CN102898387B - Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine - Google Patents
Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine Download PDFInfo
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- CN102898387B CN102898387B CN201210364209.7A CN201210364209A CN102898387B CN 102898387 B CN102898387 B CN 102898387B CN 201210364209 A CN201210364209 A CN 201210364209A CN 102898387 B CN102898387 B CN 102898387B
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- 0 FC(c1[*+]nc2[n]1CCNC2)(F)F Chemical compound FC(c1[*+]nc2[n]1CCNC2)(F)F 0.000 description 1
- RKIDLJBEMIARHI-UHFFFAOYSA-N O=C(C(F)(F)F)N/N=C1\NCCNC1 Chemical compound O=C(C(F)(F)F)N/N=C1\NCCNC1 RKIDLJBEMIARHI-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a tubular continuous production technology for generating six-membered heterocyclic compounds by means of dehydration cyclization, particularly N-((2Z)-piperazine-2-subunit)-2, 2, 2-trifluoroacetyl hydrazine (1) by taking 5-trifluoromethyl-2-chloromethyl methyl ether-1, 3, 4-NBD-F as a raw material in the presence of ethidene diamine. The channelized method for continuously producing 1 comprises the following steps of: firstly, putting methanol solution of ethidene diamine into one storage tank, putting the methanol solution of raw material NBD-F into the other storage tank, and keeping at a proper temperature T1; directly charging the methanol solution in the two storage tanks into a tubular reactor according to a certain proportion, and controlling the reaction temperature in the tubular reactor at T2, and the reaction time at t; and charging the obtained reaction liquid into a crystallization kettle to be cooled to separate out white solid. The synthesis technology provided by the invention has the advantages of being simple in device, good in technological safety, mild in reaction conditions, easy to control, continuous in production, environment-friendly, high in yield, stable in product quality and the like.
Description
(1) technical field
The present invention relates to a kind of is that raw material is under the existence of quadrol with 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole, dehydration condensation generates 6-membered heterocyclic compound, the particularly tubular type continuous production processes of N-[(2Z)-piperazine-2-subunit]-2,2,2-trifluoroacetyl hydrazines.
(2) background technology
Sitagliptin is a kind of dipeptidyl peptidase-IV (DDP-IV) inhibitor, in 2006 by FDA approval listing, is used for the treatment of type ii diabetes.3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-α] pyrazine hydrochloride (formula 2) is the important intermediate preparing sitagliptin, and the relationship between quality of product is to the height of whole sitagliptin cost.Compound (formula 2) can be synthesized through acidifying cyclization by N-[(2Z)-piperazine-2-subunit]-2,2,2-trifluoroacetyl hydrazines (formula 1).
The synthetic method of sitagliptin key intermediate (formula 2) mainly contains following three kinds: 1) shortening method.With 2-chloropyrazine for raw material, with hydrazine hydrate nucleo philic substitution reaction, acidylate, cyclization and Pd(C) reduction reaction obtains target product, its operational path is complicated, Material synthesis difficulty is large, cost is higher, total recovery is 26%(Org. Process Res. Dev. 2005,9 (5), 634-639; US 6699871).2) cyclization method.Chinese patent CN 101973997A is with 2-piperazinones through sulfiding reagent sulfuration, and obtain 2-piperidines thioketones, then react cyclization with trifluoroacetyl hydrazine through Pellizzari, acidifying salify obtains target product 1, and yield is 82.5%.The disagreeableness sulfiding reagent of environment is used in reaction and under nitrogen protection, condition is harsher.3) are that starting raw material synthesizes Yi oxadiazole.World patent WO 200408537A1 and WO2005003135A1 describes with 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole 3 for raw material, and by obtaining 1 with reacting ethylenediamine, then closed loop salify obtains 2 under hydrochloric acid effect, and total recovery is 72%.The method is the main method of current domestic production trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine.
The method drips 3 in quadrol 4 at-20 DEG C, and its amount of substance is than being 1:3.44, and be incubated 1 hour after adding, adding ethanol is slowly warming up to-5 DEG C again, and after filtering, washing with alcohol obtains product 1, and the yield of 1 is only 72%.This reaction is very strict to temperature control requirement, and energy consumption is large, and the reaction times is longer, and yield is lower.
Canalization produces the cost that N-[(2Z)-piperazine-2-subunit]-2,2,2-trifluoroacetyl hydrazines (1) can reduce sitagliptin greatly, and energy consumption is only 1/10th of still reaction, and the reaction times is short, and production capacity can significantly improve.
(3) summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind ofly realize continuous prodution, the synthetic method of production environment cleans, yield is high and security is good sitagliptin key intermediate 1.
To achieve the above object of the invention, the present invention adopts following technical scheme:
The method of a kind of canalization continuous seepage N-as shown in Equation 1 [(2Z)-piperazine-2-subunit]-2,2,2-trifluoroacetyl hydrazines, described method is:
At-20 ~ 40 DEG C, mixed by the methanol solution of 5-trifluoromethyl-2-chloromethyl-1,3, the 4-oxadiazole shown in the methanol solution of the quadrol shown in formula 4 and formula 3, obtain reaction raw materials liquid, the temperature of reaction raw materials liquid remains on-20 ~ 40 DEG C.Then reaction raw materials liquid is added in pipeline reactor, the temperature of reaction controlled in pipeline reactor is-10 ~ 50 DEG C, reaction times is 1 ~ 30 minute, gained reaction solution enters crystallization kettle and is cooled to-10 ~ 0 DEG C, separate out white solid, namely filtering separation solid obtains N-[(2Z)-piperazine-2-subunit]-2 as shown in Equation 1,2,2-trifluoroacetyl hydrazine: in described reaction raw materials liquid, 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole is 1:2.5 ~ 6.0 with the ratio of the amount of substance of quadrol;
Further, preferably at-10 ~ 30 DEG C (most preferably-5 ~ 30 DEG C at), the methanol solution of 5-trifluoromethyl-2-chloromethyl-1,3, the 4-oxadiazole shown in the methanol solution of the quadrol shown in formula 4 and formula 3 is mixed, obtains reaction raw materials liquid.The temperature of reaction raw materials liquid preferably remains on-10 ~ 30 DEG C, most preferably-5 ~ 30 DEG C.
The concentration of the methanol solution of described quadrol is generally 1 ~ 6mol/L, and the concentration of the methanol solution of described 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole is generally 1 ~ 4mol/L.
Temperature of reaction of the present invention is preferably 0 ~ 40 DEG C, most preferably 10 ~ 35 DEG C.Namely reaction can at room temperature be carried out.
Reaction times of the present invention is preferably 1 ~ 15 minute, preferably 1 ~ 10 minute, most preferably 100 ~ 400 seconds.
The cooling temperature of crystallization kettle of the present invention is preferably 0 DEG C.
After reaction of the present invention, feed liquid enters crystallization kettle and adopts mechanical stirring, and crystallization kettle stirs and can separate out N-[(2Z)-piperazine-2-subunit]-2,2,2-trifluoroacetyl hydrazines, then by solid phase by filtering separation out.
Pipeline reactor of the present invention is composed in parallel by one or more pipeline, and every root pipe range is preferably 10 ~ 20 meters, and pipe diameter is preferably 2-8mm.
Compared with original technique, the present invention has the following advantages:
1) original technique need at-20 ~-5 DEG C strict temperature control, Expenses Cost is expensive, and the present invention utilizes pipeline reactor to improve reaction efficiency, reaction can be carried out at normal temperatures, reduce the required control condition of reaction, reduce production cost, and the reaction times is short, can complete reaction within generally only needing 30min, reaction yield is up to more than 90%, product purity is high, substantially increases production efficiency.
2) controlling temperature of charge makes the temperature of reaction raw materials liquid close to the temperature of reaction required, reduces energy consumption consumption.
3) forced-flow of material in pipeline reactor substitutes in still and stirs, and energy simplified apparatus technique, can realize continuous prodution.
In sum, the method for the invention easy control of reaction conditions, can realize continuous prodution, and productive rate reaches 90 more than %, constant product quality, and industrial needs are invested on a small quantity and just can be realized scale operation.
(4) embodiment
With specific embodiment, the present invention will be further described below, but protection scope of the present invention is not limited thereto.
Embodiment 1
By the 5-trifluoromethyl-2-chloromethyl-1 of 1mol/L, 3, the methanol solution of the methanol solution of 4-oxadiazole and the quadrol of 4mol/L by volume 1:1.125 is mixed to get reaction raw materials liquid, the temperature controlling reaction raw materials liquid is 0 DEG C, by liquid delivery pump, solution is delivered to pipeline reactor (pipe range 15 meters, bore 2 millimeters), control velocity in pipes 0.04m/s in reactor, the residence time of solution in pipeline reactor is made to be 375s, temperature of reaction is 10 DEG C, the reaction solution flowed out enters crystallization kettle, stirring is cooled to 0 DEG C of crystallization, filtering separation solid obtains target product, yield 94.3%, purity is 98.1%.
Embodiment 2
By the methanol solution of the methanol solution of 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole of 1mol/L and the quadrol of 6mol/L by volume 1:0.417 be mixed to get reaction raw materials liquid, the temperature controlling reaction raw materials liquid is 10 DEG C.By liquid delivery pump, solution is delivered to pipeline reactor (pipe range 15 meters, bore 4 millimeters), control velocity in pipes 0.1m/s in reactor, temperature of reaction is 20 DEG C, retention time 150s, and the reaction solution of outflow enters crystallization kettle, stirring is cooled to 0 DEG C of crystallization, filtering separation solid obtains target product, yield 86%, and purity is 98.3%.
Embodiment 3
By the methanol solution of the methanol solution of 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole of 1mol/L and the quadrol of 4mol/L by volume 1:1.5 be mixed to get reaction raw materials liquid, the temperature controlling reaction raw materials liquid is 35 DEG C.By liquid delivery pump, solution is delivered to pipeline reactor (pipe range 15 meters, bore 4 millimeters), control velocity in pipes 0.15m/s in reactor, temperature of reaction is 35 DEG C, retention time 100s, and the reaction solution of outflow enters crystallization kettle, stirring is cooled to 0 DEG C of crystallization, filtering separation solid obtains target product, yield 89%, and purity is 97.5%.
Embodiment 4
By the methanol solution of the methanol solution of 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole of 1mol/L and the quadrol of 1mol/L by volume 1:4 be mixed to get reaction raw materials liquid, the temperature controlling reaction raw materials liquid is 30 DEG C.By liquid delivery pump, solution is delivered to pipeline reactor (pipe range 20 meters, bore 8 millimeters), control velocity in pipes 0.05m/s in reactor, temperature of reaction is 40 DEG C, retention time 400s, and the reaction solution of outflow enters crystallization kettle, stirring is cooled to 0 DEG C of crystallization, filtering separation solid obtains target product, yield 90%, and purity is 97.9%.
Embodiment 5
By the methanol solution of the methanol solution of 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole of 1mol/L and the quadrol of 4mol/L by volume 1:1 be mixed to get reaction raw materials liquid, the temperature controlling reaction raw materials liquid is-5 DEG C.By liquid delivery pump, solution is delivered to pipeline reactor (pipe range 10 meters, bore 2 millimeters), control velocity in pipes 0.025m/s in reactor, temperature of reaction is 5 DEG C, retention time 400s, and the reaction solution of outflow enters crystallization kettle, stirring is cooled to 0 DEG C of crystallization, filtering separation solid obtains target product, yield 91%, and purity is 97.0%.
Claims (1)
1. the method for canalization continuous seepage N-as shown in Equation 1 [(2Z)-piperazine-2-subunit]-2,2,2-trifluoroacetyl hydrazines, is characterized in that described method is:
At-5 ~ 30 DEG C, by the 5-trifluoromethyl-2-chloromethyl-1 shown in the methanol solution of the quadrol shown in formula 4 and formula 3,3, the methanol solution mixing of 4-oxadiazole, obtain reaction raw materials liquid, then reaction raw materials liquid is added in pipeline reactor, the temperature of reaction controlled in pipeline reactor is 10 ~ 35 DEG C, reaction times is 1 ~ 15 minute, gained reaction solution enters crystallization kettle and is cooled to-0 DEG C, and separate out white solid, namely filtering separation solid obtains N-[(2Z)-piperazine-2-subunit]-2 as shown in Equation 1,2,2-trifluoroacetyl hydrazine; In described reaction raw materials liquid, 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole is 1:2.5 ~ 6.0 with the ratio of the amount of substance of quadrol;
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Citations (6)
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| US6699871B2 (en) * | 2001-07-06 | 2004-03-02 | Merck & Co., Inc. | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| WO2005003135A1 (en) * | 2003-06-24 | 2005-01-13 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
| CN1972898A (en) * | 2004-04-05 | 2007-05-30 | 默克公司 | Process for the preparation of enantiomerically enriched beta amino acid derivatives |
| CN101175714A (en) * | 2005-01-24 | 2008-05-07 | 默克公司 | Process to chiral beta amino acid derivatives by asymmetric hydrogenation |
| CN101903390A (en) * | 2007-12-20 | 2010-12-01 | 雷迪博士实验室有限公司 | Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof |
| CN101973997A (en) * | 2010-09-30 | 2011-02-16 | 浙江大学 | Method for preparing sitagliptin phosphate side chain |
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6699871B2 (en) * | 2001-07-06 | 2004-03-02 | Merck & Co., Inc. | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| WO2005003135A1 (en) * | 2003-06-24 | 2005-01-13 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
| CN1832949A (en) * | 2003-06-24 | 2006-09-13 | 麦克公司 | Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
| CN1972898A (en) * | 2004-04-05 | 2007-05-30 | 默克公司 | Process for the preparation of enantiomerically enriched beta amino acid derivatives |
| CN101175714A (en) * | 2005-01-24 | 2008-05-07 | 默克公司 | Process to chiral beta amino acid derivatives by asymmetric hydrogenation |
| CN101903390A (en) * | 2007-12-20 | 2010-12-01 | 雷迪博士实验室有限公司 | Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof |
| CN101973997A (en) * | 2010-09-30 | 2011-02-16 | 浙江大学 | Method for preparing sitagliptin phosphate side chain |
Non-Patent Citations (1)
| Title |
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| Synthesis of [1,2,4]Triazolo[4,3-α]piperazines via Highly Reactive Chloromethyloxadiazoles;Jaume Balsells等;《ORGANIC LETTERS》;20050217;第7卷(第6期);第1040页方案3和4a的合成 * |
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Effective date of registration: 20151015 Address after: The city Zhaohui six districts Chao Wang Road Hangzhou City, Zhejiang province 310014 18 Patentee after: Zhejiang University of Technology Patentee after: Zhejiang Changming Pharmaceutical Co., Ltd. Address before: The city Zhaohui six districts Chao Wang Road Hangzhou City, Zhejiang province 310014 18 Patentee before: Zhejiang University of Technology Patentee before: Anhui Changming Pharmaceutical Co.,Ltd. |