CN104356081A - Novel diazepam midbody and preparation method thereof - Google Patents
Novel diazepam midbody and preparation method thereof Download PDFInfo
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- CN104356081A CN104356081A CN201410567096.XA CN201410567096A CN104356081A CN 104356081 A CN104356081 A CN 104356081A CN 201410567096 A CN201410567096 A CN 201410567096A CN 104356081 A CN104356081 A CN 104356081A
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Abstract
The invention discloses a novel diazepam midbody N-methyl-3-phenyl-5-chlorine-2,1-benzisoxazole methyl carbonic ester and a preparation method thereof. The preparation method comprises the following steps: in a low-grade alcohol solvent, N-methyl-3-phenyl-5-chlorine-2,1-benzisoxazole and dimethyl carbonate generate methylation reaction to obtain N-methyl-3-phenyl-5-chlorine-2,1-benzisoxazole methyl carbonic ester. Compared with an existing preparation method, the preparation method disclosed by the invention has the advantages that the preparation method is simple and convenient, the toxicity risk of reaction reagents is low, products are easily separated and purified, equipment corrosion and environmental pollution are low, and industrial production is facilitated.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, relate to a kind of diazepam new intermediate and preparation method thereof, be specifically related to chloro-2,1-benzoisoxazole methyl carbonics of diazepam new intermediate N-methyl-3-phenyl-5-and preparation method thereof.
Background technology
Diazepam (Diazepam) belongs to benzodiazepine, be commonly called as stable, developed by Roche Holding Ag (Hoffmann – La Roche), got permission in 1963 to use, chemical name: chloro-1, the 3-dihydro-2H-1 of 1-methyl-5-phenyl-7-, 4-Benzodiazepine Zhuo-2-ketone (7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-
2-one), there is anxiety, calmness, hypnosis, anticonvulsion, anti-epileptic and central myorelaxant effects.
Shen Yi equality [medicine industry, 1982,5,1-2] reports diazepam synthetic method the most frequently used at present, and its operational path is as follows:
This route for starting raw material is through condensation reaction, obtains chloro-2, the 1-benzoisoxazoles of intermediate 3-phenyl-5-with p-Nitrophenyl chloride and benzyl cyanide; Again through methyl-sulfate first, obtain chloro-2, the 1-benzoisoxazole methyl quaternary ammoniums of N-methyl-3-phenyl-5-; Iron powder reducing, chloroacetyl chloride acidylate and generate methyl acylate, methyl acylate and urotropine generation ring-closure reaction, then through refining and obtained finished product diazepam.Chloro-2, the 1-benzoisoxazole methyl quaternary ammoniums of N-methyl-3-phenyl-5-obtained by chloro-2, the 1-benzoisoxazole methylation reactions of 3-phenyl-5-are the key intermediates preparing diazepam.
The preparation of chloro-2, the 1-benzoisoxazole methyl quaternary ammoniums of N-methyl-3-phenyl-5-, how back flow reaction under anhydrous condition in benzene kind solvent, reaction conditions is relevant with methylating reagent with yield.Known preparation method is as follows:
(1) Nakagawa, Y. [Chemical and Pharmaceutical Bulletin is waited, 1972,20,2209 – 2214] and Forbes, [the e-EROS Encyclopedia of Reagents for Organic Synthesis such as David C., 2001] preparation method of six antimony chloride quaternary ammonium salts is reported: 3-phenyl-5-chloro-2,1-benzoisoxazole and dimethoxy carbonium ion chlordene antimonic salt are obtained by reacting N-methyl-3-phenyl-5-chloro-2 in methylene dichloride, 1-benzoisoxazole methyl six antimony chloride quaternary ammonium salt, yield 94%.Shortcoming is: the antimony pentachloride that chlordene antimonic salt decomposes has severe corrosive strong and stimulating, can cause human body and burn.
(2) Nakagawa, Y. [Chemical and Pharmaceutical Bulletin is waited, 1972,20,2209 – 2214] and Smalley, R. [the Science of Synthesis such as K., 2002,11,337-382] report the preparation method of tetrafluoroborate: chloro-2, the 1-benzoisoxazoles of 3-phenyl-5-, under boron trifluoride diethyl etherate catalysis, are obtained by reacting N-methyl-3-phenyl-5-chloro-2 with trimethyl orthoformate in benzene, 1-benzoisoxazole methyl a tetrafluoro borate, yield only has 74%.
(3) Smalley, R. [the Science of Synthesis such as K., 2002,11,337-382] there was reported: 3-phenyl-5-chloro-2,1-benzoisoxazole and triethyl oxygen a tetrafluoro borate are obtained by reacting chloro-2, the 1-benzoisoxazole methyl a tetrafluoro borates of N-methyl-3-phenyl-5-, and yield is not reported.Shortcoming is: the fluoroboric acid of fluoroborate decomposes has severe corrosive, and equipment corrosion is serious, has harm to human body.
(4) [the Hemijska Industrija such as Novak, 1980,34 (12), 330-336], Guan Zuowu etc. [preparation of 5-chlorine 2-methylamino-benzophenone. medicine industry, 1983,14(3), 9-10] and [the Science of Synthesis such as Smalley, R. K., 2002,11,337-382] report the preparation method of methyl sulfate quaternary ammonium salt: employing methyl-sulfate is methylating reagent, and yield only has 68 ~ 85%.Methyl-sulfate tool high toxicity, skin contact or suction all have serious harm.
The materials such as the methylating reagent dimethoxy carbonium ion chlordene antimonic salt, original acid A ester/boron trifluoride diethyl etherate and the triethyl oxygen a tetrafluoro borate that use in document, not only expensive, toxicity is comparatively large, and is difficult to a large amount of supply, cannot meet industrial needs.
And the methylating reagent often used in building-up process is the highly toxic substance such as methyl-sulfate, methyl chloride.Serious hidden danger is there is in these reagent in environment and processing safety.Such as, methyl-sulfate is deadly poisonous compound, has strong corrodibility, makes human body poisoning by respiratory tract and skin contact.During operation, danger is very large.Once reveal, there is great harm to HUMAN HEALTH.And mostly reaction process is to react under slant acidity even strong acidic condition, equipment corrosion is serious, easily introduces unnecessary corrosion impurity.Aftertreatment needs a large amount of highly basic, and create a large amount of abraum salts, intractability is large.Therefore, the methylation method finding toxicity low, green, safe has very important meaning.
Methylcarbonate is the broad-spectrum organic synthesis raw material of quite valued one in recent years.It is a kind of novel Green Chemistry reagent, and toxicity and dehydrated alcohol are suitable, and within 1992, it have passed the registration of non-toxic chemical in Europe, is called as green chemical.Owing to containing methyl in its molecule and there is good reactive behavior, the hypertoxic methylating reagents such as alternative traditional methyl-sulfate, methyl chloride.
Use methylcarbonate is reacted as methylating reagent and chloro-2, the 1-benzoisoxazoles of 3-phenyl-5-and prepares chloro-2, the 1-benzoisoxazole methyl carbonics of N-methyl-3-phenyl-5-and have no report.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of diazepam new intermediate and preparation method thereof, is specifically related to chloro-2,1-benzoisoxazole methyl carbonics of diazepam new intermediate N-methyl-3-phenyl-5-and preparation method thereof.Compare with existing synthetic method, present method has simple synthetic method, and toxicity hazard is little, and product is easy to separation and purification, equipment corrosion and environmental pollution little, the end product that purity is higher can be obtained, be suitable for the advantages such as suitability for industrialized production.
For overcoming the weak point of existing preparation method, the invention provides following technical scheme.
A kind of diazepam new intermediate and preparation method thereof, diazepam new intermediate is chloro-2, the 1-benzoisoxazole methyl carbonics of N-methyl-3-phenyl-5-that formula I indicates, and chemical structural formula is as follows:
。
A kind of diazepam new intermediate and preparation method thereof, N-methyl-3-phenyl-the 5-chloro-2 that formula I indicates, the preparation method of 1-benzoisoxazole methyl carbonic, comprise the steps: in lower alcohol solvent, chloro-2, the 1-benzoisoxazoles (II) of 3-phenyl-5-and methylcarbonate, there is methylation reaction, obtain chloro-2, the 1-benzoisoxazole methyl carbonics (I) of N-methyl-3-phenyl-5-, reaction equation is as follows:
。
A kind of diazepam new intermediate and preparation method thereof, described lower alcohol solvent is one or more in methyl alcohol, ethanol and Virahol; The volumetric usage of described lower alcohol solvent and the ratio of formula II weight consumption are 5:1 ~ 8:1.
A kind of diazepam new intermediate and preparation method thereof, the ratio of described methylcarbonate and the molar weight of formula II is 1.2:1 ~ 2.0:1.
A kind of diazepam new intermediate and preparation method thereof, described methylation reaction temperature is 90 ~ 110 DEG C.
A kind of diazepam new intermediate and preparation method thereof, described methylation reaction pressure is 0.4 ~ 0.8MPa.
Namely each optimum condition in preparation method of the present invention arbitrary combination can obtain each preferred embodiment of the present invention.
The reagent that the present invention is used and raw material are all commercially.
The present invention compared with prior art tool has the following advantages:
1) methylating reagent such as methyl-sulfate, methyl iodide, dimethoxy carbonium ion chlordene antimonic salt, original acid A ester/boron trifluoride diethyl etherate and triethyl oxygen a tetrafluoro borate has stronger toxicity and corrodibility, and the basic nontoxicity of methylcarbonate;
2) need a large amount of alkali to carry out neutralization reaction by product during the substance reaction such as methyl-sulfate and methyl iodide, after reaction terminates, a large amount of inorganic salt can be produced, need process; By the direct by product after methylcarbonate methylation reaction, the problem that methyl alcohol and carbonic acid gas also do not process, aftertreatment is simple, and environmental pollution is little;
3) reaction solution remains that alkalescence is to neutral, than in other method, almost can ignore equipment corrosion problem;
4) reaction preference is high, and byproduct of reaction is few, and reaction of atomic economy is high;
5) product is easy to be separated, and the reaction by-product of main reaction is easy to process.
The toxicity hazard in production process can be avoided as methylating reagent with methylcarbonate, the problem such as equipment corrosion and environmental pollution, greatly reduce by the cost plus corroded in the production and treating processes that bring.
To contribute to understanding the present invention by following embodiment, but not limit the present invention.
Embodiment
Embodiment 1:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 15.3g and ethanol 160 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 105 DEG C.Under pressure 0.6 ~ 0.7 MPa after insulation reaction 4.5 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.4%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2, the 1-benzoisoxazole methyl carbonics 31.3 of N-methyl-3-phenyl-5-, yield 98.1%, HPLC purity 97.8%.
Embodiment 2:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 12.6g and ethanol 140 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 95 DEG C.Under pressure 0.5 ~ 0.6 MPa after insulation reaction 6.0 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.5%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2, the 1-benzoisoxazole methyl carbonic 31.1g of N-methyl-3-phenyl-5-, yield 97.5%, HPLC purity 98.6%.
Embodiment 3:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 11.7g and Virahol 140 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 105 DEG C.Under pressure 0.7 ~ 0.8 MPa after insulation reaction 5.5 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.4%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2,1-benzoisoxazole methyl carbonic 31.2 g of N-methyl-3-phenyl-5-, yield 97.8%, HPLC purity 98.1%.
Embodiment 4:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 17.1g and Virahol 180 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 110 DEG C.Under pressure 0.4 ~ 0.5 MPa after insulation reaction 6.0 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.5%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2,1-benzoisoxazole methyl carbonic 31.3 g of N-methyl-3-phenyl-5-, yield 98.1%, HPLC purity 97.7%.
Embodiment 5:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 10.8g and methyl alcohol 120 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 105 DEG C.Under pressure 0.5 ~ 0.6 MPa after insulation reaction 6.0 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.3%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2, the 1-benzoisoxazole methyl carbonic 31.1g of N-methyl-3-phenyl-5-, yield 97.5%, HPLC purity 99.0%.
Embodiment 6:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 13.5g and methyl alcohol 150 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 110 DEG C.Under pressure 0.7 ~ 0.8 MPa after insulation reaction 4.0 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.2%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2, the 1-benzoisoxazole methyl carbonic 31.3g of N-methyl-3-phenyl-5-, yield 98.1%, HPLC purity 98.7%.
Embodiment 7:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 18.0g and methyl alcohol 170 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 105 DEG C.Under pressure 0.4 ~ 0.5 MPa after insulation reaction 6.0 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.3%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2,1-benzoisoxazole methyl carbonic 31.5 g of N-methyl-3-phenyl-5-, yield 98.7%, HPLC purity 98.3%.
Embodiment 8:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 14.4g and methyl alcohol 150 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 100 DEG C.Under pressure 0.6 ~ 0.7 MPa after insulation reaction 5.0 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.4%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2, the 1-benzoisoxazole methyl carbonic 31.4g of N-methyl-3-phenyl-5-, yield 98.4%, HPLC purity 98.0%.
Embodiment 9:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 15.3g and methyl alcohol 160 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 90 DEG C.Under pressure 0.6 ~ 0.7 MPa after insulation reaction 6.0 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.2%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2,1-benzoisoxazole methyl carbonic 31.4 g of N-methyl-3-phenyl-5-, yield 98.4%, HPLC purity 98.6%.
Embodiment 10:
Take chloro-2, the 1-benzoisoxazole 22.9g of 3-phenyl-5-, methylcarbonate 12.6g and methyl alcohol 140 mL, be placed in autoclave.Close reaction under high pressure kettle cover, screwing bolts, connect agitator motor water coolant, open heating power supply and agitator motor switch, be heated to 100 DEG C.Under pressure 0.5 ~ 0.6 MPa after insulation reaction 5.5 h, sampling analysis, recording chloro-2, the 1-benzoisoxazole content of reaction solution Raw 3-phenyl-5-is 0.3%, can stopped reaction.
Water flowing is cooled to room temperature, open purging valve, high pressure kettle cover is opened after venting, mixture in autoclave being transferred to decompression steams in bottle, decompression steams solvent and unreacted methylcarbonate, and namely resistates obtains chloro-2, the 1-benzoisoxazole methyl carbonic 31.5g of N-methyl-3-phenyl-5-, yield 98.7%, HPLC purity 98.8%.
Embodiment recited above is only be described the preferred embodiment for the present invention; not the spirit and scope of the present invention are limited; under the prerequisite not departing from design philosophy of the present invention; the various distortion that in this area, common engineering technical personnel make technical scheme of the present invention and improvement, all should belong to protection scope of the present invention.
Claims (6)
1. diazepam new intermediate and preparation method thereof, is characterized in that: diazepam new intermediate is chloro-2, the 1-benzoisoxazole methyl carbonics of N-methyl-3-phenyl-5-that formula I indicates, and chemical structural formula is as follows:
。
2. a kind of diazepam new intermediate as claimed in claim 1 and preparation method thereof, it is characterized in that: the N-methyl-3-phenyl-5-chloro-2 that formula I indicates, the preparation method of 1-benzoisoxazole methyl carbonic, comprise the steps: in lower alcohol solvent, chloro-2, the 1-benzoisoxazoles (II) of 3-phenyl-5-and methylcarbonate, there is methylation reaction, obtain chloro-2, the 1-benzoisoxazole methyl carbonics (I) of N-methyl-3-phenyl-5-, reaction equation is as follows:
。
3. a kind of diazepam new intermediate as claimed in claim 2 and preparation method thereof, is characterized in that: described lower alcohol solvent is one or more in methyl alcohol, ethanol and Virahol; The volumetric usage of described lower alcohol solvent and the ratio of formula II weight consumption are 5:1 ~ 8:1.
4. a kind of diazepam new intermediate as claimed in claim 2 and preparation method thereof, is characterized in that: the ratio of described methylcarbonate and the molar weight of formula II is 1.2:1 ~ 2.0:1.
5. a kind of diazepam new intermediate as claimed in claim 2 and preparation method thereof, is characterized in that: described methylation reaction temperature is 90 ~ 110 DEG C.
6. a kind of diazepam new intermediate as claimed in claim 2 and preparation method thereof, is characterized in that: described methylation reaction pressure is 0.4 ~ 0.8MPa.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107892653A (en) * | 2017-11-09 | 2018-04-10 | 华中药业股份有限公司 | A kind of processing method of diazepam first mother liquor |
| CN113956167A (en) * | 2021-10-19 | 2022-01-21 | 枣阳市福星化工有限公司 | Preparation process of 2-methylamino-5-chlorobenzophenone |
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2014
- 2014-10-23 CN CN201410567096.XA patent/CN104356081A/en active Pending
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| 沈怡平等: "《安定新合成路线研究》", 《医药工业》 * |
| 邹盛欧: "《碳酸二甲酯的制造技术及其应用》", 《化学工程师》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107892653A (en) * | 2017-11-09 | 2018-04-10 | 华中药业股份有限公司 | A kind of processing method of diazepam first mother liquor |
| CN113956167A (en) * | 2021-10-19 | 2022-01-21 | 枣阳市福星化工有限公司 | Preparation process of 2-methylamino-5-chlorobenzophenone |
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Application publication date: 20150218 |