CN106032380A - Industrial production method of midazolam - Google Patents
Industrial production method of midazolam Download PDFInfo
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- CN106032380A CN106032380A CN201510114968.1A CN201510114968A CN106032380A CN 106032380 A CN106032380 A CN 106032380A CN 201510114968 A CN201510114968 A CN 201510114968A CN 106032380 A CN106032380 A CN 106032380A
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- midazolam
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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Abstract
The present invention relates to an industrial production method for midazolam. The industrial production method is characterized in that a compound A and a compound B are subjected to a ring-forming reaction under the condition of a catalyst. According to the present invention, the production method is simple, and is different from the complex production way and the stringent production conditions in the prior art; the synthesis of the target product can be achieved through the one step; the yield can be increased by at least 50% compared to the multi-step synthesis in the prior art; and the production process and the synthesis route are optimized, such that the advantages of less side reaction, convenient post-treatment and mild production condition during the production process are provided, and the method is suitable for the industrial production mode.
Description
Technical field
The present invention relates to organic synthesis field, in particular it relates to the industrially preparing process of a kind of midazolam.
Background technology
Midazolam, as a kind of anxiety, calmness, sleeping, of flaccid muscles, the medicine of anticonvulsant action.
Owing to pharmacological action is fast, metabolic inactivation is fast, and the persistent period is short, be widely used in the various insomnias for the treatment of,
Sleep rhythm obstacle, injection is also widely used for splanchnoscopy and operation consent is administered.Therefore, its medicine
Precursor suffers from the extensive concern of pharmaceutical field.
The most frequently used structural formula is as follows:
In traditional preparation methods, often use to become again after first synthesizing the intermediate shown in following structural formula
The reaction of ring,
And in existing preparation method, for shown in the synthetic method following equation of above-claimed cpd:
From said synthesis route it is found that in existing technology, the synthesis for this compound is often deposited
Tediously long in synthetic route, step is complicated, by-product is complicated, separate the problem such as be difficult to, and then reduces production
Efficiency, improve production cost.
Therefore, a kind of efficiently, easily, the synthetic method of midazolam with low cost noticeable.
Summary of the invention
It is contemplated that overcome drawbacks described above, it is provided that a kind of simple to operate, with low cost, convenient post-treatment,
Productivity is high, be applicable to industrial manufacture method.
The industrially preparing process of the midazolam that the present invention provides, it is characterised in that: by compound A and chemical combination
Annulation is there is in thing B under conditions of catalyst,
Wherein, the structure of above-claimed cpd A is as follows:
The structure of above-claimed cpd B is as follows:
R is hydroxyl or halogen.
The mol ratio of above-claimed cpd A and compound B is 1:1-2.
Additionally, the industrially preparing process of the midazolam of present invention offer, also have a characteristic that above-mentionedization
Compound B may alternatively be 1,3-diaminourea-acetone and the mixture of acetyl halide；Wherein, above-mentioned 1,3-bis-
The mol ratio of amino-acetone and acetyl halide is 1:0.8-1.
Additionally, the industrially preparing process of the midazolam of present invention offer, also have a characteristic that above-mentionedization
Compound B may alternatively be 1,3-diaminourea-acetone and the mixture of compound C；
Wherein, the structure of above-claimed cpd C is as follows:
R is alkyl and derivant thereof or aryl and derivant thereof；
The mol ratio of above-mentioned 1,3-diaminourea-acetone and compound C is 1:0.8-1.
Additionally, the industrially preparing process of the midazolam of present invention offer, also have a characteristic that above-mentionedization
Compound B may alternatively be 1,3-diaminourea-acetone and the mixture of acetonitrile；Above-mentioned 1,3-diaminourea-acetone
It is 1:0.8-1 with the mol ratio of acetonitrile.
Additionally, the industrially preparing process of the midazolam of present invention offer, also have a characteristic that above-mentionedization
Compound B may alternatively be 1,3-diaminourea-acetone and the mixture of compound D；, wherein, above-mentioned chemical combination
The structure of thing D is as follows:
R is alkyl and derivant thereof or aryl and derivant thereof；
The mol ratio of above-mentioned 1,3-diaminourea-acetone and compound D is 1:0.8-1.
Additionally, the industrially preparing process of the midazolam of present invention offer, also have a characteristic that above-mentionedization
Compound B may alternatively be 1,3-dihalo-acetone, ammonia and the mixture of compound E；
Wherein, the one during above-claimed cpd E is selected from acetyl halide, compound C, acetonitrile, compound D；
The structure of above-claimed cpd C is as follows:
The structure of above-claimed cpd D is as follows:
Above-mentioned 1,3-dihalo-acetone, ammonia, the mol ratio of compound E are 1:1-10:0.8-1.
Additionally, present invention also offers the concrete manufacturing process of the industrially preparing process of above-mentioned midazolam, its
It is characterised by: raw material and organic solvent are put in reactor, after adding catalyst back flow reaction 2-8 hour
Terminating reaction, product is through filtering, hydrolyze, concentrate and the method acquisition pure products of recrystallization or distillation；
Wherein, according to the difference of reaction raw materials, the input of various raw materials can sequentially or the most sequentially be carried out；
When using the raw material of three components, it is preferable to the compositions substituting B raw material is carried out mixture reaction
After 0.5-1 hour, then compound A is put into reaction.
According to the difference of reaction raw materials, the response time can be 2-8 hour, preferably 2-4 hour,
Reaction end is controlled with HPLC in detecting.
Above-mentioned extract and recrystallization solvent are less than 120 DEG C selected from ethers, aromatics, alcohols, alkanes boiling point
Solvent in one or more mixture.Or use maleate to carry out recrystallization.
Additionally, molecular sieve, metallic catalyst, metal class Louis can also be added during above-mentioned reaction
The mixture of one or more in acid.
Additionally, the mol ratio of above-mentioned catalyst and reactant is 0.1-2.
Above-mentioned organic solvent is selected from aromatics, heteroaryl class or the alkanes organic solvent that boiling point is 40-100 DEG C,
As: toluene, benzene, oxolane, normal hexane, hexamethylene etc..
Above-mentioned catalyst is selected from Louis's acid/base, metal halide, metal complex, sterides compound
One in thing；Above-mentioned catalyst is most preferably titanium tetrachloride.
The effect of the present invention and effect
The production method that the present invention provides is simple, is different from prior art the mode of production of complexity, harshness
Working condition, the present invention one step can realize the synthesis of target product.And productivity is many relative to prior art
For step synthesis, at least 50% can be improved.And owing to production technology and synthetic route are optimized by the present invention,
In the production process of the present invention, side reaction is few, convenient post-treatment, and working condition is gentle, compared to existing
Conventional art there is the generation feature of environmental protection, be that one is suitable for production model industrialized, green.
It is worthy of note, in the preferred version of synthesis midazolam, its preferred feedstock selected is, changes
Compound A and B and substitute thereof, it is with low cost, and one pot of one step of whole course of reaction realizes, post processing
And simple, the purity that can realize more than 99.9% is purified by simple means re-crystallization.
In relatively prior art, the synthetic route of 5,6 steps easily, the intermediate raw material of great number, such as catalyst etc..
Can obtain on cost and reduce largely, substantially can reach the 1/5-1/100 of traditional handicraft.
Owing to the multistep in traditional scheme synthesizes, and it is required for the process being purified after the most often having walked,
And process conditions are harsh, therefore, its productivity is relatively low, while cost improves, too increases in production
Operating difficulties, the operation to manufacturing operator requires of a relatively high, and the present invention not only synthesis technique is simple,
Process conditions are gentle, and its productivity when synthesizing midazolam may be up to 65% and more than.
Therefore, the present invention is a kind of manufacture method being suitable for large-scale industrial production.
Specific embodiment
Embodiment one,
Reaction equation is as follows:
By in toluene 500ml, A250g and B120g and input reactor, add the backflow of 15g titanium tetrachloride anti-
End reaction after answering 8 hours, product is heavily tied through filtration, hydrolysis, ether extraction, concentration and maleic acid
Brilliant or distillation method obtains pure products 355g.
In above-mentioned reaction, the mol ratio of compound A and compound B can also be 1:1 or 1:1.2 or 1:
The different ratio such as 1.5 or 1:1.8 or 1:2, solvent is alternatively chosn to the boiling points such as hexamethylene at 40-100 DEG C
In the range of solvent, in the reaction attempt use high molar ratio catalyst such as A: catalyst=1:0.01
Or 1:0.1 or 1:0.5 or 1:1.2 or 1:2, inconspicuous, the unnecessary catalyst of degree that productivity improves
May be recovered.
Embodiment two,
Reaction equation is as follows:
Oxolane 500ml and B85g is put in reactor, is slowly added dropwise C70g while stirring, treats depletion of QI
After body is released, react 0.5 hour, add A280g, add titanium tetrachloride 20g back flow reaction and tie after 2 hours
Shu Fanying, product obtains pure products through filtration, hydrolysis, ether extraction, concentration and maleic acid recrystallization
332g。
In above-mentioned reaction, attempt using one pot of throw-in play to react, productivity slightly below substep one kettle way
Result.The mol ratio of compound A, B and C can also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1
Or the different ratio such as 1:1.8:1.5 or 1:2:1.6, C compound is used as the chemical combination of bromo or iodo
Thing, but for the consideration of cost savings, preferably chloride, solvent is alternatively chosn to the boiling points such as hexamethylene and exists
Solvent in the range of 40-100 DEG C, in the reaction catalyst such as A: catalyst=1 of trial use high molar ratio:
0.01 or 1:0.1 or 1:0.5 or 1:1.2 or 1:2, the degree that productivity improves is inconspicuous, unnecessary
Catalyst may be recovered.
Embodiment three,
Reaction equation is as follows:
Oxolane 500ml and B90g is put in reactor, drips C60g, back flow reaction 2 while stirring
Hour, it is slowly added to A245g in batches, adds titanium tetrachloride 19g back flow reaction and terminate reaction after 2 hours, instead
Answer product through filtering, hydrolyzing, ether extracts, concentrate and use maleic acid recrystallization to obtain pure products 341g.
In above-mentioned reaction, attempt using one pot of throw-in play to react, productivity and the result of substep one kettle way
Quite.The mol ratio of compound A, B and C can also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1
Or the different ratio such as 1:1.8:1.5 or 1:2:1.6, C compound is also selected from such as ethyl acetate, second
Acid phenylester, acetic acid benzyl ester etc., solvent is alternatively chosn to the boiling points such as hexamethylene in the range of 40-100 DEG C
1:0.01 solvent, attempts using catalyst such as A: catalyst=or 1:0.1 of high molar ratio in the reaction
Or 1:0.5 or 1:1.2 or 1:2, the degree that productivity improves is inconspicuous, and unnecessary catalyst can be carried out back
Receive.
Embodiment four,
Reaction equation is as follows:
A250g, B90g, C28g and ethanol 500ml are put in reactor, adds zinc chloride 80g backflow
Terminating reaction after reacting 10 hours, product is through filtering, hydrolyze, concentrate and heavily tying with maleic acid and ether
Brilliant acquisition pure products 324g.
In above-mentioned reaction, attempt using one pot of throw-in play to react, productivity and the result of substep one kettle way
Quite.The mol ratio of compound A, B and C can also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1
Or the different ratio such as 1:1.8:1.5 or 1:2:1.6, solvent is alternatively chosn to the boiling points such as hexamethylene at 40-100 DEG C
In the range of solvent, in the reaction attempt use high molar ratio catalyst such as A: catalyst=1:0.01
Or 1:0.1 or 1:0.5 or 1:1.2 or 1:2, inconspicuous, the unnecessary catalyst of degree that productivity improves
May be recovered.
Embodiment five,
Reaction equation is as follows:
A250g, B90g, C120g and normal hexane 250ml are put in reactor, add molecular sieve 100g,
Titanium tetrachloride 25g back flow reaction terminates reaction after 5 hours, product is through filtering, hydrolyze, concentrate and using
Maleic acid and methyltetrahydrofuran recrystallization obtain pure products 313g.
In above-mentioned reaction, attempt using one pot of throw-in play to react, productivity and the result of substep one kettle way
Quite.The mol ratio of compound A, B and C can also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1
Or the different ratio such as 1:1.8:1.5 or 1:2:1.6, C compound also can use triethoxy ethane, triphen
Epoxide ethane etc., solvent is alternatively chosn to the boiling points such as hexamethylene solvent in the range of 40-100 DEG C, anti-at this
Attempt using catalyst such as A: catalyst=1:0.5 or 1:1.2 or 1:2, the productivity of high molar ratio in should
The degree improved is inconspicuous, and unnecessary catalyst may be recovered.
Embodiment six,
Reaction equation is as follows:
Toluene 250ml and B111g is put in reactor, is passed through ammonia and counts roughly 15g, room temperature reaction 1 hour,
Absorb excessive gas, in reactor, be slowly added dropwise D90g, after releasing without gas, react 0.5 hour, add
Entering A228g, add titanium tetrachloride 10g back flow reaction and terminate reaction after 2 hours, product is through filtration, water
Solve, ethyl acetate extracts, concentrate and use ethyl acetate: ethanol=2:1 recrystallization obtains pure products 256g.
In above-mentioned reaction, attempt using one pot of throw-in play to react, productivity and the result of substep one kettle way
Lower slightly.The mol ratio of compound A, B, C and D can also be 1:1:1:1 or 1:1.2:2:1 or 1:
The different ratio such as 1.5:5:1.1 or 1:1.8:10:1.5 or 1:2:3:1.6, additionally, compound
D may be replaced by the compound C in embodiment three, four, five and alternative thereof, and solvent is alternatively chosn to ring
The boiling points such as hexane solvent in the range of 40-100 DEG C, attempts using the catalyst of high molar ratio in the reaction
Such as A: catalyst=1:0.5 or 1:1.2 or 1:2, inconspicuous, the unnecessary catalysis of degree that productivity improves
Agent may be recovered.
It addition, in above-described embodiment one to seven, the catalyst of selection can determine according to different material character,
Also can be selected for except other of titanium tetrachloride are usually used in Louis's acid/base of annulation, metal halide, metal
The mixture of one or more in coordination compound, steroidal compounds.
Claims (10)
1. the industrially preparing process of a midazolam, it is characterised in that: by compound A and compound B in catalysis
Annulation is there is under conditions of agent,
Wherein, the structure of described compound A is as follows:
The structure of described compound B is as follows:
The industrially preparing process of a kind of midazolam the most as claimed in claim 1, it is characterised in that:
The mol ratio of described compound A and compound B is 1:1-2.
The industrially preparing process of a kind of midazolam the most as claimed in claim 1, it is characterised in that:
Described compound B may alternatively be 1,3-diaminourea-acetone and the mixture of acetyl halide；
Wherein, the mol ratio of described 1,3-diaminourea-acetone and acetyl halide is 1:0.8-1.
The industrially preparing process of a kind of midazolam the most as claimed in claim 1, it is characterised in that:
Described compound B may alternatively be 1,3-diaminourea-acetone and the mixture of compound C；
Wherein, the structure of described compound C is as follows:
R is alkyl and derivant thereof or aryl and derivant thereof；
The mol ratio of described 1,3-diaminourea-acetone and compound C is 1:0.8-1.
The industrially preparing process of a kind of midazolam the most as claimed in claim 1, it is characterised in that:
Described compound B may alternatively be 1,3-diaminourea-acetone and the mixture of acetonitrile；
The mol ratio of described 1,3-diaminourea-acetone and acetonitrile is 1:0.8-1.
The industrially preparing process of a kind of midazolam the most as claimed in claim 1, it is characterised in that:
Described compound B may alternatively be 1,3-diaminourea-acetone and the mixture of compound D；
Wherein, the structure of described compound D is as follows:
R is alkyl and derivant thereof or aryl and derivant thereof；
The mol ratio of described 1,3-diaminourea-acetone and compound D is 1:0.8-1.
The industrially preparing process of a kind of midazolam the most as claimed in claim 1, it is characterised in that:
Described compound B may alternatively be the chloro-acetone of 1,3-bis-, ammonia and the mixture of compound E；
Wherein, the one during described compound E is selected from acetyl halide, compound C, acetonitrile, compound D；
The structure of described compound C is as follows:
The structure of described compound D is as follows:
Described 1,3-bis-chloro-2-hydroxy propane, ammonia, the mol ratio of compound E are 1:1-10:0.8-1.
8. the industrially preparing process of a kind of midazolam as described in claim 1-7 is arbitrary, it is characterised in that:
Raw material and organic solvent are put in reactor, after adding catalyst back flow reaction 2-8 hour, terminate reaction,
Product is through filtering, hydrolyze, concentrate and the method acquisition pure products of recrystallization or distillation；
Wherein, described catalyst is 0.1-2 with the mol ratio of reactant.
The industrially preparing process of a kind of midazolam the most as claimed in claim 8, it is characterised in that:
Described organic solvent is selected from aromatics, heteroaryl class or the alkanes organic solvent that boiling point is 40-100 DEG C；
Described catalyst is selected from Louis's acid/base, metal halide, metal complex, steroidal compounds
One.
The industrially preparing process of a kind of midazolam the most as claimed in claim 8, it is characterised in that:
Described metal halide compound is preferably titanium tetrachloride.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510114968.1A CN106032380A (en) | 2015-03-16 | 2015-03-16 | Industrial production method of midazolam |
| PCT/CN2016/076319 WO2016146049A1 (en) | 2015-03-16 | 2016-03-14 | Industrial preparation method of midazolam |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510114968.1A CN106032380A (en) | 2015-03-16 | 2015-03-16 | Industrial production method of midazolam |
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| CN106032380A true CN106032380A (en) | 2016-10-19 |
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| CN201510114968.1A Pending CN106032380A (en) | 2015-03-16 | 2015-03-16 | Industrial production method of midazolam |
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| WO (1) | WO2016146049A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114773348A (en) * | 2021-09-02 | 2022-07-22 | 成都硕德药业有限公司 | Preparation method and intermediate of midazolam |
| CN115232132A (en) * | 2022-07-25 | 2022-10-25 | 福安药业集团重庆礼邦药物开发有限公司 | Midazolam hydrochloride G crystal form and preparation method thereof |
| CN115385918A (en) * | 2021-08-26 | 2022-11-25 | 成都硕德药业有限公司 | Novel midazolam crystal form and preparation method thereof |
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| CN1315953A (en) * | 1999-06-30 | 2001-10-03 | 艾博特公司 | Process for preparation of imidazodiazepine intermediates |
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| US5831089A (en) * | 1996-07-01 | 1998-11-03 | Pharmacia & Upjohn Company | Process to produce midazolam |
| CN103319486B (en) * | 2012-03-22 | 2017-10-10 | 徐州市心血管病研究所 | Synthesize 4H imidazos [1,5 a] [1,4] Benzodiazepine, the particularly method of midazolam |
| CN103804384B (en) * | 2014-01-27 | 2016-01-20 | 李宏 | The preparation method of benzodiazepine compounds |
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2015
- 2015-03-16 CN CN201510114968.1A patent/CN106032380A/en active Pending
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- 2016-03-14 WO PCT/CN2016/076319 patent/WO2016146049A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315953A (en) * | 1999-06-30 | 2001-10-03 | 艾博特公司 | Process for preparation of imidazodiazepine intermediates |
Non-Patent Citations (1)
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| 郭俊峰 等: "咪达唑仑合成路线图解", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115385918A (en) * | 2021-08-26 | 2022-11-25 | 成都硕德药业有限公司 | Novel midazolam crystal form and preparation method thereof |
| CN114773348A (en) * | 2021-09-02 | 2022-07-22 | 成都硕德药业有限公司 | Preparation method and intermediate of midazolam |
| CN114773348B (en) * | 2021-09-02 | 2024-03-15 | 成都苑东生物制药股份有限公司 | Preparation method of midazolam and intermediate thereof |
| CN115232132A (en) * | 2022-07-25 | 2022-10-25 | 福安药业集团重庆礼邦药物开发有限公司 | Midazolam hydrochloride G crystal form and preparation method thereof |
| CN115232132B (en) * | 2022-07-25 | 2024-02-13 | 福安药业集团重庆礼邦药物开发有限公司 | Midazolam hydrochloride G crystal form and preparation method thereof |
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