CN106748970B - N- aryl -1-DNJ derivative and its application in preparation treatment diabetes medicament - Google Patents
N- aryl -1-DNJ derivative and its application in preparation treatment diabetes medicament Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
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- 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
Abstract
The invention discloses a kind of N- aryl -1-DNJ derivative and its applications in preparation treatment diabetes medicament.The structural formula of the derivative isR in formula1For halogen or C1~C4Alkyl；R2For substituted aryl；R3The acyl group for being 1~4 for H or carbon atom number.The compounds of this invention has the function of obvious hypoglycemic and glucose is promoted to be discharged from urine, can be used for preparing the drug for the treatment of diabetes.
Description
Technical field
The present invention relates to the preparations of a kind of novel N- aryl -1-DNJ derivative and such compound
Method treats the purposes in diabetes medicament in preparation with them.
Background technique
In diabetic, about 90%~95% is all diabetes B, i.e. non-insulin-depending type.This kind of patient's body
The ability for generating insulin not completely loses, and is only at a kind of opposite state lacked, needs to treat by drug.
In kidney, glucose can be freely from glomerular filtration, but substantially in proximal convoluted tubule in SGLT2 (sodium-
Glucose cotransporter-2, sodium glucose co-transporter 2-2) collaboration under active transport and reabsorption.SGLT2
It is a kind of transport factor of low-affinity, is the ratio cotransport glucose of 1:1 with sodium-glucose, SGLT2 is mainly expressed
The S1 section of renal tubule controls the reabsorption of 90% glucose in kidney filtrate.SGLT2 rises mainly in the reabsorption of glucose
Effect.Therefore inhibit SGLT2 activity, thus specifically inhibit reabsorption of the kidney to glucose, to reach reduction blood glucose,
The purpose for treating diabetes.
1835, French scientist had found phloridzin (Phlorizin) in the root skin of apple tree, although due to various
Reason could not finally research and develop into drug, however this is but that prelude has been pulled open in the research and development of SGLT2 inhibitor.T-1095 is
First SGLT2 inhibitor being developed, it is root skin glycoside derivates.Then, a series of SGLT2 inhibitors are come out one after another, and are
Diabetic brings more hope.In December, 2012, Dapagliflozin take the lead in through approval, and with trade name
Forxiga takes the lead in successfully listing in European Union, becomes the SGLT2 inhibitor for being used to treat diabetes B of first listing.
SGLT2 inhibitor is by inhibiting kidney to increase the reabsorption of glucose the excretion of glucose in urine thus to reduce blood glucose
Concentration, this is the great novel mechanism for having innovative significance.Because this will not only generate the risk of hypoglycemia, but also can also promote
Into the discharge of sodium ion, it can moderately alleviate hypertension symptom.As the SGLT2 such as Dapagliflozin, Canagliflozin press down
The listing successively of preparation medicine, people more believe firmly the future potential of SGLT2 inhibitor.
Summary of the invention
The object of the present invention is to provide a new class of with reactive compound that is hypoglycemic, promoting glucose to be discharged from urine
The purposes of N- aryl -1-DNJ derivative and these compounds in preparation treatment diabetes medicament.
Above-mentioned N- aryl -1-DNJ derivative is 1 compound represented of formula or its salt or its solvate:
R in formula1For halogen or C1~C4Alkyl；R2For substituted aryl；R3For H or C1~C4Acyl group.
In structure above, preferably R1For Cl or methyl；R2For substituted-phenyl, substituted pyridinyl, substituted furan base, replace
Any one in thienyl, substituted azole base, wherein the substituent group is C1~C4Alkoxy, halogenophenyl, furans oxygroup
In any one；R3For H or C1~C4Acyl group.
Any one in the above-mentioned further preferred following compounds A~L of N- aryl -1-DNJ derivative:
A: tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ
B: tetra-acetylated-N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ
C: tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ
D: tetra-acetylated-N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1- deoxidation open country buttocks
Mycin
E: tetra-acetylated-N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
F: tetra-acetylated-N- [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
G:N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ
H:N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ
I:N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ
J:N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1-DNJ
K:N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
L:N- [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
The present invention, for raw material, obtains 5- oxo-through peroxidating, hydrolysis with 1,2-O- isopropylidene-α-D- glucofuranose
Then it is de- to obtain the -1- of aryl containing N- by double reductive amination process between substituted aromatic amines and 5- oxo-D-Glucose for D-Glucose
The mixture of oxygen nojirimycin.To carry out the purifying of N- aryl -1-DNJ, it is mould that N- aryl -1- deoxidation open country buttocks will be contained
The mixture and acetic anhydride of element obtain tetra-acetylated-N- aryl -1-DNJ 1-1, and it is higher to obtain purity through extraction
1-1.N- aryl -1-DNJ 1-2 of high-purity is made after 1-1 is hydrolyzed.Synthetic route is as follows:
R in formula3Represent C1~C4Acyl group.
The inspiration of diabetes can be treated by SGLT2 inhibitor, using 1-DNJ as parent, synthesis obtains the present invention
A series of N- aryl -1-DNJ derivatives.N- aryl -1-DNJ derivative is given with oral way
After SD rat, by measuring the blood glucose and glucose in urine of mouse, it is found that these compounds can reduce SD rat blood sugar, increase glucose from
It is discharged in urine.The SD rat of synthesis compound is taken compared with model group, reduces to have in the increase with glucose in urine showing in blood glucose
Write sex differernce or significant differences.The results show that N- aryl -1-DNJ derivative of the invention can be made
The treatment of diabetes is used for for Remedies for diabetes.
Purposes of the N- aryl -1-DNJ derivative of the present invention in preparation treatment diabetes medicament, conduct
Effective component preparation treatment diabetes drug conventional galenic preparations form come using.The conventional galenic preparations are containing work
Such as it is suitable for stomach function regulating in stomach and intestine for the N- aryl -1-DNJ derivative and pharmaceutically acceptable carrier of active constituent
The solid or liquid excipient of the organic or inorganic of parenteral administration mix, and are made according to the preparation process of various preparation routines various
The dosage form of state, such as it can be configured to solid-state, semisolid, liquid formulation, such as tablet, pill, capsule, pulvis, granule, cream
Agent, emulsion, suspending agent, suppository, injection, inhalant, gelling agent, microballoon and aerosol etc..
On the other hand, the present invention also provides 1 compound pharmaceutically acceptable salt of formula and pharmaceutically acceptable solvations
Object.
Specific embodiment
Below with reference to embodiment, invention is further described in detail, but protection scope of the present invention is not limited only to these
Embodiment.
Agents useful for same is that analysis is pure in the embodiment of the present invention.Compound structure determine nuclear magnetic resonance data used by
The measurement of 300,400,600 NMR spectrometer with superconducting magnet of Bruker Avance, TMS is as internal standard；Ir data uses
Nicolet 170SXFT-IR determination of infrared spectroscopy；Fusing point uses X-6 micro melting point apparatus (the limited public affairs of Beijing Tyke instrument
Department) measurement (temperature is not corrected)；Mass spectrometric data is measured with Bruker Esquire 3000plus mass spectrograph.
Embodiment 1
Synthesize tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ (A)
1,2- methyl-5-nitro -4 '-oxethyl-diphenyl-ketone is prepared
4.52g (24.95mmol) 2- methyl-5-nitro benzoic acid is dissolved in 8mL thionyl chloride, 100 μ L pyridines are added dropwise,
50 DEG C of reaction 3h are warming up to, decompression boils off thionyl chloride, obtains 2- methyl-5-nitro chlorobenzoyl chloride and (does not have to separation directly to carry out
Subsequent reactions).
By 5.00g (38.07mmol) anhydrous AlCl3It is added to 45mL CH2Cl2In, it is cooled to 0 DEG C, is slowly added to 3.36g
(27.50mmol) phenetole, stirs 20min at 0 DEG C, and obtained 2- methyl-5-nitro chlorobenzoyl chloride is dissolved in 15mL
CH2Cl2After be added drop-wise in reaction system, continue to be stirred to react 1h at 0 DEG C, obtain blackish green solution, be vigorously stirred and cooling down
It is lower that this blackish green solution is added into 80mL2mol/L HCL aqueous solution, 20min is stirred at room temperature, separates organic phase, water phase is used
CH2Cl2Extraction merges organic phase, then successively with saturation NaHCO3Aqueous solution, saturation NaCl aqueous solution washing, silica gel after concentration
Pillar layer separation (eluant, eluent is the mixture that the volume ratio of ethyl acetate and petroleum ether is 1:20), obtains white solid 2- first
Base -5- nitro -4 '-oxethyl-diphenyl-ketone 6.30g, yield 88%.
2,2- methyl-5-nitro -4 '-ethoxy diphenyl methylmethane is prepared
1.75g (6.13mmol) 2- methyl-5-nitro -4 '-oxethyl-diphenyl-ketone is dissolved in 6mL acetonitrile, is added
Saturation is added dropwise in 6.0mL triethylsilane, the boron trifluoride ether solution that 3.0mL mass fraction is 47%, 40 DEG C of reaction 2h
NaHCO3Aqueous solution is stirred to bubble-free, separates organic phase, and water phase is extracted with ethyl acetate, and merges organic phase, then with saturation
The washing of NaCl aqueous solution, is dried in vacuo after concentration, obtains white solid 2- methyl-5-nitro -4 '-ethoxy diphenyl methylmethane
1.15g, yield 89%.
3,2- methyl -5- amino -4 '-ethoxy diphenyl methylmethane is prepared
By 1.15g (4.24mmol) 2- methyl-5-nitro -4 '-ethoxy diphenyl methylmethane, 0.63g active carbon, 0.40g
FeCl3It is added in 10mL dehydrated alcohol, the hydrazine hydrate that 1.5mL mass fraction is 80% is slowly dropped to by temperature after rising to 80 DEG C
It in reaction system, filters after isothermal reaction 40min, is added water and stirred after cooling into filtrate while hot, white solid is precipitated, filter,
It is dry, obtain white solid 2- methyl -5- amino -4 '-ethoxy diphenyl methylmethane 0.75g, yield 92%.
4,1,2-O- isopropylidene -5- oxo-α-furyl glucose is prepared
In 150mL three-necked flask be added 2.20g (10.67mmol) 1,2-O- isopropylidene-α-D- glucofuranose,
12.72g (21.34mmol) organotin copolymer, 1.3g 4A molecular sieve and 60mL chloroform, by mixture in reflux
Under the conditions of be stirred to react about 1h, until 1,2-O- isopropylidene-α-D- glucofuranose is completely dissolved.System is naturally cooled to
Room temperature is placed under condition of ice bath, and bromine is added dropwise and is stirred continuously, until rufous is no longer taken off after bromine instillation,
Continue to stir 5min, system color is still pale red brown at this time, can stop reacting.Reaction mixture is directly poured into silicagel column
Chromatography is separated, and first with chloroform is that eluant, eluent removes tin compound, then with ethyl acetate is that eluant, eluent produces target
Object elutes, and is spin-dried for after the eluent containing target product is merged, obtained pale yellow syrup liquid 1,2-O- isopropyl
Pitch base -5- oxo-α-furyl glucose 2.13g, yield 98%.
5,5- oxo-D-Glucose is prepared
1.21g (5.48mmol) 1,2-O- isopropylidene -5- oxo-α-furyl glucose is added in 25mL round-bottomed flask
With 25mL deionized water, then it is added into solution (dry through the washed acid cation exchange resin CAT600 of deionized water
Weight 2.40g), it stirs for 24 hours, filters at room temperature, filtrate freeze-drying obtains Light brown solid powder 5- oxo-D-Glucose
0.96g, yield 98%.
6, tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ (A) is prepared
By 0.52g (2.15mmol) 2- methyl -5- amino -4 '-ethoxy diphenyl methylmethane be dissolved in 15mL methylene chloride and
The in the mixed solvent of 5mL methanol adds 0.53mL (9.20mmol) acetic acid, 10min is stirred at -75 DEG C, then by 0.48g
(2.69mmol) 5- oxo-D-Glucose is dissolved in 15mL methanol, instill reaction system, add 1.3g 4A molecular sieve,
0.34g (5.38mmol) sodium cyanoborohydride, the reaction mixture stir 1 hour at -75 DEG C, are then gradually increased to room temperature,
It is stirred for 23h at room temperature, solvent is steamed under decompression, ethyl acetate and each 30mL of water is added, is sufficiently mixed rear liquid separation, organic phase
It is dried over anhydrous sodium sulfate, solvent evaporated, through silica gel column chromatography separation, (eluant, eluent is ethyl acetate and petroleum ether volume to residue
Than the mixture for 1:3), obtain N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ crude product 0.83g.
0.83g N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ crude product is dissolved in 6mL tetrahydro
In furans, 1.16mL (10.50mmol) 4- methyl morpholine, 27mg (0.21mmol) N, N- dimethylamino naphthyridine is added, be cooled to-
10 DEG C, 1.3mL acetic anhydride is then added, stirs 1h at -10 DEG C, is warmed to room temperature, is further continued for stirring 1h, is evaporated under decompression molten
Agent is extracted with ethyl acetate after the dilution of 10mL 2mol/L HCL aqueous solution is added, takes organic phase, saturated sodium bicarbonate water is added
Solution stirs until bubble-free, stands liquid separation, organic phase is taken to be evaporated, and through silica gel column chromatography separation, (eluant, eluent is second to residue
The volume ratio of acetoacetic ester and petroleum ether is the mixture of 1:3), obtain the tetra-acetylated-N- of faint yellow solid [3- (4- ethoxy benzylidene
Base) -4- aminomethyl phenyl] -1-DNJ (A) 0.32g, yield 27%, m.p.:36.3-38.1 DEG C；HRMS
(C30H37NO9)m/z[M+Na]+: 578.2351 (calculated values: 578.2366)；1H NMR(400MHz,CDCl3)δ(ppm):7.08
(d, J=8.0Hz, 1H), 6.98 (d, J=8.7Hz, 2H), 6.88 (dd, J=8.0,2.3Hz, 1H), 6.83 (d, J=2.3Hz,
1H), 6.80 (d, J=8.7Hz, 2H), 5.23 (t, J=8.3Hz, 1H), 5.17 (t, J=8.4Hz, 1H), 5.10 (td, J=
8.5,4.3Hz, 1H), 4.13 (dd, J=12.3,3.2Hz, 1H), 4.00 (q, J=7.0Hz, 2H), 3.85 (s, 2H), 3.71
(dd, J=12.3,3.2Hz, 1H), 3.38 (dd, J=11.7,4.8Hz, 1H), 3.24 (dt, J=7.9,3.2Hz, 1H), 2.99
(dd, J=11.7,9.0Hz, 1H), 2.18 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.93 (s, 3H),
1.40 (t, J=7.0Hz, 3H)；13C NMR(101MHz,CDCl3)δ(ppm):172.08,171.55,171.33,171.00,
158.68,147.06,141.92,134.83,133.19,132.49,130.97,126.77,122.67,115.86,75.16,
70.97,70.82,64.73,62.97,61.23,55.30,40.01,22.22,22.16,22.10,22.04,20.46,
16.29；IR νmax(KBr)cm-1:2981,1757,1614,1510,1446,1367,1228,1033,902,821,734.
Embodiment 2
Synthesize tetra-acetylated-N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ (B)
1, chloro- 4- nitro-the 4 '-oxethyl-diphenyl-ketone of 2- is prepared
The 2- methyl-5-nitro benzoic acid in 1 step 1 of embodiment is replaced with the chloro- 4- nitrobenzoic acid of equimolar 2-, it is other
Step is identical as 1 step 1 of embodiment, obtains the chloro- 4- nitro -4 ' of white solid 2--oxethyl-diphenyl-ketone 4.20g, yield
It is 55%.
2, the chloro- 4- nitro -4 ' of 2--ethoxy diphenyl methylmethane is prepared
2- methyl -5- the nitre in 1 step 2 of embodiment is replaced with chloro- 4- nitro-the 4 '-oxethyl-diphenyl-ketone of equimolar 2-
Base -4 '-oxethyl-diphenyl-ketone, other steps are identical as 1 step 2 of embodiment, obtain chloro- 4- nitro-the 4 '-second of white solid 2-
Oxygroup diphenyl methane 1.65g, yield 92%.
3, the chloro- 4- amino -4 ' of 2--ethoxy diphenyl methylmethane is prepared
2- methyl-the 5- in 1 step 3 of embodiment is replaced with the chloro- 4- nitro -4 ' of equimolar 2--ethoxy diphenyl methylmethane
Nitro -4 '-ethoxy diphenyl methylmethane, other steps are identical as 1 step 3 of embodiment, obtain the chloro- 4- amino-of white solid 2-
4 '-ethoxy diphenyl methylmethane 1.01g, yield 91%.
4,1,2-O- isopropylidene -5- oxo-α-furyl glucose is prepared
1,2-O- isopropylidene -5- oxo-α-furyl glucose preparation method is identical as 1 step 4 of embodiment.
5,5- oxo-D-Glucose is prepared
5- oxo-D-Glucose preparation method is identical as 1 step 5 of embodiment.
6, tetra-acetylated-N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ (B) is prepared
2- methyl-the 5- in 1 step 6 of embodiment is replaced with the chloro- 4- amino -4 ' of equimolar 2--ethoxy diphenyl methylmethane
Amino -4 '-ethoxy diphenyl methylmethane, other steps are identical as 1 step 6 of embodiment, obtain the tetra-acetylated-N- of light yellow solid
[the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ (B) 0.35g, yield 28%, m.p.:85.7-
86.5℃；RMS(C29H34ClNO9)m/z[M+Na]+: 598.1810 (calculated values: 598.1820)；1H NMR(400MHz,CDCl3)
δ(ppm):7.08(br s,1H),7.06(br s,1H),7.05-7.02(m,2H),6.85-6.83(m,2H),6.80(br s,
1H), 5.09-5.08 (m, 2H), 5.02-4.95 (m, 1H), 4.20 (dd, J=12.1,4.3Hz, 1H), 3.92 (q, J=
7.0Hz, 2H), 3.88 (s, 2H), 3.80 (dd, J=12.1,4.3Hz, 1H), 3.49 (d, J=4.5Hz, 1H), 3.38 (dd, J
=12.6,4.2Hz, 1H), 3.11 (dd, J=12.6,7.5Hz, 1H), 2.00 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H),
1.89 (s, 3H), 1.32 (t, J=7.0Hz, 3H)；13C NMR(101MHz,CDCl3)δ(ppm):172.05,171.39,
171.13,171.04,158.84,149.56,135.95,135.14,132.92,132.73,131.26,122.97,120.77,
115.88,73.42,70.66,70.29,64.78,61.45,61.40,51.63,39.07,22.28,22.21,22.19,
22.06,16.31；IR νmax(KBr)cm-1:2983,1745,1610,1510,1367,1242,1043,790,599,424.
Embodiment 3
Synthesize tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ (C)
1, chloro- 5- nitro-the 4 '-oxethyl-diphenyl-ketone of 2- is prepared
The 2- methyl-5-nitro benzoic acid in 1 step 1 of embodiment is replaced with equimolar 2- chloro-5-nitrobenzoic acid, it is other
Step is identical as 1 step 1 of embodiment, obtains the chloro- 5- nitro -4 ' of white solid 2--oxethyl-diphenyl-ketone 3.84g, yield
It is 54%.
2, the chloro- 5- nitro -4 ' of 2--ethoxy diphenyl methylmethane is prepared
2- methyl -5- the nitre in 1 step 2 of embodiment is replaced with chloro- 5- nitro-the 4 '-oxethyl-diphenyl-ketone of equimolar 2-
Base -4 '-oxethyl-diphenyl-ketone, other steps are identical as 1 step 2 of embodiment, obtain chloro- 5- nitro-the 4 '-second of white solid 2-
Oxygroup diphenyl methane 1.56g, yield 94%.
3, the chloro- 5- amino -4 ' of 2--ethoxy diphenyl methylmethane is prepared
2- methyl-the 5- in 1 step 3 of embodiment is replaced with the chloro- 5- nitro -4 ' of equimolar 2--ethoxy diphenyl methylmethane
Nitro -4 '-ethoxy diphenyl methylmethane, other steps are identical as 1 step 3 of embodiment, obtain the chloro- 5- amino-of white solid 2-
4 '-ethoxy diphenyl methylmethane 0.97g, yield 95%.
4,1,2-O- isopropylidene -5- oxo-α-furyl glucose is prepared
1,2-O- isopropylidene -5- oxo-α-furyl glucose preparation method is identical as 1 step 4 of embodiment.
5,5- oxo-D-Glucose is prepared
5- oxo-D-Glucose preparation method is identical as 1 step 5 of embodiment.
6, tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ (C) is prepared
2- methyl-the 5- in 1 step 6 of embodiment is replaced with the chloro- 5- amino -4 ' of equimolar 2--ethoxy diphenyl methylmethane
Amino -4 '-ethoxy diphenyl methylmethane, other steps are identical as 1 step 6 of embodiment, obtain the tetra-acetylated-N- of white solid
[3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ (C) 0.33g, yield 27%, m.p.:92.5-
92.8℃；HRMS(C29H34ClNO9)m/z[M+Na]+: 598.1808 (calculated values: 598.1820)；1H NMR(600MHz,
CDCl3) δ (ppm): 7.26 (d, J=2.4Hz, 1H), 7.07 (d, J=8.5Hz, 2H), 6.85 (dd, J=8.6,2.4Hz,
1H), 6.81-6.79 (m, 3H), 5.16-5.13 (m, 2H), 5.06-5.03 (m, 1H), 4.20 (dd, J=12.2,4.0Hz,
1H), 4.01 (q, J=7.0Hz, 2H), 3.97 (s, 2H), 3.75 (dd, J=12.2,4.0Hz, 1H), 3.40-3.38 (m, 2H),
3.08 (dd, J=12.3,8.0Hz, 1H), 2.06 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.91 (s, 3H), 1.40 (t,
J=7.0Hz, 3H)；13C NMR(151MHz,CDCl3) δ (ppm): 170.56,169.95,169.86,169.57,157.52,
147.57,140.14,131.05,130.17,129.81,128.96,124.39,120.75,114.56,72.60,69.28,
69.03,63.39,60.61,59.84,51.42,38.49,20.83,20.76,20.71,20.57,14.88.IR νmax(KBr)
cm-1:2983,2819,1749,1512,1475,1367,1232,1039,831,599.
Embodiment 4
It is wild to synthesize tetra-acetylated-N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1- deoxidation
Buttocks mycin (D)
1,2- (4- fluorophenyl) thiophene is prepared
By 4.98g (36mmol) 4- fluorobenzoic boric acid, 4.1g (30mmol) 2- bromothiophene, 10.98g (60mmol) Carbon Dioxide
Potassium is dissolved in 20mL DMF, and 24mg (0.5%mmol) [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride is added,
It is warming up to 120 DEG C, isothermal reaction 15h under nitrogen protection, 30mL distilled water quenching reaction is added, with 30mL CH2Cl2Extraction two
It is secondary, merge organic phase, through anhydrous Na2SO4Drying is evaporated, and residue is diluted with petroleum ether, and is filtered to obtain light green filtrate, is evaporated filter
Liquid, residue obtain white crystal 2- (4- fluorophenyl) thiophene 4.50g using petroleum ether as eluant, eluent silica gel chromatography,
Its yield is 85%.
2,2- (2- methyl-5-nitro benzoyl) -5- (4- fluorophenyl) thiophene is prepared
4.55g (25mmol) 2- methyl-5-nitro benzoic acid is dissolved in 8mL thionyl chloride, 4 drop pyridines are added dropwise, rise
Temperature boils off thionyl chloride, obtains 2- methyl-5-nitro chlorobenzoyl chloride and (directly carry out without separation subsequent anti-to 50 DEG C of reaction 3h
It answers).
By 5.01g (37.5mmol) anhydrous AlCl3It is added to 15mL CH2Cl2In, it is cooled to 0 DEG C, is slowly added to 4.45g
(25mmol) 2- (4- fluorophenyl) thiophene, after being added dropwise, stirs 15min at 0 DEG C, the 2- methyl -5- nitre that then will be obtained
Base chlorobenzoyl chloride is dissolved in 45mL CH2Cl2After be slowly dropped in reaction system, continue to be stirred to react 1h at 0 DEG C, obtain ink
The blackish green solution is added in 80mL 2mol/L HCL aqueous solution, in room temperature by green solution in the case where being vigorously stirred and cooling down
Lower stirring 20min, liquid separation, organic phase are washed with 2mol/L HCL aqueous solution, combined water phase CH2Cl2Extraction, merging have
Machine is mutually with saturation NaHCO3Aqueous solution and saturated salt solution are evaporated after washing twice, and residue is separated through silica gel column chromatography (with second
The mixture that the volume ratio of acetoacetic ester and petroleum ether is 1:20 is eluant, eluent), obtain faint yellow solid compound 2- (2- methyl-
5- nitro benzoyl) -5- (4- fluorophenyl) thiophene 6.48g, yield 76%.
3,2- (4- fluorophenyl) -5- (2- methyl-5-nitro benzyl) thiophene is prepared
By 2.05g (6mmol) 2- (2- methyl-5-nitro benzoyl) -5- (4- fluorophenyl) thiophene be dissolved in 6mL acetonitrile and
In 6mL dichloromethane mixture, 6.0mL triethylsilane is added, 3.0mL mass fraction is that 47% boron trifluoride ether is molten
Liquid is warming up to 40 DEG C of reaction 2h, and stirring separates organic phase, eaten with saturation to bubble-free after saturated sodium bicarbonate aqueous solution is added dropwise
Salt water washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtains faint yellow solid 2- (4- fluorophenyl) -5- (2- methyl-5-nitro
Benzyl) thiophene 1.88g, yield 96%.
4,4- methyl -3- [5- (4- fluorophenyl) thiophene -2- methylene] aniline is prepared
By 1.31g (4.00mmol) 2- (4- fluorophenyl) -5- (2- methyl-5-nitro benzyl) thiophene, 0.63g active carbon,
0.40g ferric trichloride is added in 10mL ethyl alcohol, is warming up to 80 DEG C, and the hydrazine hydrate that 1.71mL mass fraction is 80% is slowly added dropwise,
40min is reacted, is filtered while hot, filtrate is concentrated, solid is precipitated after cold water stirring is added, filters drying, obtains white solid chemical combination
Object 4- methyl -3- [5- (4- fluorophenyl) thiophene -2- methylene] aniline 1.15g, yield 97%.
5,1,2-O- isopropylidene -5- oxo-α-furyl glucose is prepared
1,2-O- isopropylidene -5- oxo-α-furyl glucose preparation method is identical as 1 step 4 of embodiment.
6,5- oxo-D-Glucose is prepared
5- oxo-D-Glucose preparation method is identical as 1 step 5 of embodiment.
7, tetra-acetylated-N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1- deoxidation is prepared
Nojirimycin (D)
0.68g (2.30mmol) 4- methyl -3- [5- (4- fluorophenyl) thiophene -2- methylene] aniline is dissolved in 10mL bis-
The in the mixed solvent of chloromethanes and 10mL methanol adds 0.13mL (2.30mmol) acetic acid, 10min is stirred at -73 DEG C, so
It is added drop-wise in reaction system after 0.52g (2.85mmol) 5- oxo-D-Glucose is dissolved in 10mL methanol afterwards, and 1.3g is added
4A molecular sieve, 0.36g (5.75mmol) sodium cyanoborohydride continue to stir 1h at -73 DEG C, are then gradually increased to room temperature,
It is stirred for 23h at room temperature, steams solvent, ethyl acetate is added and each 30mL of water is stirred evenly, liquid separation obtains organic phase, organic phase warp
Anhydrous sodium sulfate drying, solvent evaporated, through silica gel column chromatography separation, (eluant, eluent is ethyl acetate and petroleum ether volume ratio to residue
For the mixture of 1:3), obtain N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1- deoxidation open country buttocks
Mycin crude product 1.03g.
By 1.03g N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1-DNJ
Crude product is dissolved in 25mL tetrahydrofuran, and 1.41mL (12.6mmol) 4- methyl morpholine, 29mg (0.23mmol) N, N- diformazan is added
Aminopyridine (DMAP), is cooled to -10 DEG C, and 3mL acetic anhydride is then added, stirs 1h at -10 DEG C, is warmed to room temperature, be further continued for
1h is stirred, solvent evaporated is added 20mL 2mol/L HCL aqueous solution, is extracted with ethyl acetate, unsaturated carbonate is added in organic phase
Hydrogen sodium water solution stirs until bubble-free, stands liquid separation, organic phase is taken to be evaporated, and residue is separated through silica gel column chromatography (with second
The mixed liquor that the volume ratio of acetoacetic ester and petroleum ether is 1:3 is eluant, eluent), obtain the tetra-acetylated-N- of white solid [3- [5- (4-
Fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1-DNJ (D) 0.44g, yield 31%, m.p.:
109.9-110.8℃；HRMS(C32H34FNO8S)m/z[M+Na]+: 634.1884 (calculated values: 634.1887)；1H NMR
(600MHz,CDCl3) δ (ppm): 7.49-7.47 (m, 2H), 7.11 (d, J=8.1Hz, 1H), 7.04-7.01 (m, 3H), 6.98
(d, J=2.1Hz, 1H), 6.93 (dd, J=8.1,2.1Hz, 1H), 6.65 (d, J=3.5Hz, 1H), 5.25 (t, J=8.3Hz,
1H), 5.19 (t, J=8.5Hz, 1H), 5.12 (dt, J=8.6,4.3Hz, 1H), 4.17 (dd, J=12.3,3.2Hz, 1H),
4.07 (s, 2H), 3.74 (dd, J=12.3,3.2Hz, 1H), 3.42 (dd, J=11.7,4.8Hz, 1H), 3.30 (dt, J=
7.1,3.2Hz, 1H), 3.04 (dd, J=11.7,9.0Hz, 1H), 2.27 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.01
(s,3H),1.94(s,3H)；13C NMR(151MHz,CDCl3)δ(ppm):170.70,170.13,169.96,169.59,
162.14 (d, J=246.7Hz), 146.76,142.99,141.69,139.22,133.04,131.35,130.79 (d, J=
3.2Hz), 127.15 (d, J=8.3Hz), 125.99,124.83,122.69,121.65,115.73 (d, J=21.9Hz),
73.68,69.59,69.44,61.47,59.90,53.66,34.19,20.83,20.76,20.70,20.64,18.85；IR
νmax(KBr)cm-1:2968,2817,1741,1512,1367,1230,1028,831,788,630,599.
Embodiment 5
It is mould to synthesize tetra-acetylated-N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1- deoxidation open country buttocks
Plain (E)
1, p-methyl benzenesulfonic acid-(S)-tetrahydrofuran -3- alcohol ester is prepared
By 6.61g (75.02mmol) (S) -3- hydroxyl tetrahydrofuran, 8.35g (82.51mmol) triethylamine and 3.67g
(30.04mmol) N, N- dimethylamino naphthyridine is dissolved in 50mL methylene chloride, and after stirring 10min at 0 DEG C, 15.73g is added
(82.51mmol) paratoluensulfonyl chloride continues to stir 10min, after being warmed to room temperature reaction 30min, is heated to 50 DEG C of reflux 1h, to
50mL 2mol/LHCl aqueous solution is added in reaction system, liquid separation obtains organic phase, and organic phase is evaporated after being dried over anhydrous sodium sulfate
Solvent, gained dark red oily liquids (are the mixing of 1:6 with the volume ratio of ethyl acetate and petroleum ether through silica gel column chromatography separation
Object is eluant, eluent), obtain colourless liquid p-methyl benzenesulfonic acid-(S)-tetrahydrofuran -3- alcohol ester 17.45g, yield 96%.
2, (R) -3- phenoxy group tetrahydrofuran is prepared
By 16.91g (69.79mmol) p-methyl benzenesulfonic acid-(S)-tetrahydrofuran -3- alcohol ester, 9.85g (104.69mmol) benzene
Phenol is dissolved in 100mL DMF, adds 34.31g (104.68mmol) cesium carbonate, is warming up to 75 DEG C of reaction 12h, and distillation is added
Water is extracted with ethyl acetate, and organic phase is dried over anhydrous sodium sulfate rear solvent evaporated, residue separate through silica gel column chromatography (with
The mixture that the volume ratio of ethyl acetate and petroleum ether is 1:3 is eluant, eluent), obtain obtaining colourless oil liquid (R) -3- phenoxy group
Tetrahydrofuran 8.19g, yield 71%.
3, the chloro- 5- nitro-of 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenylmethanone is prepared
9.84g (48.82mmol) 2- chloro-5-nitrobenzoic acid is dissolved in 30mL thionyl chloride, and 3mL pyrrole is added dropwise
Pyridine, is warming up to 50 DEG C of reaction 3h, be concentrated under reduced pressure remove thionyl chloride obtain the chloro- 5- nitrobenzoyl chloride of 2- (do not have to separation directly into
Row subsequent reactions).
By 9.76g (73.22mmol) anhydrous AlCl3It is added to 100mL CH2Cl2In, it is cooled to 0 DEG C, is slowly added to
8.02g (48.82mmol) (R) -3- phenoxy group tetrahydrofuran continues to stir 20min at 0 DEG C after being added dropwise, then incite somebody to action
To the chloro- 5- nitrobenzoyl chloride of 2- be dissolved in 60mL CH2Cl2After be slowly dropped in reaction system, stir 12h at 0 DEG C,
It is added into the case where being vigorously stirred and cooling down into 80mL 2mol/L HCL aqueous solution, 20min is stirred at room temperature, liquid separation has
Machine is mutually washed with 20mL 2mol/L HCL aqueous solution, combined water phase CH2Cl2Extraction, the organic phase saturation of collection
NaHCO3Aqueous solution and saturated salt solution wash twice, merge organic layer be concentrated to dryness, residue through silica gel column chromatography separate (with
The mixture that the volume ratio of ethyl acetate and methylene chloride is 1:1000 is eluant, eluent), obtain the chloro- 5- nitre of light green solid 2-
Base-[4 '-(R)-tetrahydrofuran -3- oxygroup] diphenylmethanone 5.87g, yield 56%.
4, the chloro- 5- nitro-of 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane is prepared
The chloro- 5- nitro-of 5.86g (16.85mmol) 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenylmethanone is dissolved in
In 50mL acetonitrile, 24.55mL triethylsilane is added, being slowly added to 12.28mL mass fraction is that 47% boron trifluoride ether is molten
Saturation NaHCO is added dropwise in liquid, 40 DEG C of reaction 2h3Aqueous solution is stirred to bubble-free, separates organic phase, and water phase is extracted with ethyl acetate,
Merge organic phase, is then washed with saturation NaCl aqueous solution, be dried in vacuo after concentration, obtain the chloro- 5- nitro-of white solid 2-
[4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane 4.44g, yield 79%.
5, the chloro- 5- amino-of 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane is prepared
By the chloro- 5- nitro-of 3.63g (10.72mmol) 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane,
2.09g active carbon, 1.10g FeCl3It is added in 30mL ethyl alcohol, being warming up to 5.47mL mass fraction under 80 DEG C of reflux is 80%
Hydrazine hydrate be slowly dropped in reaction solution, back flow reaction 40min is filtered while hot, be concentrated filtrate, be added cold water stirring after be precipitated
Solid, filters, and dry cake obtains the chloro- 5- amino-of white solid 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane
3.19g, yield 98%.
6,1,2-O- isopropylidene -5- oxo-α-furyl glucose is prepared
1,2-O- isopropylidene -5- oxo-α-furyl glucose preparation method is identical as 1 step 4 of embodiment.
7,5- oxo-D-Glucose is prepared
5- oxo-D-Glucose preparation method is identical as 1 step 5 of embodiment.
8, tetra-acetylated-N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1- deoxidation open country buttocks is prepared
Mycin (E)
The chloro- 5- amino-of 1.21g (3.96mmol) 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane is dissolved in
The in the mixed solvent of 40mL methylene chloride and 60mL methanol adds 0.23mL (3.96mmol) acetic acid, stirs at -78 DEG C
10min is added dropwise to reaction system after 1.08g (4.95mmol) 5- oxo-D-Glucose is then dissolved in 40mL methanol, adds
3.9g 4A molecular sieve, 0.62g (9.90mmol) sodium cyanoborohydride continue to stir 1h at -78 DEG C, are then gradually increased to room
Temperature is stirred for 23h at room temperature, steams solvent, and ethyl acetate and each 30mL of distilled water is added, and is uniformly mixed, liquid separation obtains organic
Phase, organic phase are dried over anhydrous sodium sulfate, after solvent evaporated, and through silica gel column chromatography separation, (eluant, eluent is ethyl acetate to residue
The mixture for being 1:3 with petroleum ether volume ratio), obtain N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -
1-DNJ crude product 1.03g.
By 1.03g N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ crude product
It is dissolved in 10mL tetrahydrofuran, 0.4mL (11.45mmol) 4- methyl morpholine, 28.70mg (0.23mmol) N, N- diformazan ammonia is added
Yl pyridines are cooled to -10 DEG C, and 3mL acetic anhydride is then added, stirs 1h at -10 DEG C, is warmed to room temperature, and are further continued for stirring 1h, steam
Dry solvent is added 20mL 2mol/L HCL aqueous solution, is extracted with ethyl acetate, organic to be added to saturated sodium bicarbonate aqueous solution
Stirring stands liquid separation until bubble-free, and organic phase is evaporated, and residue is separated through silica gel column chromatography (with ethyl acetate and petroleum
The mixture that ether volume ratio is 1:3 is eluant, eluent), obtain the tetra-acetylated-N- of white solid [3- [4- (R)-tetrahydrofuran -3- oxygroup
Benzyl] -4- chlorphenyl] -1-DNJ (E) 1.41g, yield 30%, m.p.:87.9-89.1 DEG C；HRMS
(C31H36ClNO10)m/z[M+Na]+: 640.1919 (calculated values: 640.1925)；1H NMR(600MHz,CDCl3)δ(ppm):
7.20 (d, J=8.6Hz, 1H), 7.00 (d, J=8.6Hz, 2H), 6.79 (dd, J=8.6,2.7Hz, 1H), 6.76 (d, J=
2.7Hz, 1H), 6.72 (d, J=8.6Hz, 2H), 5.09-5.06 (m, 2H), 4.98 (dq, J=8.0,4.4Hz, 1H), 4.82
(ddt, J=6.4,4.4,2.0Hz, 1H), 4.14 (dd, J=12.2,4.2Hz, 1H), 3.93-3.88 (m, 5H), 3.82 (dt, J
=8.3,4.2Hz, 1H), 3.70 (dd, J=12.2,4.2Hz, 1H), 3.36-3.33 (m, 2H), 3.03 (dd, J=12.3,
8.0Hz,1H),2.14-2.07(m,2H),1.99(s,3H),1.93(s,3H),1.94(s,3H),1.83(s,3H)；13C NMR
(151MHz,CDCl3)δ(ppm):170.53,169.95,169.83,169.56,155.98,147.60,139.95,131.59,
130.21,129.90,128.89,124.34,120.69,115.44,77.32,73.13,72.56,69.30,69.05,
67.20,60.54,59.89,51.33,38.48,33.04,20.82,20.75,20.70,20.57；IR νmax(KBr)cm-1:
2960,2857,1737,1510,1373,1239,1070,1027,903,817,599,526.
Embodiment 6
It is mould to synthesize tetra-acetylated-N- [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1- deoxidation open country buttocks
Plain (F)
1, p-methyl benzenesulfonic acid-(R)-tetrahydrofuran -3- alcohol ester is prepared
(S) -3- hydroxyl tetrahydrofuran in 5 step 1 of embodiment is replaced with equimolar (R) -3- hydroxyl tetrahydrofuran, it is other
Step is identical as 5 step 1 of embodiment, obtains colourless liquid p-methyl benzenesulfonic acid-(R)-tetrahydrofuran -3- alcohol ester 17.08g, receives
Rate is 94%.
2, (S) -3- phenoxy group tetrahydrofuran is prepared
The p-methyl benzenesulfonic acid-in 5 step 2 of embodiment is replaced with equimolar p-methyl benzenesulfonic acid-(R)-tetrahydrofuran -3- alcohol ester
(S)-tetrahydrofuran -3- alcohol ester, other steps are identical as 5 step 2 of embodiment, obtain colourless liquid (S) -3- phenoxy group tetrahydro furan
Mutter 8.02g, yield 70%.
3, the chloro- 5- nitro-of 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenylmethanone is prepared
(R) -3- phenoxy group tetrahydrofuran in 5 step 3 of embodiment is replaced with equimolar (S) -3- phenoxy group tetrahydrofuran,
Other steps are identical as 5 step 3 of embodiment, obtain the chloro- 5- nitro-of white solid 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] two
Phenyl ketone 9.51g, yield 56%.
4, the chloro- 5- nitro-of 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenyl methane is prepared
5 step of embodiment is replaced with the chloro- 5- nitro-of equimolar 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenylmethanone
The chloro- 5- nitro-of 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenylmethanone in 4, other steps and 5 step 4 phase of embodiment
Together, the chloro- 5- nitro-of white solid 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenyl methane 4.56g is obtained, yield is
81%.
5, the chloro- 5- amino-of 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenyl methane is prepared
5 step of embodiment is replaced with the chloro- 5- nitro-of equimolar 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenyl methane
The chloro- 5- nitro-of 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane in 5, other steps and 5 step 5 phase of embodiment
Together, the chloro- 5- amino-of white solid 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenyl methane 3.06g is obtained, yield is
94%.
6,1,2-O- isopropylidene -5- oxo-α-furyl glucose is prepared
1,2-O- isopropylidene -5- oxo-α-furyl glucose preparation method is identical as 1 step 4 of embodiment.
7,5- oxo-D-Glucose is prepared
5- oxo-D-Glucose preparation method is identical as 1 step 5 of embodiment.
8, tetra-acetylated-N- [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1- deoxidation open country buttocks is prepared
Mycin (F)
5 step of embodiment is replaced with the chloro- 5- amino-of equimolar 2- [4 '-(S)-tetrahydrofuran -3- oxygroup] diphenyl methane
Step 8 in the chloro- 5- amino-of 2- [4 '-(R)-tetrahydrofuran -3- oxygroup] diphenyl methane in 8, other steps and embodiment 5
It is identical, it is wild to obtain the tetra-acetylated-N- of white solid [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1- deoxidation
Buttocks mycin (F) 0.71g, yield 29%, m.p.:42.6-43.8 DEG C；HRMS(C31H36ClNO10)m/z[M+Na]+:
640.1921 (calculated value: 640.1925)；1H NMR(600MHz,CDCl3) δ (ppm): 7.27 (d, J=8.6Hz, 1H), 7.05
(d, J=8.6Hz, 2H), 6.83 (dd, J=8.6,2.7Hz, 1H), 6.80 (d, J=2.7Hz, 1H), 6.77 (d, J=8.6Hz,
2H), 5.14-5.11 (m, 2H), 5.02 (dq, J=8.0,4.4Hz, 1H), 4.87 (ddt, J=6.3,4.4,2.0Hz, 1H),
4.18 (dd, J=12.2,4.2Hz, 1H), 3.96-3.94 (m, 4H), 3.87 (td, J=8.3,4.2Hz, 1H), 3.74 (dd, J
=12.2,4.2Hz, 1H), 3.40-3.36 (m, 2H), 3.07 (dd, J=12.3,8.0Hz, 1H), 2.20-2.07 (m, 3H),
2.04(s,3H),1.99(s,3H),1.98(s,3H),1.88(s,3H)；13C NMR(151MHz,CDCl3)δ(ppm):
170.54,169.96,169.85,169.57,155.98,147.59,139.95,131.60,130.22,129.90,128.93,
124.38,120.73,115.45,77.32,73.14,72.58,69.30,69.06,67.21,60.55,59.89,51.38,
38.49,33.04,20.83,20.76,20.71,20.57；IR νmax(KBr)cm-1:2960,2857,1745,1596,1510,
1369,1225,1041,807,603.
Embodiment 7
Prepare N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ (G)
By 0.32g (0.58mmol) tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1- deoxidation open country buttocks
Mycin (A is prepared according to the method for embodiment 1) is dissolved in the mixture of 3mL tetrahydrofuran and 3mL methanol, under agitation
1mL3mol/L NaOH aqueous solution is added, stirs 2h at room temperature, solvent evaporated is added distilled water dilution, is extracted with ethyl acetate,
Solvent evaporated after organic phase anhydrous sodium sulfate drying, obtains white solid N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -
1-DNJ (G) 0.22g, yield 96.6%, m.p.:140.6-141.2 DEG C；HRMS(C22H29NO5)m/z[M+
H]+: 388.2125 (calculated values: 388.2124)；1H NMR(400MHz,DMSO-d6) δ (ppm): 7.02 (d, J=8.1Hz,
2H), 6.97 (d, J=8.1Hz, 1H), 6.85 (br s, 1H), 6.82-6.79 (m, 3H), 4.97 (d, J=3.5Hz, 1H),
4.84 (t, J=5.1Hz, 2H), 4.25 (t, J=5.0Hz, 1H), 3.96 (q, J=7.0Hz, 2H), 3.80 (s, 2H), 3.61
(q, J=5.8Hz, 1H), 3.52-3.43 (m, 3H), 3.38-3.24 (m, 1H), 3.13-3.02 (m, 2H), 2.92-2.79 (m,
1H), 1.99 (s, 3H), 1.20 (t, J=7.0Hz, 3H)；13C NMR(101MHz,DMSO-d6)δ(ppm):158.51,
150.84,141.45,134.09,132.33,131.27,129.78,123.13,119.27,116.07,77.78,72.54,
71.92,66.41,64.72,60.80,55.81,40.14,20.28,16.58；IR νmax(KBr)cm-1:3382,2918,
1612,1510,1384,1240,1045,918,815,541.
Embodiment 8
Synthesize N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ (H)
With equimolar tetra-acetylated-N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ (B, root
Prepared according to 2 method of embodiment) replace tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1- deoxidation open country buttocks mould
Element, other steps are same as Example 7, and it is wild to obtain brown solid N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1- deoxidation
Buttocks mycin (H) 0.33g, yield 99%, m.p.:56.6-58.2 DEG C；HRMS(C21H26ClNO5)m/z[M+H]+:
408.1576 (calculated value: 408.1578)；1H NMR(400MHz,CDCl3) δ (ppm): 7.14 (br s, 1H), 7.01 (d, J=
8.6Hz, 2H), 6.97-6.95 (m, 1H), 6.88 (d, J=7.7Hz, 1H), 6.75 (d, J=8.6Hz, 2H), 5.77 (br s,
1H), 5.45 (br s, 1H), 5.01 (br s, 1H), 3.92 (q, J=7.0Hz, 2H), 3.87 (s, 2H), 3.80 (br s, 2H),
3.73-3.59(m,2H),3.53(br s,1H),3.47-3.38(m,1H),3.24-3.11(m,1H),2.84(br s,1H),
2.73 (br s, 1H), 1.34 (t, J=7.0Hz, 3H)；13C NMR(101MHz,CDCl3)δ(ppm):158.85,150.17,
137.50,135.82,132.81,132.60,131.33,126.74,124.24,115.92,79.58,78.67,72.10,
71.16,66.24,64.78,60.49,39.24,16.30；IRνmax(KBr)cm-1:3361,2977,2893,1606,1510,
1392,1247,1039,815,531.
Embodiment 9
Synthesize N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ (I)
With the tetra-acetylated-N- of equimolar [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ (C, according to
The preparation of 3 method of embodiment) tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ is replaced,
Other steps are in the same manner as in Example 7, obtain white solid N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1- deoxidation open country buttocks
Mycin (I) 0.22g, yield 97%, m.p.:126.9-127.1 DEG C；HRMS(C21H26ClNO5)m/z[M+Na]+:
430.1389 (calculated value: 430.1397)；1H NMR(600MHz,DMSO-d6) δ (ppm): 7.16 (d, J=8.8Hz, 1H),
7.10 (d, J=8.6Hz, 2H), 6.93 (d, J=2.8Hz, 1H), 6.83-6.81 (m, 3H), 5.06 (d, J=4.2Hz, 1H),
4.92 (d, J=5.4Hz, 1H), 4.90 (d, J=5.5Hz, 1H), 4.53 (t, J=5.4Hz, 1H), 3.96 (q, J=7.0Hz,
2H), 3.89 (s, 2H), 3.68 (q, J=5.1Hz, 1H), 3.59-3.51 (m, 3H), 3.40 (q, J=5.4Hz, 1H), 3.37
(q, J=5.0Hz, 1H), 3.20 (dd, J=12.4,3.7Hz, 1H), 3.10 (dd, J=12.4,6.4Hz, 1H), 1.29 (t, J
=7.0Hz, 3H)；13C NMR(101MHz,DMSO-d6)δ(ppm):157.28,150.39,139.06,132.03,129.94,
129.73,122.08,119.18,116.20,114.69,74.70,70.80,70.67,64.40,63.33,59.47,49.86,
38.53,15.15；IR νmax(KBr)cm-1:3344,2906,1610,1510,1477,1251,1166,1047,998,827,
538.
Embodiment 10
Synthesize N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1-DNJ (J)
It is de- with the tetra-acetylated-N- of equimolar [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1-
Oxygen nojirimycin (D is prepared according to 4 method of embodiment) replaces tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- methylbenzene
Base] -1-DNJ, other steps are same as Example 7, obtain white solid N- [3- [5- (4- fluorophenyl) thiophene -
2- methylene] -4- aminomethyl phenyl] -1-DNJ (J) 0.23g, yield 97%, m.p.:118.1-119.0
℃；HRMS(C24H26FNO4S)m/z[M+H]+: 444.1642 (calculated values: 444.1645)；1H NMR(600MHz,DMSO-d6)δ
(ppm): 7.58 (dd, J=8.6,5.4Hz, 2H), 7.27 (d, J=3.5Hz, 1H), 7.20 (t, J=8.8Hz, 2H), 7.01
(d, J=8.2Hz, 1H), 6.97-6.93 (m, 1H), 6.83 (dd, J=8.2,2.1Hz, 1H), 6.80 (d, J=3.5Hz, 1H),
4.99 (d, J=4.2Hz, 1H), 4.86 (t, J=5.3Hz, 2H), 4.29 (t, J=5.3Hz, 1H), 4.06 (s, 2H), 3.63
(q, J=5.9Hz, 1H), 3.51 (d, J=4.9Hz, 3H), 3.32 (d, J=4.5Hz, 1H), 3.13 (dd, J=11.7,
3.8Hz, 1H), 3.11 (m, 1H), 2.92 (dd, J=11.7,7.8Hz, 1H), 2.18 (s, 3H)；13C NMR(151MHz,DMSO-
d6)δ(ppm):162.16,160.54,149.09,143.90,140.13,138.43,130.60,130.56,130.54,
127.38,126.95,126.89,126.16,123.37,120.36,117.60,115.93,115.79,75.64,70.59,
70.03,64.42,58.90,53.32,33.73,18.16；IR νmax(KBr)cm-1:3415,2910,1641,1608,1506,
1228,1151,1076,1012,808,622,493.
Embodiment 11
Synthesize N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ (K)
It is wild with the tetra-acetylated-N- of equimolar [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1- deoxidation
Buttocks mycin (E is prepared according to 5 method of embodiment) replaces tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-
1-Deoxynojirimycin, other steps are in the same manner as in Example 7, obtain faint yellow solid N- [3- [4- (R)-tetrahydrofuran -3- oxygen
Base benzyl] -4- chlorphenyl] -1-DNJ (K) 0.23g, yield 88%, m.p.:56.1-57.6 DEG C；HRMS
(C23H28ClNO6)m/z[M+H]+: 450.1683 (calculated values: 450.1683)；1H NMR(400MHz,DMSO-d6)δ(ppm):
7.17 (d, J=8.8Hz, 1H), 7.12 (d, J=8.6Hz, 2H), 6.94 (d, J=2.7Hz, 1H), 6.83-6.81 (m, 3H),
5.08 (d, J=3.5Hz, 1H), 4.97-4.91 (m, 3H), 4.55 (t, J=4.9Hz, 1H), 3.89 (s, 2H), 3.88-3.77
(m, 3H), 3.76-3.67 (m, 4H), 3.60-3.50 (m, 3H), 3.21 (dd, J=12.4,3.6Hz, 1H), 3.11 (dd, J=
12.4,6.3Hz,1H),2.22-2.13(m,1H),1.96-1.90(m,1H)；13C NMR(151MHz,DMSO-d6)δ(ppm):
155.39,149.91,138.48,131.90,129.56,129.25,121.56,118.68,115.70,115.11,76.92,
74.18,72.26,70.30,70.18,66.36,63.90,58.98,49.32,38.01,32.42；IR νmax(KBr)cm-1:
3375,2923,2862,1606,1510,1475,1242,1082,1008,903,815,515.
Embodiment 12
Synthesize N- [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ (L)
It is wild with the tetra-acetylated-N- of equimolar [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1- deoxidation
Buttocks mycin (F is prepared according to 6 method of embodiment) replaces tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-
1-Deoxynojirimycin, other steps are in the same manner as in Example 7, obtain light yellow solid N- [3- [4- (S)-tetrahydrofuran -3- oxygen
Base benzyl] -4- chlorphenyl] -1-DNJ (L) 0.25g, yield 95%, m.p.:43.7-44.4 DEG C；HRMS
(C23H28ClNO6)m/z[M+Na]+: 472.1497 (calculated values: 472.1503)；1H NMR(600MHz,DMSO-d6)δ(ppm):
7.16 (d, J=8.8Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 6.93 (d, J=2.7Hz, 1H), 6.82 (m, 3H), 4.95
(m, 2H), 3.89 (s, 2H), 3.86 (dd, J=10.1,4.6Hz, 1H), 3.80 (q, J=7.9Hz, 1H), 3.75-3.71 (m,
2H), 3.68 (t, J=4.8Hz, 1H), 3.58-3.55 (m, 2H), 3.51 (dd, J=11.0,4.4Hz, 1H), 3.41-3.38
(m, 1H), 3.20 (dd, J=12.4,3.7Hz, 1H), 3.10 (dd, J=12.4,6.4Hz, 1H), 2.20-2.14 (m, 1H),
1.94-1.90(m,1H)；13C NMR(151MHz,DMSO-d6)δ(ppm):155.39,149.92,138.48,131.90,
129.56,129.24,121.55,118.68,115.70,115.11,76.92,74.22,72.26,70.32,70.17,
66.36,63.91,58.98,49.35,38.01,32.42；IR νmax(KBr)cm-1:3342,2930,1730,1510,1475,
1244,1074,1012,800,507.
Embodiment 13
Application of the N- aryl -1-DNJ derivative of the present invention in preparation treatment diabetes medicament
Inventor is used matter respectively using compound G, H, I, J, K and L of above-described embodiment synthesis as test medicine
The Tween-80 aqueous solution that amount score is 0.5% is configured to the compound solution of 1.0mg/mL, and testing it reduces blood glucose to SD rat
The effect being discharged with promotion glucose in urine, specific test situation are as follows:
Test reagent: glucose: Tianjin chemical reagent wholesaling firm；Tween-80: three factory of Tianjin reagent；Glucose is surveyed
Determine kit (hexokinase method): Zhongsheng Beikong Biological Science & Technology Co., Ltd.；Animal feed, Tianjin Huarong experimental animal
Science and Technology Ltd., credit number: SCXK (saliva) 2012-0001.
Animal for research: SD kind rat, SPF grades, research institute, the Chinese military medicine academy of sciences provides, licensing number:
SCXK (army) 2014-0001.
Laboratory apparatus: GT-1640 type blood glucose meter, ARKRAY product；Blood sugar test paper (Test Strip II), ARKRAY has
The effect phase is extremely: 2017.09；7080 type full automatic biochemical apparatus, Hitachi product.
Animal Lab.: room temperature is controlled by central air-conditioning in (23 ± 3) DEG C, and humidity is (55 ± 15) %.
1, influence of the compound to glucose load SD rat blood sugar
Select male SD rat 56, after weight 180-200g, fasting 16h, tail vein takes blood to survey 0h blood glucose, by blood glucose with
Machine is divided into 7 groups, respectively model control group, compound G, H, I, J, K and L administration group.Each administration group respectively give accordingly by stomach-filling
Compound, dosage 10mg/kg, administered volume 10mL/kg；Isometric mass fraction is given in model control group stomach-filling
0.5% Tween-80 aqueous solution.After 1h is administered, 3.5g/kg glucose (10mL/kg) is given in each group stomach-filling.It measures to after sugar
0.5h, 1h and 3h blood glucose calculate area (AUC) under blood sugar concentration-time graph.Experimental result is as shown in table 1.
1 compound of table on glucose load SD rat blood sugar influence (N=8)
Note: compared with model control group: * indicates that P < 0.05, * * indicate P < 0.01.
In table 1 under blood sugar concentration-time graph area (AUC) statistics indicate that, the compounds of this invention and model control group phase
Comparing glucose load SD rat has significant hypoglycemic effect.
2, influence of the compound to glucose load SD rat glucose in urine
Select male SD rat 56, after weight 180-200g, fasting 16h, tail vein takes blood to survey 0h blood glucose, by blood glucose with
Machine is divided into 7 groups, respectively model control group, compound G, H, I, J, K and L administration group.Each administration group respectively give accordingly by stomach-filling
Compound, dosage 10mg/kg, administered volume 10mL/kg；Isometric mass fraction is given in model control group stomach-filling
0.5% Tween-80 aqueous solution.After 1h is administered, 3.5g/kg glucose (10mL/kg) is given in each group stomach-filling.Administration is collected respectively
The urine of 0-6h, 6-24h afterwards measures the glucose in urine amount of 0-6h, 6-24h.Experimental result is as shown in table 2.
2 compound of table to glucose load SD rat glucose in urine influence (N=8)
Note: compared with model control group, * indicates that P < 0.05, * * indicate P < 0.01.
Total glucose in urine discharge rate of the compounds of this invention between 0-24h has aobvious table 2 compared with model control group as the result is shown
The difference of work or very significant.
The above result shows that the compounds of this invention all has the effect for reducing blood glucose and promoting glucose in urine discharge, it can be used as glycosuria
The therapeutic agent of disease.
Claims (3)
1. one kind N- aryl -1-DNJ derivative, it is characterised in that the derivative be formula 1 shown in compound or its
Salt:
R in formula1For Cl or methyl；R2For substituted-phenyl, substituted pyridinyl, substituted furan base, substituted thiophene base, substituted azole base
In any one, wherein substituent group be C1~C4Alkoxy, halogenophenyl, any one in furans oxygroup；R3For H or C1
~C4Acyl group.
2. N- aryl -1-DNJ derivative according to claim 1, it is characterised in that the derivative is following
Any one in compound A~L:
A: tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ
B: tetra-acetylated-N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ
C: tetra-acetylated-N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ
D: tetra-acetylated-N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1-DNJ
E: tetra-acetylated-N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
F: tetra-acetylated-N- [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
G:N- [3- (4- ethoxy benzyl) -4- aminomethyl phenyl] -1-DNJ
H:N- [the chloro- 4- of 3- (4- ethoxy benzyl) phenyl] -1-DNJ
I:N- [3- (4- ethoxy benzyl) -4- chlorphenyl] -1-DNJ
J:N- [3- [5- (4- fluorophenyl) thiophene -2- methylene] -4- aminomethyl phenyl] -1-DNJ
K:N- [3- [4- (R)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
L:N- [3- [4- (S)-tetrahydrofuran -3- oxy-benzyl] -4- chlorphenyl] -1-DNJ
3. purposes of the N- aryl -1-DNJ derivative described in claim 1 in preparation treatment diabetes medicament.
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