CN106632288B - En Gelie net preparation method - Google Patents
En Gelie net preparation method Download PDFInfo
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- CN106632288B CN106632288B CN201610975986.3A CN201610975986A CN106632288B CN 106632288 B CN106632288 B CN 106632288B CN 201610975986 A CN201610975986 A CN 201610975986A CN 106632288 B CN106632288 B CN 106632288B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 229940126214 compound 3 Drugs 0.000 claims abstract description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229940125898 compound 5 Drugs 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims description 95
- 238000003756 stirring Methods 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 239000000047 product Substances 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000012074 organic phase Substances 0.000 claims description 28
- 238000012545 processing Methods 0.000 claims description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 229940125782 compound 2 Drugs 0.000 claims description 21
- 239000012071 phase Substances 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000012298 atmosphere Substances 0.000 claims description 17
- 229940125904 compound 1 Drugs 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 14
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 238000010792 warming Methods 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 claims description 8
- 229960003019 loprazolam Drugs 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000005352 clarification Methods 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 239000000284 extract Substances 0.000 claims description 5
- 238000005292 vacuum distillation Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 230000000630 rising effect Effects 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 abstract description 4
- -1 bromo- 2- chlorobenzyl Chemical group 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 56
- 239000012535 impurity Substances 0.000 description 14
- 238000010791 quenching Methods 0.000 description 13
- 230000000171 quenching effect Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 238000001514 detection method Methods 0.000 description 6
- 238000006266 etherification reaction Methods 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000011056 performance test Methods 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010583 slow cooling Methods 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
- 108091006269 SLC5A2 Proteins 0.000 description 2
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000005360 mashing Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of preparation methods that En Gelie is net, midbody compound 3 is made through coupling using (S) -3- (4- (the bromo- 2- chlorobenzyl of 5-) phenoxy group) tetrahydrofuran and glucolactone as starting material, is etherified obtained midbody compound 4, the obtained net crude Compound 5 of En Gelie of reduction, is refining to obtain the qualified net finished product of En Gelie.
Description
Technical field
The invention belongs to technical field of medicine synthesis more particularly to a kind of preparation methods that En Gelie is net.
Background technique
Diabetes are one group of metabolic diseases characterized by hyperglycemia.Hyperglycemia be then due to defect of insulin secretion or
Its biological effect is impaired, or both have concurrently and cause.Long-standing hyperglycemia when diabetes, cause various tissues, especially eye,
Kidney, heart, blood vessel, the chronic lesion of nerve, dysfunction.
En Gelie is a kind of 2 type sodium glucose of selectivity collaboration of German Boehringer Ingelheim company research and development only
Transport protein (SGLT2) inhibitor obtains FDA approval for treating diabetes B in August, 2014.SGLT2 inhibitor is mainly led to
The SGLT2 for inhibiting to be expressed in kidney is crossed, reabsorption of the kidney to glucose is reduced, increases the excretion of glucose in urine, thus
Plasma glucose levels are reduced, and the hypoglycemic effect is independent of β cell function and insulin resistance.
Currently, the net method of En Gelie is prepared, since synthesis route is relatively complicated, severe reaction conditions are not easy to reach
It arrives, the reasons such as starting material is not easy to obtain, the En Gelie net products yield caused is not high and unstable quality.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods that En Gelie is net, it is intended to solve prior art preparation En Gelie
Net method synthesis route is cumbersome, severe reaction conditions, starting material are not easy to obtain, the En Gelie net products caused
Not the problem of yield is not high and unstable quality.
The invention is realized in this way a kind of preparation method that En Gelie is net, comprising the following steps:
The THF solution of compound 1 is provided, under an inert atmosphere, the THF that n-BuLi is added dropwise in temperature control -90~-85 DEG C is molten
Liquid, 30~60min of stir process；Continue temperature control -90~-85 DEG C, the THF solution of compound 2 is added dropwise, is stirred to react 1~3 hour
After be quenched, compound 3 is prepared, reaction equation is as follows:
The compound 3 is dissolved in methanol and obtains 3 solution of compound, stirring is warming up to 40~43 after Loprazolam is added
DEG C, reaction is quenched after 3-5 hours, compound 4 is prepared, reaction equation is as follows:
The compound 4 is dissolved in methylene chloride and obtains 4 solution of compound, stir process after acetonitrile is added, in inertia
Under atmosphere, triethylsilane is added dropwise in temperature control -20~-10 DEG C, after being stirred to react 30~60min, boron chloride ether is added dropwise, stirs
It is quenched after mixing reaction 2~5 hours, compound 5 is prepared, reaction equation is as follows:
The compound 5, ethyl alcohol are placed in reaction kettle, stirring temperature rising reflux dissolved clarification obtains 5 solution of compound；Described
After 30~60min of active carbon reflux decoloration is added in 5 solution of compound, heat filtering processing is carried out, filtrate is collected；By the filtrate
55~60 DEG C are warming up to, crystal seed is added, is cooled to 45~50 DEG C, after white solid is precipitated, stirring and crystallizing 1~2 hour；It is cooled to
10~15 DEG C, stirring and crystallizing 1~2 hour, filter cake is collected by filtration, it is net (EMPA) to obtain En Gelie after cleaned, drying process.
En Gelie provided by the invention net preparation method, with (S) -3- (4- (the bromo- 2- chlorobenzyl of 5-) phenoxy group) tetrahydro
Furans and glucolactone are that starting material is coupled obtained midbody compound 3, midbody compound 4 is made in etherificate, also
The obtained net crude Compound 5 of En Gelie of original, is refining to obtain the qualified net finished product of En Gelie.En Gelie provided by the invention net system
Preparation Method, not only preparation process is simple, convenient, but also preparation efficiency is high, can get quality stabilization, controllable En Gelie is produced only
Product.Specifically, according to the method for the present invention preparation different batches En Gelie net products in, the chemical combination of compound 4, following structures
Object 6, compound 7, compound 8, compound 9 are not detected, 10 content≤0.058% of isomeric compound of following structures；
And in the En Gelie net products of obtained different batches, maximum unknown list is miscellaneous≤0.040%, total impurities≤
0.066%, residue on ignition≤0.11%, heavy metal satisfaction≤20ppm standard, chloride meet≤0.01% standard, grace
Lattice column net products purity >=99.39%；Molar yield >=84.15%.
Specific embodiment
In order to which technical problems, technical solutions and advantageous effects to be solved by the present invention are more clearly understood, below in conjunction with
Embodiment, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only used to explain
The present invention is not intended to limit the present invention.
The embodiment of the invention provides a kind of preparation methods that En Gelie is net, comprising the following steps:
S01. the THF solution of compound 1 is provided, under an inert atmosphere, the THF of n-BuLi is added dropwise in temperature control -90~-85 DEG C
Solution, 30~60min of stir process；Continue temperature control -90~-85 DEG C, the THF solution of compound 2 is added dropwise, it is small to be stirred to react 1~3
When after be quenched, compound 3 is prepared, reaction equation is as follows:
S02. the compound 3 is dissolved in methanol and obtains 3 solution of compound, stirring is warming up to 40 after Loprazolam is added
~43 DEG C, reaction is quenched after 3-5 hours, compound 4 is prepared, reaction equation is as follows:
S03. the compound 4 is dissolved in methylene chloride and obtains 4 solution of compound, stir process after acetonitrile is added,
Under inert atmosphere, triethylsilane is added dropwise in temperature control -20~-10 DEG C, and after being stirred to react 30~60min, boron chloride second is added dropwise
Ether is quenched after being stirred to react 2~5 hours, compound 5 is prepared, reaction equation is as follows:
S04. the compound 5, ethyl alcohol are placed in reaction kettle, stirring temperature rising reflux dissolved clarification obtains 5 solution of compound；?
After 30~60min of active carbon reflux decoloration is added in 5 solution of compound, heat filtering processing is carried out, filtrate is collected；It will be described
Filtrate is warming up to 55~60 DEG C, and crystal seed is added, and is cooled to 45~50 DEG C, after white solid is precipitated, stirring and crystallizing 1~2 hour；Drop
Filter cake is collected by filtration to 10~15 DEG C, stirring and crystallizing 1~2 hour in temperature, and it is net to obtain En Gelie after cleaned, drying process
(EMPA)。
In above-mentioned steps S01, the compound 1, the compound 2 and n-BuLi form reactant in organic solvent
System, is prepared compound 3 by coupling reaction.
Wherein, the compound 2 can buy acquisition on the market, can also voluntarily prepare.When voluntarily preparing institute
When stating compound 2, the compound 2 the preparation method is as follows:
Addition glucolactone, N- methyl woods, THF in a kettle, stir process, under an inert atmosphere, temperature control-
5~0 DEG C, trim,ethylchlorosilane is added dropwise, is warming up to 20~25 DEG C, is stirred to react 15-20 hours, compound 2 is prepared.This hair
Bright embodiment, by the effect of alkaline matter N- methyl woods, using the trim,ethylchlorosilane as protection reagent, described
Trimethyl silyl protecting group is introduced on the hydroxyl of glucolactone.
Specifically, above-mentioned preparation reaction carries out in an inert atmosphere, the oxidation of product is avoided.The inert atmosphere include but
It is not limited to nitrogen atmosphere.Since heat release is more acute when the trim,ethylchlorosilane and N- methyl woods reaction generate complex compound
It is strong, therefore, the trim,ethylchlorosilane is added dropwise, needs temperature control -5~0 DEG C, it is excessively violent to avoid reacting.Further, it is being added dropwise
After the trim,ethylchlorosilane, 20~25 DEG C are warming up to, is stirred to react 15-20 hours, concretely 15 hours, 16 hours, 17
Hour, 18 hours, 19 hours, 20 hours to promote reacting for complex compound and the glucolactone compound is prepared
2。
Preferably, after completion of the reaction, quencher quenching reaction can be added.Polarity of the embodiment of the present invention due to compound 2
It is smaller, normal heptane is preferably added in the reaction system, is cooled to -5 DEG C.Temperature control -5~5 DEG C are slowly added dropwise purified water and are quenched, can
It is excessively violent to avoid exothermic reaction.5~10 DEG C of stir process of Bi Shengzhi are added dropwise, quenching reaction occurs, the time is 20-40 points
Clock, concretely 30 minutes.
It is further preferred that 10 DEG C of temperature control hereinafter, reaction system is layered, use again by collection organic phase, water phase after quenching reaction
Normal heptane extracts primary, merging organic phase.10 DEG C of temperature control of the embodiment of the present invention hereinafter, reaction system layered effect is be more good,
And it is conducive to the extraction of the reactant 2, improve yield.After collecting organic phase, successively with saturation biphosphate sodium water solution, purifying
Water, saturated sodium chloride solution respectively washed once, the preferred washing system, can integrate and reduce possible introducing in reaction system
Various impurity.Continue 10 DEG C of temperature control or less (being conducive to extraction, improve yield), is collected after layering and merge organic phase, use anhydrous slufuric acid
Sodium is dry.Organic phase after drying is filtered processing, solid material is collected normal heptane phase after being eluted with normal heptane, has been incorporated into
In machine phase.40 DEG C of temperature control is steamed primary with normal heptane band, obtains the compound 2 of high-purity hereinafter, organic filtrate is decompressed to dry.
Coupling reaction between compound 1, the compound 2 described in the embodiment of the present invention carries out under an inert atmosphere, can
It is aoxidized to avoid reactant, and then improves the purity and yield of product.The inert atmosphere includes but is not limited to nitrogen gas
Atmosphere.Specifically, being filled with inert atmosphere protection after the compound 1 is added in reaction kettle, other raw materials are sequentially added.
In the embodiment of the present invention, first the solution of the compound 1 is added in reaction kettle, n-BuLi is then added dropwise
The solution of the compound 2 is added dropwise after processing is sufficiently stirred in solution.Specifically, the solution of the compound 1, the positive fourth
The solution of the solution of base lithium, the compound 2, it is preferred to use same organic solvent dissolves to be formed respectively.Specifically, using
THF can obtain preferable solute effect as solubilising reagent, each substance.The embodiment of the present invention respectively by the compound 1,
Compound 2, n-BuLi are dissolved in TFA, obtain the THF solution of corresponding compound 1, THF solution, the normal-butyl of compound 2
The THF solution of lithium.Preferably, in the step of preparing compound 3, the compound 1, compound 2 mass ratio be (3.0
~3.5): (5.5~6.0) are particularly preferred as the compound 1, the mass ratio of compound 2 is 3.2:5.9.Pass through above-mentioned quality
The regulation of ratio can improve the yield and purity of compound 3, in addition, may be used also under the premise of guaranteeing reaction efficiency as far as possible
To avoid the waste of material.
Since the n-BuLi chemical reactivity is very high, in order to avoid excessively acute reaction, rate of addition is unsuitable too fast, answers
It is slowly added dropwise as far as possible.When the THF solution of the n-BuLi is added dropwise, temperature fluctuation be should not be too large, and need temperature control -90~-85 DEG C, and one
Aspect can be to avoid reacting excessively violent, on the other hand, it is often more important that, this temperature can be excellent with formation condition, non-caking
Reaction system, so that reaction is sufficiently, completely, and then product that is with high purity, generating substantially without miscellaneous point.When temperature is reaction temperature
When degree is -80~-70 DEG C, though can fully reacting, to more, product purity and income are low for the impurity phase of reaction system；When
When reaction temperature is lower than the temperature range, reaction solution solidification agglomeration causes reaction incomplete.After being added dropwise, stir process 30
~60min reacts the compound 1 sufficiently with the n-BuLi, specifically, mixing time can for 30min, 45min,
60min.Based on same reason, when the THF solution of the compound 2 is slowly added dropwise, temperature control -90~-85 DEG C avoid reacting
In violent.Further, compound 3 is generated in order to which reactant substantially efficiently reacts, is stirred to react 1~3 hour, concretely
1 hour, 2 hours, 3 hours etc..During being stirred to react, reaction monitoring detection reaction end can be carried out.Specifically, after sampling,
The point sample on TCL is then considered as and has been reacted when raw material point disappears on TCL as mobile phase for the EA:PE of 5:1 using volume ratio
Entirely.
After the completion of reaction, quencher quenching reaction is added in the reaction system.Preferably, described that being quenched for use is quenched
Agent is the aqueous ammonium chloride solution that mass percentage concentration is 20~28%, is particularly preferred as the ammonium chloride that mass percentage concentration is 25%
Aqueous solution.Specifically, 10 DEG C of temperature control is warmed to room temperature (15-30 DEG C) stirring 10-20min hereinafter, finish when addition quencher, tool
Body can be 10min, 15min, 20min.Processing is quenched solutions of weak acidity in the embodiment of the present invention, reduces the absorption of solid, together
When two-phase is clear when making to extract liquid separation, since the acidity of the ammonium chloride is suitable, will not have to other sensitive groups too strong
Effect, relatively safety.
In the embodiment of the present invention, it is preferred that further include successively being layered, being extracted to obtained product, washed after being quenched
And concentration, method particularly includes:
After product system layering, collected organic layer after water phase is mentioned with ethyl acetate, is collected ethyl acetate phase, is associated with
It after machine phase, is washed with saturated sodium chloride solution, the organic phase after washing is carried out to be dried under reduced pressure processing, it is described to be dried under reduced pressure
40 DEG C of the temperature < of processing.
The preferred post-processing approach not only can be by describedization in reaction system using ethyl acetate as extractant
It closes object 3 sufficiently to extract, and the other impurities generated in the coupling reaction process can be avoided during processing
It introduces；Using saturated sodium chloride solution as cleaning solution, the impurity introduced in the step reaction system can be effectively removed, into one
Walk the purity of the compound 3；Preferred drying mode and drying temperature, not only can to avoid the compound 3 loss (such as
Pyrolytic), and it is avoided that the introducing of other impurities, and then improve the yield and purity of the compound 3.
In above-mentioned steps S02, the compound 3 forms reaction system with the Loprazolam in organic solvent, through ether
Change reaction and compound 4 is prepared.Preferably, the mass ratio of the compound 3 and the Loprazolam is (6.0~7.0):
(0.1~0.2), the mass ratio for being particularly preferred as the compound 3 and the Loprazolam is 6.57:0.167.Pass through above-mentioned matter
Measure ratio regulation, can the fully reacting within the relatively short time, and substantially free of impurities generate, so as to guarantee reaction effect
Under the premise of rate, the yield and purity of compound 4 are improved as far as possible.
The embodiment of the present invention is using methanol as reaction dissolvent, and not only effect is good, and subsequent easily removes in the product.This hair
In bright embodiment, 40~43 DEG C of temperature of the etherificate countercharge.Reaction temperature is affected to the etherification reaction, specifically, its
In the case where its parameter constant, if the temperature of the etherification reaction is excessively high, reaction speed is fast, but is easy to produce more impurity；
If the temperature of the etherification reaction is too low, reaction speed is slow, and reaction is not easy sufficiently.
Preferably, after completion of the reaction, quencher quenching reaction can be added.With preferred, matter is added in the reaction system
The sodium bicarbonate solution that percentage concentration is 8-12% is measured, is particularly preferred as that mass percentage concentration is added in the reaction system to be 10%
Sodium bicarbonate solution.Specifically, being cooled to 5 DEG C after etherification reaction, sodium bicarbonate solution is added dropwise, avoids reaction excessively
Acutely.After dripping, 20~25 DEG C of temperature control, it is stirred to react 10-20min, concretely 10min, 15min, 20min, quenched
It goes out reaction.The embodiment of the present invention using the sodium bicarbonate solution of 8-12% as quencher, not only can be in effective neutralization reaction
The acid or alkali of generation；And be conducive to improve aqueous ion intensity, separation condition has been created for extraction in next step.
It further include successively being layered, being extracted to obtained product, washed and dense it is further preferred that after quenching reaction
Contracting processing, method particularly includes:
Vacuum distillation removes the methanol in reaction system, and ethyl acetate is added in residue and purified water extracts, receives
Collect organic phase, water phase collects organic phase after being extracted with ethyl acetate again, merge organic phase, after being washed with saturated sodium chloride solution again
Secondary collection organic phase, is dried with anhydrous sodium sulfate.Organic phase after drying is filtered processing, solid material acetic acid second
Ethyl acetate phase is collected after ester elution, is incorporated into organic phase.40 DEG C of temperature control obtains light hereinafter, organic filtrate is decompressed to dry
The compound 4 of yellow.
The preferred post-processing approach not only can will be in reaction system using ethyl acetate as extractant and solvent
The compound 4 sufficiently extracts, and can avoid generating during the etherification reaction during processing other
The introducing of impurity；Using saturated sodium chloride solution as cleaning solution, can effectively remove introduced in the step reaction system it is miscellaneous
Matter, the purity of compound 4 described further；Preferred drying mode and drying temperature, not only can be to avoid the compound 4
It is lost (such as pyrolytic), and is avoided that the introducing of other impurities, and then improve the yield and purity of the compound 4.
In above-mentioned steps S03, compound 5 is prepared through reduction reaction in the compound 4.Described in the embodiment of the present invention also
Original reaction carries out under an inert atmosphere, can introduce side reaction to avoid occurring to aoxidize, and then improve the purity and yield of product.Institute
Stating inert atmosphere includes but is not limited to nitrogen atmosphere.Specifically, being filled after the solution of the compound 4 is added in reaction kettle
Enter inert atmosphere protection, adds other raw materials.
Specifically, by the compound 4 be dissolved in organic solvent in obtain 4 solution of compound, wherein it is described for dissolving
There are many organic solvents of compound 4, including but not limited to acetone, methylene chloride, ethyl acetate, isopropyl acetate.The present invention
Embodiment selects methylene chloride as organic solvent, can effectively dissolve the compound 4 and excellent impurity-eliminating effect.
Further, it is stirred to react after acetonitrile being added, under an inert atmosphere, temperature control -20~-10 DEG C obtain reaction efficiency height, reaction is filled
Point and the few product system of impurity.Further, triethylsilane is added dropwise as reaction reducing agent, is stirred to react 30~60min
Afterwards, boron chloride ether is added dropwise to be stirred to react 2~5 hours, prepare compound 5.
Preferably, the compound 4, triethylsilane, boron chloride ether mass ratio be (4.0-4.5): (2.3-
2.8): (2.4-2.8), so that the compound 4, triethyl group silicon can be particularly preferred as with the reaction system of fully reacting by being formed
Alkane, boron chloride ether mass ratio be 4.18:2.53:2.63.
Preferably, after completion of the reaction, quencher quenching reaction can be added.With preferred, matter is added in the reaction system
The sodium bicarbonate solution that percentage concentration is 8-12% is measured, is particularly preferred as that mass percentage concentration is added in the reaction system to be 10%
Sodium bicarbonate solution.Specifically, being cooled to 0 DEG C after reduction reaction, sodium bicarbonate solution is added dropwise, avoids reaction excessively
Acutely.After dripping, room temperature (15-30 DEG C) is stirred to react 10-20min, and concretely 10min, 15min, 20min, quench
It goes out reaction.The embodiment of the present invention using the sodium bicarbonate solution of 8-12% as quencher, not only can be in effective neutralization reaction
The acid or alkali of generation；And be conducive to improve aqueous ion intensity, separation condition has been created for extraction in next step.
It further include successively being layered, being extracted to obtained product, washed and dense it is further preferred that after quenching reaction
Contracting processing, method particularly includes:
Vacuum distillation removes methylene chloride and acetonitrile, up to the outflow of no fraction, collects a large amount of off-white powders (product), adds
Enter isopropyl acetate and water, is cooled to 15~20 DEG C, stirring and crystallizing 12 hours or more.Then it is filtered, is eluted with purified water,
It is filtered dry collection filter cake.It is dried in vacuo at 55~60 DEG C, obtains 5 crude product of compound.
Further, methylene chloride is added in 5 crude product of compound, flow back mashing 20-40 minutes, concretely
30 minutes；It is cooled to 10~15 DEG C, stirring and crystallizing 2-4 hours, concretely 3 hours.Then it is filtered processing, filter cake is with two
Chloromethanes elution, is filtered dry, is dried in vacuo 8-10 hours at 55~60 DEG C, and concretely 9 hours to get high-purity compound 5.Hair
The sample that the reduction reaction obtains is sampled detection, HPLC >=97.0% by bright embodiment.
The preferred post-processing approach (including Extraction solvent, crystallization system include temperature and processing mode, drying mode and
The comprehensive selection of drying temperature), not only the compound 5 in reduction reaction system can sufficiently be extracted, Er Qieke
To avoid the introducing of loss (such as pyrolytic) and impurity of the compound 5 during processing, and then improve finished product
Yield and purity.The sample that the reduction reaction obtains is sampled detection by the embodiment of the present invention, and the yield of compound 5 is
55-65%.
In above-mentioned steps S04, the obtained compound 5 is subjected to refinement treatment, it is net (EMPA) to obtain En Gelie.Purification
Processing is one of committed step of the embodiment of the present invention.Specifically, first the compound 5 is dissolved in ethyl alcohol, stirring is warming up to
75-85 DEG C, more preferably 80 DEG C, reflux dissolved clarification (i.e. reflux dissolution) obtain 5 solution of compound.
Active carbon is added in 5 solution of compound, the sample after decolorization is subjected to heat filtering processing, collects high
The filtrate of purity removes foreign pigment.
The filtrate is warming up to 55~60 DEG C, crystal seed is added, is cooled to 45~50 DEG C, after white solid is precipitated, stirring
Crystallization 1~2 hour；Slow cooling is to 10~15 DEG C, stirring and crystallizing 1~2 hour.Temperature hierarchy of the embodiment of the present invention is to crystallization
Purity and efficiency are affected, and the embodiment of the present invention first controls temperature at 55~60 DEG C, and En Gelie net energy is enough dissolved completely in
In ethyl alcohol；Further crystallization yield can be made to reach 80%, purity is greater than between 45~50 DEG C crystallization temperature control
99.5%；Again by slow cooling, with further crystallization yield.
Sample yield after purification of the embodiment of the present invention is 80-90%.By the decoloration of step S04, hot filter, crystallization, mistake
Filter processing, can effectively remove the various impurity for generating in above-mentioned steps S01-03 or introducing step by step, and obtain high-purity qualification
Net (EMPA) product of En Gelie.
En Gelie provided in an embodiment of the present invention net preparation method, not only preparation process is simple, convenient, but also prepares effect
Rate is high, can get quality stabilization, controllable En Gelie net products.Specifically, the difference prepared according to present invention method
In the En Gelie net products of batch, compound 4, the compound 6 of following structures, compound 7, compound 8, compound 9 are not examined
Out, 10 content≤0.058% of isomeric compound of following structures；
And maximum unknown list it is miscellaneous≤0.040%, total impurities≤0.066%, residue on ignition≤0.11%, heavy metal meets≤
The standard of 20ppm, chloride meet≤0.01% standard, En Gelie net products purity >=99.39%；Molar yield >=
84.15%.
It is worth noting that, the available high yield of preparation method of En Gelie described in the embodiment of the present invention net (EMPA) and
Net (EMPA) product of the En Gelie of high-purity, not a step both can achieve the effect that, but each step forms an entirety
Comprehensive realization.
It is illustrated combined with specific embodiments below.
The preparation of 1 compound 2 of embodiment
Compound 1 (2.25kg) is added into 100L reaction kettle, N-methylmorpholine (8.17kg), THF (15.0kg), stirring
And nitrogen charging gas shielded, it is cooled to -5 DEG C.TMSCl (7.00kg) is slowly added dropwise in temperature control -5~0 DEG C, and system generates during dropwise addition
A large amount of smog.It is added dropwise and finishes, rise to 20~25 DEG C and stir 16 hours.
Normal heptane (30kg) is added in the reaction system, is cooled to -5 DEG C.Purified water is slowly added dropwise in temperature control -5~5 DEG C
(34kg) is quenched.5~10 DEG C of Bi Shengzhi stirrings, 30 minutes (quenching reaction) is added dropwise.
For 10 DEG C of reaction system temperature control after being quenched hereinafter, layering, it is primary that water phase uses normal heptane (16.5kg) to extract again；Control
10 DEG C of temperature is hereinafter, layering, and organic phase is successively with saturation biphosphate sodium water solution (23kg), purified water (23kg), saturation chlorination
Sodium solution (23kg) respectively washed once；It is small with anhydrous sodium sulfate (3.0kg) dry 1 to merge organic phase hereinafter, layering for 10 DEG C of temperature control
When.
By the organic phase filtering after drying, solid material is eluted with normal heptane (1.5kg)；40 DEG C of temperature control hereinafter, filtrate is subtracted
It is depressed into dry, is steamed with normal heptane (5kg) band primary, obtain 2 grease of compound about 5.9kg.The compound 2 can be used THF
(12.68kg) dissolution, it is spare.
The preparation of 2 compound 3 of embodiment
Load weighted compound 1 (3.2kg) is added into 100L reaction kettle, THF (30kg) stirs simultaneously nitrogen charging gas shielded.
- 85 DEG C of cooling or less.- 90 DEG C~-85 DEG C of temperature control, the THF solution (4.18L) of n-BuLi is slowly added dropwise.It is added dropwise and finishes, temperature control-
It 90 DEG C~-85 DEG C, stirs 30 minutes.- 90 DEG C~-85 DEG C of temperature control, the THF (12.68kg) of compound 1 (5.9kg) is slowly added dropwise
Solution.It is added dropwise and finishes, -90 DEG C~-85 DEG C of temperature control, stir 1 hour.
10 DEG C of temperature control is quenched hereinafter, 25% aqueous ammonium chloride solution (12kg) is added in the reaction system.It finishes, is warmed to room temperature
Stir 10 minutes (quenching reaction).
After reaction system layering after being quenched, it is primary that water phase uses ethyl acetate (15kg) to extract again.It is full to merge organic phase
It washed once with sodium chloride solution (10kg)；40 DEG C of temperature control is hereinafter, organic phase is decompressed to dry.Obtain oily compounds 3 about
6.57Kg.The compound 3, the raw material for standby as following etherification reactions can be dissolved with methanol (25.34kg).
The preparation of 3 compound 4 of embodiment
Addition compound 3 (6.57kg) and methanol (25.34kg) into 100L reaction kettle, Loprazolam (0.167kg), and
Stirring heating.It 40~43 DEG C of temperature control, reacts 3 hours.Sampling, TLC detection, raw material point disappearance be considered as fully reacting (methylene chloride:
MeOH=20:1).
Reaction is finished, and is cooled to 5 DEG C, and 10% sodium bicarbonate solution (10kg) quenching reaction is added dropwise.It is added dropwise and finishes, temperature control 20~25
DEG C, stir 10 minutes (quenching reaction).
Reaction system vacuum distillation after being quenched removes methanol, and ethyl acetate (30kg) and purified water is added in residue
(13kg) is extracted, and water phase uses ethyl acetate (10kg) to extract again.Merge organic phase washed once with saturated salt solution (10kg)；Have
Machine phase anhydrous sodium sulfate is 1 hour dry.
Organic phase is filtered, is eluted, is filtered dry with a small amount of ethyl acetate (2kg)；Merging filtrate is concentrated under reduced pressure at 40 DEG C
It is extremely dry.Obtain faint yellow 4 grease of compound about 4.18kg.
The preparation of 4 compound 5 of embodiment
Compound 4 (4.18kg) is dissolved with methylene chloride (22.2kg), to being added in 100L reaction kettle, acetonitrile is added
(26.3kg) stirs simultaneously nitrogen charging gas shielded.- 20 DEG C of cooling or less.- 20 DEG C~-10 DEG C of temperature control, triethylsilane is added dropwise
(2.53kg).It is added dropwise and finishes, -20 DEG C~-10 DEG C of temperature control, stir 30 minutes.- 20 DEG C~-10 DEG C of temperature control, boron trifluoride is slowly added dropwise
Ether (2.63kg).It is added dropwise and finishes, -20 DEG C~-10 DEG C of temperature control, stir 2 hours.Sampling, HPLC detection.When compound 4≤1.0%
When, that is, it is considered as fully reacting.
Reaction is finished, and 0 DEG C of temperature control is hereinafter, be added dropwise 10% sodium bicarbonate solution (20kg).It finishes, is warmed to room temperature 15 points of stirring
Clock.Vacuum distillation removes methylene chloride and acetonitrile.No fraction outflow, stops distillation, a large amount of off-white powders (product) is precipitated, adds
Enter isopropyl acetate (18.2kg) and water (18.2kg) (crystallization).It is cooled to 15~20 DEG C, stirring and crystallizing 12 hours or more.
Reaction system filtering after being quenched, is eluted with purified water (20kg), is filtered dry.Filter cake is collected, at 55~60 DEG C
Vacuum drying 8 hours to get 5 crude product of compound about 3.28Kg.5 crude product of above compound is added in 100L reaction kettle, then plus
Enter methylene chloride (62.2kg) reflux mashing 30 minutes.It is cooled to 10~15 DEG C, stirring and crystallizing 2 hours.Filtering, uses methylene chloride
(5kg) elution, is filtered dry.
8 hours are dried in vacuo at 55~60 DEG C to get the about 2.36kg of compound 5, sample detection, HPLC >=97.0%.
The product yield of the embodiment is 55~65%.
The preparation of 5 compound 6 of embodiment
First by compound 5 (2.36kg), ethyl alcohol (18.62kg) investment 50L reaction kettle, temperature rising reflux dissolved clarification is stirred.It is molten
It after clear, is added active carbon (0.24kg), reflux decoloration 30 minutes.Heat filtering, a small amount of ethanol rinse collect filtrate.Filtrate is turned
It in the 50L reaction kettle for entering another cleaning, heats up 55-60 DEG C, a small amount of crystal seed is added, cool down 45-50 DEG C.A large amount of white solids are precipitated
Afterwards, stirring and crystallizing 1 hour.10-15 DEG C of slow cooling, stirring and crystallizing 1 hour.
Filtering, filter cake are eluted with the ethyl alcohol (5kg) cooled down.It is filtered dry, obtains white solid.Filter cake is in 55~60 DEG C, vacuum
It is 8 hours dry.Obtain finished product EMPA about 2kg.The full review of sampling.
The product yield of the embodiment is 80~90%.
Embodiment 6
En Gelie net preparation method is prepared according to the method for embodiment 1-5, the net lot number difference of obtained En Gelie
For EMPA-2014001F, the performance test results of En Gelie net products are as shown in the following table 1 embodiment 6.
Embodiment 7
En Gelie net preparation method is prepared according to the method for embodiment 1-5, the net lot number difference of obtained En Gelie
For EMPA-2014002F, the performance test results of En Gelie net products are as shown in the following table 1 embodiment 7.
Embodiment 8
En Gelie net preparation method is prepared according to the method for embodiment 1-5, the net lot number difference of obtained En Gelie
For EMPA-2014003F, the performance test results of En Gelie net products are as shown in the following table 1 embodiment 8.
Table 1
Seen from table 1, En Gelie of the embodiment of the present invention net preparation method has good reproducibility and controllability, exploitation
Technique be able to satisfy commercialization mass production demand.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (4)
1. a kind of preparation method that En Gelie is net, comprising the following steps:
The THF solution of compound 1 is provided, under an inert atmosphere, the THF solution of n-BuLi is added dropwise in temperature control -90~-85 DEG C, stirs
Mix 30~60min of processing；Continue temperature control -90~-85 DEG C, the THF solution of compound 2 is added dropwise, quenches after being stirred to react 1~3 hour
It goes out, obtained product is successively layered after being quenched, is extracted, is washed and concentration, compound 3 is prepared, wherein institute
State the aqueous ammonium chloride solution that the quencher for being quenched and using is 20~28% for mass percentage concentration；Obtained product is successively carried out
Layering, extraction, washing and concentration method particularly includes: after product system layering, collected organic layer, water phase acetic acid second
After ester extracts, ethyl acetate phase is collected, after merging organic phase, is washed with saturated sodium chloride solution, it will be described organic after washing
It mutually carries out being dried under reduced pressure processing, 40 DEG C of the temperature < for being dried under reduced pressure processing；Prepare the following institute of reaction equation of the compound 3
Show:
The compound 3 is dissolved in methanol and obtains 3 solution of compound, stirring is warming up to 40~43 DEG C after Loprazolam is added,
Reaction is quenched after 3-5 hours, is successively layered, is extracted to obtained product after being quenched, washed and concentration, is prepared
Compound 4, wherein described that the sodium bicarbonate solution that the quencher used is 8-12% for mass percentage concentration is quenched；After being quenched
It obtained product is successively layered, is extracted, is washed and concentration method particularly includes: vacuum distillation removes reaction system
In methanol, ethyl acetate is added in residue and purified water extracts, collects organic phase, water phase is extracted with ethyl acetate again
After collect organic phase, merge organic phase, collect organic phase after being washed with saturated sodium chloride solution again, it is dry with anhydrous sodium sulfate
Processing；The reaction equation for preparing the compound 4 is as follows:
The compound 4 is dissolved in methylene chloride and obtains 4 solution of compound, stir process after acetonitrile is added, in inert atmosphere
Under, triethylsilane is added dropwise in temperature control -20~-10 DEG C, after being stirred to react 30~60min, boron chloride ether is added dropwise, stirring is anti-
It is quenched after answering 2~5 hours, obtained product is successively layered after being quenched, is extracted, is washed and concentration, be prepared
Compound 5, wherein described that the sodium bicarbonate solution that the quencher used is 8-12% for mass percentage concentration is quenched；After being quenched
Obtained product is successively layered, is extracted, is washed and concentration method particularly includes: 10 DEG C of temperature control hereinafter, to product
After system layering, organic phase is collected, water phase collects organic phase after being extracted with normal heptane, after merging organic phase, use saturated sodium-chloride
Organic phase is collected again after solution washing, carries out being dried under reduced pressure processing, 40 DEG C of the temperature < for being dried under reduced pressure processing；Preparation institute
The reaction equation for stating compound 5 is as follows:
The compound 5, ethyl alcohol are placed in reaction kettle, stirring temperature rising reflux dissolved clarification obtains 5 solution of compound；In the chemical combination
After 30~60min of active carbon reflux decoloration is added in 5 solution of object, heat filtering processing is carried out, filtrate is collected；The filtrate is heated up
To 55~60 DEG C, crystal seed is added, is cooled to 45~50 DEG C, after white solid is precipitated, stirring and crystallizing 1~2 hour；It is cooled to 10~
15 DEG C, stirring and crystallizing 1~2 hour, filter cake is collected by filtration, it is net to obtain En Gelie after cleaned, drying process.
2. En Gelie as described in claim 1 net preparation method, which is characterized in that in the step of preparing compound 3,
The compound 1, compound 2 mass ratio be (3.0~3.5): (5.5~6.0).
3. En Gelie as described in claim 1 net preparation method, which is characterized in that in the step of preparing compound 4,
The mass ratio of the compound 3 and the Loprazolam is (6.0~7.0): (0.1~0.2).
4. En Gelie as described in claim 1 net preparation method, which is characterized in that in the step of preparing compound 5,
The compound 4, triethylsilane, boron chloride ether mass ratio be (4.0-4.5): (2.3-2.8): (2.4-2.8).
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| CN109988161A (en) * | 2017-12-29 | 2019-07-09 | 徐州万邦金桥制药有限公司 | A kind of preparation method that suitable industrialized production En Gelie is net |
| CN109456314A (en) * | 2018-10-19 | 2019-03-12 | 威海迪素制药有限公司 | A kind of preparation method that En Gelie is net |
| CN112574186A (en) * | 2020-12-22 | 2021-03-30 | 山东永丞制药有限公司 | Refining method of engagliflozin |
| CN116239582A (en) * | 2021-12-07 | 2023-06-09 | 山东新时代药业有限公司 | Engliflozin intermediate compound and preparation method thereof |
| CN114380775A (en) * | 2021-12-22 | 2022-04-22 | 江苏德源药业股份有限公司 | A kind of empagliflozin intermediate and preparation method thereof |
| WO2023217058A1 (en) * | 2022-05-12 | 2023-11-16 | 浙江华海药业股份有限公司 | Method for preparing glucopyranosyl-containing compound |
| CN116063294A (en) * | 2022-12-13 | 2023-05-05 | 山东能源集团新材料有限公司 | A kind of preparation method and process system of empagliflozin bulk drug |
| CN116462670B (en) * | 2023-04-26 | 2025-08-12 | 福安药业集团重庆博圣制药有限公司 | One-pot method for preparing empagliflozin |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104250272A (en) * | 2013-06-27 | 2014-12-31 | 上海方楠生物科技有限公司 | Method for preparing Invokana medicine intermediate by using micro-reactor |
| CN104710486A (en) * | 2015-04-07 | 2015-06-17 | 安润医药科技（苏州）有限公司 | Method for synthesizing SGLT2 inhibitor drugs |
| CN102549005B (en) * | 2009-09-30 | 2015-08-26 | 贝林格尔.英格海姆国际有限公司 | The preparation method of the crystal formation of the chloro-4-of 1-(β-D-Glucopyranose-1-base)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene |
| CN105481915A (en) * | 2014-09-19 | 2016-04-13 | 北京万生药业有限责任公司 | Preparation method of SGLT-2 inhibitor compound |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102549005B (en) * | 2009-09-30 | 2015-08-26 | 贝林格尔.英格海姆国际有限公司 | The preparation method of the crystal formation of the chloro-4-of 1-(β-D-Glucopyranose-1-base)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene |
| CN104250272A (en) * | 2013-06-27 | 2014-12-31 | 上海方楠生物科技有限公司 | Method for preparing Invokana medicine intermediate by using micro-reactor |
| CN105481915A (en) * | 2014-09-19 | 2016-04-13 | 北京万生药业有限责任公司 | Preparation method of SGLT-2 inhibitor compound |
| CN104710486A (en) * | 2015-04-07 | 2015-06-17 | 安润医药科技（苏州）有限公司 | Method for synthesizing SGLT2 inhibitor drugs |
Non-Patent Citations (1)
| Title |
|---|
| Xiao-jun Wang et al..Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing an AlCl3‑Promoted Silane Reduction of a β‑Glycopyranoside.《Org. Lett.》.2014,第16卷第4090-4093页. |
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