CN105001178B - The synthetic method of Azasetron hydrochloride intermediate - Google Patents
The synthetic method of Azasetron hydrochloride intermediate Download PDFInfo
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- CN105001178B CN105001178B CN201510367401.5A CN201510367401A CN105001178B CN 105001178 B CN105001178 B CN 105001178B CN 201510367401 A CN201510367401 A CN 201510367401A CN 105001178 B CN105001178 B CN 105001178B
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- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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Abstract
The present invention relates to the preparations of Azasetron hydrochloride intermediate, in particular to the chloro- 4- methyl -3- oxo -3 of intermediate 6-, 4- dihydro -2H-1, the synthetic method of 4- benzoxazine -8- carboxylate methyl ester, methylation reaction occurs including chloro- 3- oxo -3,4- dihydro -2H-1, the 4- benzoxazine -8- carboxylate methyl ester of 6- and iodomethane, and promote reaction to carry out to positive direction by the way that water is added during the reaction, final product is obtained after processing.The present invention solves the problems, such as that methylation reaction is incomplete in the prior art, the reaction time is long, while the related content of material of product made from the method is more stable, with high purity, improves production efficiency, is applicable to industrialized production.
Description
Technical field
The present invention relates to the synthesis technical fields of chemical intermediate, in particular to Azasetron hydrochloride intermediate 6-
The synthetic method of chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1,4- benzoxazine -8- carboxylate methyl ester.
Background technique
Azasetron hydrochloride, alias N- (1- azabicyclo 2.2.2 octyl- 8- yl) chloro- 4- methyl -3- oxo -3,4- bis- of -6-
Hydrogen -2H-1,4- benzoxazine -8- carboxamide hydrochloride is a kind of colourless or almost colourless clear and bright aqueous solution, assists for anticancer
Drug, molecular formula: Cl7H20ClN303HCI, suitable for Nausea and vomiting and gynecological surgery caused by cytotoxic drug and outside
Nausea and vomiting caused by section performs the operation.
Existing chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1, the 4- benzo of synthetic hydrochloric acid Azasetron intermediate 6- is disliked
The method of piperazine -8- carboxylate methyl ester, there is the following two kinds synthetic method:
1) by chloro- 3- oxo -3, the 4- dihydro -2H-1 of DMF (dimethylformamide), 6-, 4- benzoxazine -8- carboxylate methyl ester
It sequentially adds in four-hole boiling flask, stirs evenly with Anhydrous potassium carbonate.With the cooling reaction solution of ice-water bath to 15 DEG C hereinafter, dripping in three times
Add iodomethane.It is added dropwise, reaction is stirred at room temperature overnight.The synthetic method causes there are the incomplete problem of methylation reaction
The related substance of finished product is higher, and reaction speed is slow, and the reaction time is long, and production efficiency is not high.
2) chloro- 3- oxo -3,4- dihydro -2H-1,4- benzoxazine-the 8- carboxylate methyl ester of 6-, DMF are sequentially added, under stirring
Anhydrous potassium carbonate is added, dimethyl suflfate is added dropwise, reacts at room temperature 3h, is warming up to 60 DEG C of reaction 1h.Yield 91% after post-processing.It should
Because dimethyl suflfate toxicity is stronger, waste liquid has greater environmental impacts technology.
In conclusion there is reaction in the technology disclosed in existing patent document and other documents not exclusively, causing
By-product is higher, and final product purity is not high, and production efficiency is low, and waste liquid is not easy to handle, the problems such as having greater environmental impacts.
Summary of the invention
The present invention provides a kind of chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1,4- benzene of Azasetron hydrochloride intermediate 6-
And the synthetic method of oxazines -8- carboxylate methyl ester, it is low to solve to exist in the prior art intermediate purity, production efficiency it is low and
The big problem of environmental pollution.
Technical key point is that chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1, the 4- benzo of synthetic intermediate 6- is disliked
Piperazine -8- carboxylate methyl ester, chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1, the 4- benzo of the intermediate 6- of high-content is disliked in order to obtain
Piperazine -8- carboxylate methyl ester and high efficiency improve the synthetic method of Azasetron intermediate, make methylation reaction more
Thoroughly, while shortening the reaction time, impurity does not interfere chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1, the 4- benzo of intermediate 6-
The content of oxazines -8- carboxylate methyl ester.
The method of the present invention provides a kind of chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1 of Azasetron hydrochloride intermediate 6-,
The synthetic method of 4- benzoxazine -8- carboxylate methyl ester, specific preparation process is as follows:
To solvent DMF, chloro- 3- oxo -3,4- dihydro -2H-1, the 4- benzoxazine-of raw material 6- under (1) 25 DEG C of stirring
Anhydrous potassium carbonate is added in 8- carboxylate methyl ester mixed solution, after being warming up to 55-60 DEG C, keeps the temperature 0.5-1.5h；
(2) iodomethane is added into the solution after step (1) heat preservation, after reacting 5-15min, water, insulation reaction 1- is added
3h slowly pours into reaction solution in appropriate ice water, and filtering obtains filter cake, Washing of Filter Cake to eluate pH is in neutrality, dry, obtains
Chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1, the 4- benzoxazine -8- carboxylate methyl ester of target product 6-；
The quality of material ratio is chloro- 3- oxo -3,4- dihydro -2H-1, the 4- benzoxazine -8- carboxylate methyl ester of 6-: anhydrous
Potassium carbonate: iodomethane: water=1:0.8-1.2:0.8-1.0:1.5-2.0.
Further, the dosage of the solvent DMF is chloro- 3- oxo -3,4- dihydro -2H-1, the 4- benzoxazine -8- carboxylic of 6-
3-5 times of volume of sour methyl esters inventory.
Further, the reaction temperature is 55 DEG C.
Further, the reaction time is 2h.
Through research, the inventor has found that first by chloro- 3- oxo -3,4- dihydro -2H-1, the 4- benzoxazine -8- of raw material 6-
Carboxylate methyl ester and Anhydrous potassium carbonate are dissolved in reaction dissolvent DMF solution, then at a certain temperature with the mistake of iodomethane reaction
Suitable water is added in Cheng Zhong, increases the solubility of potassium carbonate, promotes reaction forward to carry out, because iodomethane is met under alkaline condition
Water decomposition, thus the time of water is added and dosage be it is crucial, as a result, reaction is very complete, speed is fast this results in extraordinary,
It post-processes relatively easy.Because iodomethane stability is poor, can hydrolyze under alkaline condition, therefore those skilled in the art are general
All over thinking that water should not be added in iodomethane methylation reaction, this method is creative to be passed through during iodomethane methylation reaction
The amount and time of control plus water improve the incomplete problem of methylation, shorten the time of methylation reflection, improve product and contain
Amount, obtained product finished product is not only more stable in relation to content of material, but also is conducive to the preparation of Azasetron next step intermediate.
So chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1, the 4- benzoxazine -8- carboxylate methyl ester of intermediate 6- is carried out for Ah
The whole synthesis of Zha Siqiong and quality are very important.
The present invention has the beneficial effect that: the present invention provides a kind of chloro- 4- methyl -3- oxygen of Azasetron hydrochloride intermediate 6-
The synthetic method of generation -3,4- dihydro -2H-1,4- benzoxazine -8- carboxylate methyl ester, increases the dissolution of potassium carbonate by the way that water is added
Time and the dosage of water is added in degree, control, so that reaction yield and reaction efficiency improve, product quality raising is simultaneously more stable.
Reaction forward is promoted to carry out, this method improves the incomplete problem of methylation reaction, shortens reaction time, product obtained
Related content of material is more stable, improves production efficiency.
Detailed description of the invention
Fig. 1 is chloro- 4- methyl -3- oxo -3, the 4- dihydro -2H-1 of Azasetron hydrochloride intermediate 6- prepared by the present invention,
The liquid chromatogram of 4- benzoxazine -8- carboxylate methyl ester, wherein 5.195 peaks are the chloro- 4- methyl -3- oxo -3,4- of intermediate 6-
Dihydro -2H-1,4- benzoxazine -8- carboxylate methyl ester, peak height 546.92948, peak area 4873.15283, content
95.4319%；
Fig. 2 is chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1, the 4- benzo of Azasetron hydrochloride intermediate 6- of the present invention
The synthetic route of the synthetic method of oxazines -8- carboxylate methyl ester.
Specific embodiment
The embodiment of the present invention is described in further detail with reference to the accompanying drawings of the specification.Each material in the method for the present invention
It can be synthesized by the prior art or by commercially available.
Embodiment 1
(1) at room temperature, DMF (dimethylformamide) 500ml (472.25g), the chloro- 3- of 6- are sequentially added in four-hole boiling flask
Anhydrous potassium carbonate 85g, heating are added under stirring by oxo -3,4- dihydro -2H-1,4- benzoxazine -8- carboxylate methyl ester 100g
To after 55 DEG C, 1.5h is kept the temperature,
(2) 200g water is added into the solution after step (1) heat preservation, 80g iodomethane is added dropwise, in 55 DEG C of insulation reaction 2h.
After reaction, reaction solution is slowly poured into appropriate ice water, is filtered, Washing of Filter Cake to eluate pH is in neutrality.After drying
Product.Yield 94%.
Embodiment 2:
(1) at room temperature, chloro- 3- oxo -3,4- dihydro -2H-1, the 4- benzene of DMF500ml, 6- is sequentially added in four-hole boiling flask
And oxazines -8- carboxylate methyl ester 100g, it is added with stirring Anhydrous potassium carbonate 85g, after being warming up to 55 DEG C, continues to keep the temperature 1h；
(2) iodomethane 100g is added into the solution after step (1) heat preservation, after 55 DEG C of reaction 1h, 150g water is added, after
Continue in 55 DEG C of insulation reaction 1h.After reaction, reaction solution is slowly poured into appropriate ice water, is filtered, Washing of Filter Cake to wash-off
Liquid pH is in neutrality.Product is obtained after drying.Yield 98%.
Embodiment 3:
(1) at room temperature, chloro- 3- oxo -3,4- dihydro -2H-1, the 4- benzene of DMF500ml, 6- is sequentially added in four-hole boiling flask
And oxazines -8- carboxylate methyl ester 100g, it is added with stirring Anhydrous potassium carbonate 85g, after being warming up to 60 DEG C, continues to keep the temperature 1h；
(2) iodomethane 80g is added into the solution after step (1) heat preservation, after 60 DEG C of insulation reaction 1h, 170g is added
Water continues insulation reaction 1h.After reaction, reaction solution is slowly poured into appropriate ice water, is filtered, Washing of Filter Cake to eluate
PH is in neutrality.Product is obtained after drying.Yield 96%.
The technological parameter and interpretation of result of one this method of table and background technique 1,2
| Background technique 1 | Background technique 2 | This method | |
| Reactant | Iodomethane | Dimethyl suflfate | Iodomethane |
| Reaction temperature | 15 DEG C or less | 25℃ | 55-60℃ |
| Add water | - | - | Add water |
| Reaction yield | Average 92% | Average 91% | Average 96% |
| Reaction efficiency | Reaction is overnight | 4 hours | 3 hours |
| Product assay | 93% | 93% | 98% |
Related substance detecting method are as follows: high performance liquid chromatography, C18 column, acetonitrile-phosphate buffer solution-(18:82),
Fig. 1 and table two are shown in UV220nm, n >=1000,20.00 μ L sample introductions, flow velocity 1.300ml/min, testing result and data analysis.
Table two is the report of Fig. 1 liquid chromatogram area percent analysis
It is provided for the embodiments of the invention technical solution above to be described in detail, specific case used herein
The principle and embodiment of the embodiment of the present invention are expounded, the explanation of above embodiments is only applicable to help to understand this
The principle of inventive embodiments；At the same time, for those skilled in the art, according to an embodiment of the present invention, in specific embodiment party
There will be changes in formula and application range, in conclusion the contents of this specification are not to be construed as limiting the invention.
Claims (1)
1. chloro- 4- methyl -3- oxo -3,4- dihydro -2H-1,4- the benzoxazine -8- carboxylic acid first of Azasetron hydrochloride intermediate 6-
The synthetic method of ester, specific preparation process is as follows:
(1) at room temperature, DMF(dimethylformamide is sequentially added in four-hole boiling flask) 500ml(472.25g), the chloro- 3- oxygen of 6-
For -3,4- dihydro -2H-1,4- benzoxazine -8- carboxylate methyl ester 100g, Anhydrous potassium carbonate 85g is added under stirring, is warming up to
After 55 DEG C, 1.5h is kept the temperature；
(2) 200g water is added into the solution after step (1) heat preservation, 80g iodomethane is added dropwise, in 55 DEG C of insulation reaction 2h, reaction
After, reaction solution is slowly poured into appropriate ice water, is filtered, Washing of Filter Cake to eluate pH is in neutrality, and obtains product after dry.
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| CA1304082C (en) * | 1987-10-22 | 1992-06-23 | Tetsuya Tahara | Benzoxazine compounds and pharmaceutical use thereof |
| CN103804373A (en) * | 2012-11-12 | 2014-05-21 | 四川新斯顿制药有限责任公司 | Synthesis process of azasetron hydrochloride |
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