CN104177305B - The new method of triazine ring is synthesized using mixed solvent - Google Patents
The new method of triazine ring is synthesized using mixed solvent Download PDFInfo
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- CN104177305B CN104177305B CN201410386187.3A CN201410386187A CN104177305B CN 104177305 B CN104177305 B CN 104177305B CN 201410386187 A CN201410386187 A CN 201410386187A CN 104177305 B CN104177305 B CN 104177305B
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- mixed solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members 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
- C07D253/075—Two hetero atoms, in positions 3 and 5
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Abstract
The present invention relates to the new method that a kind of use mixed solvent synthesizes triazine ring, synthesis technique is：2 methylthiosemicarbazones, mixed solvent, diethy-aceto oxalate, sodium methoxide carry out ring-closure reaction generation triazine ring sodium salt at 0 45 DEG C, then obtain triazine ring through hydrochloric acid acidifying.Pass through the use of mixed solvent, the system viscosity of building-up process is significantly improved, TTZ cyclization yields have brought up to more than 90% (in terms of 2 methylthiosemicarbazones), the sulfydryl 1 of 1 methyl of accessory substance 5,2, the carboxylate methyl ester content of 4 triazole 3 is below 0.002%, i.e., less than below 20ppm.
Description
Technical field
The invention belongs to chemosynthesis technical field, it is related to a kind of synthesis of medicine intermediate, and in particular to one kind is used
Mixed solvent synthesizes the new method of triazine ring.
Background technology
After triazine ring (TTZ) is the key intermediate for synthesizing Ceftriaxone Sodium, and 7-ACA synthesis 7-ACT, then with DAMA it is
Ceftriaxone Sodium can be synthesized, therefore is the important intermediate for producing Ceftriaxone Sodium, the production to Ceftriaxone Sodium plays key
Effect.Ceftriaxone Sodium, also known as ceftriaxone, are the third generation heads with milestone significance developed by Roche Holding Ag of Switzerland
Spore class antibiotic (trade name Ceftriaxone), is first semi-synthetic broad-spectrum long-acting cephalo in nineteen eighty-two in Switzerland's Initial Public Offering
Rhzomorph, is mainly used in the infection illness caused by sensitive bacteria, such as infection of infection in respiratory system (especially pneumonia), ear nose larynx, uropoiesis
System infections, pyemia, meningitis, preventing post-operation infection, bone and the infection of joint, Skin and soft tissue infection, system genitale togetherness
Contaminate (including gonorrhoea), general satisfactory effect, it may also be used for wound infection, abdominal infection etc..In 1992 first in Discussion on Chinese Listed.
By the development of twenties years, by its has a broad antifungal spectrum, determined curative effect, and the advantages of the huge market space, ceftriaxone
Sodium has become the very important leading products of antibiotic in the market.In the sales achievement of recent years, rank among the best always.
The medicines such as Ceftriaxone Sodium have been put into《National Basic Medical Insurance for Urban Employees medicine》, make in national various big hospital antibiotic
With very big share is occupied in total amount, the status in national health industry is particularly significant.
The method of current triazine ring synthesis mainly has following two：
Route 1, molecule inner ring condensation：1996, Clive L.Branch synthesized TZT by the method for molecule inner ring condensation.
Its concrete scheme is to be synthesized using 2- methylthiosemicarbazones and methyl malonyl chloride as raw material in tetrahydrofuran in the presence of reagent
1- oxamoyl thiosemicarbazides, then obtains triazine ring after cyclization in self-molecules present under alkaline reagent after ion exchange resin.
The intermolecular cyclization of route 2：Be with 2- methylthiosemicarbazones (or salt of 2- methylthiosemicarbazones) be initiation material, and
Diethy-aceto oxalate reaction generation 2- methylthiosemicarbazones, then carry out condensation reaction with diethy-aceto oxalate in the basic conditions, raw
Into triazine ring sodium salt, finally carry out being refining to obtain final finished product triazine ring in acid condition.
Comprehensive analysis above two lines, have the following disadvantages：
1st, synthetic route 1, the route of the technique of molecule inner ring condensation is more complicated, especially the preparation of raw material methyl malonyl chloride
Complexity, yield is relatively low (80% or so), and its be high activity acyl chloride intermediate, operation inconvenience, while its must use from
Sub-exchange resin is purified, and complex process, cost is very high, is not suitable for industrialized production, no actual production meaning.
2nd, synthetic route 2, intermolecular cyclization process is in second step cyclization process, it is necessary to which substantial amounts of dicyandiamide solution could be complete
Into while traditional course of reaction uses single dicyandiamide solution, causing system very sticky, cause local concentration uneven
It is even, in the presence of local excess base, accessory substance 1- methyl -5- sulfydryls -1,2 are generated, 4- triazole -3- carboxylate methyl esters cause
Cyclization yield is relatively low.The accessory substance is difficult to remove and turn into the important miscellaneous of influence product quality in follow-up separation process simultaneously
Matter.
The content of the invention
It is an object of the invention to provide the new method that a kind of use mixed solvent synthesizes triazine ring, during cyclization
Reaction system optimize, reaction is carried out in a uniform environment, make accessory substance (1- methyl -5- sulfydryls -1,2,4-
Triazole -3- carboxylate methyl esters) content control is in below 20ppm, and triazine ring cyclization yield brings up to 90% (with 2- methylthioureas
Meter) more than.
The technical solution adopted for the present invention to solve the technical problems is：A kind of use mixed solvent synthesizes the new of triazine ring
Method, synthesis technique is：2- methylthiosemicarbazones, mixed solvent, diethy-aceto oxalate, sodium methoxide carry out ring-closure reaction at 0-45 DEG C
Triazine ring sodium salt is generated, then triazine ring is obtained through hydrochloric acid acidifying.
Specifically, the mass ratio of mixed solvent and the 2- methylthiosemicarbazone is 10:1-20:1.
Specifically, the mixed solvent is a kind of polar aprotic solvent and a kind of mixture of polar non-solute, institute
The mass ratio for stating proton solvent and aprotic solvent is 1:0.75-1:3.5.
Specifically, the proton solvent is one kind in aliphatic C1-C4 alcohols, aliphatic tertiary amine.
It is preferred that, the proton solvent is methanol.
Specifically, the aprotic solvent is one in DMF, DMSO, NMP, HMPA, acetone, acetonitrile, dioxane, THF
Kind.
It is preferred that, the aprotic solvent is DMSO.
Specifically, the mass ratio of diethy-aceto oxalate and the 2- methylthiosemicarbazone is 3:1-5:1.
Specifically, the mass ratio of sodium methoxide and the 2- methylthiosemicarbazone is 6:1-15:1.
Specifically, the consumption of the hydrochloric acid is the 15-50% of 2- methylthiosemicarbazone consumptions.
The invention has the advantages that：By the use of mixed solvent, the system viscosity of building-up process is obtained greatly
Amplitude improves, and TTZ cyclization yields have brought up to more than 90% (in terms of 2- methylthiosemicarbazones), and accessory substance 1- methyl -5- sulfydryls -
1,2,4- triazole -3- carboxylate methyl ester contents are below 0.002%, i.e., less than below 20ppm.
Embodiment
The following is the specific embodiment of the present invention, technical scheme is described further, but the present invention
Protection domain is not limited to these embodiments.Every change or equivalent substitute without departing substantially from present inventive concept is included in the present invention
Protection domain within.
Embodiment 1：
In mass ratio 1：10：4：10 add 2- methylthiosemicarbazones, mixed solvent, diethy-aceto oxalate, first into reactor
Sodium alkoxide, wherein, mixed solvent is methanol, DMSO mixture, and methanol and DMSO mass ratio are 1:3, carry out ring at 0-45 DEG C
Reaction is closed, reaction is finished, is acidified through hydrochloric acid, the consumption of hydrochloric acid is the 30% of 2- methylthiosemicarbazone consumptions, then filtering, dry
To triazine ring, yield 91.6%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] } is secondary
Product assay (HPLC) 0.0005% (5ppm).
Embodiment 2：
In mass ratio 1：20：3：6 add 2- methylthiosemicarbazones, mixed solvent, diethy-aceto oxalate, methanol into reactor
Sodium, wherein, mixed solvent is ethanol, NMP mixture, and ethanol and NMP mass ratio are 1:0.75, carry out cyclization at 0-45 DEG C
Reaction, reaction is finished, and is acidified through hydrochloric acid, and the consumption of hydrochloric acid is the 40% of 2- methylthiosemicarbazone consumptions, then filters, is dried to obtain
Triazine ring, yield 90.5%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] }, by-product
Thing content (HPLC) 0.0008% (8ppm).
Embodiment 3：
In mass ratio 1：15：5：15 add 2- methylthiosemicarbazones, mixed solvent, diethy-aceto oxalate, first into reactor
Sodium alkoxide, wherein, mixed solvent is methanol, DMF mixture, and methanol and DMF mass ratio are 1:2, carry out cyclization at 0-45 DEG C
Reaction, reaction is finished, and is acidified through hydrochloric acid, and the consumption of hydrochloric acid is the 50% of 2- methylthiosemicarbazone consumptions, then filters, is dried to obtain
Triazine ring, yield 90.8%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] }, by-product
Thing content (HPLC) 0.0011% (11ppm).
Embodiment 4：
In mass ratio 1：20：4：8 add 2- methylthiosemicarbazones, mixed solvent, diethy-aceto oxalate, methanol into reactor
Sodium, wherein, mixed solvent is ethanol, the mixture of acetonitrile, and the mass ratio of ethanol and acetonitrile is 1:3.5, carry out ring at 0-45 DEG C
Reaction is closed, reaction is finished, is acidified through hydrochloric acid, the consumption of hydrochloric acid is the 15% of 2- methylthiosemicarbazone consumptions, then filtering, dry
To triazine ring, yield 91.1%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] } is secondary
Product assay (HPLC) 0.0006% (6ppm).
Embodiment 5：
In mass ratio 1：10：5：12 add 2- methylthiosemicarbazones, mixed solvent, diethy-aceto oxalate, first into reactor
Sodium alkoxide, wherein, mixed solvent is methanol, the mixture of acetone, and the mass ratio of methanol and acetone is 1:1.5, in 0-45 DEG C of progress
Ring-closure reaction, reaction is finished, and is acidified through hydrochloric acid, and the consumption of hydrochloric acid is the 25% of 2- methylthiosemicarbazone consumptions, is then filtered, is dried
Obtain triazine ring, yield 90.6%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] },
By-products content (HPLC) 0.0014% (14ppm).
Claims (7)
1. a kind of use mixed solvent synthesizes the new method of triazine ring, it is characterised in that synthesis technique is：2- methylamino sulphur
Urea, mixed solvent, diethy-aceto oxalate, sodium methoxide carry out ring-closure reaction generation triazine ring sodium salt at 0-45 DEG C, then through hydrochloric acid acid
Change obtains triazine ring；The mixed solvent be a kind of polar aprotic solvent and a kind of mixture of polar non-solute, it is described
Proton solvent for aliphatic C1-C4 alcohols in one kind, the aprotic solvent be DMF, DMSO, NMP, HMPA, acetone,
One kind in acetonitrile, dioxane, THF, the mass ratio of the proton solvent and aprotic solvent is 1:0.75-1:3.5.
2. use mixed solvent according to claim 1 synthesizes the new method of triazine ring, it is characterised in that the mixing is molten
The mass ratio of agent and 2- methylthiosemicarbazones is 10:1-20:1.
3. use mixed solvent according to claim 1 synthesizes the new method of triazine ring, it is characterised in that the proton is molten
Agent is methanol.
4. use mixed solvent according to claim 1 synthesizes the new method of triazine ring, it is characterised in that described non-proton
Solvent is DMSO.
5. use mixed solvent according to claim 1 synthesizes the new method of triazine ring, it is characterised in that the oxalic acid two
The mass ratio of ethyl ester and 2- methylthiosemicarbazones is 3:1-5:1.
6. use mixed solvent according to claim 1 synthesizes the new method of triazine ring, it is characterised in that the sodium methoxide
Mass ratio with 2- methylthiosemicarbazones is 6:1-15:1.
7. use mixed solvent according to claim 1 synthesizes the new method of triazine ring, it is characterised in that the hydrochloric acid
Consumption is the 15-50% of 2- methylthiosemicarbazone consumptions.
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| CN106749063A (en) * | 2016-11-14 | 2017-05-31 | 山东汇海医药化工有限公司 | The method that a kind of self-control organic alkali catalyst of use with Graphene as carrier synthesizes triazine ring |
| CN107235837B (en) * | 2017-03-22 | 2020-08-04 | 扬子江药业集团有限公司 | Preparation method of fenofibric acid |
| CN109336831B (en) * | 2018-11-23 | 2020-07-28 | 山东汇海医药化工有限公司 | Method for recovering triazine ring from triazine ring wastewater |
| CN109293590A (en) * | 2018-11-23 | 2019-02-01 | 山东汇海医药化工有限公司 | A method of promoting triazine ring product quality |
| CN110950814A (en) * | 2019-12-11 | 2020-04-03 | 山东汇海医药化工有限公司 | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring refining wastewater |
| CN111057017B (en) * | 2019-12-27 | 2021-07-30 | 山东汇海医药化工有限公司 | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring cyclization mother liquor |
| CN110981823B (en) * | 2019-12-27 | 2021-08-03 | 山东汇海医药化工有限公司 | Method for preparing 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring |
| CN112209892A (en) * | 2020-10-20 | 2021-01-12 | 山东汇海医药化工有限公司 | Preparation method of high-melting-point triazine ring product |
| CN112694448B (en) * | 2020-12-30 | 2022-02-22 | 山东金城柯瑞化学有限公司 | Process for the preparation of triazine rings |
| CN112759558B (en) * | 2020-12-30 | 2022-06-14 | 山东金城柯瑞化学有限公司 | Process for the preparation of triazine rings |
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Denomination of invention: A new method for synthesis of triazine ring using mixed solvent Effective date of registration: 20211130 Granted publication date: 20170915 Pledgee: Dongying Hekou District sub branch of China Post Savings Bank Co.,Ltd. Pledgor: SHANDONG HUIHAI PHARMACEUTICAL& CHEMICAL Co.,Ltd. Registration number: Y2021980013568 |