CN103483218B - Preparation method for 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine - Google Patents
Preparation method for 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine Download PDFInfo
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- CN103483218B CN103483218B CN201310437076.6A CN201310437076A CN103483218B CN 103483218 B CN103483218 B CN 103483218B CN 201310437076 A CN201310437076 A CN 201310437076A CN 103483218 B CN103483218 B CN 103483218B
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- hydrazine
- chloracetyl
- trifluoroacetyl
- binding agent
- preparation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- DYKIVKLXFDNBMY-UHFFFAOYSA-N n'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide Chemical compound FC(F)(F)C(=O)NNC(=O)CCl DYKIVKLXFDNBMY-UHFFFAOYSA-N 0.000 title abstract 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 10
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 229940059260 amidate Drugs 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical group CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 3
- 239000000543 intermediate Substances 0.000 abstract 2
- 238000004134 energy conservation Methods 0.000 abstract 1
- 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 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](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=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 229960004115 sitagliptin phosphate Drugs 0.000 description 2
- 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 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of medical intermediates, in particular to a preparation method for a new diabetes drug sitagliptin intermediate 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine. The preparation method comprises the steps as follows: hydrazine hydrate is used as a raw material, and reacts with trifluoroacetic acid ethyl ester in a solvent to obtain trifluoroacetyl single hydrazine, then the trifluoroacetyl single hydrazine reacts with chloroacetyl chloride under the action of an acid-binding agent to obtain a crude 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine reaction liquid, and finally, a water layer of the reaction liquid is removed, and the reaction liquid is directly concentrated to obtain the finished product 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine. According to the invention, the raw material is easy to obtain, the cost is low, environmental protection and energy conservation are realized, the process is simple, the industrialization can be realized easily, the product yield is high, the purity is good, the quality is stable, and the 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine completely meets the use requirement of being used as a medical intermediate.
Description
Technical field
The present invention relates to Novel diabetes new drug-sitagliptin intermediate technology field, be specifically related to 1-(chloracetyl)-2-(trifluoroacetyl group) the preparation method field of hydrazine.
Background technology
1-(chloracetyl)-2-(trifluoroacetyl group) important intermediate of new drug sitagliptin phosphate of Jing Shi Merck company.Sitagliptin phosphate is the first medicine that DDP-4 inhibitor is applied to treatment type II diabetes, within 2006, has just obtained the approval of FDA (Food and Drug Adminstration) (FDA).The action character of this medicine is, it can suppress DDP-4, improve the activity of GLP-1 and GIP in blood plasma, its content of slight increase, feeling sick of producing because of GLP-1 too high levels can not be caused while performance blood sugar reducing function, the side effects such as vomiting, separately because it can stimulate insulin secretion, there is blood sugar dependency, therefore greatly can reduce the hypoglycemic incidence of oral antidiabetic drug, this medicine is while stimulating insulin secretion simultaneously, hunger sensation can be alleviated, body weight can not be made to increase, blood fat and blood pressure are also beneficial to, be very suitable for glycemic control bad and hypoglycemic diabetic subject often occurs use.
At present, the 1-(chloracetyl of domestic and international report)-2-(trifluoroacetyl group) hydrazine synthetic route is less, WO2005/003135 reports with the aqueous solution of hydrazine as starting raw material, trifluoroacetyl list hydrazine is obtained with Trifluoroacetic Acid Ethyl Ester amidate action under solvent acetonitrile exists, then under the effect of acid binding agent sodium hydroxide, 1-(chloracetyl is obtained by reacting with chloroacetyl chloride)-2-(trifluoroacetyl group) hydrazine crude product reaction solution, then water and ethanol are removed in molecular distillation, add a large amount of acetonitriles again, cross and filter inorganic salt sodium-chlor, finally obtain finished product 1-(chloracetyl except after desolventizing)-2-(trifluoroacetyl group) hydrazine.
This technological line last handling process is complicated, use a large amount of acetonitrile solvent, and acetonitrile price is high in reaction process, and toxicity is large, and aqueous acetonitrile is large, and repeatedly need concentrate and anhydrate, cause cost significantly to rise, the production cycle is long, is unfavorable for suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of high yield, low stain, be easy to the 1-(chloracetyl realizing suitability for industrialized production)-2-(trifluoroacetyl group) preparation method of hydrazine.For this reason, by the following technical solutions, it is realized by following reaction in the present invention:
There is amidate action in the presence of solvent and obtain trifluoroacetyl list hydrazine in hydrazine hydrate and Trifluoroacetic Acid Ethyl Ester; 1-(chloracetyl is obtained with chloroacetyl chloride generation amidate action again under acid binding agent effect)-2-(trifluoroacetyl group) hydrazine crude product reaction solution, directly concentrate after reaction solution branch vibration layer and obtain finished product 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine.
As one embodiment of the invention, solvent used is one or more the mixture in methyl tertiary butyl ether, ether, 2-methyltetrahydrofuran, tetrahydrofuran (THF), glycol dimethyl ether, ethylene glycol diethyl ether, isopropyl ether.
As a preferred embodiment of the present invention, solvent used is preferably methyl tertiary butyl ether.
As one embodiment of the invention, acid binding agent used is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or sodium bicarbonate.
As a preferred embodiment of the present invention, acid binding agent used is preferably sodium hydroxide.
As one embodiment of the invention, in reaction, the mol ratio of hydrazine hydrate and Trifluoroacetic Acid Ethyl Ester, chloroacetyl chloride, acid binding agent is 1:(1.0 ~ 2.0): (1.0 ~ 2.0): (1.0 ~ 2.0).
As a preferred embodiment of the present invention, in reaction, the mol ratio of hydrazine hydrate and Trifluoroacetic Acid Ethyl Ester, chloroacetyl chloride, acid binding agent is preferably 1:(1.1 ~ 1.3): (1.1 ~ 1.2): (1.1 ~ 1.3).
As one embodiment of the invention, in reaction, the mass ratio of hydrazine hydrate and solvent is 1:(5 ~ 20).
As a preferred embodiment of the present invention, in reaction, the mass ratio of hydrazine hydrate and solvent is preferably 1:(8 ~ 10).
Owing to adopting technical scheme of the present invention, especially use methyl tert-butyl ether solvent and simple post-processing technology, obtain product 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine; this technological line not only yield is high; environmental friendliness, and good product purity, steady quality.
Embodiment
Embodiment 1 1-(chloracetyl)-2-(trifluoroacetyl group) preparation of hydrazine
Agitator is being housed, and in the 1L there-necked flask of thermometer, drop into methyl tertiary butyl ether 400ml, 60% hydrazine hydrate 41.6g (0.5mol), adds Trifluoroacetic Acid Ethyl Ester 85.2g (0.6mol) under stirring, reacts 1 hour under room temperature.Drip 63.3g(0.56mol again) chloroacetyl chloride, then adjust PH with 46.4g50% sodium hydroxide solution, control reaction solution PH=6 ~ 7.Chloroacetyl chloride drips rear continuation incubation at room temperature 2 hours, and reaction solution leaves standstill, branch vibration layer, and methyl tertiary butyl ether 385g is reclaimed in simple distillation, obtains 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine 99.5g, yield 97.3%, purity 98%.
Embodiment 2 1-(chloracetyl)-2-(trifluoroacetyl group) preparation of hydrazine
By embodiment 1, replace t-butyl methyl ether solution with 400ml tetrahydrofuran (THF), reaction terminates rear recovery tetrahydrofuran (THF) 382ml, obtains 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine 95.2g, yield 93.1%, purity 97.5%.
Embodiment 3 1-(chloracetyl)-2-(trifluoroacetyl group) preparation of hydrazine
By embodiment 1, Trifluoroacetic Acid Ethyl Ester reduces to 78.1g(0.55mol), methyl tertiary butyl ether 384g is reclaimed in reaction, obtains 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine 97.2g, yield 95 %, purity 97.0%.
Embodiment 4 1-(chloracetyl)-2-(trifluoroacetyl group) preparation of hydrazine
By embodiment 1, with 65g50%(0.58mol) potassium hydroxide solution replaces 50% sodium hydroxide solution, methyl tertiary butyl ether 384g is reclaimed in reaction, obtains 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine 99.2g, yield 97 %, purity 97.9%.
Claims (2)
1. a preparation method for 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine, is characterized in that, it is realized by following reaction:
There is amidate action in the presence of solvent and obtain trifluoroacetyl list hydrazine in hydrazine hydrate and Trifluoroacetic Acid Ethyl Ester, under acid binding agent effect, obtain 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine crude product reaction solution with chloroacetyl chloride generation amidate action again, directly concentrate after reaction solution branch vibration layer and obtain finished product 1-(chloracetyl)-2-(trifluoroacetyl group) hydrazine;
Wherein said solvent is methyl tertiary butyl ether; Described acid binding agent is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or sodium bicarbonate;
The mol ratio of hydrazine hydrate and Trifluoroacetic Acid Ethyl Ester, chloroacetyl chloride, acid binding agent is 1:(1.1 ~ 1.3): (1.1 ~ 1.2): (1.1 ~ 1.3);
The mass ratio of hydrazine hydrate and solvent is 1:(8 ~ 10).
2. method according to claim 1, is characterized in that the acid binding agent described in reacting is sodium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310437076.6A CN103483218B (en) | 2013-09-24 | 2013-09-24 | Preparation method for 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine |
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| CN201310437076.6A CN103483218B (en) | 2013-09-24 | 2013-09-24 | Preparation method for 1-(chloracetyl)-2-(trifluoroacetyl) hydrazine |
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| CN103483218B true CN103483218B (en) | 2015-06-03 |
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| CN104788338A (en) * | 2014-10-17 | 2015-07-22 | 上海益生源药业有限公司 | Preparation method of benserazide hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005003135A1 (en) * | 2003-06-24 | 2005-01-13 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005003135A1 (en) * | 2003-06-24 | 2005-01-13 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| 3- 三氟甲基-5,6,7,8- 四氢-1,2,4- 三唑[4,3-α] 吡嗪盐酸盐的制备;田志高 等;《中国医药工业杂志》;20101130;第41卷(第11期);805-806页 * |
| 5,6,7,8-四氢-3-三氟甲基-1,2,4-三唑并[4,3-a]吡嗪盐酸盐的合成;朱高峰 等;《广州化工》;20130731;第41卷(第13期);97-98页 * |
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