CN113121414A - Synthetic method of trelagliptin intermediate - Google Patents
Synthetic method of trelagliptin intermediate Download PDFInfo
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- CN113121414A CN113121414A CN202010044091.4A CN202010044091A CN113121414A CN 113121414 A CN113121414 A CN 113121414A CN 202010044091 A CN202010044091 A CN 202010044091A CN 113121414 A CN113121414 A CN 113121414A
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- IWYJYHUNXVAVAA-OAHLLOKOSA-N trelagliptin Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 title claims abstract description 15
- 229950010728 trelagliptin Drugs 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract description 13
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012069 chiral reagent Substances 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 26
- 238000010438 heat treatment Methods 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 238000001308 synthesis method Methods 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- ODHCTXKNWHHXJC-GSVOUGTGSA-N 5-oxo-D-proline Chemical compound OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 5
- MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 claims 1
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 10
- GGPNYXIOFZLNKW-ZJIMSODOSA-N (3r)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCCNC1 GGPNYXIOFZLNKW-ZJIMSODOSA-N 0.000 abstract description 9
- 230000003287 optical effect Effects 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 7
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 28
- 238000001914 filtration Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- RYSICGXZRVMXDP-UHFFFAOYSA-N 3-bromopiperidine-2,6-dione Chemical compound BrC1CCC(=O)NC1=O RYSICGXZRVMXDP-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000010948 rhodium Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 2
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000004645 aluminates Chemical class 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-SCSAIBSYSA-N D-Ornithine Chemical class NCCC[C@@H](N)C(O)=O AHLPHDHHMVZTML-SCSAIBSYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 1
- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- JVYIBLHBCPSTKF-UHFFFAOYSA-N n-pyridin-3-ylacetamide Chemical compound CC(=O)NC1=CC=CN=C1 JVYIBLHBCPSTKF-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- SYBXSZMNKDOUCA-UHFFFAOYSA-J rhodium(2+);tetraacetate Chemical compound [Rh+2].[Rh+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O SYBXSZMNKDOUCA-UHFFFAOYSA-J 0.000 description 1
- XQHDACFBTAVCTK-UHFFFAOYSA-K rhodium(3+);2,2,2-trifluoroacetate Chemical compound [Rh+3].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F XQHDACFBTAVCTK-UHFFFAOYSA-K 0.000 description 1
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012609 strong anion exchange resin Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- 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)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of a trelagliptin intermediate (R) -3-aminopiperidine dihydrochloride, which specifically comprises the following steps: 1) reducing carbonyl in an organic solvent A by using a reducing agent to prepare a compound shown in a formula II; 2) resolving the compound of formula II in an organic solvent B by using a chiral reagent to obtain a compound of formula III; 3) the compound of the formula III is subjected to benzyl removal by palladium carbon in an organic solvent C to prepare (R) -3-aminopiperidine dihydrochloride, the yield and the purity of the (R) -3-aminopiperidine dihydrochloride prepared by the method are high, the HPLC purity is higher than 98.16%, and the optical purity is higher than 98.92%; the invention has cheap starting raw materials, is beneficial to reducing the industrial cost, has short synthetic process route and mild reaction conditions, and is easy to realize industrially.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a synthetic method of a trelagliptin intermediate.
Background
Trelagliptin succinate (Trelagliptin succinate) is a dipeptidyl peptidase IV (DPP-4) inhibitor. The japan wutian company filed a new drug application for the new drug trelagliptin succinate for diabetes for the treatment of type 2 diabetes mellitus on 3/7/2014 to the ministry of health and labor, having the following chemical structural formula:
patent US2012197018a1 discloses a process for synthesizing trelagliptin, the synthetic process route of which is as follows:
among them, (R) -3-aminopiperidine dihydrochloride is an important intermediate for synthesizing trelagliptin, and many methods for synthesizing (R) -3-aminopiperidine dihydrochloride have been published and reported at present.
Patent WO2011160037 takes 3-acetamidopyridine as a raw material, and obtains (R) -3-aminopiperidine dihydrochloride by sequentially carrying out hydrogenation reduction, amide hydrolysis, and D- (+) dibenzoyl tartaric acid (D-DBTA) resolution, and then forming hydrochloride. In the route, the reduction reaction needs to be carried out under the pressure higher than 10bar, the pressure is higher, the requirement on reaction equipment is higher, and the amplification production is not facilitated.
Patent CN103319399A uses 3-piperidine formamide as a raw material, under the action of 1-fluoronaphthalene, an oxidant and fluoroboric acid, Hofmann rearrangement reaction is carried out to obtain 3-aminopiperidine, then concentrated hydrochloric acid is acidified to prepare salt, then alkalization is carried out to free 3-aminopiperidine, tartaric acid is used for resolution, and the product is acidified by concentrated hydrochloric acid to obtain a target product. In the method, the raw materials are expensive, and the fluoroboric acid reagent has higher requirements on reaction equipment.
WO2007112368 and the document Bioorg.Med.chem.2006,14(7),2131-2150 report that D-ornithine salt is used as a raw material and is subjected to esterification, cyclization and acidification in turn to form salt, and then hydrogenation reduction and salt formation are carried out to finally obtain a target product. In the method, the chiral raw material is expensive, the esterification process needs to be carried out at low temperature (-78 ℃), and IRA-400 (OH) needs to be used after methanol esterification-) Purification with ion exchange resins increases industrial costs.
Patent CN104211702A discloses that D-ornithine hydrochloride is used as a raw material, and is reacted with thionyl chloride at-80 ℃, purified by 717(OH-) anion exchange resin, and then reacted with lithium aluminum hydride at-80 ℃ to obtain a reddish brown oily substance. The raw materials used in the process are expensive, ultralow temperature of-80 ℃ is difficult to realize industrially, the 717(OH-) anion exchange resin with high price is used, the industrial cost is increased, and the obtained oily product contains a large amount of impurities and has low purity.
Patent CN107445887A discloses the use of compounds(2) Obtaining a compound (3) through imidization; the compound (3) is subjected to asymmetric hydrogenation reaction to prepare a chiral compound (4); finally, the chiral compound (4) is subjected to an acid hydrolysis reaction to obtain the compound (1), and a rhodium catalyst [ Rh ] is used for asymmetrically hydrogenating the compound (3)2(pfb)4、Rh2(OAc)4、RhCl3、Rh2(OCOt-Bu)4Rhodium mandelate, rhodium trifluoroacetate and [ Rh (cod) ]2]BF4]The price is high, the industrial cost is increased, and the synthetic route is as follows:
disclosure of Invention
Aiming at the problems of long production period, expensive raw materials and high equipment requirement in the process of preparing (R) -3-aminopiperidine dihydrochloride at present, the invention provides a novel method for synthesizing a trelagliptin intermediate.
The technical scheme of the invention specifically comprises the following steps:
a synthetic method of a trelagliptin intermediate specifically comprises the following steps:
1) reducing carbonyl in an organic solvent A by using a reducing agent to prepare a compound shown in a formula II;
2) resolving the compound of formula II in an organic solvent B by using a chiral reagent to obtain a compound of formula III;
3) removing benzyl from the compound in the formula III in an organic solvent C by palladium carbon to prepare a trelagliptin intermediate compound in the formula IV, namely (R) -3-aminopiperidine dihydrochloride;
the reaction route is as follows:
in the synthesis method, the reducing agent in the step 1 is selected from one of red aluminum and lithium aluminum hydride.
Preferably, step 1 specifically comprises the following steps: adding a reducing agent into the organic solvent A in which the compound of the formula I is suspended at-10-0 ℃, stirring, and heating for reaction.
Further preferably, the reducing agent is added dropwise or in a flow manner.
The synthesis method is characterized in that the heating reaction temperature in the step 1 is 50-66 ℃.
Preferably, the molar ratio of the reducing agent to the compound of formula I is preferably 4-6: 1.
In the synthesis method, the organic solvent A in the step 1 is one or two of anhydrous toluene and anhydrous tetrahydrofuran.
The following procedure further details the preparation of the compounds of formula II of the present invention:
suspending the compound of the formula I in an organic solvent A under the protection of inert gas, cooling to-10-0 ℃, stirring, slowly dropwise adding an organic solution A dissolved with a reducing agent, heating to 50-66 ℃, and stirring for reaction for 4-7 hours. Cooling the reactant to 0-5 ℃, quenching the reactant by using a saturated ammonium chloride solution, filtering, and concentrating the filtrate under reduced pressure to obtain the compound shown in the formula II.
Preferably, the inert gas is selected from nitrogen or argon.
Further preferably, in one embodiment the inert gas is nitrogen.
In the synthesis method, the chiral reagent in the step 2 is selected from one of D- (+) -camphorsulfonic acid and D-pyroglutamic acid.
Preferably, the molar ratio of the compound of formula II in step 2 to the chiral resolving agent is 1: 1.95 to 2.50.
In the synthesis method, the organic solvent B in the step 2 is the combination of ethyl acetate and an alcohol solvent.
Preferably, the volume ratio of ethyl acetate to alcohol solvent is 1: 2 to 9.
Preferably, the alcoholic solvent is selected from one or a mixture of methanol and ethanol.
The preparation of the compounds of formula III of the present invention is further detailed by the following steps:
dissolving a chiral reagent in an organic solvent B, heating to dissolve, adding a compound shown in the formula II, carrying out reflux reaction, cooling for crystallization, cooling, filtering, washing a filter cake, and recrystallizing the filter cake with ethanol/water. And dissolving the solid obtained by recrystallization in methanol/water, adjusting the pH value by using alkali, extracting, washing, drying, filtering and concentrating to obtain the compound shown in the formula III.
Preferably, the base is selected from NaOH, KOH, Na2CO3And K2CO3One kind of (1).
In one embodiment, the base is NaOH.
Preferably, the pH is 8.5-9.5.
In one embodiment, the pH is 9.0.
The synthesis method comprises the step 3, wherein the reaction temperature is 40-50 ℃.
In the synthesis method, the organic solvent C in the step 3 is selected from one or a mixture of methanol and ethanol.
In the synthesis method, in the step 3, the amount of the palladium-carbon is 3.0-5.0% of the mass of the compound shown in the formula III.
The following steps further detail the preparation of the compounds of formula IV of the present invention:
adding the compound shown in the formula III, palladium carbon, methanol and concentrated hydrochloric acid into a hydrogenation kettle, sequentially replacing with nitrogen and hydrogen for three times, heating to 40-50 ℃ for reaction for 10-14 hours, cooling to room temperature, filtering, concentrating the filtrate under reduced pressure, adding isopropanol, distilling under reduced pressure, adding methanol, heating for dissolution, adding ethyl acetate, cooling for crystallization, filtering, washing a filter cake, and drying to obtain the compound shown in the formula IV.
Preferably, the heating and dissolving temperature is 40-50 ℃.
Preferably, the temperature for cooling and crystallization is-10 to-5 ℃.
The synthetic method, the compound of formula I, can be obtained commercially or synthesized according to the method described in reference examples 1-3.
The compound of the formula I is obtained by reacting 3-bromopiperidine-2, 6-diketone with benzylamine under the action of alkali.
Preferably, the solvent used for synthesizing the compound of formula I is one or more selected from tetrahydrofuran, DMF and propylene glycol.
Preferably, the base used for synthesizing the compound of formula I is selected from one of triethylamine, potassium carbonate and sodium carbonate.
Preferably, the reaction temperature for synthesizing the compound of the formula I is 60-66 ℃.
Further preferably, the molar ratio of the 3-bromopiperidine-2, 6-dione to the base in the reaction for synthesizing the compound of formula I is 1: 1.0-1.2.
Preferably, the molar ratio of the 3-bromopiperidine-2, 6-dione to benzylamine is 1: 1.05-1.20.
Compared with the prior art, the invention has the following remarkable progress:
(1) the price of the starting raw material is low, and is lower than 1/35 of the price of D-ornithine hydrochloride, thus being beneficial to reducing the industrial cost;
(2) the synthetic route is short, and the industrial implementation is easy;
(3) the product purity is high, the HPLC purity is higher than 98.16%, and the optical purity is higher than 98.92%;
(4) the process does not need to use expensive strong anion exchange resin, thereby obviously reducing the industrial cost.
Detailed Description
The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention. Variations of those skilled in the art in light of the teachings of this invention are intended to be within the scope of the claims appended hereto.
The reagents used in the present invention are either commercially available or prepared by the methods described herein.
The trelagliptin intermediate is (R) -3-aminopiperidine dihydrochloride; the red aluminum is sodium dihydrobis (2-methoxyethoxy) aluminate (consisting of 70 percent of sodium dihydrobis (2-methoxyethoxy) aluminate and 30 percent of toluene, namely 70 percent of toluene solution, CAS: 22722-98-1); the DMF is N, N-dimethylformamide; the anhydrous tetrahydrofuran can be obtained by adding metal sodium into a commercial tetrahydrofuran solution, heating and refluxing, and distilling; the anhydrous toluene can be obtained by adding metallic sodium into a commercial toluene solution, heating and refluxing, and distilling.
Reference example 1 preparation of a Compound of formula I
Benzylamine (12.86g, 1.20eq) and triethylamine (11.13g, 0.11mol) were dissolved in 200mL tetrahydrofuran, heated to reflux, and then a solution of 3-bromopiperidine-2, 6-dione (19.20g, 0.10mol) in tetrahydrofuran (200mL) was added dropwise, and the reaction was continued under reflux for 2 hours after dropping. Filtering, collecting filtrate, concentrating under reduced pressure to obtain crude compound of formula I, purifying with silica gel column (chloroform/methanol 10:1) to obtain pure compound of formula I, yield 53.21%, HPLC purity: 98.65 percent.
Reference example 2 preparation of the Compound of formula I
Benzylamine (11.79g, 1.10eq) and potassium carbonate (16.59g, 0.12mol) were dissolved in 200mL propylene glycol, heated to 60-66 deg.C, and a solution of 3-bromopiperidine-2, 6-dione (19.20g, 0.10mol) in propylene glycol (200mL) was added dropwise, and the reaction was continued for 2 hours after completion of the addition. Filtering, collecting filtrate, concentrating under reduced pressure to obtain crude compound of formula I, purifying with silica gel column (chloroform/methanol 10:1) to obtain pure compound of formula I, yield 52.56%, HPLC purity: 98.95 percent.
Reference example 3 preparation of the Compound of formula I
Benzylamine (11.25g, 1.05eq) and sodium carbonate (10.60g, 0.10mol) were dissolved in 200mL DMF, heated to 60-66 deg.C, and 3-bromopiperidine-2, 6-dione (19.20g, 0.10mol) in DMF (200mL) was added dropwise, and the reaction was continued for 2.5 hours after completion of the dropwise addition. Filtering, collecting filtrate, concentrating under reduced pressure to obtain crude compound of formula I, purifying with silica gel column (chloroform/methanol 10:1) to obtain pure compound of formula I, yield 52.34%, HPLC purity: 98.22 percent.
EXAMPLE 1 preparation of the Compound of formula II
Under the protection of nitrogen, suspending the compound (10.91g, 0.05mol) of the formula I in anhydrous tetrahydrofuran (60mL), cooling to-10-5 ℃, and dropwise adding LiAlH into the solution4(7.59g, 0.20mol, 4eq) of tetrahydrofuran solution 100mL, after dropping, the reaction mixture was heated under reflux for 5 hours. The reaction was cooled to 0 ℃ and carefully quenched with saturated ammonium chloride solution, then filtered and the filtrate was concentrated under reduced pressure to give the compound of formula II in 94.73% yield, HPLC purity: 97.63 percent.
EXAMPLE 2 preparation of the Compound of formula II
Under the protection of nitrogen, dissolving a compound (10.91g, 0.05mol) of the formula I in 150mL of anhydrous toluene, cooling to-5-0 ℃, slowly dropwise adding red aluminum (70% toluene solution) (64.9g, 0.225mol, 4.5eq, dissolved in anhydrous toluene), controlling the dropwise adding speed to keep the reaction temperature at-5-0 ℃, continuously stirring for 30min after the dropwise adding is finished, and heating to 60-66 ℃ for reaction for 4 hours. After cooling to room temperature, 150mL of a 5% HCl solution was added to the reaction system, the solvent was distilled off under reduced pressure, and the solid was collected by filtration under reduced pressure and washed with water. The resulting solid was suspended in methanol (80mL) and heated under reflux for 30 minutes, cooled to room temperature, added 10% potassium carbonate solution (70mL), stirred vigorously at room temperature for 2 hours, the solid collected by filtration, washed with water, and dried under vacuum at 60 ℃ to give the compound of formula II as a solid in 96.25% yield, HPLC purity: 98.26 percent.
EXAMPLE 3 preparation of the Compound of formula II
Under the protection of nitrogen, dissolving a compound (10.91g, 0.05mol) of the formula I in 150mL of anhydrous toluene, cooling to-5-0 ℃, slowly dropwise adding red aluminum (70% toluene solution, 86.5g, 0.30mol, 6.0eq, dissolved in anhydrous toluene), controlling the dropwise adding speed to keep the reaction temperature at-10 to-5 ℃, continuously stirring for 30min after the dropwise adding is finished, and heating to 60-66 ℃ for reaction for 4 hours. After cooling to room temperature, 150mL of a 5% HCl solution was added to the reaction system, the solvent was distilled off under reduced pressure, and the solid was collected by filtration under reduced pressure and washed with water. The resulting solid was suspended in methanol (80mL) and heated under reflux for 30 minutes, cooled to room temperature, added 10% potassium carbonate solution (70mL), stirred vigorously at room temperature for 2 hours, the solid collected by filtration, washed with water, and dried under vacuum at 60 ℃ to give the compound of formula II as a solid in 95.70% yield, HPLC purity: 97.85 percent.
EXAMPLE 4 preparation of the Compound of formula II
Under the protection of argon, suspending the compound (10.91g, 0.05mol) of the formula I in anhydrous tetrahydrofuran (60mL), cooling to-20-15 ℃, and dropwise adding LiAlH into the solution4(3.80g, 0.10mol, 2eq) of tetrahydrofuran solution 100mL, after dropping, the reaction mixture was heated under reflux for 5 hours. The reaction was cooled to 0 ℃ and carefully quenched with saturated ammonium chloride solution, thenFiltration and concentration of the filtrate under reduced pressure gave the compound of formula II in 90.16% yield, HPLC purity: 94.58 percent.
EXAMPLE 5 preparation of the Compound of formula III
Adding D-pyroglutamic acid (58.54g, 0.39mol) into 500mL of solvent (50mL of ethyl acetate +450mL of ethanol), heating and refluxing, adding the compound (38.06g, 0.20mol) of the formula II after clearing, stirring and refluxing for 2 hours, naturally cooling to room temperature to separate out white solid, then cooling at 0 ℃ for 1 hour, filtering, washing with ethanol, and recrystallizing a filter cake with ethanol/water (volume ratio 1: 1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water ═ 2:8), the pH was adjusted to 9 with a 6M NaOH solution, and then extracted with dichloromethane (200mL × 3), the organic phase was washed with 200mL of saturated brine and 200mL of water, respectively, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a white solid in a yield of 45.25% (relative to 50% of the maximum yield), which was the compound of formula III, HPLC purity: 98.85%, optical purity: 99.95 percent.
EXAMPLE 6 preparation of the Compound of formula III
Adding D-pyroglutamic acid (60.04g, 0.40mol) into 500mL of solvent (100mL of ethyl acetate + 400mL of methanol), heating and refluxing, adding the compound (38.06g, 0.20mol) of the formula II after dissolving, stirring and refluxing for 2 hours, naturally cooling to room temperature to separate out white solid, then cooling at 0 ℃ for 1 hour, filtering, washing with ethanol, and recrystallizing a filter cake with ethanol/water (volume ratio 1: 1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water ═ 2:8), the pH was adjusted to 8.5 with 6M KOH solution, and then extracted with dichloromethane (200mL × 3), the organic phase was washed with 200mL of saturated brine and 200mL of water, respectively, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a white solid in a yield of 46.72% (relative to 50% of the maximum yield), which was the compound of formula III, HPLC purity: 98.90%, optical purity: 99.97 percent.
EXAMPLE 7 preparation of the Compound of formula III
Adding D- (+) -camphorsulfonic acid (115.64g, 0.50mol) into 500mL of solvent (150mL of ethyl acetate +350mL of ethanol), heating and refluxing, adding the compound (38.06g, 0.20mol) of the formula II after dissolution, stirring and refluxing for 2 hours, naturally cooling to room temperature to separate out white solid, then cooling at 0 ℃ for 1 hour, filtering, washing with ethanol, and recrystallizing a filter cake with ethanol/water (volume ratio 1: 1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water ═ 2:8), and then the mixture was dissolved in 6M Na2CO3The solution was adjusted to pH 9.5, extracted with dichloromethane (200mL × 3), the organic phase was washed with 200mL of saturated brine and 200mL of water, respectively, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give a white solid in 45.41% (relative to 50% of maximum yield) which was the compound of formula III, HPLC purity: 98.87%, optical purity: 99.93 percent.
EXAMPLE 8 preparation of the Compound of formula III
Adding D-pyroglutamic acid (45.03g, 0.30mol) into 500mL ethanol, heating and refluxing, adding the compound (38.06g, 0.20mol) of the formula II after dissolving, stirring and refluxing for 2 hours, naturally cooling to room temperature, separating out white solid, cooling at 0 ℃ for one hour, filtering, washing with ethanol, and recrystallizing a filter cake with ethanol/water (volume ratio 1: 1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water ═ 2:8), and 6M K was used2CO3The solution was adjusted to pH 10, extracted with dichloromethane (200mL × 3), the organic phase washed with 200mL of saturated brine and 200mL of water, respectively, the organic layer dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give a white solid in 43.11% yield (relative to 50% maximum yield) which is the compound of formula III, HPLC purity: 98.20%, optical purity: 99.76 percent.
EXAMPLE 9 preparation of Compounds of formula IV
Adding 19.00g of a compound shown in the formula III, 0.60g (dry basis) of 10% palladium carbon, 180mL of methanol and 20.0mL of concentrated hydrochloric acid into a 250mL dry hydrogenation kettle with a thermometer and a mechanical stirrer in sequence, loading the mixture into the reaction kettle after the addition is finished, replacing the mixture with nitrogen for three times, replacing the mixture with hydrogen for three times, pressurizing to 1.0MPa, heating to 40-45 ℃, stirring and reacting for 12 hours, stopping the reaction, cooling to room temperature, filtering, distilling the filtrate under reduced pressure until no fraction is produced, adding isopropanol (20mL multiplied by 3), distilling under reduced pressure to remove the isopropanol, adding 25mL of methanol, heating and dissolving at 40-50 ℃, slowly dropping 55mL of ethyl acetate into the methanol, cooling to-10-5 ℃ for crystallization, filtering, washing a filter cake with ethyl acetate, and drying to obtain a compound shown in the formula IV, wherein the yield is 92.73%, the HPLC purity is 99.75%, and the optical purity: 99.92 percent.
EXAMPLE 10 preparation of Compounds of formula IV
Adding 19.00g of a compound shown in the formula III, 0.95g (dry basis) of 10% palladium carbon, 180mL of ethanol and 20.0mL of concentrated hydrochloric acid into a 250mL dry hydrogenation kettle with a thermometer and mechanical stirring in sequence, loading the mixture into the reaction kettle after the addition is finished, replacing the mixture with nitrogen for three times, replacing the mixture with hydrogen for three times, pressurizing to 1.0MPa, heating to 45-50 ℃, stirring and reacting for 10 hours, stopping the reaction, cooling to room temperature, filtering, distilling the filtrate under reduced pressure until no fraction is produced, adding isopropanol (20mL multiplied by 3), distilling under reduced pressure to remove the isopropanol, adding 25mL of ethanol, heating and dissolving at 40-50 ℃, slowly dropping 55mL of ethyl acetate into the ethanol, cooling to-10 to-5 ℃ for crystallization, filtering, washing a filter cake with ethyl acetate, and drying to obtain a compound shown in the formula IV, wherein the yield is 93.83%, the HPLC purity is 99.64%, and the optical purity: 99.90 percent.
EXAMPLE 11 preparation of a Compound of formula IV
Adding 19.00g of the compound shown in the formula III, 0.76g (dry basis) of 10% palladium carbon, 180mL of mixed solvent (80mL of ethanol and 100mL of methanol) and 20.0mL of concentrated hydrochloric acid into a 250mL dry hydrogenation kettle with a thermometer and mechanical stirring in sequence, loading the mixture into the reaction kettle after the addition, replacing the mixture with nitrogen for three times, replacing the mixture with hydrogen for three times, pressurizing to 1.0MPa, heating to 45-50 ℃, stirring and reacting for 11 hours, stopping reaction, cooling to room temperature, filtering, distilling the filtrate under reduced pressure until no fraction is produced, adding isopropanol (20mL multiplied by 3), distilling under reduced pressure to remove the isopropanol, adding 25mL of methanol, heating and dissolving at 40-50 ℃, slowly dropping 55mL of ethyl acetate into the methanol, after the addition, the temperature is reduced to-10 to-5 ℃ for crystallization, the crystallization is carried out, the filter cake is washed by ethyl acetate and dried to obtain the compound shown in the formula IV, the yield is 93.37%, the HPLC purity is 99.83%, and the optical purity is as follows: 99.91 percent.
EXAMPLE 12 preparation of a Compound of formula IV
Adding 19.00g of a compound shown in the formula III, 1.25g (dry basis) of 10% palladium carbon, 180mL of isopropanol and 20.0mL of concentrated hydrochloric acid into a 250mL dry hydrogenation kettle with a thermometer and a mechanical stirrer in sequence, loading the mixture into the reaction kettle after the addition, replacing the mixture with nitrogen for three times, replacing the mixture with hydrogen for three times, pressurizing the mixture to 1.0MPa, heating the mixture to 60-65 ℃, stirring the mixture for reaction for 10 hours, stopping the reaction, cooling the mixture to room temperature, filtering the mixture, distilling the filtrate under reduced pressure until no fraction is produced, adding 25mL of ethanol into the mixture, heating and dissolving the mixture at 40-50 ℃, slowly dropping 55mL of ethyl acetate into the ethanol, cooling the mixture to-10 to-5 ℃ after the addition, crystallizing the mixture, filtering the filtrate, washing the filtrate with ethyl acetate, and drying the mixture to obtain a compound shown in the formula I V, wherein the yield is 90.15%: 98.92 percent.
Claims (10)
1. The synthetic method of the trelagliptin intermediate is characterized by comprising the following steps of:
1) reducing carbonyl in an organic solvent A by using a reducing agent to prepare a compound shown in a formula II;
2) resolving the compound of formula II in an organic solvent B by using a chiral reagent to obtain a compound of formula III;
3) removing benzyl from the compound in the formula III in an organic solvent C by palladium carbon to obtain a trelagliptin intermediate compound in a formula IV;
the reaction route is as follows:
2. the synthesis method according to claim 1, wherein the reducing agent in step 1 is selected from one of red aluminum and lithium aluminum hydride; the molar ratio of the reducing agent to the compound of formula I is preferably 4-6: 1.
3. The synthesis method according to claim 1, wherein step 1 specifically comprises the steps of: adding a reducing agent into the organic solvent A in which the compound of the formula I is suspended at-10-0 ℃, stirring, and heating for reaction.
4. The synthesis method according to claim 1, wherein the organic solvent A in step 1 is one or two selected from anhydrous toluene and anhydrous tetrahydrofuran.
5. The method of claim 1, wherein the chiral agent in step 2 is selected from one of D- (+) -camphorsulfonic acid and D-pyroglutamic acid.
6. The synthesis method according to claim 1, wherein the molar ratio of the compound of formula II in step 2 to the chiral resolving agent is 1: 1.95 to 2.50.
7. The synthesis method according to claim 1, wherein the organic solvent B in the step 2 is a combination of ethyl acetate and an alcoholic solvent, preferably methanol or ethanol.
8. The synthesis method according to claim 1, wherein the reaction temperature in step 3 is 40-50 ℃.
9. The synthesis method according to claim 1, wherein the organic solvent C in step 3 is selected from one or a mixture of methanol and ethanol.
10. The synthesis method of claim 1, wherein in step 3, the amount of palladium on carbon is 3.0-5.0% of the compound of formula III.
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