CN109553585A - A kind of synthetic method of 3- chloromethyl -1,2,4- triazoline -5- ketone - Google Patents
A kind of synthetic method of 3- chloromethyl -1,2,4- triazoline -5- ketone Download PDFInfo
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- CN109553585A CN109553585A CN201811639765.4A CN201811639765A CN109553585A CN 109553585 A CN109553585 A CN 109553585A CN 201811639765 A CN201811639765 A CN 201811639765A CN 109553585 A CN109553585 A CN 109553585A
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- ketone
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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)
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Abstract
The present invention relates to a kind of 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone is mixed with using chloroacetonitrile, alcohol and solvent A, and compared with traditional handicraft, the present invention has selected the lower raw material of price, significantly reduces production cost.For entire process flow, present invention reduces synthetic routes, improve production efficiency.While simplifying production technology, the operation and quality control of production are easily facilitated.
Description
Technical field
The present invention relates to a kind of synthetic method more particularly to a kind of 3- chloromethyl -1,2, the synthesis sides of 4- triazoline -5- ketone
Method.
Background technique
Aprepitant (Aprepitant), entitled 5- [[(2R, 3S) -2- [(1R) -1- [3,5- bis- (trifluoromethyls) of chemistry
Phenyl] ethyoxyl] -3- (4- fluorophenyl) -4- morpholinyl] methyl] -1,2- dihydro -3H-1,2,4- triazole -3- ketone, are the U.S.
Neurokinine-1 (NK-1) receptor antagonist of Merck&Co company research and development is ratified to list, is used for for 2003 through U.S. FDA
Prevention is high to be caused acute caused by spitting property antineoplastic chemotherapy medicine (including High-dose Cisplatin Chemotherapy therapeutic scheme) and Delayed onset nausea, vomits
It spits.Aprepitant can pass through blood-brain barrier, play antiemetic effect [Huang Donglin .2003 with brain nk 1 receptor selective binding
The Shanghai new drug [J] the medicine of U.S.'s approval, 2004,25 (9): 418-422], [Nie Ying, Bi little Ling, You Qidong aprepitant
[J] Chinese Journal of New Drugs, 2006,15 (3): 238-239].
In view of the above shortcomings, the designer, is actively subject to research and innovation, to found a kind of 3- chloromethyl -1,2,
The synthetic method of 4- triazoline -5- ketone makes it with more the utility value in industry.
Summary of the invention
In order to solve the above technical problems, the object of the present invention is to provide a kind of 3- chloromethyl -1,2,4- triazoline -5- ketone
Synthetic method.
A kind of 3- chloromethyl -1,2 of the invention, the synthetic method of 4- triazoline -5- ketone comprising following steps: (1) chlorine
Acetonitrile, alcohol and solvent A mixing, are passed through HCl gas while stirring under conditions of 0.5 to 10 DEG C, 5 to 25 are reacted after ventilation
Hour, imino group chloroethyl alkyl ether hydrochloride is obtained after purification；(2) solvent B is warming up to 50 DEG C, the imino group chloroethene is added
Base alkyl ether hydrochloride, reaction are cooled to -10 to 3 DEG C after 1 to 7 hour, filter to take filtrate, which is warming up to 15 to 45 again
DEG C, semicarbazide hydrochloride is added, reacts 24 to 82 hours, obtains 3- chloromethyl -1,2,4- triazoline -5- ketone；
Wherein, the alcohol is the single hydroxyl alcohol of the alkyl containing 1~6 carbon atom；The moisture content of the preparation of the alcohol is
0.3% or less；The solvent A is methyl tertiary butyl ether(MTBE) or methylene chloride；The solvent B is methanol or ethyl alcohol；The chloroacetonitrile,
The molar ratio of alcohol, HCl and semicarbazide hydrochloride is 1:1~1.05:1.025~1.1:0.275~0.22175.
Further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the alcohol is methanol
Or ethyl alcohol.
Further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the alcohol formulations
Moisture content be 0.05% or less.
Further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the chloroacetonitrile
The mass ratio that feeds intake with solvent A is 1:5~12.
Further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the imino group
The mass ratio that feeds intake of chloroethyl alkyl ether hydrochloride and solvent B are 1:0.34~2.34.
Further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the 3- chloromethane
The purifying of base -1,2,4- triazoline -5- ketone is the following steps are included: the 3- chloromethyl -1,2,4- triazole that the step (2) obtains
Filtrate a, the filtrate a is taken to be evaporated under reduced pressure after the filtering of quinoline -5- ketone in 50 DEG C, solvent C, heating stirring reflux is added in obtained solid
30min filters to take filtrate b while hot, and the filtrate b cooling crystallization obtains filter residue c after filtering, the filter residue c be dried in vacuo
3- chloromethyl -1,2,4- triazoline -5- the ketone of white powder；Wherein, the solvent C is isopropanol or acetone.
Further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the semicarbazides
Hydrochloride and the mass ratio that feeds intake of solvent C are 1:6~12.
Further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the cooling analysis
Brilliant temperature is -15 to 35 DEG C.
Still further, above-mentioned 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, wherein the vacuum is dry
Dry temperature is 25 to 70 DEG C.
The above description is only an overview of the technical scheme of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, with presently preferred embodiments of the present invention, detailed description is as follows below.
Specific embodiment
With reference to embodiment, the embodiment of the present invention is furthur described in detail.Following embodiment is used for
Illustrate the present invention, but is not intended to limit the scope of the invention.
Embodiment 1
Chloroacetonitrile 30.2g (0.4mol), methanol (moisture content 0.08%) 13.4g are put into magnetic agitation reactor
(0.42mol) and methyl tertiary butyl ether(MTBE) 300g, for cooling down to 0 DEG C, control is slowly equably passed through drying below the temperature
HCl gas 15g (0.41mol), after ventilation, be stirred to react 20h, it is seen that there are a large amount of white needle-like crystals to generate；Filtering
Filter residue is taken to get imino group chloroethyl methyl ether hydrochloride is arrived.Methanol 120g is placed in reaction kettle, stirring is warming up to 50 DEG C,
Then the imino group chloroethyl methyl ether hydrochloride 55g is added, and maintains 40 lower DEG C and is stirred to react 4 hours；Reaction solution stirs
It mixes and is cooled to 0 DEG C, filter；Filtrate stirring is warming up to 20 DEG C, is added semicarbazide hydrochloride 7.7g (0.07mol), and maintain the temperature
It is stirred to react under degree 72 hours；Reaction solution filtering, filtrate are concentrated to dryness in 50 DEG C~50 DEG C, and isopropanol is added in obtained solid
77g, heating stirring reflux 30min, filters to take filtrate, which obtains white needle crystals, i.e., in 0 DEG C of cooling crystallization while hot
For 3- chloromethyl -1,2,4- triazoline -5- ketone, filtering, be dried in vacuo in 50 DEG C white powder chloromethyl -1 solid 3-,
2,4- triazoline -5- ketone 5.3g, total moles yield (in terms of semicarbazide hydrochloride) are 57%, HPLC purity 99.6%, fusing point 181
DEG C~183 DEG C.
Embodiment 2
Chloroacetonitrile 60.4g (0.8mol), ethyl alcohol (moisture content 0.06%) 36.8g are put into magnetic agitation reactor
(0.8mol) and methylene chloride 400g, for cooling down to 5 DEG C, control is slowly equably passed through dry HCl below the temperature
Gas 32g (0.88mol), after ventilation, is stirred to react 10h, it is seen that has a large amount of white needle-like crystals to generate；Filter to take filter
Slag to get arrive imino group chloroethylethyl ether hydrochloride.Ethyl alcohol 300g is placed in reaction kettle, stirring is warming up to 50 DEG C, then
The imino group chloroethyl methyl ether hydrochloride 128g is added, and maintains 45 lower DEG C and is stirred to react 6 hours；Reaction solution stirring drop
Temperature is filtered to -5 DEG C；Filtrate stirring is warming up to 40 DEG C, is added semicarbazide hydrochloride 15.5g (0.14mol), and maintain the temperature
Under be stirred to react 35 hours；Reaction solution filtering, filtrate are concentrated to dryness in 50 DEG C~50 DEG C, and acetone is added in obtained solid
150g, heating stirring reflux 30min, filters to take filtrate while hot, which is placed in -5 DEG C of cooling crystallizations, and it is brilliant to obtain white fine acicular
Body, as 3- chloromethyl -1,2,4- triazoline -5- ketone, filtering, be dried in vacuo in 55 DEG C white powder solid 3- chloromethane
Base -1,2,4- triazoline -5- ketone 11.5g, total moles yield (in terms of semicarbazide hydrochloride) are 62%, HPLC purity 99.5%,
181 DEG C~183 DEG C of fusing point.
Embodiment 3
Chloroacetonitrile 3.02kg (40mol), methanol (moisture content 0.05%) are put into mechanically stirred reactor
1.28kg (40mol) and methyl tertiary butyl ether(MTBE) 33kg, to 2 DEG C, control is slowly equably passed through cooling down below the temperature
Dry HCl gas 1.6kg (44mol), after ventilation, is stirred to react 15h, it is seen that has a large amount of white needle-like crystals to generate；
Filter residue is filtered to take to get imino group chloroethyl methyl ether hydrochloride is arrived.Methanol 18kg is placed in reaction kettle, stirring is warming up to 50
DEG C, the imino group chloroethyl methyl ether hydrochloride 6.1kg is then added, and maintain 45 lower DEG C and be stirred to react 2.5 hours；Instead
It answers liquid stirring to be cooled to 0 DEG C, filters；Filtrate stirring is warming up to 20 DEG C, is added semicarbazide hydrochloride 0.9kg (8.07mol), and tie up
It holds and is stirred to react at this temperature 70 hours；Reaction solution filtering, filtrate are concentrated to dryness in 50 DEG C~50 DEG C, and obtained solid is added
Isopropanol 6.5kg, heating stirring reflux 30min, filters to take filtrate, which is placed in 5 DEG C of cooling crystallizations, obtains white fine needle while hot
Shape crystal, as 3- chloromethyl -1,2,4- triazoline -5- ketone, filtering, be dried in vacuo in 50 DEG C white powder solid 3-
Chloromethyl -1,2,4- triazoline -5- ketone 0.64kg, total moles yield (in terms of semicarbazide hydrochloride) are 60%, HPLC purity
99.3%, 181 DEG C~183 DEG C of fusing point.
It can be seen that after applying the present invention by above-mentioned character express, gather around and have the following advantages:
1, compared with traditional handicraft, the present invention has selected the lower raw material of price, significantly reduces production cost.
2, for entire process flow, present invention reduces synthetic routes, improve production efficiency.
3, while simplifying production technology, the operation and quality control of production are easily facilitated.
The above is only a preferred embodiment of the present invention, it is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (9)
1. a kind of 3- chloromethyl -1,2, the synthetic method of 4- triazoline -5- ketone, it is characterised in that the following steps are included: (1) chloroethene
Nitrile, alcohol and solvent A mixing, are passed through HCl gas while stirring under conditions of 0.5 to 10 DEG C, and it is small that 5 to 25 are reacted after ventilation
When, imino group chloroethyl alkyl ether hydrochloride is obtained after purification；(2) solvent B is warming up to 50 DEG C, the imino group chloroethyl is added
Alkyl ether hydrochloride, reaction are cooled to -10 to 3 DEG C after 1 to 7 hour, filter to take filtrate, which is warming up to 15 to 45 DEG C again,
Semicarbazide hydrochloride is added, reacts 24 to 82 hours, obtains 3- chloromethyl -1,2,4- triazoline -5- ketone；
Wherein, the alcohol is the single hydroxyl alcohol of the alkyl containing 1~6 carbon atom；The moisture content of the preparation of the alcohol is 0.3%
Below；The solvent A is methyl tertiary butyl ether(MTBE) or methylene chloride；The solvent B is methanol or ethyl alcohol；The chloroacetonitrile, alcohol,
The molar ratio of HCl and semicarbazide hydrochloride is 1:1~1.05:1.025~1.1:0.275~0.22175.
2. 3- chloromethyl -1,2 as described in claim 1, the synthetic method of 4- triazoline -5- ketone, it is characterised in that: the alcohol
For methanol or ethyl alcohol.
3. 3- chloromethyl -1,2 as described in claim 1, the synthetic method of 4- triazoline -5- ketone, it is characterised in that: the alcohol
The moisture content of preparation is 0.05% or less.
4. 3- chloromethyl -1,2 as described in claim 1, the synthetic method of 4- triazoline -5- ketone, it is characterised in that: the chlorine
The mass ratio that feeds intake of acetonitrile and solvent A is 1:5~12.
5. 3- chloromethyl -1,2 as described in claim 1, the synthetic method of 4- triazoline -5- ketone, it is characterised in that: the Asia
The mass ratio that feeds intake of amino chloroethyl alkyl ether hydrochloride and solvent B are 1:0.34~2.34.
6. 3- chloromethyl -1,2 as described in claim 1, the synthetic method of 4- triazoline -5- ketone, which is characterized in that the 3-
The purifying of chloromethyl -1,2,4- triazoline -5- ketone is the following steps are included: the 3- chloromethyl -1,2,4- three that the step (2) obtains
Filtrate a, the filtrate a is taken to be evaporated under reduced pressure after the filtering of oxazoline -5- ketone in 50 DEG C, solvent C, heating stirring reflux is added in obtained solid
30min filters to take filtrate b while hot, and the filtrate b cooling crystallization obtains filter residue c after filtering, the filter residue c be dried in vacuo
3- chloromethyl -1,2,4- triazoline -5- the ketone of white powder；Wherein, the solvent C is isopropanol or acetone.
7. 3- chloromethyl -1,2 as claimed in claim 6, the synthetic method of 4- triazoline -5- ketone, it is characterised in that: the ammonia
Base urea hydrochloride and the mass ratio that feeds intake of solvent C are 1:6~12.
8. 3- chloromethyl -1,2 as claimed in claim 6, the synthetic method of 4- triazoline -5- ketone, it is characterised in that: described cold
But the temperature of crystallization is -15 to 35 DEG C.
9. 3- chloromethyl -1,2 as claimed in claim 6, the synthetic method of 4- triazoline -5- ketone, it is characterised in that: described true
The dry temperature of sky is 25 to 70 DEG C.
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|---|---|---|---|
| CN201811639765.4A CN109553585A (en) | 2018-12-29 | 2018-12-29 | A kind of synthetic method of 3- chloromethyl -1,2,4- triazoline -5- ketone |
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| CN201811639765.4A CN109553585A (en) | 2018-12-29 | 2018-12-29 | A kind of synthetic method of 3- chloromethyl -1,2,4- triazoline -5- ketone |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104628663A (en) * | 2013-11-08 | 2015-05-20 | 中山奕安泰医药科技有限公司 | Synthesis method of 3-chloromethyl-1,2,4-triazoline-5-one |
-
2018
- 2018-12-29 CN CN201811639765.4A patent/CN109553585A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104628663A (en) * | 2013-11-08 | 2015-05-20 | 中山奕安泰医药科技有限公司 | Synthesis method of 3-chloromethyl-1,2,4-triazoline-5-one |
Non-Patent Citations (1)
| Title |
|---|
| CAMERON J COWDEN，等: "A new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an NK1 antagonist", 《TETRAHEDRON LETTERS》 * |
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