CN105294574B - A kind of synthetic method of trimethoprim - Google Patents
A kind of synthetic method of trimethoprim Download PDFInfo
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- CN105294574B CN105294574B CN201510825772.3A CN201510825772A CN105294574B CN 105294574 B CN105294574 B CN 105294574B CN 201510825772 A CN201510825772 A CN 201510825772A CN 105294574 B CN105294574 B CN 105294574B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
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Abstract
The invention discloses a kind of synthetic methods of trimethoprim, are for Material synthesis with 3,4,5 trimethoxybenzaldehyde and cyan-acetic ester, method of the invention has high conversion rate, and the time is short, conducive to the advantage of industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic methods of trimethoprim, belong to organic chemical synthesis field.
Background technology
Trimethoprim, English/latin name：Trimethoprim, abbreviation TMP.This product is white or off-white color crystallinity
Powder；It is odorless, bitter.This product is slightly molten in chloroform, the slightly soluble in ethyl alcohol or acetone, almost insoluble in water；In glacial acetic acid
It is readily soluble.Its molecular formula is as follows：
。
Trimethoprim has the applicating history of decades as classical dihydrofolate reductase inhibitor, since it is good
Bacteriostasis and antibacterial synergistic effect and be widely used.Trimethoprim is expanded to from sulfonamide use in conjunction in recent years
It is used in combination with antimalarial agent, cephalosporins medicine, antidiarrheal etc., there is good cooperative synergism effect, extensive use
In one of pillar product on clinical treatment and animal husbandry, becoming China's pharmaceuticals industry.
For a long time, China use one improvement with 'beta '-methoxy propionitrile and 3,4,5-Trimethoxybenzaldehyde（TMB）
The synthetic route of TMP is prepared through " monomethyl ether ", " dimethyl ether " for raw material.Since yield is relatively low, cause the cost of TMP to increase.Cause
The technique that this research prepares TMP in high yield has larger economic benefit.
United States Patent (USP) US3697512, US3878252 of early stage discloses a kind of trimethoprim synthesis side of higher yields
Method.This method is with β-anilino--α -3, and 4,5- trimethoxy benzyl acrylonitrile are raw material, with 94% yield and guanidine hydrochloride cyclization
TMP is made.However, β-anilino--α -3,4,5- trimethoxy benzyl acrylonitrile are not simply obtained raw material, need to use TMB and
β-anilino- propionitrile condensation.
The total synthesis method for having researched and proposed trimethoprim of Ji Yafei etc.（Ji Yafei, Ma Hongmei, Yu Xinhong etc., methoxy
The synthesis of benzyl pyridine --- the teaching cases from technical study to production process, Higher education of chemical industry, 2008（2）, 32-35）.The party
Method is the fully synthetic route using paracresol as starting material.Wherein unlike United States Patent (USP), this method is with acrylonitrile and first
Sodium alkoxide is intermediate raw material, synthesizes β -3,4,5- trimethoxyphenyl-α methoxyl methyl acrylonitrile, later in the work of sodium methoxide-methanol
With lower TMP is condensed to yield with guanidine cyclization.
The defects of above-mentioned reaction is more there are by-product, and atom utilization is not high.
Invention content
The invention discloses a kind of synthetic methods of trimethoprim, have higher atom utilization and mild reaction item
Part.The route is high to the utilization rate of raw material, and reaction yield is good.
This method comprises the following steps：
A, 3,4,5-Trimethoxybenzaldehyde and cyan-acetic ester in molar ratio 1：1 feeds intake, in the effect of alkali and crown ether
Lower condensation；
B, hydro-reduction is carried out to the product of step a；
C, the product of step b and guanidine in molar ratio 1：1 ~ 1.4 feeds intake, and is condensed in acetic anhydride and aprotic solvent, Zhi Hou
Secondary condensation, rearrangement under the action of alkali and crown ether；
D, the product of step c and p-methyl benzene sulfonic chloride in molar ratio 1：1 ~ 1.05 feeds intake reaction, and product carries out hydrogen again
Change restores to obtain product trimethoprim；It is characterized in that, the step a reaction products such as following formula：
；
The step b products such as following formula：
；
The step C products such as following formula：
；
The dosage molar ratio of the crown ether and alkali is 1：0.8~1.2.
This synthetic route can be represented with following formula：
Further, the method further includes step E, purifying to product trimethoprim.
Method of purification used can be the general method of purification of any chemical field, such as column chromatography, crystallisation.It is excellent
Choosing uses crystallisation.Especially with volume ratio 1：The ethanol-water solution of 0.8 ~ 1.2 mixing is recrystallized, and can be obtained
Preferable effect（Purity >=98.8%）.It is furthermore preferred that it is with volume ratio acetic acid：Ethyl alcohol：Water=0.5：0.7~1.1：0.7 ~ 1 it is mixed
Bonding solvent is recrystallized, and obtains better result（Purity >=99.5%）.
Further, the hydro-reduction agent that the step b of the method is used is under diborane, sodium borohydride or Pd-C catalysis
Hydrogen in one kind, the preferably hydrogen under sodium borohydride or Pd-C catalysis, more preferably sodium borohydride.
Further, aprotic solvent used in the step c of the method is DMF.
The hydro-reduction agent used in the step d of the method is the hydrogen under sodium borohydride or Pd-C catalysis.
The synthetic route of the present invention is briefly described as follows：
In step A, raw material cyan-acetic ester loses the hydrogen of α under the action of alkali and crown ether, makes the carbon ribbon of α, cyano
Negative electricity, the carbonyl carbon of attack 3,4,5-Trimethoxybenzaldehyde occur nucleophilic addition and obtain product.Alkali used is highly basic,
Can be alkoxylated alkali metal, such as sodium methoxide or sodium ethoxide.To be smoothed out reaction, solvent used is non-aqueous
Agent, solvent are preferably DMSO（Dimethyl sulfoxide）、DMF（Diformamide）, reaction temperature is 98-125 DEG C.Crown ether used is 15-
Crown- 5 or 18- crown-s 6.The molar ratio of alkali used and raw material cyan-acetic ester is 0.8 ~ 1.2：1.
In step B, the hydroxyl on benzyl is through negative hydrogen reduction, deoxidation generation methylene.Reducing agent used is a series of negative
Hydrogen under hydrogen reduction agent or hydrogen, preferably diborane, sodium borohydride, potassium borohydride or Pd-C catalysis, more preferably boron hydrogen
Change sodium.Particularly, tetrahydrochysene lithium aluminium should not be used herein, and reason is that tetrahydrochysene lithium aluminium reproducibility is too strong, can restore cyano together.
In addition, which can also be oxidized to benzyl hydroxy ketone, then reduction method such as Huang Min-lon reduction or Clemmensen with classics
Ketone is reduced into methylene by reduction.
In step C, an amino of guanidine is condensed in acetic anhydride and aprotic solvent first with the ester group of upper step products,
After adding alkali, another amino and the cyano of guanidine radicals are condensed cyclization, and aromatisation resets to obtain the step in the presence of alkali
Product.The alkali is highly basic, can be alkoxylated alkali metal, such as sodium methoxide, potassium methoxide or sodium ethoxide.Used is non-proton
Solvent can be DMSO or DMF, and crown ether used is 15- crown-s 5 or 18- crown-s 6.Reaction temperature is reflux temperature, preferably 80-
120℃。
In step D, p-methyl benzene sulfonic chloride（TsCl）P-methyl benzenesulfonic acid ester is generated with the hydroxyl reaction on pyrimidine ring, is being passed through
Hydro-reduction sloughs ester group and obtains product.Hydro-reduction agent used is negative hydrogen reduction agent or hydrogen, preferably diborane, boron hydrogen
Change one kind in the hydrogen under sodium or Pd-C catalysis, the more preferably hydrogen under sodium borohydride or Pd-C catalysis.Reaction system is
Aprotic polar solvent, such as tetrahydrofuran, preferably dichloromethane, dichloromethane；Preferably, weak base is additionally added in system and ties up acid
Agent, such as triethylamine, triethanolamine, imidazoles, pyridine, preferably triethylamine.Because of the nucleophilic substitution of N atom vicinals on pyrimidine ring
It is activated, need to only keep 0-25 DEG C of reaction temperature.
The beneficial effects of the present invention are：
1st, reaction condition is mild, almost no coupling product, and atom utilization is high, and product is easily handled and purifies；
2nd, raw materials used is medical industry common raw material or intermediate, and source is simple and easy to get, and cost is controllable, conducive to work
Industry metaplasia is produced；
3rd, reaction yield is significantly improved using crown ether.
Specific embodiment
It is further illustrated the present invention below by way of several specific embodiments.It should be noted that the embodiment enumerated
It only helps to understand, not limitation of the invention further.In addition, embodiment is it is not possible that the ginseng of each exhaustive reaction condition
Number range, because those skilled in the art have the ability after the present invention is understood, is inferred to suitably according to ordinary technical knowledge
Parameter area.
Synthesis material and reagent source used：
3,4,5-Trimethoxybenzaldehyde, No. CAS：86-81-7, commercial product；
Cyan-acetic ester, No. CAS：105-56-6, commercial product；
Remaining is common common chemical raw material.
Embodiment 1
Step A：Take 3,4,5-Trimethoxybenzaldehyde 196.2g（1 mol）, cyan-acetic ester 113.12g（1 mol）,
5 220g of DMSO 750ml, sodium methoxide 60g, 15- crown- is placed in reactor, is warming up to 105 ± 2 DEG C of back flow reactions, with TLC with
Track reaction process, until 2.5h reactions are basically completed.
Step B：At 0-5 DEG C, 56.7g sodium borohydrides are added in into reactor（1.5mol）, it is stirred to react, temperature liter
To 20 DEG C, 1h is reacted.
Step C：59g guanidines are put into reactor（1 mol）Acetic anhydride 350ml, DMF 250ml, heating reflux reaction 1h, then
Add in 5 220g of sodium methoxide 50g, 15- crown- the reaction was continued 1h.Stop reaction, decompression boils off solvent, adds water 700ml, taken out after stirring
Filter, is dried after draining.
Step D：Step c products are transferred in reactor, 750ml dichloromethane, 110g triethylamines, in 0-5 DEG C of ice water
Under bath, into reactor, input a small amount of by several times amounts to the paratoluensulfonyl chloride of 200g（TsCl）.After adding paratoluensulfonyl chloride,
The temperature of reaction system allows to be warming up to 25 DEG C, is stirred to react 1h.52g sodium borohydrides are put into, maintain 25-30 DEG C of reaction 1.5h.
Stop reaction, decompression pumps solvent, and water 650ml is added to stir, filtering, and washing solids for several times, dries to obtain trimethoprim crude product
278.2g.（Yield 95.8%）.
Embodiment 2
In addition to step D is without using acid binding agent, remaining is the same as embodiment 1.It is final to obtain crude product trimethoprim 264.2g（Yield
91.0%）.
Embodiment 3
The crude product trimethoprim 100.00g that Example 1 obtains, with 1：The ethanol-water solution of 1 volume ratio is tied again
Crystalline substance obtains trimethoprim sterling 89.56g, presses《Chinese Pharmacopoeia version in 2010》Method specified in two carries out assay,
Content is 98.96%.
The crude product trimethoprim 100g that Example 2 obtains, equally handles to obtain trimethoprim sterling 81.32g according to upper method, presses
《Chinese Pharmacopoeia version in 2010》Method specified in two carries out assay, content 99.10%.
Embodiment 4
Except recrystallization solvent uses acetic acid：Ethyl alcohol：Water=0.5：1：Outside 0.8 mixed solvent, remaining is the same as embodiment 3.
Sterling 90.04g, content 99.61% are purified to obtain to the crude product of embodiment 1.
Sterling 82.45g, content 99.78% are purified to obtain to the crude product of embodiment 2.
5 pilot experiment example of embodiment
Step A：Take 3,4,5-Trimethoxybenzaldehyde 196.2kg, cyan-acetic ester 113.12kg, DMSO 800L, first
5 230kg of sodium alkoxide 65kg, 15- crown- is placed in reaction kettle, is warming up to 105 ± 2 DEG C of back flow reactions, and reaction process is tracked with TLC,
It is basically completed to 2.5h reactions.
Step B：Reaction kettle is cooled to 0-5 DEG C, 58kg sodium borohydrides are added in into reactor, are stirred to react, pays attention to adjusting
Condensed water is saved, control temperature is risen to no more than 20 DEG C, reacts 1h.
Step C：60kg guanidines, acetic anhydride 400 L, DMF 250L, 1.2 h of heating reflux reaction are put into reactor, then is added
Enter 5 220kg of sodium methoxide 50kg, 15- crown-, the reaction was continued 1h.Stop reaction, decompression boils off solvent, adds water 780L, taken out after stirring
Filter, is dried after draining.
Step D：Step c products are transferred in reactor, 780 L dichloromethane, 126kg triethylamines, in 0-5 DEG C of ice water
Under bath, into reactor, input a small amount of by several times amounts to the paratoluensulfonyl chloride of 200 kg（TsCl）.Add paratoluensulfonyl chloride
Afterwards, the temperature of reaction system allows to be warming up to 25 DEG C, is stirred to react 1.2h.58kg sodium borohydrides are put into, maintain 25-30 DEG C of reaction
1.5h.Stop reaction, decompression pump solvent, add 650 L of water stir, filtering, washing solids for several times, dry trimethoprim is thick
Product 265.4kg.（Yield 91.4%）.
Step E：Trimethoprim crude product is fully transferred to decoloration crystallizing tank, ethyl alcohol and activated carbon are added in, in reflux temperature
Decoloration purifying, filtering take filtrate, boil off ethyl alcohol, centrifuge, solid is with acetic acid：Ethyl alcohol：Water=0.5：1.1：1 solvent recrystallization,
Obtain sterling trimethoprim 239.6kg, yield 90.3%.
Sterling trimethoprim sample is taken, is pressed《Chinese Pharmacopoeia version in 2010》Two progress full inspections, meet regulation.Wherein content
Measurement result is 99.68%.
Comparative example 1
In addition to crown ether is not added in former synthesis step, with embodiment 1, it is 90.3% to obtain trimethoprim crude yield for remaining；
Crude product is taken, for process for purification with embodiment 3, it is 98.89% to obtain sterling content.
Claims (5)
1. a kind of synthetic method of trimethoprim, using following steps：
A, 3,4,5-Trimethoxybenzaldehyde and cyan-acetic ester in molar ratio 1：1 feeds intake, and contracts under the action of alkali and crown ether
It closes；
B, hydro-reduction is carried out to the product of step A；
C, the product of step B and guanidine in molar ratio 1：1~1.4 feeds intake, and is condensed in acetic anhydride and aprotic solvent, later in alkali and
Secondary condensation, rearrangement under the action of crown ether；
D, the product of step C and p-methyl benzene sulfonic chloride in molar ratio 1：1~1.05 feeds intake reaction, and product carries out hydrogenating again also
It is former to obtain product trimethoprim；
It is characterized in that, the step A reaction products such as following formula：
The step B products such as following formula：
The step C products such as following formula：
The dosage molar ratio of the crown ether and alkali is 1：0.8~1.2；
Wherein step D reaction systems are dichloromethane, and weak base acid binding agent triethylamine is additionally added in system；
The alkali is sodium methoxide or sodium ethoxide；
The aprotic solvent used in step C is DMF.
2. it according to the method described in claim 1, it is characterized in that, further includes step E, product trimethoprim is purified.
3. according to the method described in claim 1, it is characterized in that, the hydro-reduction agent used in step B is diborane, boron hydrogen
Change one kind in the hydrogen under sodium or Pd-C catalysis.
4. according to the method described in claim 2, it is characterized in that, the method for purification to trimethoprim of the step E is：Make
To volume ratio 1：The ethanol-water solution of 0.8~1.2 mixing is recrystallized.
5. according to the method described in claim 2, it is characterized in that, the method for purification to trimethoprim of the step E is：Make
To volume ratio acetic acid：Ethyl alcohol：Water=0.5：0.7~1.1：The solvent of 0.7~1 mixing is recrystallized.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2165362A1 (en) * | 1970-12-29 | 1972-07-27 | Nisshin Flour Milling Co. Ltd., Tokio | 5-benzyl-2,4-diaminopyrimidines prepn - by 5-stage process from benzaldehydes and alkyl cyanoacetates |
| US3697512A (en) * | 1969-03-06 | 1972-10-10 | Burroughs Wellcome Co | 5-benzyl pyrimidines intermediates |
| US3878252A (en) * | 1970-09-24 | 1975-04-15 | Burroughs Wellcome Co | Ring substituted beta-hydroxy-phenyethylmethyl sulphone or sulphoxide |
| CA989840A (en) * | 1971-12-01 | 1976-05-25 | Manasse Nussim | Process for the preparation of benzylpyrimidines |
-
2015
- 2015-11-25 CN CN201510825772.3A patent/CN105294574B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3697512A (en) * | 1969-03-06 | 1972-10-10 | Burroughs Wellcome Co | 5-benzyl pyrimidines intermediates |
| US3878252A (en) * | 1970-09-24 | 1975-04-15 | Burroughs Wellcome Co | Ring substituted beta-hydroxy-phenyethylmethyl sulphone or sulphoxide |
| DE2165362A1 (en) * | 1970-12-29 | 1972-07-27 | Nisshin Flour Milling Co. Ltd., Tokio | 5-benzyl-2,4-diaminopyrimidines prepn - by 5-stage process from benzaldehydes and alkyl cyanoacetates |
| CA989840A (en) * | 1971-12-01 | 1976-05-25 | Manasse Nussim | Process for the preparation of benzylpyrimidines |
Non-Patent Citations (2)
| Title |
|---|
| Knoevenagel缩合反应研究的新进展;边延江,等.;《有机化学》;20060930;第26卷(第9期);第1165-1172页 * |
| 甲氧苄啶的合成;冀亚飞,等.;《合成化学》;20080630;第16卷(第6期);第716-718页 * |
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