CN117946039A - Chiral synthesis process of englitz intermediate - Google Patents
Chiral synthesis process of englitz intermediate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000008569 process Effects 0.000 title claims abstract description 30
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 26
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 239000000376 reactant Substances 0.000 claims abstract description 9
- -1 alcohol compound Chemical class 0.000 claims abstract description 7
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 7
- 239000003223 protective agent Substances 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 14
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 12
- 239000000411 inducer Substances 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 6
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 6
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 3
- IYBHYVVVEDETKW-UHFFFAOYSA-N NC[SiH2]Cl Chemical compound NC[SiH2]Cl IYBHYVVVEDETKW-UHFFFAOYSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 claims description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims 1
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000002829 reductive effect Effects 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 2
- 239000012069 chiral reagent Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 1
- 125000004185 ester group Chemical group 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000005194 fractionation Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000010586 diagram Methods 0.000 description 3
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229960001713 canagliflozin Drugs 0.000 description 2
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KNYGUQLVFSPVRI-UHFFFAOYSA-N (2-chloro-5-iodophenyl)-(4-fluorophenyl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC(I)=CC=C1Cl KNYGUQLVFSPVRI-UHFFFAOYSA-N 0.000 description 1
- XDPCNPCKDGQBAN-SCSAIBSYSA-N (3r)-oxolan-3-ol Chemical compound O[C@@H]1CCOC1 XDPCNPCKDGQBAN-SCSAIBSYSA-N 0.000 description 1
- YLUHNGIWRCCQMQ-INIZCTEOSA-N (3s)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]oxolane Chemical compound ClC1=CC=C(I)C=C1CC(C=C1)=CC=C1O[C@@H]1COCC1 YLUHNGIWRCCQMQ-INIZCTEOSA-N 0.000 description 1
- GEBYSTBEDVQOTK-UHFFFAOYSA-N 2-chloro-5-iodobenzoic acid Chemical compound OC(=O)C1=CC(I)=CC=C1Cl GEBYSTBEDVQOTK-UHFFFAOYSA-N 0.000 description 1
- CRBYUOHFEZMJTE-UHFFFAOYSA-N 2-chloro-5-iodobenzoyl chloride Chemical compound ClC(=O)C1=CC(I)=CC=C1Cl CRBYUOHFEZMJTE-UHFFFAOYSA-N 0.000 description 1
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 1
- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Canagliflozin Chemical compound CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- 229950002375 englitazone Drugs 0.000 description 1
- 229940110266 farxiga Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940121068 invokana Drugs 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a chiral synthesis process of an englitjing intermediate, which comprises the steps of dissolving a reactant I in an organic solvent, carrying out chiral oxidation to form alcohol, adding a protective agent for protection, further reducing carbonyl in ester groups in the product, and carrying out deprotection to obtain a chiral intermediate compound (S) - (+) -3-hydroxytetrahydrofuran of a target product. The beneficial effects of the invention are as follows: the chiral alcohol compound is obtained through the oxidation reaction of cheaper raw materials under the action of chiral reagents, the chiral product can be obtained with higher yield, the reaction selectivity is good, the yield is high, the loss of raw materials is reduced, the purchasing of expensive chiral compound (S) - (+) -3-hydroxytetrahydrofuran is avoided, the production cost is effectively reduced, meanwhile, the method has the advantages of simple steps, easy operation, easily obtained raw materials, easy treatment of the product and suitability for industrialized large-scale production.
Description
Technical Field
The invention relates to the technical field related to synthesis of medical intermediates, in particular to a chiral synthesis process of an englitazone intermediate.
Background
Engliflozin (Empagliflozin, EBI-10773), CAS No. is: [864070-43-9], chinese cultural name (1S) -1, 5-dehydrated-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol, developed by Boringer 'S Johnson company (Boehringer Ingelheim) and Gift company (Eli LillyCompany), obtained in 2014, month 8, was FDA approved by Canagliflozin (canagliflozin, invokana) of Qiansheng' S pharmaceutical company and by Daglizin (dapagliflozin, farxiga) of 2014, month 1, month 8, and 3 rd was a new drug for treating diabetes with a mechanism of inhibiting the novel action of SGLT 2.
Chemical name of enggliflozin: (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol of formula: C23H27ClO7 with molecular weight 450.91 and chemical structural formula as follows:
。
The synthesis method of (S) -3- [4- (5-iodo-2-chlorobenzyl) phenoxy ] tetrahydrofuran compound is described in documents such as US7579449B2, US7713938B2, US7745414B2, WO2006120208A, US7776830B2, CN102574829A, CN102549005A and the like, wherein 2-chloro-5-iodobenzoic acid is used as a starting material, the starting material reacts with oxalyl chloride under the catalysis of fluorobenzene and DMF to generate 2-chloro-5-iodobenzoyl chloride, then friedel-crafts reaction with fluorobenzene to generate (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone compound 1, then substitution reaction with (S) -3-hydroxytetrahydrofuran is carried out to generate an intermediate compound, and finally carbonyl reduction is carried out.
The method is widely applied to the process for synthesizing the englitine in industry at present, but the reaction steps are more, the Friedel-crafts acylation reaction easily generates fluorine ortho-position impurities, the mixture of fluorine ortho-position substituted intermediate impurities and products is finally obtained, the reaction selectivity is poor, the properties of the impurities and the products are similar, the separation is difficult, and the key intermediate compounds are synthesized by the following steps:
Route one
OrganicLetters ,16(16) ,4090-4093；2014 ,PCTInt .Appl .,2006120208
The literature discloses a synthetic method (such as a route II), although the route is slightly short, the butt joint of phenol and (R) -3-hydroxytetrahydrofuran needs Mitsunobu reaction to generate more urea compounds and phosphorus tribenzoxide, and the post-reaction treatment is troublesome and is unfavorable for process amplification; the method of the subsequent steps in the route is basically consistent with the patent, the selectivity and the yield are lower, the total reaction yield is insufficient, the steps of the route are complicated, and the overall efficiency is lower.
The synthetic process flow of the (3S) -3- [4- [ (2-chloro-5-iodophenyl) methyl ] phenoxy ] tetrahydrofuran is shown as follows:
Route two
The chiral intermediate compound (S) - (+) -3-hydroxytetrahydrofuran is adopted as the introduction mode of chiral structure in the above routes, and expensive chiral materials are often needed when the chiral intermediate (S) - (+) -3-hydroxytetrahydrofuran is synthesized at present, so that the price is high, the cost of the production route is high, and the large-scale industrial production is not facilitated.
Disclosure of Invention
Aiming at the defects that the raw material price of the chiral compound (S) - (+) -3-hydroxytetrahydrofuran in the route is high and the preparation cost is high, so that the cost of the whole route is improved, the invention aims to provide a chiral synthesis process of the enggliflozin intermediate, which can obtain the (S) - (+) -3-hydroxytetrahydrofuran of the chiral intermediate compound with high yield and low cost, and effectively reduce the production cost of the whole route, and the route is shown as follows:
The technical scheme of the invention is as follows:
a chiral synthesis process of an Engliflozin intermediate comprises the following steps,
Firstly, dissolving a reactant I in an organic solvent, adding an oxidant, adding a catalyst, adding an alkali reagent and a chiral inducer, stirring and mixing, reacting for 6-8 hours at room temperature, and separating a product after the reaction is finished to obtain a compound II;
Secondly, under the protection of nitrogen, dissolving a reactant compound II in an organic solvent, adding a protective agent, adding an alkali reagent, stirring at room temperature for reaction for 6-8 hours, and separating a product after the reaction is finished to obtain a compound III;
Thirdly, dissolving the compound III in an organic solvent, adding a reducing agent into the solution, heating for reaction, and separating a product after the reaction is finished to obtain a compound IV;
And fourthly, dissolving the compound IV in an organic solvent, adding a deprotection reagent, and separating a product after the deprotection of the protecting group to obtain a final chiral intermediate compound V.
Further, the solvents used in the above reaction are tetrahydrofuran THF.
Furthermore, the oxidant used in the first step is carbamic acid MCPBA, and the dosage of the oxidant is 1.0-1.1 eq of the compound I.
Furthermore, the alkali reagent used in the first step is NaHMDS, and the dosage of the alkali reagent used in the first step is 2-3 eq of the compound I.
Furthermore, the chiral inducer of the first reaction is camphorsulfonic acid, and the chiral inducer is used in an amount of 0.8-1 mol% of the reactant I.
Further, the alkali reagent used in the second step is triethylamine, and the dosage of the alkali reagent in the second step is 1.0eq of the compound II
Furthermore, the protective agent used in the second reaction step is trimethylchlorosilane, and the molar ratio of the aminomethylchlorosilane to the compound II is 1:1.
Further, the reducing agent used in the third step is lithium aluminum hydride, and the reducing amount and the reactant compound III are 1:1.
Further, the reducing agent in the third step is used in an amount such that the molar ratio of the compound IV is 1.0eq.
Further, the deprotection agent used in the fourth reaction step is 1mol/L methanol solution of sodium hydroxide.
The beneficial effects of the invention are as follows: 1. the chiral alcohol compound is obtained through the oxidation reaction of cheaper raw materials under the action of chiral reagents, the chiral product can be obtained with higher yield, the reaction selectivity is good, the yield is high, and the loss of raw materials is reduced; 2. the invention provides a chiral carbon construction method of chiral compound (S) - (+) -3-hydroxytetrahydrofuran, which effectively reduces the production cost required by purchasing; 3. the method has the advantages of simple steps, easy operation, easily obtained raw materials, easily processed products and suitability for industrialized large-scale production.
Drawings
FIG. 1 is a schematic diagram of a route process according to the present invention;
FIG. 2 is a schematic diagram of a route process according to the present invention;
FIG. 3 is a schematic illustration of a reaction scheme of the present invention;
FIG. 4 is a schematic diagram of the chemical structure of Englibenclamide according to the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The first step of reaction, 12.8g (0.1 mol) of compound I is dissolved in 250ml of organic solvent tetrahydrofuran, 0.2mol of alkaline reagent NaHMDS is added, 0.1mol of oxidant peroxybenzoic acid MCPBA is added, 0.001mol of chiral inducer camphorsulfonic acid is added, stirring reaction is carried out at room temperature for 6-8 hours, TLC tracking shows that the reaction is finished, the solvent is recovered by vacuum fractionation, 100ml of dichloromethane is added after the fractionation is finished, the pH value is regulated to about 7.0 by dilute acid water, stirring is carried out until the solvent is fully dissolved, layering is carried out, the aqueous layer is extracted by dichloromethane, the organic layer is combined, the organic layer is washed by saturated saline water, the organic layer is decompressed and desolventized until the solvent is dried, 40ml of toluene is added for recrystallization, 9.3g of compound II is obtained, the yield is 91.1%, and the purity is 96.5%;
In the second step, 10.2g (0.1 mol) of compound II tetrahydrofuran is added with 0.1mol of trimethylchlorosilane as a protective agent, 0.1mol of triethylamine as an alkaline reagent is added for reaction for 6 to 8 hours at room temperature, the solvent is evaporated, 100ml of water and 100ml of dichloromethane dissolution product are slowly added, diluted hydrochloric acid is added for neutralization, the organic phase is separated, the organic phase is washed for 2 to 3 times by saturated saline, the organic phase is separated, the solvent is evaporated, the product is recrystallized by 30ml of toluene to 16.8g of compound III, the yield is 96.5%, and the purity is 96.8%.
And thirdly, under the protection of nitrogen, 17.4g (0.1 mol) of the compound III obtained in the second step after drying is dissolved in 250ml of dry organic solvent tetrahydrofuran, 0.10mol of reducing agent lithium aluminum hydride is added, heating reaction is carried out for 4-5 h at 30-40 ℃, after HPLC detection is finished, water is added at 0 ℃ to quench and remove redundant lithium aluminum hydride, stirring filtration is carried out, tetrahydrofuran is washed for 2-3 times, decompression desolventizing is carried out, 100ml of dichloromethane and 100ml of water are used for dissolving the product, an organic phase is washed for 2-3 times with saturated saline solution, the solvent is evaporated, and the product is recrystallized by 50ml of toluene to obtain 15.3g of compound IV, and the yield is 15.3% and the purity is 96.9%.
Fourth, adding 16.0g (0.1 mol) of the compound IV obtained in the third step into 100ml of tetrahydrofuran, adding 100ml of a methanol solution (1 mol/L) of sodium hydroxide, stirring and mixing, dropwise adding diluted hydrochloric acid to neutralize until neutrality after the reaction is detected by HPLC, spin-drying, adding 50ml of dichloromethane and 50ml of water for dissolving, extracting the product with dichloromethane for 2-3 times, washing with saturated saline for 2-3 times, separating an organic phase, and distilling under reduced pressure to obtain 8.5g of compound V, wherein the yield is 96.6% and the purity is 97.3%.
The first step of reaction, 12.8g (0.1 mol) of compound I is dissolved in 250ml of organic solvent tetrahydrofuran, 0.3mol of alkaline reagent NaHMDS is added, 0.1mol of oxidant peroxybenzoic acid MCPBA is added, 0.001mol of chiral inducer camphorsulfonic acid is added, stirring reaction is carried out at room temperature for 6-8 hours, TLC tracking shows that the reaction is finished, the solvent is recovered by vacuum fractionation, 100ml of dichloromethane is added after the fractionation is finished, the pH value is regulated to about 7.0 by dilute acid water, stirring is carried out until the solvent is fully dissolved, layering is carried out, the aqueous layer is extracted by dichloromethane, the organic layer is combined, the organic layer is washed by saturated saline water, the organic layer is decompressed and desolventized until the solvent is dried, 40ml of toluene is added for recrystallization, 9.2g of compound II is obtained, the yield is 90.2%, and the purity is 96.3%;
The first step of reaction, 12.8g (0.1 mol) of compound I is dissolved in 250ml of organic solvent tetrahydrofuran, 0.1mol of alkaline reagent NaHMDS is added, 0.11mol of oxidant peroxybenzoic acid MCPBA is added, 0.001mol of chiral inducer camphorsulfonic acid is added, stirring reaction is carried out at room temperature for 6-8 hours, TLC tracking shows that the reaction is finished, the solvent is recovered by vacuum fractionation, 100ml of dichloromethane is added after the fractionation is finished, the pH value is regulated to about 7.0 by dilute acid water, stirring is carried out until the solvent is fully dissolved, layering is carried out, the aqueous layer is extracted by dichloromethane, the organic layer is combined, the organic layer is washed by saturated saline water, the organic layer is decompressed and desolventized until the solvent is dried, 40ml of toluene is added for recrystallization, 9.0g of compound II is obtained, the yield is 88.2%, and the purity is 96.3%;
the first step of reaction, 12.8g (0.1 mol) of compound I is dissolved in 250ml of organic solvent tetrahydrofuran, 0.2mol of alkaline reagent NaHMDS is added, 0.1mol of oxidant peroxybenzoic acid MCPBA is added, 0.0008mol of chiral inducer camphorsulfonic acid is added, stirring reaction is carried out at room temperature for 6-8 hours, TLC tracking shows that the reaction is finished, the solvent is recovered by vacuum fractionation, 100ml of dichloromethane is added after the fractionation is finished, the pH value is regulated to about 7.0 by dilute acid water, stirring is carried out until the solvent is fully dissolved, layering is carried out, the aqueous layer is extracted by dichloromethane, the organic layer is combined, the organic layer is washed by saturated saline, the organic layer is decompressed and desolventized until the organic layer is dried, 40ml of toluene is added for recrystallization, 9.2g of compound II is obtained, the yield is 88.2%, and the purity is 96.4%;
it will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (10)
1. A chiral synthesis process of an englitjing intermediate is characterized by comprising the following steps of:
firstly, dissolving a reactant I in an organic solvent, adding an oxidant, adding a catalyst, adding an alkali reagent and a chiral inducer, stirring and mixing, reacting for 6-8 hours at room temperature, and separating a product after the reaction is finished to obtain a compound II;
Secondly, under the protection of nitrogen, dissolving a reactant compound II in an organic solvent, adding a protective agent, adding an alkali reagent, stirring at room temperature for reaction for 6-8 hours, and separating a product after the reaction is finished to obtain a compound III;
Thirdly, dissolving the compound III in an organic solvent, adding a reducing agent into the solution, heating for reaction, and separating a product after the reaction is finished to obtain a compound IV;
And fourthly, dissolving the compound IV in an organic solvent, adding a deprotection reagent, and separating a product after the deprotection of the protecting group to obtain a final chiral intermediate compound V.
2. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the solvents used in the above reaction are tetrahydrofuran THF.
3. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the oxidant used in the first step is carbamic acid peroxide MCPBA, and the dosage of the oxidant is 1.0-1.1 eq of the compound I.
4. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the alkali reagent used in the first step is NaHMDS, and the dosage of the alkali reagent used in the first step is 2-3 eq of the compound I.
5. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the chiral inducer of the first reaction is camphorsulfonic acid, and the dosage of the chiral inducer is 0.8-1 mol% of the easy I of the reactant.
6. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the alkali reagent used in the second step of reaction is triethylamine, and the dosage of the alkali reagent in the second step is 1.0eq of the compound II.
7. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the protective agent used in the second step is trimethylchlorosilane, and the molar ratio of the aminomethylchlorosilane to the compound II is 1:1.
8. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the reducing agent used in the third step is lithium aluminum hydride, and the reducing amount and the reactant compound III are 1:1.
9. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the reducing agent in the third step is used in an amount of 1.0eq of the molar ratio of the compound IV.
10. The chiral synthesis process of the englitjing intermediate according to claim 1, wherein the chiral synthesis process is characterized in that: the deprotection agent used in the fourth step is 1mol/L methanol solution of sodium hydroxide.
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