin-dependent, the diabetes Relevant disease includes insulin resistance disease and obesity etc..
Further requirement protection of the present invention, which treats and/or prevents various diabetes, (includes the diabetes of insulin-dependent And Non-Insulin Dependent Diabetes Mellitus) or various diabetes related diseases (including insulin resistance disease and obesity) method, This method includes to the formula (II) and/or formula of the invention for needing its mammal including people to apply effective dose (III) compound or its medicinal acceptable salt.
The compounds of this invention has the characteristics that：
(1) the compounds of this invention has SGLT-2 the selectivity of height, can be each for treating and/or preventing by safety Plant the diabetes of mammal (including mankind) and by the various diseases caused by diabetes.
(2) the compounds of this invention has efficient inhibiting effect and significant hypoglycemic effect to SGLT-2, rapid-action, malicious It is Small side effects, safe.
(3) the compounds of this invention shows preferable physicochemical property, and purity is high, and stability is good, easy to control the quality, is appropriate for big Technical scale produces.
4, specific implementation mode
For convenience, well-known abridge used in the present invention includes but not limited to：
Me：Methyl；
Et：Ethyl；
Ms：Methyl sulphonyl；
Ac：Acetyl group；
TBS：T-butyldimethylsilyi；
THF：Tetrahydrofuran；
DMAP：4-dimethylaminopyridine；
DIPEA：N, N- diisopropylethylamine；
n-BuLi：N-BuLi；
TMS:Trimethylsilyl.
In the present invention, room temperature refers to 10 DEG C to 30 DEG C.
Below by way of pharmacological evaluation the present invention is further explained compound advantageous effect, but this should not be interpreted as to the present invention Compound only has following advantageous effect.
The external activity of 1 the compounds of this invention of experimental example is tested
Test sample：Formula (II), formula (III), formula (IV) and formula (V) compound, chemical name and preparation method See the preparation embodiment of each compound.
Comparison medicine 1：Compound 4 in patent WO2013/000275A1, (preparation method is with reference to patent WO2013/ for self-control 000275A1), structural formula is as follows：
That is formula (I) compound.
Meaning representated by the abbreviation of following middle experiments is as follows：
NMG N- methyl glucoses osamines (N-methyl-glucosamine)
KRH Krebs-Ringer-Henseleit
Experimental method：SGLT-2 the and SGLT-1 sequences of people are transfected on Chinese hamster ovary cell and stablize expression, are led to Cross inhibition cell to [14C]-label-R- methyl-D-glucopyranoses glycosides (AMG) sodium dependence absorption, it is dense to measure semi-inhibit IC50 is spent, determination of activity is carried out.
Buffer A(KRH-Na+)：120mM NaCl, 4.7mM KCl, 1.2mM MgCl2, 2.2mM CaCl2, 10mM HEPES(PH 7.4with 1mM Tris)。
Buffer A-(KRH-NMG)：120mM NMG, 4.7mM KCl, 1.2mM MgCl2, 2.2mM CaCl2, 10mM HEPES(PH 7.4with 1mM Tris)。
Buffer D：120mM NaCl, 4.7mM KCl, 1.2mM MgCl2, 2.2mM CaCl2, 10mM HEPES, 0.5mM phlorizin(PH 7.4with 1mM Tris)。
Experimental method：The sequence of the SGLT-2 and SGLT-1 of people stablize expression on Chinese hamster ovary celI, are the cells on 96 orifice plates Culture 12 hours, uses KRH-Na+200 holes μ L/ of (Buffer A) or KRH-NMG (Buffer A-) buffer solution are rinsed 3 times. Again be added containing Buffer A or Buffer A-plus [14C]-AMG (10 μ Ci/mL) 100 holes μ L/ of buffer solution, 37 DEG C It is incubated 1 hour.Then, 100 μ L of ice-cold buffer solution (Buffer D) are added and stop experiment, clean 5 times.Add use 20 holes μ L/ of lysis buffer (100mM NaOH) solution of ice precooling, 600rpm centrifugations, 5 minutes and Microscint 40 molten 80 holes μ L/ of liquid, 600rpm centrifugations, 5 minutes.Finally (PerkinElmer is purchased from scintillation counting technique MicroBeta Trilux Company) detection [14C]-AMG radioactivity, calculate 503nhibiting concentration IC50.
Experimental result and conclusion：
The inhibiting effect evaluation result of 1 the compounds of this invention of table
As shown in Table 1, formula (II) compound has good inhibiting effect and preferable selectivity to SGLT-2, Compared with comparison medicine 1, apparent advantage is shown.
The Pharmacokinetics in Rat of 2 the compounds of this invention of experimental example is tested
Animal subject：6-8 week old male SD rat (is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.), 3/ Compound, weight 200-240g.
Test sample：Formula (II) compound of the present invention, chemical name and preparation method are shown in embodiment 1 below.
Comparison medicine 1：Compound 4 in patent WO2013/000275A1, (preparation method is with reference to patent WO2013/ for self-control 000275A1), structural formula is as follows：
That is formula (I) compound.
Comparison medicine 2：Compound 22 in patent WO2013/000275A1, (preparation method is with reference to patent WO2013/ for self-control 000275A1), structural formula is as follows：
Solvent：0.5%MC (methylcellulose) solution+0.1%SDS (lauryl sodium sulfate).
Experimental method：
Gastric infusion (PO) medication refers to table 2
P of Rats K (pharmacokinetics) medication of 2 compound of table
Blood sampling：0.17 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 30 hours, 48 Hour, 54 hours, 72 hours, each time point took 200 μ L or so whole blood, low-temperature and high-speed centrifuge (5415R, Eppendorf 4 DEG C of conditions in), centrifuge 6 minutes separated plasmas by 8000 revs/min, and blood plasma is preserved in -80 DEG C of refrigerators.
Plasma sample analysis：Precision pipettes 20 μ L blood plasma, and 600 μ l internal standards MTBE (methyl tertiary butyl ether(MTBE)) solution are added and (contain Internal standard Dapagliflozin 25ng/mL), after 1500 revs/min of vortex 10min, 5min (12000 revs/min) is centrifuged, is taken on 400 μ L Clear liquid, nitrogen drying redissolve liquid (acetonitrile with 200 μ L：Water=7:3) redissolve, vortex 10min, using LC-MS/MS (API4000, Aplplied Biosystems) analysis.
P of Rats K (pharmacokinetics) evaluation result (PO) of 3 compound of table
T1/2Represent half-life period
Tmax represent drug blood plasma peak time
Plasma drug level when Cmax is represented up to peak
AUClastRepresent area under the drug-time curve0→t
AUCinfRepresent area under the drug-time curve0→∞
Conclusion:From 3 experimental result of table as it can be seen that the peak time of formula (II) compound blood concentration in rat body of the present invention It is shorter, it works rapid, and compared with comparison medicine 1 and comparison medicine 2, exposed amount higher has significant difference, illustrates formula (II) compound has apparent progress.
The specific implementation mode of form by the following examples makees further specifically the above of the present invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
In embodiment, used raw material compound is commercially available, and it is limited to be obtained from AlfaAesar (Tianjin) chemistry Company, Sinopharm Chemical Reagent Co., Ltd., Tianjin Fu Yu Fine Chemical Co., Ltd, Shanghai nation are at the limited public affairs of chemical industry Department, Tianjin are extensively at chemical reagent Co., Ltd, Tianjin recovery Fine Chemical Co., Ltd, Tianjin Ke Miou chemical reagent The companies such as Co., Ltd.
Embodiment 1 (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygen Base) benzyl) -4- chlorphenyls) and -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols (formula (II) compound) preparation
(1) preparation of the bromo- 2- chlorobenzoyl chlorides of 5-
The bromo- 2- chlorobenzoic acids (270g, 1.15mol) of 5- are suspended in dichloromethane (2700mL), N, N- diformazans is added Oxalyl chloride (288mL, 3.46mol) is added dropwise under the conditions of 0 DEG C for base formamide (1mL).It is added dropwise, moves to 20 DEG C of reaction 3h, reaction Liquid becomes clarification, and TLC (thin-layered chromatography) display reactions are completed, obtain product in 30~35 DEG C of rotary evaporations, be directly used in next step Reaction.
(2) preparation of (the bromo- 2- chlorphenyls of 5-) (4- methoxyphenyls) ketone
Under nitrogen protection, aluminum trichloride (anhydrous) (155g, 1.16mol) is suspended in dichloromethane (2050mL), -5 DEG C Under the conditions of, it is added at one time methyl phenyl ethers anisole (125mL, 1.15mol), after stirring 20min, the two of the bromo- 2- chlorobenzoyl chlorides of 5- are added dropwise Chloromethanes solution (300mL), -5 DEG C of reaction 3h.TLC display reactions are completed, and are poured into 2N hydrochloric acid, are layered.Organic phase is taken, with full It washes with sodium bicarbonate solution and is washed twice, again with saturated nacl aqueous solution, anhydrous sodium sulfate drying, rotary evaporation obtains solid.It is added After ethyl alcohol (150mL) washes and starches 30min, filter cake is dried to obtain product (265g, yield 71%) by filtering.
(3) preparation of the chloro- 2- of the bromo- 1- of 4- (4- methoxy-benzyls) benzene
(the bromo- 2- chlorphenyls of 5-) (4- methoxyphenyls) ketone (265g, 0.81mol) is dissolved in dichloromethane (515mL) With acetonitrile (1030mL), triethylsilane (352mL, 2.22mol) is added.Under nitrogen protection, it is added dropwise under the conditions of 0 DEG C borontrifluoride Borate ether (273mL, 2.22mol).It is added dropwise, stirs 20min, move to room temperature reaction 2h.TLC display reactions are completed, and are added Methyl tertiary butyl ether(MTBE) (1.5L) and saturated sodium bicarbonate solution (1.5L) separate organic phase, use unsaturated carbonate after stirring 30min Hydrogen sodium solution wash four times, saturated nacl aqueous solution wash once, anhydrous sodium sulfate drying, rotary evaporation obtains grease, and ethyl alcohol is added, 30min is stirred at room temperature, 30min is stirred under ice bath, a large amount of solids are precipitated, filters, filtration cakes torrefaction is obtained into product (226g, yield 89%).
(4) preparation of 4- (the bromo- 2- chlorobenzyls of 5-) phenol
It under nitrogen protection, is protected from light, the bromo- 1- of 4- chloro- 2- (4- methoxy-benzyls) benzene (226g, 0.73mol) is dissolved in dichloro In methane (2240mL), the dichloromethane (1416mL) that Boron tribromide (357g, 1.42mol) is slowly added dropwise under the conditions of -78 DEG C is molten Liquid.It is added dropwise, moves to room temperature reaction 2h.TLC display reactions are completed, and water is slowly added dropwise under the conditions of ice-water bath, takes dichloromethane Phase, remaining water phase are extracted twice with dichloromethane (1L) again, merge organic phase, be washed with water twice, saturated nacl aqueous solution wash one Secondary, anhydrous sodium sulfate drying, rotary evaporation obtains product (210g, yield 97%).
(5) preparation of (1R, 3r, 5S)-two ring [3.1.0] hexane -3- alcohol
Under the conditions of 0 DEG C, diethyl zinc (7.16L, 7.14mol) is added drop-wise in dichloromethane (9L), is added dropwise, waits for When in bottle without white cigarette, the dichloromethane solution (1L) of trifluoroacetic acid (816g, 7.16mol) is slowly added dropwise.It is added dropwise, stirs After 30min, the dichloromethane solution (1L) of diiodomethane (1918g, 7.14mol) is added dropwise.It is added dropwise, after stirring 30min, drop The dichloromethane solution (800mL) for adding pentamethylene -3- alkene -1- alcohol (200g, 2.38mol), is added dropwise, is warmed to room temperature reaction 30min.TLC shows that the reaction was complete, pours into saturated ammonium chloride, and after stirring 10min, dichloromethane (2L) is mutually used in liquid separation, water intaking Extraction is primary, takes organic phase to be washed with saturated sodium sulfite, saturated sodium bicarbonate is washed, saturated sodium-chloride wash, and anhydrous sodium sulfate is done Dry, residue obtains product (112g, yield 48%) through column chromatography.
(6) preparation of (1R, 3r, 5S)-two ring [3.1.0] hexane -3- base methanesulfonates
Under the conditions of ice-water bath, (1R, 3r, 5S)-two ring [3.1.0] hexane -3- alcohol (112g, 1.14mol) is dissolved in dichloro In methane (1250mL), after triethylamine (174g, 1.69mol) is added, methylsufonyl chloride (197g, 1.72mol) is slowly added dropwise.Drop It adds complete, reacts 30min under the conditions of 0 DEG C.TLC shows that the reaction was complete, and reaction solution is poured into water, liquid separation, takes organic phase with dilute Salt pickling is primary, is washed with water twice, then is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, and rotary evaporation obtains product (138g, production Rate 68%).
(7) preparation of (1R, 3s, 5S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) two rings [3.1.0] hexane
(1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases methanesulfonates (138g, 0.78mol) is dissolved into N- methyl pyrroles In pyrrolidone (2.1L), add 4- (the bromo- 2- chlorobenzyls of 5-) phenol (210g, 0.71mol), cesium carbonate (462g, 1.42mol), benzyltriethylammoinium chloride (5.46g, 24mmol).After 10min is stirred at room temperature, moves to 50 DEG C of conditioned responses and stay overnight. TLC shows that the reaction was complete, after water is added, with petroleum ether and methyl tertiary butyl ether(MTBE) (petroleum ether：Methyl tertiary butyl ether(MTBE)=1:1) mixed Close solution be extracted twice, merge organic phase, with saturated sodium bicarbonate solution wash twice, saturated sodium-chloride wash twice, anhydrous slufuric acid Sodium is dried, and rotary evaporation, residue is through column chromatography (petroleum ether：Ethyl acetate=50：1) product (135g, yield 50%) is obtained.
Molecular formula：C19H18BrClO molecular weight：377.71
1H-NMR (400MHz, CDCl3)δ:7.28-7.21(m,3H),7.07-7.05(d,2H),6.82-6.78(m,2H), 4.42-4.35(m,1H),3.98(s,2H),2.36-2.31(m,2H),1.96-1.90(m,2H),1.40-1.33(m,2H), 0.47-0.44(m,1H),0.07-0.02(m,1H).
(8) (3R, 4S, 5R, 6R) -3,4,5- three ((trimethylsilyl) oxygroup) -6- (((trimethylsilyl) oxygroup) Methyl) tetrahydrochysene -2H- pyran-2-ones preparation
(D)-(+)-gluconic acid -1,5- lactone (85g, 0.47mol) is suspended in THF (tetrahydrofuran) (932mL), N-methylmorpholine (405mL, 4.78mol) is added, under nitrogen protection, -5 DEG C are cooled to, by TMSCl (trim,ethylchlorosilane) (360mL, 4.78mol), is added dropwise, and 1h is stirred at room temperature, and 35 DEG C are stirred 5 hours, are maintained 25 DEG C and are stirred overnight, and TLC detections are anti- It should complete.Toluene (200mL) is added, water (1L) is added dropwise under ice-water bath, takes organic phase, primary, washing one is washed with sodium dihydrogen phosphate Secondary, saturated nacl aqueous solution is washed once, and drying is concentrated to give product (218g, yield 100%).
(9) (3R, 4S, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
Under nitrogen protection, by (1R, 3s, 5S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) two rings [3.1.0] hexane (135g, 0.358mol) is dissolved in tetrahydrofuran (813mL) with toluene (813mL), and after being cooled to -78 DEG C, n-BuLi is added dropwise (194mL, 0.465mol), is added dropwise, after stirring 2h.The reaction solution, which is extracted, with syringe is added to (3R, 4S, 5R, 6R) -3,4, 5- tri- ((trimethylsilyl) oxygroup) -6- (((trimethylsilyl) oxygroup) methyl) tetrahydrochysene -2H- pyran-2-ones (218g, In toluene (950mL) solution 0.47mol), continues after stirring 1h, the methanol of pyrovinic acid (44.9mL, 2.15mol) is added (1.2L) solution stirs 1h at -78 DEG C, is warmed to room temperature reaction overnight.The reaction was complete for TLC detections, and it is molten that saturated sodium bicarbonate is added Liquid is quenched, and ethyl acetate (2L) extraction takes organic phase to be washed with water, after saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, rotation Evaporate to obtain product (173g, yield 98%).
(10) (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
Under the conditions of -78 DEG C and nitrogen protection, by (3R, 4S, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two rings [3.1.0] hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- Triol (173g, 0.352mol) is dissolved in triethylsilane (180mL, 1.05mol) in dichloromethane (2L), and trifluoro is slowly added dropwise Change borate ether (134mL, 1.05mol), be added dropwise, react 1h at -78 DEG C, is slowly increased to room temperature reaction 1h.HPLC detections are anti- Should be complete, saturated sodium bicarbonate solution is instilled, ethyl acetate (1L) extraction, organic phase is washed through water, saturated nacl aqueous solution, anhydrous Sodium sulphate is dried, and rotary evaporation obtains product (143g, yield 88%).
(11) (2R, 3R, 4R, 5S, 6S) -2- (acetoxy-methyl) -6- (3- (4- (((1R, 3s, 5S)-two rings [3.1.0] hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) tetrahydrochysene -2H- pyrans -3,4,5- three base triacetate preparation
By (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyl) - 4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols (143g, 0.311mol) are dissolved in dichloromethane (720mL) In, pyridine (252mL, 3.11mol) and DMAP (4-dimethylaminopyridine) (1.9g, 15.6mmol) is added, then under ice-water bath Acetic anhydride (292mL, 3.11mol) is added dropwise, after 3h is stirred at room temperature.Water quenching is added to go out reaction, ethyl acetate (1.5L) extracts, and has taken Machine layer, dilute hydrochloric acid wash three times, saturated sodium bicarbonate washes primary, washing, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, rotation is steamed Hair, residue obtain product (81g, yield 42%) through ethyl alcohol recrystallization.
(12) (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) Benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (2R, 3R, 4R, 5S, 6S) -2- (acetoxy-methyl) -6- (3- (4- (((1R, 3s, 5S)-two rings [3.1.0] Hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) tetrahydrochysene -2H- pyrans -3,4, tri- base triacetates (81g, 0.129mol) of 5- are molten In the in the mixed solvent of tetrahydrofuran (313mL), methanol (470mL) and water (156mL), be added monohydrate lithium hydroxide (6.32g, 150mmol), it is stirred overnight at room temperature.TLC shows that the reaction was complete, and rotary evaporation removes solvent, and it is molten that ethyl acetate (400mL) is added Solution, organic phase is through saturated sodium-chloride water solution, KHSO4Aqueous solution is washed, is washed twice, and anhydrous sodium sulfate drying, rotary evaporation remains Excess is prepared into final product (54.2g, yield 91%) through C18 reversed-phase preparative chromatographies.
Molecular formula：C25H29ClO6Molecular weight：460.95LC-MS(m/z)：478.3[M+NH4]+
1H-NMR (400MHz, MeOD) δ:7.35-7.26(m,3H),7.08-7.06(d,2H),6.76-6.74(d,2H), 4.45-4.41(m,1H),4.10-4.00(m,3H),3.89-3.88(d,1H),3.71-3.69(m,1H),3.45-3.38(m, 3H),3.31-3.26(m,1H),2.34-2.29(m,2H),1.87-1.81(m,2H),1.37-1.33(m,2H),0.43-0.42 (m,1H),0.11-0.10(m,1H).
Embodiment 2：(2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygen Base) benzyl) -4- chlorphenyls) and -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols (formula (III) compound) preparation
(1) preparation of (1R, 3r, 5S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) two rings [3.1.0] hexane
Will according to 4- (the bromo- 2- chlorobenzyls of 5-) phenol that 1 step of embodiment (1)-(4) method is prepared (29.7g, It 0.10mol) is dissolved into toluene (450mL), sequentially adds sodium hydroxide (8g, 0.20mol), water (27mL), according to embodiment 1 (1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases methanesulfonates that step (5)-(6) method is prepared (17.6g, 0.10mol), benzyltriethylammoinium chloride (1.05g, 4.61mmol).70 DEG C of reaction 2h.TLC shows that the reaction was complete, and acetic acid is added Ethyl ester 500mL extractions, organic phase drying, rotary evaporation remove solvent, and residue is through silica gel column chromatography (petroleum ether：Ethyl acetate =50：1) product (10.1g, yield 27%) is obtained.
Molecular formula：C19H18BrClO molecular weight：377.71
1H-NMR (400MHz, CDCl3)δ:7.28-7.21(m,3H),7.07-7.05(d,2H),6.76-6.72(d,2H), 4.79-4.76(m,1H),3.98(s,2H),2.22-2.16(m,2H),2.05-2.01(m,2H),1.35-1.31(m,2H), 0.62-0.58(m,1H),0.51-0.46(m,1H).
(2) (3R, 4S, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (1R, 3r, 5S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) two rings [3.1.0] hexane (1.5g, It 3.97mmol) is dissolved in tetrahydrofuran (100mL), under nitrogen protection, is cooled to -78 DEG C.Dropwise addition n-BuLi (2mL, 4.8mmol), after being added dropwise, 1h is stirred under the conditions of -78 DEG C.Three ((trimethyl silicanes of (3R, 4S, 5R, 6R) -3,4,5- are added dropwise Alkyl) oxygroup) -6- (((trimethylsilyl) oxygroup) methyl) tetrahydrochysene -2H- pyran-2-ones (3.0g, 6.4mmol) toluene (25mL) solution keeps -78 DEG C of reaction 1h.Methanol (50mL) solution of methanesulfonic acid (3.8g, 39.6mmol) is added, keep- After 78 DEG C of reaction 0.5h, 18h is reacted at room temperature.Reaction solution is quenched with saturated sodium bicarbonate aqueous solution (100mL), then with acetic acid second Ester (100mL × 3) extracts, and merges organic phase, is dried with anhydrous sodium sulfate, filters, and filtrate is taken to be obtained through removing solvent is concentrated under reduced pressure Product (1.5g, yield 77%).
(3) (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By ((3R, 4S, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols (1.40g, 2.86mmol) dissolving In the mixed solution of dichloromethane (40mL) and acetonitrile (40mL), triethylsilane (1.0g, 8.6mmol) is added, room temperature is stirred It mixes down, boron trifluoride ether (1.2g, 8.45mmol) is added dropwise, after adding, react at room temperature 16h.Saturation is added into reaction system Sodium bicarbonate aqueous solution (100mL) adds ethyl acetate (100mL × 3) extraction, merges organic phase, dry with anhydrous sodium sulfate Dry, filtering takes filtrate to obtain crude product (1.0g, yield 76%) through removing solvent is concentrated under reduced pressure.
(4) (2R, 3R, 4R, 5S, 6S) -2- (acetoxy-methyl) -6- (3- (4- ((1R, 3r, 5S)-two rings [3.1.0] Hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) tetrahydrochysene -2H- pyrans -3,4,5- three base triacetate preparation
By ((3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols (1.0g, 2.2mmol) are dissolved in dichloromethane In (40mL), pyridine (1.76mL) and DMAP (13mg) is added, acetic anhydride (2.07mL) is added dropwise under condition of ice bath, is stirred at room temperature 3h is added water (10mL) and reaction is quenched, and is layered to obtain organic phase, and water phase is extracted with ethyl acetate (50mL × 2), merges organic phase, Anhydrous sodium sulfate is dried, silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) product (400mg, yield 29%) is obtained.
(5) (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (2R, 3R, 4R, 5S, 6S) -2- (acetoxy-methyl) -6- (3- (4- ((1R, 3r, 5S)-two ring [3.1.0] oneself Alkane -3- bases) oxygroup) benzyl) -4- chlorphenyls) three base triacetates (400mg, 0.64mmol) of tetrahydrochysene -2H- pyrans -3,4,5- are molten Solution in the in the mixed solvent of tetrahydrofuran (5mL), water (5mL) and methanol (5mL), be added monohydrate lithium hydroxide (107.5mg, 2.56mmol), 2h is stirred at room temperature, TLC display reactions are completed.After rotary evaporation removes solvent, residue is through silica gel column chromatography (two Chloromethanes：Methanol=10:1) final product (200mg, yield 68%) is obtained.
Molecular formula：C25H29ClO6Molecular weight：460.95
1H-NMR(400MHz,MeOD)d:7.23-7.38(m,3H),7.07(m,2H),6.69(m,2H),4.79(m, 1H),4.06-4.11(m,1H),3.94-4.05(m,2H),3.87(m,1H),3.64-3.73(m,1H),3.36-3.24(m, 4H),2.19(m,2H),1.88-2.02(m,2H),1.26-1.41(m,2H),0.52-0.60(m,1H),0.39-0.50(m, 1H).
Embodiment 3：(2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases)OxygenBase) benzyl) -4- chlorphenyls) and -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols (formula (IV) compound) preparation
(1) (3R, 4S, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (1R, 3s, 5S) -3- (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) two rings [3.1.0] hexane (5g, 13.3mmol) It is dissolved in tetrahydrofuran (100mL), under nitrogen protection, is cooled to -78 DEG C.N-BuLi (6.7mL, 15.8mmol), drop is added dropwise It is stirred to react 1 hour for -78 DEG C after adding.By (3R, 4S, 5R, 6R) -3,4,5- three ((trimethylsilyl) oxygroup) -6- (((three Methyl-monosilane base) oxygroup) methyl) tetrahydrochysene -2H- pyran-2-ones (10g, 21.4mmol) are dissolved in toluene (50mL), then are added dropwise to In reaction system, kept for -78 DEG C react 1 hour.It adds methanesulfonic acid (12.7g, 132mmol) and is dissolved in methanol (60mL) solution, Room temperature reaction 18 hours.Reaction solution is quenched with saturated sodium bicarbonate aqueous solution (100mL), then with ethyl acetate (100mL × 3) Extraction merges organic phase, is dried with anhydrous sodium sulfate, filters, and filtrate decompression concentration removes solvent and obtains product (4.5g, yield 69%).
(2) (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (3R, 4S, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyl) - 4- chlorphenyls) -6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols (4g, 8.16mmol) are dissolved in dichloromethane In the mixed solution of alkane (30mL) and acetonitrile (30mL), triethylsilane (2.86g, 24.6mmol) is added, is stirred at room temperature down, drips Add boron trifluoride ether (3.43g, 24.2mmol), is reacted at room temperature 16 hours after adding.Unsaturated carbonate is added into reaction system Hydrogen sodium water solution (50mL) adds ethyl acetate (50mL × 3) extraction, merges organic phase, dried with anhydrous sodium sulfate, mistake Filter, filtrate decompression concentration remove the crude product silica gel column chromatography (dichloromethane obtained by solvent:Methanol=10:1) production is purified to obtain Object (2mg, yield 53%).
(3) (2R, 3R, 4R, 5S, 6R) -2- (acetoxy-methyl) -6- (3- (4- (((1R, 3s, 5S)-two rings [3.1.0] Hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) tetrahydrochysene -2H- pyrans -3,4,5- three base triacetate preparation
By (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyl) - 4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols (1.0g, 2.17mmol) are dissolved in dichloromethane In (20mL), n,N-diisopropylethylamine (2.8g, 21.7mmol), acetic anhydride (2.2g, 21.7mmol) and catalytic amount is added 4-dimethylaminopyridine (25mg).2h is stirred at room temperature, reaction mixture is washed with 1N hydrochloric acid (15mL), is layered to obtain organic phase, has Machine is mutually dried with anhydrous sodium sulfate, filtering, and filtrate decompression concentration removes crude product silica gel column chromatography (petroleum ether obtained by solvent:Second Acetoacetic ester=5:1) product (0.55g, yield 40%) is purified to obtain.
(4) (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (2R, 3R, 4R, 5S, 6R) -2- (acetoxy-methyl) -6- (3- (4- (((1R, 3s, 5S)-two rings [3.1.0] Hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) three base triacetates (0.55g, 0.87mmol) of tetrahydrochysene -2H- pyrans -3,4,5- Be dissolved in water, methanol and tetrahydrofuran mixed solvent (25mL, 2:2:1) in, addition monohydrate lithium hydroxide (0.37g, 8.7mmol), it is stirred overnight at room temperature.After rotary evaporation removes solvent, ethyl acetate (10mL × 3) is added and extracts, merges organic Phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration remove crude product silica gel column chromatography (dichloromethane obtained by solvent:Methanol =10:1) final product (0.27mg, yield 67.5%) is purified to obtain.
Molecular formula：C25H29ClO6Molecular weight：460.95
1H-NMR (400MHz, MeOD) d:7.21-7.31(m,3H),6.93-7.09(m,2H),6.74-6.79(m,2H), 4.53-4.63(m,1H),4.39-4.48(m,1H),4.14-4.20(m,1H),3.89-4.11(m,5H),3.82(m,1H), 3.67(m,1H),2.32(m,2H),1.84(m,2H),1.34(m,2H),0.43(m,1H),0.10(m,1H).
Embodiment 4：(2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygen Base) benzyl) -4- chlorphenyls) and -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols (formula (V) compound) preparation
(1) preparation of the chloro- 5- iodobenzoyl chlorides of 2-
The chloro- 5- iodo-benzoic acids (10.0g, 35.5mmol) of 2- are suspended in dichloromethane (200mL), N, N- diformazans is added Oxalyl chloride (11.3g, 89.0mmol) is added dropwise at 0 DEG C for base formamide (0.05mL), and after being added dropwise, it is small to be warmed to room temperature stirring 4 When.Gained clear solution rotary evaporation is gone out solvent, product (10.7g, yield 100%) is obtained, is directly used in without further purification The next step.
(2) preparation of (the chloro- 5- iodophenyls of 2-) (4- methoxyphenyls) ketone
The chloro- 5- iodobenzoyl chlorides (10.7g, 35.5mmol) of 2- are dissolved in dichloromethane (200mL), ice-water bath is cold But, alchlor (10.4g, 78.2mmol) is added.The dichloromethane dissolved with methyl phenyl ethers anisole (4.2g, 38.9mmol) is added dropwise again (50mL) solution, after being added dropwise, is warmed to room temperature, and stirs 3 hours.Reaction solution is poured into ice water and is quenched, 3mol/L salt is added Acid, liquid separation, water phase extract (150mL × 2) with dichloromethane, and organic phase merges, saturated nacl aqueous solution washing, anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate：Petroleum ether=0~1:100) product (12.0g, production are purified to obtain Rate 91%).
(3) preparation of 1- chlorine-4-iodines -2- (4- methoxy-benzyls) benzene
By (the chloro- 5- iodophenyls of 2-) (4- methoxyphenyls) ketone (12.0g, 32.2mmol) and triethylsilane (9.86g, 84.8mmol) is dissolved in acetonitrile (200mL), at 0 DEG C be added boron trifluoride etherate (13.7g, 96.5mmol), after being added dropwise, 70 DEG C are warming up to, is stirred 3 hours.It is cooled to room temperature, saturated sodium bicarbonate solution is added and quenches It goes out, ethyl acetate extracts (200mL × 3), and organic phase merges, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, and decompression is dense Contracting, crude product is through silica gel column chromatography (ethyl acetate：Petroleum ether=0~1:100) purifying obtains product (10.0g, yield 87%).
(4) preparation of 4- (the chloro- 5- iodine benzyls of 2-) phenol
1- chlorine-4-iodines -2- (4- methoxy-benzyls) benzene (10.0g, 27.9mmol) is dissolved in dichloromethane (150mL) In, ice-water bath cooling is added dropwise Boron tribromide (21g, 83.7mmol), after being added dropwise, is warmed to room temperature, stirs 3 hours.It is added full It is quenched with sodium bicarbonate solution, liquid separation, water phase extracts (150mL × 2) with dichloromethane, and organic phase merges, and saturated sodium-chloride is molten Liquid washs, and anhydrous sodium sulfate drying is concentrated under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate：Petroleum ether=0~1:20) it purifies Obtain product (8.5g, yield 88%).
(5) preparation of (4- (the chloro- 5- iodine benzyls of 2-) phenyl oxygroup) t-butyldimethyl silane
4- (the chloro- 5- iodine benzyls of 2-) phenol (8.5g, 24.7mmol) and triethylamine (5.0g, 49.5mmol) are dissolved in two In chloromethanes (200mL), tert-butyl chloro-silicane (5.6g, 37.1mmol) and 4- (dimethylamino) pyridine is added at 0 DEG C (305mg, 2.5mmol) is warmed to room temperature stirring 18 hours after adding.Water (100mL) is added, liquid separation, water phase is extracted with dichloromethane It takes (100mL × 2), organic phase merges, saturated common salt water washing, and anhydrous sodium sulfate drying is concentrated under reduced pressure, crude product is through silica gel column layer Analyse (ethyl acetate：Petroleum ether=0~1:100) product (10.0g, yield 88%) is purified to obtain.
(6) (3R, 4S, 5S, 6R)-2- (3- (4-((t-butyldimethylsilyi) oxygroup) benzyl)-4- chlorphenyls)-6- The preparation of (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols
(4- (the chloro- 5- iodine benzyls of 2-) phenyl oxygroup) t-butyldimethyl silane (10.0g, 21.8mmol) is dissolved in nothing In the mixed solution of water tetrahydrofuran (80mL) and toluene (80mL), -78 DEG C are cooled to, n-BuLi (2.4mol/ is slowly added dropwise L hexane solutions) (13.6mL, 32.6mmol), -78 DEG C are reacted 2 hours, are warming up to -60 DEG C, will be dissolved with (3R, 4S, 5R, 6R) - 3,4,5- tri- ((trimethylsilyl) oxygroup) -6- (((trimethylsilyl) oxygroup) methyl) tetrahydrochysene -2H- pyran-2-ones Toluene (60mL) solution of (15.3g, 32.7mmol), is added at one time in reaction solution, is reacted 2 hours at -60 DEG C.It is added dropwise molten There is pyrovinic acid (14.6g, 152.1mmol) methanol (50mL) solution, after being added dropwise, is stirred to react at room temperature 17 hours.Add Enter saturated sodium bicarbonate solution to be quenched, liquid separation, water phase is extracted with ethyl acetate (200mL × 3), merges organic phase, is saturated chlorination Sodium solution washs, and anhydrous sodium sulfate drying is concentrated under reduced pressure to obtain crude product (9.0g), is directly used in the next step without further purification.
(7) (3R, 4S, 5S, 6R) -2- (the chloro- 3- of 4- (4- hydroxybenzyls) phenyl) -6- (methylol) -2- methoxyl groups tetrahydrochysene - The preparation of 2H- pyrans -3,4,5- triols
By (3R, 4S, 5S, 6R)-2- (3- (4-((t-butyldimethylsilyi) oxygroup) benzyl)-4- chlorphenyls)-6- (methylol) -2- methoxyl group tetrahydrochysene -2H- pyrans -3,4,5- triols crude product (9.0g) are dissolved in tetrahydrofuran (70mL), are added Three hydration tetrabutyl ammonium fluorides (22.1g, 70mmol), are stirred 2 hours at room temperature, are concentrated under reduced pressure, and ethyl acetate (400mL) is added With water (200mL), liquid separation, organic phase washed with water washs (200mL × 3), saturated nacl aqueous solution washing, and anhydrous sodium sulfate is dry It is dry, it is concentrated under reduced pressure to give crude product (6.5g), is directly used in the next step without further purification.
(8) (3R, 4R, 5S, 6R) -2- (the chloro- 3- of 4- (4- hydroxybenzyls) phenyl) -6- (methylol) tetrahydrochysene -2H- pyrans - The preparation of 3,4,5- triols
By (3R, 4S, 5S, 6R) -2- (the chloro- 3- of 4- (4- hydroxybenzyls) phenyl) -6- (methylol) -2- methoxyl groups tetrahydrochysene - 2H- pyrans -3,4,5- triols crude products (6.5g) and triethylsilane (4.03g, 34.7mmol) are dissolved in dichloromethane (100mL) With the in the mixed solvent of acetonitrile (100mL), boron trifluoride etherate (5.6g, 39.5mmol) is added dropwise at 0 DEG C, is added dropwise Afterwards, it is warmed to room temperature, stirs 16 hours.Saturated sodium bicarbonate solution is added to be quenched, ethyl acetate extracts (250mL × 3), organic phase Merge, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying is concentrated under reduced pressure, crude product is through silica gel column chromatography (methanol：Dichloromethane Alkane=0~1:15) purifying obtains product (3.8g, 3 step yields 46%).
(9) (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyls Base) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (3R, 4R, 5S, 6R)-2- (the chloro- 3- of 4- (4- hydroxybenzyls) phenyl) pyrans-3-6- (methylol) tetrahydrochysene-2H-, 4,5- triols (3.8g, 10mmol) and (1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases methanesulfonates (3.5g, 20mmol) are outstanding Float in toluene (100mL) and water (10mL), sequentially adds sodium hydroxide (1.0g, 25mmol) and benzyltriethylammoinium chloride (114mg, 0.5mmol) is heated to 80 DEG C and reacts 16 hours, be cooled to room temperature, water (50mL), liquid separation, water phase acetic acid is added Ethyl ester extracts (50mL × 3), and organic phase merges, saturated nacl aqueous solution washing, and crude product is concentrated under reduced pressure to obtain in anhydrous sodium sulfate drying (5.0g), is directly used in the next step without further purification.
(10) (2R, 3R, 4R, 5S, 6R) -2- (acetoxy-methyl) -6- (3- (4- (((1R, 3r, 5S)-two rings [3.1.0] hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) tetrahydrochysene -2H- pyrans -3,4,5- three base triacetate preparation
By (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) benzyl) - 4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols crude product (5.0g) is dissolved in dichloromethane (50mL), Pyridine (7.9g, 100mmol) and 4- (dimethylamino) pyridine (122mg, 1mmol) is added, addition acetic anhydride under ice bath (10.2g, 100mmol), it is warmed to room temperature, stirs 4 hours, water is added, ethyl acetate extracts (150mL × 3), and organic phase merges, and uses successively 1mol/L salt acid elution (150mL × 3), saturated sodium bicarbonate solution wash (150mL), saturated nacl aqueous solution washing, anhydrous Sodium sulphate is dried, and is concentrated under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate：Petroleum ether=0~1:4) purifying obtains product (350mg, 2 step yields 5.6%).
(11) (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3r, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) Benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols preparation
By (2R, 3R, 4R, 5S, 6R) -2- (acetoxy-methyl) -6- (3- (4- (((1R, 3r, 5S)-two rings [3.1.0] Hexane -3- bases) oxygroup) benzyl) -4- chlorphenyls) three base triacetates (350mg, 0.56mmol) of tetrahydrochysene -2H- pyrans -3,4,5- It is dissolved in the in the mixed solvent (1 of water, methanol and tetrahydrofuran:2:2) LiOHH is added in (25mL)2O(118mg, 2.8mmol), it is stirred at room temperature 16 hours, is concentrated under reduced pressure, water (20mL), ethyl acetate extraction (30mL × 3) is added, merges organic Phase, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying are concentrated under reduced pressure, crude product is through silica gel column chromatography (methanol：Dichloromethane =0~1:15) purifying obtains product (140mg, yield 54.7%).
Molecular formula：C25H29ClO6Molecular weight：460.95
1H-NMR(400MHz,MeOD)δ:7.29-7.31(m,3H),7.04-7.07(m,2H),6.68-6.71(m,2H), 4.77-4.81(m,1H),4.57-4.61(m,1H),4.15-4.19(m,1H),3.98-4.05(4H,m),3.92-3.93(m, 1H),3.80-3.83(m,1H),3.63-3.68(m,1H),2.16-2.21(m,2H),1.94-1.97(m,2H),1.24-1.34 (m,2H),0.54-0.56(m,1H),0.39-0.49(m,1H)。

Claims (4)

1. the intermediate of formula (II) compound as follows,
Its entitled (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- bases) oxygroup) Benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triols,
The intermediate is
Wherein, X represents fluorine, chlorine, bromine or iodine.
2. the intermediate of formula (II) compound as described in claim 1,
Wherein, X represents bromine or iodine.
3. the preparation method of intermediate as described in claim 1, this method include, formula b is dissolved in organic solvent, is added Formula a, control temperature are reacted under the conditions of 0 DEG C to 70 DEG C, and formula c is prepared,
Wherein, X represents fluorine, chlorine, bromine or iodine；
The wherein described organic solvent is selected from N-Methyl pyrrolidone, N,N-dimethylformamide, tetrahydrofuran, dioxane and second Nitrile.
4. preparation method as claimed in claim 3, wherein the organic solvent is selected from N-Methyl pyrrolidone.
CN201610635305.9A 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls Active CN106349201B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610635305.9A CN106349201B (en) 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610635305.9A CN106349201B (en) 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls
CN201410004395.2A CN104761522B (en) 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201410004395.2A Division CN104761522B (en) 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives

Publications (2)

Publication Number Publication Date
CN106349201A CN106349201A (en) 2017-01-25
CN106349201B true CN106349201B (en) 2018-09-18

Family

ID=53643666

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201410004395.2A Active CN104761522B (en) 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives
CN201610635305.9A Active CN106349201B (en) 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201410004395.2A Active CN104761522B (en) 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives

Country Status (4)

Country Link
JP (1) JP6008892B2 (en)
KR (1) KR101837488B1 (en)
CN (2) CN104761522B (en)
HK (1) HK1207626A1 (en)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153137A (en) * 2015-09-17 2015-12-16 上海应用技术学院 Preparation method of empagliflozin
RU2739024C2 (en) * 2016-01-04 2020-12-21 Че Иль Фармасьютикал Ко., Лтд. C-glycoside derivatives containing a condensed phenyl ring, or their pharmaceutically acceptable salts, a method of producing such and a pharmaceutical composition containing such
KR102226465B1 (en) * 2016-05-28 2021-03-11 하이난 수안주 파마 코포레이션 리미티드 Crystalline form of inhibitor for sodium-glucose cotransporter 2
CN108285439B (en) * 2017-01-09 2023-05-02 江苏天士力帝益药业有限公司 Carbonoside sodium glucose transport protein body 2 inhibitor
WO2019185026A1 (en) * 2018-03-30 2019-10-03 南京明德新药研发有限公司 Glucoside derivatives acting as inhibitors of sglts, and use thereof
CN110551088B (en) * 2018-06-01 2022-10-21 北京惠之衡生物科技有限公司 Deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives
CN112047915B (en) * 2019-06-05 2023-02-17 北京惠之衡生物科技有限公司 Novel preparation process of C-glycoside derivatives
CN110683998A (en) * 2019-11-20 2020-01-14 杭州华东医药集团浙江华义制药有限公司 Preparation method of empagliflozin intermediate
CN113045525B (en) * 2021-05-31 2021-09-17 北京惠之衡生物科技有限公司 Preparation method of C-glucoside derivative and preparation thereof
CN113336733B (en) * 2021-05-31 2022-02-18 北京惠之衡生物科技有限公司 Preparation method of L-proline co-crystal of SGLT-2 inhibitor
CN113248464B (en) * 2021-05-31 2021-10-26 北京惠之衡生物科技有限公司 Synthesis method of C-glycoside derivatives
CN113248554A (en) * 2021-06-25 2021-08-13 北京惠之衡生物科技有限公司 Method for synthesizing impurities of C-glucoside derivatives
CN113372315B (en) * 2021-08-12 2021-10-29 北京惠之衡生物科技有限公司 Method for synthesizing impurities of C-glucoside derivatives
CN115073271A (en) * 2022-06-08 2022-09-20 苏州敬业医药化工有限公司 Preparation method of 4' - (5-bromo-2-chlorobenzyl) phenol

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1653075A (en) * 2002-05-20 2005-08-10 百时美施贵宝公司 C-aryl glucoside SGLT2 inhibitors and method
CN103030617A (en) * 2004-03-16 2013-04-10 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004063209A2 (en) * 2003-01-03 2004-07-29 Bristol-Myers Squibb Company Methods of producing c-aryl glucoside sglt2 inhibitors
US7772191B2 (en) * 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
PH12012501473A1 (en) * 2010-03-18 2012-10-22 Daiichi Sankyo Co Ltd Cycloalkyl-substituted imidazole derivative
WO2012025857A1 (en) * 2010-08-23 2012-03-01 Hetero Research Foundation Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors
US9562029B2 (en) * 2011-06-25 2017-02-07 Xuanzhu Pharma Co., Ltd. C-glycoside derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1653075A (en) * 2002-05-20 2005-08-10 百时美施贵宝公司 C-aryl glucoside SGLT2 inhibitors and method
CN103030617A (en) * 2004-03-16 2013-04-10 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture

Also Published As

Publication number Publication date
KR20150081220A (en) 2015-07-13
CN104761522B (en) 2017-02-15
CN106349201A (en) 2017-01-25
JP2015129106A (en) 2015-07-16
JP6008892B2 (en) 2016-10-19
KR101837488B1 (en) 2018-03-12
HK1207626A1 (en) 2016-02-05
CN104761522A (en) 2015-07-08

Similar Documents

Publication Publication Date Title
CN106349201B (en) The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls
CN102656165B (en) Glycoside derivatives and uses thereof
CN1989132B (en) Novel glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes
ES2369030T3 (en) DERIVATIVES OF 1-TIO-D-GLUCITOL.
CN102482290B (en) C-aryl glucoside derivatives, preparation rpocess and pharmaceutical use thereof
JP4115105B2 (en) Pyrazole derivative
CN103596944B (en) Process for the preparation of compounds useful as inhibitors of SGLT2
BR112012008939B1 (en) PROCESS FOR PREPARING COMPOUNDS USEFUL AS SGLT2 INHIBITORS
CN102827122B (en) Glucoside derivate
EP2725031B1 (en) C-glycoside derivatives
CN101495494A (en) Fused ring spiroketal derivative and use thereof as drug for treating diabetes
Haider et al. Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A review
TW200901965A (en) C-glycoside derivatives or salts thereof
CN102510867A (en) Glycoside derivative and uses thereof
CN102159206A (en) Glucoside derivatives and uses thereof as sglt inhibitors
HU228514B1 (en) Propiophenone derivatives, process for preparing them and medicaments containing the said compounds
WO2011091710A1 (en) Phenyl c-glucoside derivatives, preparation methods and uses thereof
WO2004099230A1 (en) Monosaccharide compounds
ES2928634T3 (en) C-mannoside compounds useful for the treatment of urinary tract infections
EP2891654B1 (en) Optically pure benzyl-4-chlorophenyl-C-glucoside derivatives as SGLT inhibitors (diabetes mellitus)
CN104619713A (en) Oxabicyclo derivatives, preparation method and use thereof
US9914688B2 (en) Optically pure benzyl-4-chlorophenyl-C-glucoside derivative
TW200836748A (en) Adenosine analogs and their use
BR112014026198B1 (en) pyrazole compounds as inhibitors of sglt1, and pharmaceutical composition
CN108883122A (en) There are the C- glycoside compounds for treating disease

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20191022

Address after: Room 510, building 2, No. 88, Kechuang 6th Street, Beijing Economic and Technological Development Zone, Beijing 100176

Patentee after: Xuanzhu (Beijing) Pharmaceutical Technology Co.,Ltd.

Address before: Tianchen high tech Development Zone, 250101 Ji'nan Road, Shandong, No. 2518

Patentee before: XUANZHU PHARMA Co.,Ltd.

TR01 Transfer of patent right

Effective date of registration: 20200924

Address after: 135000 No. 666, Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province

Patentee after: Jilin Huisheng biopharmaceutical Co.,Ltd.

Patentee after: Beijing huizhiheng Biotechnology Co.,Ltd.

Address before: Room 510, building 2, No. 88, Kechuang 6th Street, Beijing Economic and Technological Development Zone, Beijing 100176

Patentee before: Xuanzhu (Beijing) Pharmaceutical Technology Co.,Ltd.

TR01 Transfer of patent right
CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: 135007 No. 666, Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province

Patentee after: Jilin Huisheng Biopharmaceutical Co.,Ltd.

Patentee after: Beijing huizhiheng Biotechnology Co.,Ltd.

Address before: NO.666 Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province

Patentee before: Jilin Huisheng biopharmaceutical Co.,Ltd.

Patentee before: Beijing huizhiheng Biotechnology Co.,Ltd.

PE01 Entry into force of the registration of the contract for pledge of patent right
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Optically pure C-glycoside derivatives of benzyl-4-chlorophenyl

Effective date of registration: 20231013

Granted publication date: 20180918

Pledgee: Jilin Bank Co.,Ltd. Tonghua Meihekou Branch

Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd.

Registration number: Y2023220000102

PC01 Cancellation of the registration of the contract for pledge of patent right
PC01 Cancellation of the registration of the contract for pledge of patent right

Granted publication date: 20180918

Pledgee: Jilin Bank Co.,Ltd. Tonghua Meihekou Branch

Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd.

Registration number: Y2023220000102

PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Optically pure C-glycoside derivatives of benzyl-4-chlorophenyl

Granted publication date: 20180918

Pledgee: Industrial and Commercial Bank of China Limited Meihekou Branch

Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd.

Registration number: Y2024220000070