CN104628663A - Synthesis method of 3-chloromethyl-1,2,4-triazoline-5-one - Google Patents
Synthesis method of 3-chloromethyl-1,2,4-triazoline-5-one Download PDFInfo
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- CN104628663A CN104628663A CN201310552813.7A CN201310552813A CN104628663A CN 104628663 A CN104628663 A CN 104628663A CN 201310552813 A CN201310552813 A CN 201310552813A CN 104628663 A CN104628663 A CN 104628663A
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- chloromethyl
- triazoline
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- 0 *NC(CCl)O* Chemical compound *NC(CCl)O* 0.000 description 1
- UUPVUMKLHSAVFK-UHFFFAOYSA-N CCC(N1)=CCCNC1=O Chemical compound CCC(N1)=CCCNC1=O UUPVUMKLHSAVFK-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a synthesis method of 3-chloromethyl-1,2,4-triazoline-5-one. The synthesis method comprises two steps: taking chloroacetonitrile, alcohol, and HCl as the raw materials to synthesize iminochloroethylalkyl ether hydrochloride and then carrying out synthesis reactions between iminochloroethylalkyl ether hydrochloride and semicarbazide hydrochloride in an alcohol solvent to obtain 3-chloromethyl-1,2,4-triazoline-5-one. The synthesis method has the advantages of short synthesis route, simple operation, easily-available raw materials, and low cost.
Description
Technical field
The present invention relates to a kind of compou nd synthesis method, particularly relate to a kind of synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone.
Background technology
Aprepitant (Aprepitant), chemistry 5-[[(2R by name, 3S)-2-[(1R)-1-[3, 5-bis-(trifluoromethyl) phenyl] oxyethyl group]-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2, 4-triazole-3-ketone, it is neurokinine-1 (NK-1) receptor antagonist of Merck & Co company of U.S. research and development, 2003 through U.S. FDA approval listing, feel sick for preventing the high acute and Delayed onset caused caused by telling property antineoplastic chemotherapy medicine (comprising High-dose Cisplatin Chemotherapy treatment plan), vomiting.Aprepitant can pass through hemato encephalic barrier, with brain nk 1 receptor selective binding play antiemetic effect [new drug [J] that the yellow eastern woods .2003 U.S. ratifies. Shanghai medicine, 2004,25 (9): 418-422], [Nie Ying, Bi little Ling, You Qidong. aprepitant [J]. Chinese Journal of New Drugs, 2006,15 (3): 238-239].
1,2,4-triazoline-5-ketone derivatives is the very important medicine intermediate of a class, can be used to synthesis multi-medicament effective constituent (API).Especially, 3-chloromethyl-1,2,4-triazoline-5-ketone (chemical compounds I) is one of key intermediate of antiemetic aprepitant, and its production technique quality directly has influence on the synthesis cost of this medicine.Directly synthesizing aprepitant with 3-chloromethyl-1,2,4-triazoline-5-ketone as intermediate is at present most simple and fast, effect the best way in development technology, therefore has good market outlook.
MERCK SHARP & AMP and DOHME LTD company disclose a kind of synthetic method [Dolling, the U.H. of 3-chloromethyl-1,2,4-triazoline-5-ketone in their patent; Wilson, R.D.; Hands, D.; Cottrell, I.F.; Chemical synthesis of morpholine derivs..WO9965900A1,1999; Cowden, C.J.; Process for the preparation of1,2,4-triazolin-5-one derivs.WO0196315,1999; COTTRELL I.F.; DOLLING U.H.; HANDS D.; WILSON R.D.Chemical synthesis of morpholine derivatives.US20020019524A1,2002], concrete route is as follows:
With benzyloxyacetyl chloride and carbamylhydrazine hydrochloride through Schotten – Baumann condensation, cyclisation, hydrolysis, chloro to 3-chloromethyl-1,2,4-triazoline-5-ketone.The obvious defect of this synthetic method is that operational path is oversize, and technique and complex operation complexity, total recovery is low, and the intermediate feed benzyloxyacetyl chloride price of use is high, less economical, therefore current production does not adopt this route substantially.
MERCK SHARP & DOHME company develops with commercial 2-chloro-1 subsequently, 1,1-trimethoxy-ethane is synthesis route [the COWDEN C.J.Process for the preparation of 1 that raw material and carbamylhydrazine hydrochloride enter direct polycondensation cyclisation in methanol solvate and prepare 3-chloromethyl-1,2,4-triazoline-5-ketone, 2,4-triazolin-5-one derivatives, US2003187274A1, US20030311389,2003], as follows:
Cowden is this synthetic method of play-by-play in its paper delivered, and has carried out investigating and analyzing [Cowden, C.J. to the key factor in technique; Et al.; A new synthesis of1,2,4-triazolin-5-ones:Application to the convergent synthesis of an NK1 antagonist.Tetrahedron Lett, 2000,41,44,8661-8664].But although the method simple and fast, the market value of chloro-1,1, the 1-trimethoxy-ethane of intermediate 2-used is higher, causes cost to remain high, and the character of IV also less stable, be difficult to accept for productivity synthesis.SEIBERT K. etc. are on above synthetic method basis, use Urea,amino-methylsulfonic acid (MSA) salt or tosic acid (PTSA) salt and 2-chloro-1 instead, the condensation of 1,1-trimethoxy-ethane, cyclisation, define novel process, speed of reaction is improved significantly [SEIBERT K., SHULTZ C.S., TELLERS D.M., US2006052355A1,, but use Urea,amino-mesylate or tosilate to bring difficulty to the aftertreatment of product and purification refine again 2006].
Summary of the invention
The object of the invention is for overcoming the deficiencies in the prior art, the synthetic method of 3-chloromethyl-1,2, the 4-triazoline-5-ketone that a kind of technical process is short, simple to operate, with low cost and quality product is good is provided.
For reaching above technical purpose, the technical solution used in the present invention is as follows:
A kind of synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone, it comprises the following steps:
(1) compounds Ⅳ (chloromethyl cyanide), compound V (alcohol) and solvent orange 2 A mixing, passes into HCl gas while stirring under the condition of 0 ~ 5 DEG C, reacts 10 ~ 20 hours after ventilation, obtains compound ii (imino-chloroethyl methyl ether hydrochloride) after purifying;
(2) solvent B is warming up to 45 DEG C, add compound ii, react and be cooled to-5 ~ 0 DEG C after 2.5 ~ 6 hours, cross leaching filtrate, this filtrate is warming up to 20 ~ 40 DEG C again, add compound III (carbamylhydrazine hydrochloride), react 35 ~ 72 hours, obtain chemical compounds I, i.e. 3-chloromethyl-1,2,4-triazoline-5-ketone;
Wherein, described compound V is the single hydroxyl alcohol of the alkyl containing 1 ~ 6 carbon atom; The moisture content of the preparation of described compound V is less than 0.5%; Described solvent orange 2 A is methyl tertiary butyl ether or methylene dichloride; Described solvent B is methyl alcohol or ethanol; The molar ratio of described compounds Ⅳ, compound V, HCl and compound III is 1:1 ~ 1.05:1.025 ~ 1.1:0.175 ~ 0.20175.
Further, compound V is stated for methyl alcohol or ethanol; And the moisture content of the preparation of this compound V is less than 0.1%.
Further, the mass ratio that feeds intake of described compounds Ⅳ and solvent orange 2 A is 1:6.62 ~ 10.93.The mass ratio that feeds intake of described compound ii and solvent B is 1:0.34 ~ 2.34.
Preferably, the purifying of described chemical compounds I comprises the following steps: the chemical compounds I that described step (2) obtains gets filtrate a after filtering, described filtrate a is in 50 DEG C of underpressure distillation, gained solid adds solvent C, heated and stirred backflow 30min, filtered while hot gets filtrate b, described filtrate b cooling crystallization, obtain filter residue c after filtration, described filter residue c carries out the chemical compounds I that vacuum-drying obtains white powder; Wherein, described solvent C is Virahol or acetone.
Further, the mass ratio that feeds intake of described compound III and solvent C is 1:7.22 ~ 10.
Particularly, the temperature of described cooling crystallization is-10 ~ 30 DEG C.
Further, described vacuum drying temperature is 30 ~ 60 DEG C.
Compared with prior art, the present invention has following advantage:
A) compared with traditional technology, the present invention has selected the starting material that price is lower, significantly reduces production cost;
B) for whole technical process, present invention reduces synthetic route, improve production efficiency;
C), while simplifying production technique, operation and the quality control of production is more convenient to.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
In magnetic agitation reactor, drop into chloromethyl cyanide 30.2g(0.4mol), methyl alcohol (moisture content is 0.08%) 13.4g(0.42mol) and methyl tertiary butyl ether 300g, cooling down to 0 DEG C, control slowly to pass into dry HCl gas 15g(0.41mol equably below this temperature), after ventilation, stirring reaction 20h, has a large amount of white needle-like crystals to generate as seen; Cross leaching filter residue, namely obtain imino-chloroethyl methyl ether hydrochloride.Methyl alcohol 120g is placed in reactor, stirs and be warming up to 45 DEG C, then add described imino-chloroethyl methyl ether hydrochloride 55g, and maintain 40 times DEG C of stirring reactions 4 hours; Reaction solution stirs and is cooled to 0 DEG C, suction filtration; Filtrate stirring is warming up to 20 DEG C, adds carbamylhydrazine hydrochloride 7.7g(0.07mol), and stirring reaction 72 hours under maintaining this temperature; Reacting liquid filtering, filtrate is evaporated to dry in 45 DEG C ~ 50 DEG C, gained solid adds Virahol 77g, heated and stirred backflow 30min, filtered while hot gets filtrate, and this filtrate, in 0 DEG C of cooling crystallization, obtains white needle crystals, be 3-chloromethyl-1,2,4-triazoline-5-ketone, filters, the solid 3-chloromethyl-1 of white powder is obtained in 50 DEG C of vacuum-dryings, 2,4-triazoline-5-ketone 5.3g, total molar yield (in carbamylhydrazine hydrochloride) is 57%, HPLC purity 99.6%, fusing point 181 DEG C ~ 183 DEG C.
Embodiment 2
In magnetic agitation reactor, drop into chloromethyl cyanide 60.4g(0.8mol), ethanol (moisture content is 0.06%) 36.8g(0.8mol) and methylene dichloride 400g, cooling down to 5 DEG C, control slowly to pass into dry HCl gas 32g(0.88mol equably below this temperature), after ventilation, stirring reaction 10h, has a large amount of white needle-like crystals to generate as seen; Cross leaching filter residue, namely obtain imino-chloroethylethyl ether hydrochloride.Ethanol 300g is placed in reactor, stirs and be warming up to 45 DEG C, then add described imino-chloroethyl methyl ether hydrochloride 128g, and maintain 45 times DEG C of stirring reactions 6 hours; Reaction solution stirs and is cooled to-5 DEG C, suction filtration; Filtrate stirring is warming up to 40 DEG C, adds carbamylhydrazine hydrochloride 15.5g(0.14mol), and stirring reaction 35 hours under maintaining this temperature; Reacting liquid filtering, filtrate is evaporated to dry in 45 DEG C ~ 50 DEG C, gained solid adds acetone 150g, heated and stirred backflow 30min, filtered while hot gets filtrate, and this filtrate is placed in-5 DEG C of cooling crystallizations, obtains white needle crystals, be 3-chloromethyl-1,2,4-triazoline-5-ketone, filters, the solid 3-chloromethyl-1 of white powder is obtained in 55 DEG C of vacuum-dryings, 2,4-triazoline-5-ketone 11.5g, total molar yield (in carbamylhydrazine hydrochloride) is 62%, HPLC purity 99.5%, fusing point 181 DEG C ~ 183 DEG C.
Embodiment 3
In mechanically stirred reactor, drop into chloromethyl cyanide 3.02kg(40mol), methyl alcohol (moisture content is 0.05%) 1.28kg(40mol) and methyl tertiary butyl ether 33kg, cooling down to 2 DEG C, control slowly to pass into dry HCl gas 1.6kg(44mol equably below this temperature), after ventilation, stirring reaction 15h, has a large amount of white needle-like crystals to generate as seen; Cross leaching filter residue, namely obtain imino-chloroethyl methyl ether hydrochloride.Methyl alcohol 18kg is placed in reactor, stirs and be warming up to 45 DEG C, then add described imino-chloroethyl methyl ether hydrochloride 6.1kg, and maintain 45 times DEG C of stirring reactions 2.5 hours; Reaction solution stirs and is cooled to 0 DEG C, suction filtration; Filtrate stirring is warming up to 20 DEG C, adds carbamylhydrazine hydrochloride 0.9kg(8.07mol), and stirring reaction 70 hours under maintaining this temperature; Reacting liquid filtering, filtrate is evaporated to dry in 45 DEG C ~ 50 DEG C, gained solid adds Virahol 6.5kg, heated and stirred backflow 30min, filtered while hot gets filtrate, and this filtrate is placed in 5 DEG C of cooling crystallizations, obtains white needle crystals, be 3-chloromethyl-1,2,4-triazoline-5-ketone, filters, the solid 3-chloromethyl-1 of white powder is obtained in 50 DEG C of vacuum-dryings, 2,4-triazoline-5-ketone 0.64kg, total molar yield (in carbamylhydrazine hydrochloride) is 60%, HPLC purity 99.3%, fusing point 181 DEG C ~ 183 DEG C.
Above-described embodiment is the present invention's preferably embodiment; but be not merely restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be all included within protection scope of the present invention.
Claims (9)
1. the synthetic method of 3-chloromethyl-1,2, a 4-triazoline-5-ketone, it comprises the following steps:
(1) chloromethyl cyanide, alcohol and solvent A mix, under the condition of 0 ~ 5 DEG C, pass into HCl gas while stirring, react 10 ~ 20 hours after ventilation, obtain imino-chloroethyl alkyl oxide hydrochloride after purifying;
(2) solvent B is warming up to 45 DEG C, add described imino-chloroethyl alkyl oxide hydrochloride, react and be cooled to-5 ~ 0 DEG C after 2.5 ~ 6 hours, cross leaching filtrate, this filtrate is warming up to 20 ~ 40 DEG C again, adds carbamylhydrazine hydrochloride, react 35 ~ 72 hours, obtain 3-chloromethyl-1,2,4-triazoline-5-ketone;
Wherein, described alcohol is the single hydroxyl alcohol of the alkyl containing 1 ~ 6 carbon atom;
The moisture content of the preparation of described alcohol is less than 0.5%;
Described solvent orange 2 A is methyl tertiary butyl ether or methylene dichloride;
Described solvent B is methyl alcohol or ethanol;
The molar ratio of described chloromethyl cyanide, alcohol, HCl and carbamylhydrazine hydrochloride is 1:1 ~ 1.05:1.025 ~ 1.1:0.175 ~ 0.20175.
2. the synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone as claimed in claim 1, is characterized in that: described alcohol is methyl alcohol or ethanol.
3. the synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone as claimed in claim 1, is characterized in that: the moisture content of described alcohol formulations is less than 0.1%.
4. the synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone as claimed in claim 1, is characterized in that: the mass ratio that feeds intake of described chloromethyl cyanide and solvent orange 2 A is 1:6.62 ~ 10.93.
5. the synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone as claimed in claim 1, is characterized in that: the mass ratio that feeds intake of described imino-chloroethyl alkyl oxide hydrochloride and solvent B is 1:0.34 ~ 2.34.
6. 3-chloromethyl-1 as claimed in claim 1, 2, the synthetic method of 4-triazoline-5-ketone, it is characterized in that, described 3-chloromethyl-1, 2, the purifying of 4-triazoline-5-ketone comprises the following steps: the 3-chloromethyl-1 that described step (2) obtains, 2, 4-triazoline-5-ketone gets filtrate a after filtering, described filtrate a is in 50 DEG C of underpressure distillation, gained solid adds solvent C, heated and stirred backflow 30min, filtered while hot gets filtrate b, described filtrate b cooling crystallization, filter residue c is obtained after filtration, described filter residue c carries out the 3-chloromethyl-1 that vacuum-drying obtains white powder, 2, 4-triazoline-5-ketone, wherein, described solvent C is Virahol or acetone.
7. the synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone as claimed in claim 6, is characterized in that: the mass ratio that feeds intake of described carbamylhydrazine hydrochloride and solvent C is 1:7.22 ~ 10.
8. the synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone as claimed in claim 6, is characterized in that: the temperature of described cooling crystallization is-10 ~ 30 DEG C.
9. the synthetic method of 3-chloromethyl-1,2,4-triazoline-5-ketone as claimed in claim 6, is characterized in that: described vacuum drying temperature is 30 ~ 60 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503392A (en) * | 2018-12-29 | 2019-03-22 | 凯瑞斯德生化(苏州)有限公司 | A kind of synthetic method of (S) -3- amino -3- (4- chlorphenyl) -1- propyl alcohol |
| CN109553585A (en) * | 2018-12-29 | 2019-04-02 | 凯瑞斯德生化(苏州)有限公司 | A kind of synthetic method of 3- chloromethyl -1,2,4- triazoline -5- ketone |
| CN115636790A (en) * | 2022-10-21 | 2023-01-24 | 池州东升药业有限公司 | Synthetic refining process of naphazoline hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1131864C (en) * | 1998-06-16 | 2003-12-24 | 默克·夏普-道姆公司 | Chemical synthesis of morpholine derivatives |
| WO2004017898A2 (en) * | 2002-08-21 | 2004-03-04 | Merck & Co., Inc. | Process for preparing 3-chloromethyl-1,2,4-triazolin-5-one |
| CN1906155A (en) * | 2003-12-03 | 2007-01-31 | 利奥制药有限公司 | Novel hydroxamic acid esters and pharmaceutical use thereof |
-
2013
- 2013-11-08 CN CN201310552813.7A patent/CN104628663A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1131864C (en) * | 1998-06-16 | 2003-12-24 | 默克·夏普-道姆公司 | Chemical synthesis of morpholine derivatives |
| WO2004017898A2 (en) * | 2002-08-21 | 2004-03-04 | Merck & Co., Inc. | Process for preparing 3-chloromethyl-1,2,4-triazolin-5-one |
| CN1906155A (en) * | 2003-12-03 | 2007-01-31 | 利奥制药有限公司 | Novel hydroxamic acid esters and pharmaceutical use thereof |
Non-Patent Citations (2)
| Title |
|---|
| CAMERON J. COWDEN ET AL: "A new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an NK1 antagonist", 《TETRAHEDRON LETTERS》 * |
| S.M.MCELVA ET AL: "The Preparation of Orthoesters", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503392A (en) * | 2018-12-29 | 2019-03-22 | 凯瑞斯德生化(苏州)有限公司 | A kind of synthetic method of (S) -3- amino -3- (4- chlorphenyl) -1- propyl alcohol |
| CN109553585A (en) * | 2018-12-29 | 2019-04-02 | 凯瑞斯德生化(苏州)有限公司 | A kind of synthetic method of 3- chloromethyl -1,2,4- triazoline -5- ketone |
| CN115636790A (en) * | 2022-10-21 | 2023-01-24 | 池州东升药业有限公司 | Synthetic refining process of naphazoline hydrochloride |
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