CN103058856B - Method for preparing 4-(2,4,5-trifluorophenyl)-5-oxobutyric acid - Google Patents
Method for preparing 4-(2,4,5-trifluorophenyl)-5-oxobutyric acid Download PDFInfo
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- CN103058856B CN103058856B CN201210592501.4A CN201210592501A CN103058856B CN 103058856 B CN103058856 B CN 103058856B CN 201210592501 A CN201210592501 A CN 201210592501A CN 103058856 B CN103058856 B CN 103058856B
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- 238000000034 method Methods 0.000 title claims abstract description 18
- -1 Grignard reagent compound Chemical class 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- JMXPOOVDUVHJRO-UHFFFAOYSA-N 1-(chloromethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CCl)C=C1F JMXPOOVDUVHJRO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011630 iodine Substances 0.000 claims abstract description 5
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 229910052749 magnesium Inorganic materials 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- MAPGNFOESSJGBG-UHFFFAOYSA-N 1-[chloro(difluoro)methyl]-2-fluorobenzene Chemical class FC1=CC=CC=C1C(F)(F)Cl MAPGNFOESSJGBG-UHFFFAOYSA-N 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003929 acidic solution Substances 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 4
- 230000000977 initiatory effect Effects 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- IPOVOSHRRIJKBR-UHFFFAOYSA-N 2-ethylpropanedioyl dichloride Chemical compound CCC(C(Cl)=O)C(Cl)=O IPOVOSHRRIJKBR-UHFFFAOYSA-N 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000011777 magnesium Substances 0.000 description 23
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 19
- FDNNQIVFHJDIIX-UHFFFAOYSA-N 3-oxo-4-(2,4,5-trifluorophenyl)butanoic acid Chemical compound OC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F FDNNQIVFHJDIIX-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- HGINADPHJQTSKN-UHFFFAOYSA-M 3-ethoxy-3-oxopropanoate Chemical compound CCOC(=O)CC([O-])=O HGINADPHJQTSKN-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 229960004115 sitagliptin phosphate Drugs 0.000 description 3
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003672 processing method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- YSQLGGQUQDTBSL-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=C(F)C=C1F YSQLGGQUQDTBSL-UHFFFAOYSA-N 0.000 description 1
- HCEQQASHRRPQFE-UHFFFAOYSA-N 5-chloro-n-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxybenzamide;3-(diaminomethylidene)-1,1-dimethylguanidine;hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N.COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 HCEQQASHRRPQFE-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940112611 glucovance Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for preparing a 4-(2,4,5-trifluorophenyl)-5-oxobutyric acid. The method comprises the following steps: step 1, allowing 2, 4, 5-trifluorobenzyl chloride and Mg to react in an organic solvent 1 by taking iodine or ethylene dibromide as an initiating agent, so as to obtain a Grignard reagent compound (III); step 2, allowing ethyl malonyl chloride and the Grignard reagent compound (III) to react in an organic solvent 2 to obtain a compound (II); and step 3, adding an alkaline matter in a reaction liquid of the compound (II) for hydrolysis, and then adding an acid solution for adjusting the pH value to 4-5, so as to obtain a compound (I). The invention mainly has the benefits that through the adoption of the method, the raw material is easily obtained with low cost, lots of waste acid water is not generated, the yield is relatively high, the product quality is stable, and the method is a process method having an industrial prospect.
Description
(1) technical field
The present invention relates to the preparation method of a kind of 4-(2,4,5-trifluorophenyl)-3-ketobutyric acid.
(2) background technology
4-(2,4,5-trifluorophenyl)-3-ketobutyric acid is a kind of important pharmaceutical-chemical intermediate, the key intermediate of especially synthetic treatment Glucovance sitagliptin phosphate.Only need afterwards two steps can obtain sitagliptin phosphate.In the document synthetic route of sitagliptin phosphate (ZL02813558.X), raw material is for more unobtainable 2,4,5-trifluoro benzene acetic acid and expensive mayer ketone acid.And in the building-up process of 4-(2,4,5-trifluorophenyl)-3-ketobutyric acid, the raw material that is easy acquisition of employing, 1,3,4-trifluoro-benzene and diethyl malonate, cheaply many compared with these two kinds of raw materials are raw materials used with document.Therefore this new synthesis technique is to have good industrialization, also has good innovative significance.
(3) summary of the invention
The object of this invention is to provide the processing method that one is easy, synthesize 4-(2,4,5-trifluorophenyl)-3-ketobutyric acid safety and efficiently.
The technical solution used in the present invention is:
The preparation method of 4-(2,4,5-the trifluorophenyl)-3-ketobutyric acid shown in a kind of formula (I), described method comprises:
(1) 2,4,5-, tri-fluorobenzyl chlorides and Mg, in organic solvent 1, taking iodine or ethylene dibromide as initiator, react and make Grignard reagent compound (III); Described organic solvent 1 is one of following: tetrahydrofuran (THF), ether, methyltetrahydrofuran; Described 2,4,5-tri-fluorobenzyl chlorides and Mg molar ratio are 1:1～2 (being preferably 1:1.41～1.7); Wherein Mg need pass through the activation of acetone, dilute hydrochloric acid, deionized water, ethanol, MTBE, is this area routine operation; Reaction environment should be anhydrous and oxygen-free condition in addition, therefore organic solvent 1 processing of need anhydrating; Mg generally participates in reaction with magnesium chips situation, needs to remove surface oxide layer through conventional processing before use.
(2) monoethyl malonate acyl chlorides and compound (III), in organic solvent 2, react and make compound (II); Described organic solvent 2 is one of following: tetrahydrofuran (THF), ether, methyltetrahydrofuran; Compound (III) is 1:1.1～2.5 (being preferably 1:1.5～1.7) with monoethyl malonate acyl chlorides molar ratio; The complete solid of unreacted in step (1) can add in the reaction system of step (2) after solvent cleaning;
(3) make in step (2) containing adding alkaline matter to be hydrolyzed in the reaction solution of compound (II), then add acidic solution to pH be 4～5, make compound (I); Described alkaline matter is one of following: sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, Calcium hydrogen carbonate; Compound (II) is 1:1～2 (being preferably 1:1.3～1.6) with the molar ratio of alkaline matter;
Preferably, in step (1), the molar ratio of initiator and 2,4,5-, tri-fluorobenzyl chlorides is 1:50～100 (1:70～80).
Step (1) reaction is carried out at 30～40 DEG C.
Step (2) reaction is carried out at-20 DEG C～0 DEG C, preferably at 0 DEG C, carries out.
Step (2) passes into N in reaction process
2to ensure the anaerobic water-less environment of reaction system.
Acidic solution is one of following in step (2): hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.
Beneficial effect of the present invention is mainly reflected in: adopt the inventive method, raw material is cheaply easy to get, and does not produce a large amount of waste acid waters, and yield is relatively high, and constant product quality is a processing method with industrial prospect.
(4) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1: remove magnesium chips surface oxide layer and remove surface oxide layer and activation magnesium chips
Take 2.4g magnesium chips (100mmol), first wash twice with 20ml acetone soln, re-use 10mmol/L hydrochloric acid soln 20ml and react 30s with magnesium chips mix and blend, make magnesium chips surface reappear metalluster, filter, use deionized water 40ml to rinse magnesium chips twice, filter, with 40ml alcohol flushing magnesium chips twice, filter, rinse twice of magnesium chips with 40ml tetrahydrofuran solution, filter, with 40ml methyl tertiary butyl ether flushing magnesium chips twice, filter, magnesium chips dries up with nitrogen, seals up for safekeeping stand-by.
Embodiment 2: the preparation of monoethyl malonate acyl chlorides
In the four-hole bottle of 100ml, lead to N
2gas, deep fat heating, temperature is made as 60 DEG C, makes system temperature remain on 42 DEG C of left and right, is the micro-backflow of cold water.To the methylene dichloride that adds fast 30ml in system, stir, then add the monoethyl malonate (75 mmole) of 8.85 milliliters.In system, slowly drip the thionyl chloride (150 mmole) of 11.0 milliliters, dropwise heated and stirred 2h.Question response is complete, uses water pump pressurization solvent evaporated, until drop disappears, and vacuum concentration at 45 DEG C.At logical N
2under condition, use frozen water cooling for subsequent use gained solid.
Embodiment 3:
At logical N
2the environment of anhydrous and oxygen-free under, in the there-necked flask of 100ml, add 5 milliliters of anhydrous methyltetrahydrofurans, then by: the dry magnesium chips of processing adds in system, add again several iodine grains, after stir about 10min, add at ambient temperature partial reaction thing 2,4,5-tri-fluorobenzyl chlorides (by 2,4 of about 6～7g, 5-tri-fluorobenzyl chlorides are dissolved in the methyltetrahydrofuran of 20ml), the color of system is thin out, temperature rise, has Bubble formation, and this is the initiation of reaction.Bubble formation to be had, add remaining 2,4,5-tri-fluorobenzyl chlorides, temperature can rise, solution colour changes.2, the mol ratio of 4,5-, tri-fluorobenzyl chlorides and magnesium chips is 1:1.5,2,4, the total mass of 5-tri-fluorobenzyl chlorides is 9.03 grams (50 mmoles), and the quality of magnesium chips is 1.82 grams (75 mmoles), question response 2h, still have magnesium chips residual, if reaction bubble is too much, cooling that can be suitable, stirring reaction 1h under normal temperature.After reaction finishes, at 0 DEG C, stirring reaction 1 hour is stand-by.
Monoethyl malonate acyl chlorides methyltetrahydrofuran solution (12.2g monoethyl malonate acyl chlorides is dissolved in the 25 milliliters of methyltetrahydrofurans) system temperature of having prepared keeps 0 DEG C.The grignard reagent preparing is slowly added drop-wise in system, and the complete solid of unreacted is poured solid-liquid in system after washing with anhydrous methyltetrahydrofuran together.At 0 DEG C, react 1 hour, TCL analyzes, and reaction finishes.In system, add 2.30 grams of sodium hydroxide (75 mmole), stir half hour, drip dilute hydrochloric acid, until pH value becomes 4, recrystallization under low temperature, filtration drying, obtain 9.54 grams of product 4-(2,4,5-trifluorophenyl)-3-ketobutyric acid, yield is 82.18%, with 2,4,5-, tri-fluorobenzyl chloride charging capacitys are calculated, GC (gas-chromatography) content: 99.3%.
Product 1H-NMR (CDCl
3, 400MHz) and data: δ 4.43 (s, 4H), 6.91～6.98 (t, 2H), 3.71～3.73 (t, 2H), 6.91～6.99 (m, 1H), 7.22～7.30 (m, 1H).
Embodiment 4:
At logical N
2the environment of anhydrous and oxygen-free under, in the there-necked flask of 100ml, add anhydrous THF20 milliliter, the drier magnesium chips of processing by embodiment 1 method added in system, add again several iodine grains, after stir about 10min, add at ambient temperature partial reaction thing 2,4,5-tri-fluorobenzyl chlorides (by 2,4 of about 7～8g, 5-tri-fluorobenzyl chlorides are dissolved in the THF of 20ml), the color of system is thin out, temperature rise, has Bubble formation, and this is the initiation of reaction.Bubble formation to be had, add remaining 2,4,5-tri-fluorobenzyl chlorides, temperature can rise, solution colour changes.The mol ratio of 2,4,5-, tri-fluorobenzyl chlorides and magnesium chips is 1:2, and the total mass of 2,4,5-, tri-fluorobenzyl chlorides is 9.03 grams (50 mmoles), and the quality of magnesium chips is 2.43 grams (100 mmoles).Question response 2h, still has magnesium chips residual, if reaction bubble is too much, cooling that can be suitable, is cooled to 0 DEG C by reaction system with frozen water.
In the monoethyl malonate acyl chlorides tetrahydrofuran solution (12.2g monoethyl malonate acyl chlorides is dissolved in 25 milliliters of tetrahydrofuran (THF)s) of having prepared, system temperature keeps 0 DEG C.The grignard reagent preparing is slowly added drop-wise in system, and the complete solid of unreacted is poured solid-liquid in system after washing with anhydrous tetrahydro furan together.At 3 DEG C, react 1 hour, TCL analyzes, and reaction finishes.In system, add 2.30 grams of sodium hydroxide (75 mmole), stir half hour, drip dilute hydrochloric acid (1mol/L), until pH value becomes 4, recrystallization under low temperature, filtration drying, obtain 9.57 grams of product 4-(2,4,5-trifluorophenyl)-3-ketobutyric acid, yield is 82.44%, with 2,4,5-, tri-fluorobenzyl chloride charging capacitys are calculated, GC content 99.5%.
Claims (6)
1. the preparation method of the 4-shown in a formula (I) (2,4,5-trifluorophenyl)-3-ketobutyric acid, described side
Method comprises:
(1) 2,4,5-, tri-fluorobenzyl chlorides and Mg, in organic solvent 1, taking iodine or ethylene dibromide as initiator, react and make Grignard reagent compound (III); Described organic solvent 1 is one of following: tetrahydrofuran (THF), ether, methyltetrahydrofuran; Described 2,4,5-tri-fluorobenzyl chlorides and Mg molar ratio are 1:1～2;
(2) monoethyl malonate acyl chlorides and compound (III), in organic solvent 2, react and make compound (II); Described organic solvent 2 is one of following: tetrahydrofuran (THF), ether, methyltetrahydrofuran; Compound (III) is 1:1.1～2.5 with monoethyl malonate acyl chlorides molar ratio;
(3) make in step (2) containing adding alkaline matter to be hydrolyzed in the reaction solution of compound (II), then add acidic solution to pH be 4～5, make compound (I); Described alkaline matter is one of following: sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, Calcium hydrogen carbonate; Compound (II) is 1:1～2 with the molar ratio of alkaline matter;
2. the method for claim 1, is characterized in that the molar ratio of the middle initiator of step (1) and 2,4,5-, tri-fluorobenzyl chlorides is 1:50～100.
3. the method for claim 1, is characterized in that step (1) reaction carries out at 30～40 DEG C.
4. the method for claim 1, is characterized in that step (2) reaction carries out at-20 DEG C～0 DEG C.
5. the method for claim 1, is characterized in that step (2) passes into N2 in reaction process.
6. the method for claim 1, is characterized in that in step (2) that acidic solution is one of following: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.
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| CN104987338B (en) * | 2015-07-30 | 2017-07-21 | 新发药业有限公司 | A kind of preparation method of Sitagliptin phosphate key intermediate |
| CN105418436B (en) * | 2015-11-16 | 2017-08-25 | 成都倍特药业有限公司 | A kind of preparation method of melitracen hydrochloride |
| CN107311862B (en) * | 2017-06-19 | 2020-06-19 | 南京红杉生物科技有限公司 | Preparation method of sitagliptin intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1827568A (en) * | 2006-04-10 | 2006-09-06 | 西安近代化学研究所 | Process for synthesizing 4-[2-(trans-4-alkyl-cyclohexyl)ethyl] phenol |
| CN101928219A (en) * | 2010-06-08 | 2010-12-29 | 太仓浦源医药原料有限公司 | Method for preparing ethyl 2-oxo-4-phenylbutyrate |
| CN102320957A (en) * | 2011-07-28 | 2012-01-18 | 浙江大学 | Method for preparing 4-(2,4,5-trifluorophenyl)-3-oxo-butanoic acid |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1827568A (en) * | 2006-04-10 | 2006-09-06 | 西安近代化学研究所 | Process for synthesizing 4-[2-(trans-4-alkyl-cyclohexyl)ethyl] phenol |
| CN101928219A (en) * | 2010-06-08 | 2010-12-29 | 太仓浦源医药原料有限公司 | Method for preparing ethyl 2-oxo-4-phenylbutyrate |
| CN102320957A (en) * | 2011-07-28 | 2012-01-18 | 浙江大学 | Method for preparing 4-(2,4,5-trifluorophenyl)-3-oxo-butanoic acid |
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