CN110128258A - The synthetic method of sitagliptin intermediate 2,4,5- trifluoro benzene acetic acid - Google Patents
The synthetic method of sitagliptin intermediate 2,4,5- trifluoro benzene acetic acid Download PDFInfo
- Publication number
- CN110128258A CN110128258A CN201910331211.6A CN201910331211A CN110128258A CN 110128258 A CN110128258 A CN 110128258A CN 201910331211 A CN201910331211 A CN 201910331211A CN 110128258 A CN110128258 A CN 110128258A
- Authority
- CN
- China
- Prior art keywords
- trifluoro
- benzene
- reaction
- methylene chloride
- acetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 title claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 105
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 11
- CPHORTCGMDXMEI-UHFFFAOYSA-N C(C)(=O)O.FC1=CC=C(C(=C1)F)F Chemical class C(C)(=O)O.FC1=CC=C(C(=C1)F)F CPHORTCGMDXMEI-UHFFFAOYSA-N 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 29
- 239000007788 liquid Substances 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 16
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 16
- 230000003213 activating effect Effects 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 14
- 229910021536 Zeolite Inorganic materials 0.000 claims description 13
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 13
- 239000010457 zeolite Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical group [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 8
- 239000011592 zinc chloride Substances 0.000 claims description 8
- 235000005074 zinc chloride Nutrition 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000010813 municipal solid waste Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- XRRONFCBYFZWTM-UHFFFAOYSA-N octadecanoic acid;sodium Chemical compound [Na].CCCCCCCCCCCCCCCCCC(O)=O XRRONFCBYFZWTM-UHFFFAOYSA-N 0.000 claims 1
- 238000007265 chloromethylation reaction Methods 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000012805 post-processing Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 12
- YGGXZTQSGNFKPJ-UHFFFAOYSA-N methyl 2-naphthalen-1-ylacetate Chemical compound C1=CC=C2C(CC(=O)OC)=CC=CC2=C1 YGGXZTQSGNFKPJ-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 7
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 5
- 229960004034 sitagliptin Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- -1 diester malonate Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- JMXPOOVDUVHJRO-UHFFFAOYSA-N 1-(chloromethyl)-2,4,5-trifluorobenzene Chemical class FC1=CC(F)=C(CCl)C=C1F JMXPOOVDUVHJRO-UHFFFAOYSA-N 0.000 description 1
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical class FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- SCSHFLIEEIYUPB-UHFFFAOYSA-N acetic acid;1,2,3-trifluorobenzene Chemical compound CC(O)=O.FC1=CC=CC(F)=C1F SCSHFLIEEIYUPB-UHFFFAOYSA-N 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 108010021916 duodenin Proteins 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
- C07C17/269—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of only halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of synthetic method of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate, 1,2,4- trifluoro-benzene is reacted to obtain 2,4,5- trifluoro benzene acetic acids with methylene chloride, cyanide under the effect of the catalyst.Operation of the present invention is simple, after the completion of chloromethylation, can directly carry out cyanalation reaction without post-processing;Reaction yield is higher, and cost is relatively low;By-product is less, and three waste discharge is less.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to a kind of synthesis side of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate
Method.
Background technique
Sitagliptin is developed by United States Merck company, and in 2006 through Food and Drug Adminstration of the US
(FDA) newly-developed hypoglycemic agent of the treatment type II diabetes of approval.Sitagliptin is as a kind of dipeptidyl peptidase-IV (DPP-
IV) inhibitor, different from traditional hypoglycemic medicine, it is the effect by inhibiting DPP-IV degradation duodenin (Incretin)
To generate hypoglycemic effect, new therapeutic strategy has been opened up for treatment type II diabetes.Sitagliptin energy concentration dependent
The advantages that ground plays hypoglycemic effect and is provided simultaneously with good safety, validity and tolerance, and side effect is light.
The synthetic method of sitagliptin is mainly that starting material is synthesized with 2,4,5- trifluoro benzene acetic acids, technique road
Line has several following:
Route 1
Route 2
Route 3
2,4,5- trifluoro benzene acetic acid is the important intermediate for synthesizing sitagliptin.Current 2,4,5- trifluoro-benzene reported in the literature
The synthetic method of acetic acid mainly has four routes: 1. making using 1,2,4- trifluoro-benzene as raw material by chloromethylation, cyaniding, hydrolysis
, more 2. 2,4, the 5- trifluorobromobenzenes of the route three wastes under alkaline condition, through transition metal-catalyzed, occur with diester malonate
Coupling reaction, then hydrolysis obtains 2,4,5- trifluoro benzene acetic acids, and this method atom economy type is poor, and catalyst usage amount is more,
It is unsuitable for industrialized production.After 3. Grignard Reagent is made in 2,4,5- trifluorobromobenzenes, coupling reaction is carried out with allyl bromide, bromoallylene, it is then double
Key aoxidizes to obtain 2,4,5- trifluoro benzene acetic acids, and oxidant used in the method is that ruthenium and sodium metaperiodate composite oxidant, price are more expensive.④
2,4,5- trifluoro benzyl chlorides are obtained by 1,2,4- trifluoro-benzene chloromethylation, it is anti-with carbon dioxide again then to form corresponding Grignard Reagent
2,4,5- trifluoro benzene acetic acids should be obtained, which still remains the more disadvantage of the chloromethylation three wastes.
Summary of the invention
To overcome disadvantages mentioned above, the present invention provides a kind of synthesis side of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate
Method, this method step is simple, and yield is high, and cost is relatively low, and three waste discharge is less.
To achieve the above object, the present invention adopts the following technical scheme:
The synthetic method of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate, which is characterized in that 1,2,4- trifluoro-benzene exists
React to obtain 2,4,5- trifluoro benzene acetic acids, the reaction process with methylene chloride, cyanide under the action of catalyst are as follows:
1) cyanide, alkali, activating agent A1 and deionized water are mixed, obtains mixture M 1;
2) in the case where protecting gas shielded, catalysts and solvents S is mixed, control reaction temperature is 100~120 DEG C, reaction pressure
Power is 3~5 atmospheric pressure, after stirring 30~50min, starts 1,2,4- trifluoro-benzene of dropwise addition and methylene chloride, and drop finishes, control reaction
Temperature is 130~150 DEG C, and reaction pressure is 4~8 atmospheric pressure, reacts 1~2h, obtains mixture M 2, and control reaction temperature is
50~70 DEG C, reaction pressure is 3~4 atmospheric pressure, and mixture M 1 is added dropwise, and drop finishes, and control reaction temperature is 70~80 DEG C, reaction
Pressure is 5~7 atmospheric pressure, and the reaction was continued, and 3~5h terminates, and cools down and obtains mixture M 3 after being down to room temperature;
3) mixture M 3 is filtered to remove insoluble matter, be layered, after washing, desiccant dryness, concentration is evaporated off molten organic phase
Agent obtains liquid L;
4) liquid L, activating agent A2 and acid-mixed is even, control reaction temperature is 80~110 DEG C, and reaction pressure is 3~5
Atmospheric pressure, 1~1.5h of reaction terminate, pour into trash ice after system is cooled down, and 2,4,5- trifluoro benzene acetic acid of white solid is precipitated.
The catalyst the preparation method comprises the following steps: by zeolite, zinc chloride be added aqueous hydrochloric acid solution in, impregnate 2~3h, then use
Rotary Evaporators concentration is evaporated, and obtained solid activates 5~7h in 160~200 DEG C of bakings and obtains;The zeolite is HY-25, HY-
50 or HY-98 type;The mass ratio of the zinc chloride, zeolite and aqueous hydrochloric acid solution is 1:(3~5): (8~15);The hydrochloric acid
The concentration of aqueous solution is mass fraction 5%.
The cyanide is Cymag or potassium cyanide;The alkali is sodium hydroxide or potassium hydroxide;The activating agent
A1 is odium stearate;The activating agent A2 is tetrabutylammonium chloride;The protection gas is nitrogen or argon gas;The solvent S is
Nitrobenzene;The acid is the hydrochloric acid of mass fraction concentration 20%;The desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate.
Described 1, the dropwise addition mode of 2,4- trifluoro-benzenes and methylene chloride are as follows: methylene chloride is first added dropwise, the drop to methylene chloride
When dosage reaches itself 5%, start 1,2,4- trifluoro-benzene of dropwise addition;The 1,2,4- trifluoro-benzene and methylene chloride drop rate phase
Deng.
The molar ratio of the 1,2,4- trifluoro-benzene and methylene chloride is 1:(1~1.05);Described is the 1,2,4- trifluoro
The molar ratio of benzene and cyanide is 1:(1~1.08);The mass ratio of the 1,2,4- trifluoro-benzene and catalyst be 1:(0.15~
0.22);The amount ratio of the 1,2,4- trifluoro-benzene and solvent S are 1g:(3~5.5) mL;The cyanide, alkali, activating agent A1 and
The molar ratio of deionized water is 1:(0.12~0.2): (0.05~0.08): (10~15);The liquid L's and activating agent A2
Mass ratio is 1:(0.08~0.11);The mass ratio of the liquid L and acid is 1:(5~7).
Reaction principle of the present invention is shown below:
The present invention loads to zinc chloride on zeolite by processing, required catalyst is made, the catalyst is in the reaction
Play the role of similar " Friedel-Crafts reaction " catalyst, chloromethylation is occurred into for 1,2,4- trifluoro-benzene and methylene chloride and obtains chlorine
Methylate 1.Control the addition sequence and mode of two kinds of compounds of 1,2,4- trifluoro-benzene and methylene chloride, it is possible to reduce secondary anti-
Answer: being first added methylene chloride, and during entire be added dropwise, the moment keeps methylene chloride slightly excessive, can to avoid because of 1,2,
4- trifluoro-benzene is excessive, and chloromethylation products 1 is caused to continue that the further pair for replacing chlorine atom occurs with 1,2,4- trifluoro-benzenes
Reaction;Meanwhile control drop rate is equal, and it is anti-can to continue generation chloromethylation with methylene chloride to avoid chloromethylation products 1
Answer (although reaction odds in system is very low).
Mixture M 2 is obtained after completing chloromethylation, mixture M 1 is added, carries out cyanalation reaction: in alkali, activity
Under the effects of agent, CN-Nucleophilic substitution occurs with the chlorine atom of chloromethylation products 1, generates cyanalation product 2.The present invention
Corresponding reaction condition is taken, can quickly and efficiently be carried out cyanalation under the premise of being not required to chloromethylation products 1 to be separated
Reaction.
Cyanalation product 2 is obtaining target product by hydrolysis: hydrolysis can be made more efficient using activating agent.
Compared with the existing technology, advantages of the present invention has:
1, operation is simple, after the completion of chloromethylation, can directly carry out cyanalation reaction without post-processing;
2, reaction yield is higher, and cost is relatively low;
3, by-product is less, and three waste discharge is less.
Specific embodiment
Combined with specific embodiments below, the present invention is further illustrated.
Embodiment 1
The synthetic method of 2,4,5- trifluoro benzene acetic acids, comprising the following steps:
1) Cymag, sodium hydroxide, odium stearate and deionized water are mixed, obtains mixture M 1, Cymag, hydroxide
The molar ratio of sodium, odium stearate and deionized water is 1:0.16:0.07:13.
2) under protection of argon gas, catalyst and nitrobenzene are mixed, control reaction temperature is 115 DEG C, reaction pressure 4.5
A atmospheric pressure is first added dropwise methylene chloride, when the dripping quantity of methylene chloride reaches itself 5%, starts to drip after stirring 45min
Add 1,2,4- trifluoro-benzenes, and keeps 1,2,4- trifluoro-benzenes and methylene chloride Drop volumes rate equal.
After completion of dropwise addition, control reaction temperature is 142 DEG C, and reaction pressure is 7 atmospheric pressure, reacts 1.5h, is mixed
Object M2 is closed, control reaction temperature is 6 DEG C, and reaction pressure is 3~4 atmospheric pressure, and mixture M 1 is added dropwise, and drop finishes, control reaction temperature
Degree is 76 DEG C, and reaction pressure is 6 atmospheric pressure, and the reaction was continued, and 4.5h terminates, and cools down and obtains mixture M 3 after being down to room temperature.
In the step, the molar ratio of 1,2,4- trifluoro-benzene and methylene chloride is 1:1.02,1,2,4- trifluoro-benzene and nitrobenzene
Amount ratio be 1g:4.5mL, the molar ratio of 1,2,4- trifluoro-benzene and Cymag is 1:1.06,1,2,4- trifluoro-benzene and catalyst
Mass ratio be 1:0.18.
The step used catalyst the preparation method comprises the following steps: by HY-98 type zeolite, zinc chloride be added mass fraction 5% salt
In aqueous acid, 3h is impregnated, is then evaporated with Rotary Evaporators concentration, obtained solid is obtained in 200 DEG C of baking activation 7h, chlorination
The mass ratio of zinc, zeolite and aqueous hydrochloric acid solution is 1:4:13.
3) mixture M 3 is filtered to remove insoluble matter, be layered, organic phase after washing, anhydrous sodium sulfate are dry, steam by concentration
Except solvent obtains liquid L.
4) hydrochloric acid of liquid L, tetrabutylammonium chloride and mass fraction concentration 20% mix, and control reaction temperature is 108
DEG C, reaction pressure is 4 atmospheric pressure, and reaction 80min terminates, pours into trash ice after system is cooled down, white solid 2,4 is precipitated,
5- trifluoro benzene acetic acid.In the step, the mass ratio of liquid L and tetrabutylammonium chloride is 1:0.1;The mass ratio of liquid L and hydrochloric acid
For 1:6.5.
Molar yield 99.2%, GC purity 98.7%.
Embodiment 2
The synthetic method of 2,4,5- trifluoro benzene acetic acids, comprising the following steps:
1) potassium cyanide, potassium hydroxide, odium stearate and deionized water are mixed, obtains mixture M 1, potassium cyanide, hydroxide
The molar ratio of potassium, odium stearate and deionized water is 1:0.12:0.05:10.
2) under nitrogen protection, catalyst and nitrobenzene are mixed, control reaction temperature is 100 DEG C, and reaction pressure is 3
Atmospheric pressure is first added dropwise methylene chloride, when the dripping quantity of methylene chloride reaches itself 5%, starts to be added dropwise after stirring 30min
1,2,4- trifluoro-benzene, and keep 1,2,4- trifluoro-benzenes and methylene chloride Drop volumes rate equal.
After completion of dropwise addition, control reaction temperature is 130 DEG C, and reaction pressure is 4 atmospheric pressure, reacts 1h, obtains mixture
M2, control reaction temperature are 50 DEG C, and reaction pressure is 3 atmospheric pressure, and mixture M 1 is added dropwise, and drop finishes, and control reaction temperature is 70
DEG C, reaction pressure is 5 atmospheric pressure, and the reaction was continued, and 3~5h terminates, and cools down and obtains mixture M 3 after being down to room temperature.
In the step, the molar ratio of 1,2,4- trifluoro-benzene and methylene chloride is 1:1, the use of 1,2,4- trifluoro-benzene and nitrobenzene
For amount than being 1g:3mL, the molar ratio of 1,2,4- trifluoro-benzene and potassium cyanide is 1:1, and the mass ratio of 1,2,4- trifluoro-benzene and catalyst is
1:0.15。
The step used catalyst the preparation method comprises the following steps: by HY-25 type zeolite, zinc chloride be added mass fraction 5% salt
In aqueous acid, 2h is impregnated, is then evaporated with Rotary Evaporators concentration, obtained solid is obtained in 160 DEG C of baking activation 5h, chlorination
The mass ratio of zinc, zeolite and aqueous hydrochloric acid solution is 1:3:8.
3) mixture M 3 is filtered to remove insoluble matter, be layered, organic phase after washing, anhydrous magnesium sulfate are dry, steam by concentration
Except solvent obtains liquid L.
4) hydrochloric acid of liquid L, tetrabutylammonium chloride and mass fraction concentration 20% mix, and control reaction temperature is 80 DEG C,
Reaction pressure is 3 atmospheric pressure, and reaction 1h terminates, pours into trash ice after system is cooled down, and 2,4,5- trifluoro of white solid is precipitated
Phenylacetic acid.In the step, the mass ratio of liquid L and activating agent A2 are 1:0.08;The mass ratio of liquid L and hydrochloric acid is 1:5.
Molar yield 98.2%, GC purity 98.1%.
Embodiment 3
The synthetic method of 2,4,5- trifluoro benzene acetic acids, comprising the following steps:
1) Cymag, sodium hydroxide, odium stearate and deionized water are mixed, obtains mixture M 1, Cymag, hydroxide
The molar ratio of sodium, odium stearate and deionized water is 1:0.2:0.08:15.
2) under protection of argon gas, catalyst and nitrobenzene are mixed, control reaction temperature is 120 DEG C, and reaction pressure is 5
Atmospheric pressure is first added dropwise methylene chloride, when the dripping quantity of methylene chloride reaches itself 5%, starts to be added dropwise after stirring 50min
1,2,4- trifluoro-benzene, and keep 1,2,4- trifluoro-benzenes and methylene chloride Drop volumes rate equal.
After completion of dropwise addition, control reaction temperature is 150 DEG C, and reaction pressure is 8 atmospheric pressure, reacts 2h, obtains mixture
M2, control reaction temperature are 70 DEG C, and reaction pressure is 4 atmospheric pressure, and mixture M 1 is added dropwise, and drop finishes, and control reaction temperature is 80
DEG C, reaction pressure is 7 atmospheric pressure, and the reaction was continued, and 5h terminates, and cools down and obtains mixture M 3 after being down to room temperature.
In the step, the molar ratio of 1,2,4- trifluoro-benzene and methylene chloride is 1:1.05,1,2,4- trifluoro-benzene and nitrobenzene
Amount ratio be 1g:5.5mL, the molar ratio of 1,2,4- trifluoro-benzene and Cymag is 1:1.08,1,2,4- trifluoro-benzene and catalyst
Mass ratio be 1:0.22.
The step used catalyst the preparation method comprises the following steps: by HY-50 type zeolite, zinc chloride be added mass fraction 5% salt
In aqueous acid, 3h is impregnated, is then evaporated with Rotary Evaporators concentration, obtained solid is obtained in 180 DEG C of baking activation 6h, chlorination
The mass ratio of zinc, zeolite and aqueous hydrochloric acid solution is 1:5:15.
3) mixture M 3 is filtered to remove insoluble matter, be layered, organic phase after washing, anhydrous sodium sulfate are dry, steam by concentration
Except solvent obtains liquid L.
4) hydrochloric acid of liquid L, tetrabutylammonium chloride and mass fraction concentration 20% mix, and control reaction temperature is 110
DEG C, reaction pressure is 5 atmospheric pressure, and reaction 1.5h terminates, pours into trash ice after system is cooled down, and white solid 2,4,5- is precipitated
Trifluoro benzene acetic acid.In the step, the mass ratio of liquid L and activating agent A2 are 1:0.11;The mass ratio of liquid L and hydrochloric acid is 1:7.
Molar yield 98.7%, GC purity 98.5%.
Embodiment 4
System is added in 1,2,4- trifluoro-benzene in advance, then is starting that other reaction conditions of methylene chloride and material use are added dropwise
Than same embodiment 1, molar yield 35.3%, GC purity 55.2%.
Embodiment 5
Tetrabutylammonium chloride is not added, other reaction conditions and material are with than same embodiment 1, and molar yield 75.5%, GC is pure
Degree 80.3%.
Embodiment 6
Catalyst is not added, target product is not detected with than same embodiment 1 in other reaction conditions and material.
Embodiment 7
Reaction pressure before starting 1,2,4- trifluoro-benzene of dropwise addition is set as 2 atmospheric pressure, and reaction temperature is set as 80 DEG C, other
Reaction condition and material are with than same embodiment 1, molar yield 55.2%, GC purity 72.2%.
Embodiment 8
Reaction pressure before starting 1,2,4- trifluoro-benzene of dropwise addition is set as 7 atmospheric pressure, and reaction temperature is set as 150 DEG C,
His reaction condition and material are with than same embodiment 1, molar yield 61.3%, GC purity 69.2%.
Embodiment 9
Reaction pressure after 1,2,4- trifluoro-benzenes and methylene chloride will be added dropwise is set as 2 atmospheric pressure, and reaction temperature is set as
110 DEG C, other reaction conditions and material are with than same embodiment 1, molar yield 65.3%, GC purity 77.1%.
Embodiment 10
Reaction pressure after 1,2,4- trifluoro-benzenes and methylene chloride will be added dropwise is set as 12 atmospheric pressure, and reaction temperature is set as
180 DEG C, other reaction conditions and material are with than same embodiment 1, molar yield 72.1%, GC purity 82.1%.
The identification of 11 product structure of embodiment
By taking 1 product of embodiment as an example, structural analysis data are as follows.
1) fusing point
123~124 DEG C, 121~125 DEG C of literature value
2) mass spectrum
Molecular ion peak 190.
3) nucleus magnetic hydrogen spectrum is analyzed
1H-NMR (DMSO): δ 11.5 (1H), δ 6.82 (1H), δ 6.58 (1H), δ 3.72 (1H).Various hydrogen are in product structure
On ownership such as following formula:
Nmr analysis, product structure meet object, i.e., 2,4,5- trifluoro benzene acetic acids.
Claims (5)
1. the synthetic method of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate, which is characterized in that urging 1,2,4- trifluoro-benzene
React to obtain 2,4,5- trifluoro benzene acetic acids, the reaction process with methylene chloride, cyanide under the action of agent are as follows:
1) cyanide, alkali, activating agent A1 and deionized water are mixed, obtains mixture M 1;
2) in the case where protecting gas shielded, catalysts and solvents S is mixed, control reaction temperature is 100~120 DEG C, reaction pressure 3
~5 atmospheric pressure after stirring 30~50min, start 1,2,4- trifluoro-benzene of dropwise addition and methylene chloride, and drop finishes, and controls reaction temperature
It is 130~150 DEG C, reaction pressure is 4~8 atmospheric pressure, reacts 1~2h, obtains mixture M 2, control reaction temperature is 50~
70 DEG C, reaction pressure is 3~4 atmospheric pressure, and mixture M 1 is added dropwise, and drop finishes, and control reaction temperature is 70~80 DEG C, reaction pressure
For 5~7 atmospheric pressure, the reaction was continued, and 3~5h terminates, and cools down and obtains mixture M 3 after being down to room temperature;
3) mixture M 3 is filtered to remove insoluble matter, be layered, after washing, desiccant dryness, concentration is evaporated off solvent and obtains organic phase
Liquid L;
4) liquid L, activating agent A2 and acid-mixed is even, control reaction temperature is 80~110 DEG C, and reaction pressure is 3~5 atmosphere
Pressure, 1~1.5h of reaction terminate, pour into trash ice after system is cooled down, and 2,4,5- trifluoro benzene acetic acid of white solid is precipitated.
2. the synthetic method of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate as described in claim 1, which is characterized in that institute
State catalyst the preparation method comprises the following steps: zeolite, zinc chloride are added in aqueous hydrochloric acid solution, are impregnated 2~3h, are then used Rotary Evaporators
Concentration is evaporated, and obtained solid activates 5~7h in 160~200 DEG C of bakings and obtains;The zeolite is HY-25, HY-50 or HY-98
Type;The mass ratio of the zinc chloride, zeolite and aqueous hydrochloric acid solution is 1:(3~5): (8~15);The concentration of the aqueous hydrochloric acid solution
For mass fraction 5%.
3. the synthetic method of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate as described in claim 1, which is characterized in that institute
Stating cyanide is Cymag or potassium cyanide;The alkali is sodium hydroxide or potassium hydroxide;The activating agent A1 is stearic acid
Sodium;The activating agent A2 is tetrabutylammonium chloride;The protection gas is nitrogen or argon gas;The solvent S is nitrobenzene;It is described
Acid is the hydrochloric acid of mass fraction concentration 20%;The desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate.
4. the synthetic method of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate as described in claim 1, which is characterized in that institute
State the dropwise addition mode of 1,2,4- trifluoro-benzenes and methylene chloride are as follows: methylene chloride is first added dropwise, the dripping quantity to methylene chloride reaches certainly
Body 5% when, start 1,2,4- trifluoro-benzene of dropwise addition;The 1,2,4- trifluoro-benzene and methylene chloride drop rate are equal.
5. the synthetic method of 2,4,5- trifluoro benzene acetic acid of sitagliptin intermediate as described in claim 1, which is characterized in that institute
The molar ratio for stating 1,2,4- trifluoro-benzene and methylene chloride is 1:(1~1.05);Described is the 1,2,4- trifluoro-benzene and cyanide
Molar ratio be 1:(1~1.08);The mass ratio of the 1,2,4- trifluoro-benzene and catalyst is 1:(0.15~0.22);Described 1,
The amount ratio of 2,4- trifluoro-benzene and solvent S are 1g:(3~5.5) mL;The cyanide, alkali, activating agent A1 and deionized water are rubbed
You are than being 1:(0.12~0.2): (0.05~0.08): (10~15);The mass ratio of the liquid L and activating agent A2 is 1:
(0.08~0.11);The mass ratio of the liquid L and acid is 1:(5~7).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910331211.6A CN110128258B (en) | 2019-04-24 | 2019-04-24 | Synthetic method of sitagliptin intermediate 2,4, 5-trifluorophenylacetic acid |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910331211.6A CN110128258B (en) | 2019-04-24 | 2019-04-24 | Synthetic method of sitagliptin intermediate 2,4, 5-trifluorophenylacetic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110128258A true CN110128258A (en) | 2019-08-16 |
CN110128258B CN110128258B (en) | 2022-04-01 |
Family
ID=67571132
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910331211.6A Expired - Fee Related CN110128258B (en) | 2019-04-24 | 2019-04-24 | Synthetic method of sitagliptin intermediate 2,4, 5-trifluorophenylacetic acid |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110128258B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111393282A (en) * | 2020-05-21 | 2020-07-10 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
WO2022099439A1 (en) * | 2020-11-10 | 2022-05-19 | 杭州臻挚生物科技有限公司 | Preparation method for 2,4,5-trifluorophenylacetic acid |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040077901A1 (en) * | 2002-10-08 | 2004-04-22 | Norihiro Ikemoto | Process for the synthesis of trifluorophenylacetic acids |
CN1749232A (en) * | 2005-09-29 | 2006-03-22 | 上海康鹏化学有限公司 | Process for preparing 2,4,5-triflorophenylacetic acid |
CN101092345A (en) * | 2007-04-04 | 2007-12-26 | 浙江永太化学有限公司 | Method for preparing 2,4,5 trifluorobenzene acetic acid |
CN101659611A (en) * | 2009-09-28 | 2010-03-03 | 浙江永太科技股份有限公司 | Method for preparing 2, 4, 5-trifluoro-phenylacetic-acid |
CN102690166A (en) * | 2012-06-12 | 2012-09-26 | 南通施美康药物化学有限公司 | Preparation methods of 2, 4, 5-trifluoro-benzyl chloride and 2, 4, 5-trifluoro-phenylacetic acid |
CN106748716A (en) * | 2016-11-14 | 2017-05-31 | 江苏汉阔生物有限公司 | A kind of new method for preparing 2,4,5 trifluoro benzene acetic acids |
-
2019
- 2019-04-24 CN CN201910331211.6A patent/CN110128258B/en not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040077901A1 (en) * | 2002-10-08 | 2004-04-22 | Norihiro Ikemoto | Process for the synthesis of trifluorophenylacetic acids |
CN1749232A (en) * | 2005-09-29 | 2006-03-22 | 上海康鹏化学有限公司 | Process for preparing 2,4,5-triflorophenylacetic acid |
CN101092345A (en) * | 2007-04-04 | 2007-12-26 | 浙江永太化学有限公司 | Method for preparing 2,4,5 trifluorobenzene acetic acid |
CN101659611A (en) * | 2009-09-28 | 2010-03-03 | 浙江永太科技股份有限公司 | Method for preparing 2, 4, 5-trifluoro-phenylacetic-acid |
CN102690166A (en) * | 2012-06-12 | 2012-09-26 | 南通施美康药物化学有限公司 | Preparation methods of 2, 4, 5-trifluoro-benzyl chloride and 2, 4, 5-trifluoro-phenylacetic acid |
CN106748716A (en) * | 2016-11-14 | 2017-05-31 | 江苏汉阔生物有限公司 | A kind of new method for preparing 2,4,5 trifluoro benzene acetic acids |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111393282A (en) * | 2020-05-21 | 2020-07-10 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
WO2022099439A1 (en) * | 2020-11-10 | 2022-05-19 | 杭州臻挚生物科技有限公司 | Preparation method for 2,4,5-trifluorophenylacetic acid |
Also Published As
Publication number | Publication date |
---|---|
CN110128258B (en) | 2022-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105669398B (en) | Produce the device and method of benzaldehyde | |
CN110128258A (en) | The synthetic method of sitagliptin intermediate 2,4,5- trifluoro benzene acetic acid | |
CN102516122B (en) | Environment friendly method for preparing DMF (Dimethyl Formamide) solution of 2-hydroxy-benzonitril | |
CN101891621A (en) | Compounding method for 3- ethyoxyl-4-ethoxycarbonyl phenylacetic acid | |
CN108358760B (en) | Application of metalate/palladium compound catalytic reduction system in debenzylation reaction and deuteration reaction | |
CN106892808A (en) | A kind of preparation method of 2,4 dichlorphenoxyacetic acids | |
CN101659611B (en) | Method for preparing 2, 4, 5-trifluoro-phenylacetic-acid | |
CN103396318B (en) | Synthetic process for 2,4-dinitroanisole | |
CN109970580B (en) | Extraction and preparation method of R-3-aminobutanol | |
CN1942422B (en) | Method for producing hydrate of fluoroalkyl ketone | |
CN105130869B (en) | A kind of synthetic method of the ketone of Entresto intermediates (S) 5 (carbonyl of biphenyl 4) pyrrolidines 2 | |
CN102417486B (en) | Method for synthesizing valsartan | |
CN107827742A (en) | A kind of CO2The method that direct carboxylation method prepares aromatic acid | |
CN114835605B (en) | Synthesis method of diphenyl ketone hydrazone | |
CN101575348A (en) | Method for synthesizing beta-sodium glycero-phosphate | |
CN101941905B (en) | Method for producing ester of 2, 4-dichlorphenoxyacetic acid | |
CN105237340B (en) | Novel synthesis method for 4,4,4-trifluorobutanol | |
CN101362752A (en) | Synthesis method of lamivudine intermediate | |
CN112174798B (en) | Synthesis method of Sakuba/valsartan sodium LCZ696 | |
CN102924362A (en) | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride | |
CN102838482B (en) | Preparation method of 3,6-dichlorosalicylic acid | |
CN106966940B (en) | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyl -2S- cyano methyl acridine | |
CN106588584A (en) | Dehydration method for ether solvent | |
CN104557512B (en) | A kind of 3-(bromo phenyl)-2, the preparation method of 2 '-difluoro propionic acid | |
CN103772151A (en) | Preparation method of 2-methyl-3-phenyl benzyl alcohol |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220401 |
|
CF01 | Termination of patent right due to non-payment of annual fee |