CN117903067A - Synthesis method of trimethoprim - Google Patents
Synthesis method of trimethoprim Download PDFInfo
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- CN117903067A CN117903067A CN202410065716.3A CN202410065716A CN117903067A CN 117903067 A CN117903067 A CN 117903067A CN 202410065716 A CN202410065716 A CN 202410065716A CN 117903067 A CN117903067 A CN 117903067A
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960001082 trimethoprim Drugs 0.000 title claims abstract description 60
- 238000001308 synthesis method Methods 0.000 title description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims abstract description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 17
- 238000006482 condensation reaction Methods 0.000 claims abstract description 16
- 238000007670 refining Methods 0.000 claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 13
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 12
- 229960000789 guanidine hydrochloride Drugs 0.000 claims abstract description 11
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- OOWFYDWAMOKVSF-UHFFFAOYSA-N 3-methoxypropanenitrile Chemical compound COCCC#N OOWFYDWAMOKVSF-UHFFFAOYSA-N 0.000 claims abstract description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- 239000008213 purified water Substances 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims description 31
- 238000010438 heat treatment Methods 0.000 claims description 27
- 238000005406 washing Methods 0.000 claims description 25
- 235000019441 ethanol Nutrition 0.000 claims description 23
- 239000012043 crude product Substances 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- RGDTYYUKYIGECG-UHFFFAOYSA-N methanol prop-2-enenitrile Chemical compound OC.C=CC#N RGDTYYUKYIGECG-UHFFFAOYSA-N 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 11
- 238000004321 preservation Methods 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000006386 neutralization reaction Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 239000010865 sewage Substances 0.000 abstract description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- IGJKPBJUVZCBSM-UHFFFAOYSA-N 2-(benzylamino)propanenitrile Chemical compound N#CC(C)NCC1=CC=CC=C1 IGJKPBJUVZCBSM-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing trimethoprim, which relates to the technical field of pharmacy and comprises the following steps: the method comprises the steps of (1) preparing 3-methoxypropionitrile by reacting acrylonitrile with methanol under the catalysis of sodium methoxide, and then performing condensation reaction with 3,4, 5-trimethoxybenzaldehyde to generate an intermediate A; the intermediate A reacts with ethanol under the catalysis of sodium methoxide to generate an intermediate B; and (3) carrying out cyclization reaction on the intermediate B and guanidine hydrochloride to obtain trimethoprim. The invention discloses a method for synthesizing trimethoprim, which adopts an organic solvent in the process of producing trimethoprim, is convenient to recycle, reduces sewage discharge and production cost, and improves the reaction yield of a final product through adjusting the reaction process and parameters. In the refining process, the decoloring and impurity removing process is simple, and the neutralization temperature of ammonia water is controlled by adjusting the proportion of the crude trimethoprim, purified water, acetic acid and active carbon, so that the full crystallization of the trimethoprim is realized.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of an antibacterial drug, and specifically relates to a synthetic method of trimethoprim.
Background
Trimethoprim (TMP) is a broad spectrum, highly effective, low-toxic antimicrobial and bactericidal agent. The bactericidal composition is widely applied to the pharmaceutical industry for decades as a bactericide and a bactericidal synergist, has excellent synergistic effect when being combined with sulfonamides, and also has excellent synergistic effect on various biological antibiotics and synthetic antibiotics, so that the bactericidal composition is widely applied to clinical medicine and veterinary livestock industry and becomes one of the pillar products of the pharmaceutical industry in China.
At present, 3,4, 5-trimethoxybenzaldehyde and benzylaminopropionitrile can be used for synthesizing trimethoprim. The synthesis process uses aniline, the aniline reacts with acrylonitrile to protect 3-position and activate 2-position, but the aniline pollution is serious after the reaction, recovery treatment is needed, and investment is increased.
However, the existing method has the problems of high raw material cost, high manufacturing difficulty, low yield and complex operation, and the method for synthesizing trimethoprim is disclosed for solving the problems.
Disclosure of Invention
The invention provides a method for synthesizing trimethoprim, which aims to solve the problems of high cost of raw materials, high manufacturing difficulty, low yield and complex operation of the prior trimethoprim.
The invention is realized by adopting the following technology:
the invention provides a method for synthesizing trimethoprim, which comprises the following steps:
a, acrylonitrile and methanol react under the catalysis of sodium methoxide to generate 3-methoxy propionitrile, and then the 3-methoxy propionitrile and 3,4, 5-trimethoxybenzaldehyde undergo condensation reaction to generate an intermediate A; the method specifically comprises the following steps:
aa, mixing
Mixing 48-58 parts of acrylonitrile and 30-32.5 parts of methanol, wherein the mass concentration of sodium methoxide is 20% -30%, and the mass concentration of acrylonitrile is 95% -99%, so as to prepare an acrylonitrile-methanol mixed solution for later use; 340-360 parts of sodium methoxide is added into a reactor, the temperature is reduced to 5-10 ℃ by ice water, and the mixture of acrylonitrile and methanol is prepared by uniformly dropwise adding, wherein the reaction temperature is not more than 25 ℃, and the dropwise adding time is 50-60 min, so that 3-methoxy propionitrile is prepared, the reaction can be effectively and stably carried out, and the generation of byproducts is reduced; the synthetic route can be represented by the following formula:
ab, condensation reaction
After the dripping is finished, maintaining the temperature at 23-26 ℃, adding 100 parts of 3,4, 5-trimethoxybenzaldehyde with the mass concentration of 95% -98%, carrying out heat preservation reaction for 9-15 h, cooling to below 10 ℃ after the condensation reaction is finished, dripping 450-500 parts of water at the temperature of not more than 20 ℃, cooling to below 10 ℃ after the water is added, carrying out centrifugal separation, and washing by using anhydrous mixed alcohol to obtain an intermediate A; the synthetic route can be represented by the following formula:
B, preparation of intermediate B
The intermediate A reacts with ethanol under the catalysis of sodium methoxide to generate an intermediate B;
the structural formula of the intermediate A is
；
The structural formula of the intermediate B is
。
The method specifically comprises the following steps:
126-145 parts of sodium methoxide, 125-130 parts of absolute ethyl alcohol and 5 parts of ethyl acetate are added into a reactor, the temperature is raised, the reflux is carried out for 30min, the temperature is reduced to 45 ℃, 110 parts of intermediate A is added, the temperature is raised to 80 ℃, the reflux reaction is carried out for 4 hours, and the temperature is reduced to below 60 ℃ to obtain intermediate B. The synthetic route can be represented by the following formula:
c, cyclization reaction
The intermediate B and guanidine hydrochloride undergo a cyclization reaction to obtain trimethoprim; the trimethoprim is a crude product, and specifically comprises the following steps:
continuously adding 72-86 parts of guanidine hydrochloride into a reactor, heating and refluxing for reaction for 2 hours, after the reaction is finished, reacting distilled alcohol at 95-100 ℃ for 4 hours, increasing the temperature and refluxing for reaction, increasing the product yield, after the reaction is finished, adding 400 parts of water while the reaction is hot, heating and refluxing for 30 minutes, then cooling to below 15 ℃, filtering, washing with mixed alcohol, and washing with water to obtain a trimethoprim crude product. Yield is more than 79.1%; the synthetic route can be represented by the following formula:
d, refining
Refining the trimethoprim crude product prepared in the step c, which specifically comprises the following steps:
Adding 860-960 parts of purified water into a reactor, adding 40 parts of acetic acid and 100 parts of trimethoprim crude product, heating to 90 ℃ for heat preservation and dissolution, cooling to 80 ℃, adding active carbon, heating to 90 ℃, decolorizing for 30min to obtain a trimethoprim product (pharmacopoeia standard) with the purity of 99.4-100%, filtering for removing carbon, washing carbon with a proper amount of heat purification water, mixing filtrate and a crystallization reactor, heating to 80-90 ℃, neutralizing with ammonia water to the pH value of 9, keeping the mass content of ammonia water (analytically pure) to 25-27%, keeping the temperature for 30min, cooling to 10 ℃, filtering and washing to obtain a dried trimethoprim fine product.
Compared with the prior art, the invention has the following beneficial effects:
The invention discloses a method for synthesizing trimethoprim, which adopts an organic solvent in the process of producing trimethoprim, is convenient to recycle, reduces sewage discharge and production cost, and improves the reaction yield of a final product through adjusting the reaction process and parameters. In the refining process, the decoloring and impurity removing processes are simple, the neutralization temperature of ammonia water is controlled by adjusting the proportion of the crude product of the trimethoprim, purified water, acetic acid and active carbon, the full crystallization of the trimethoprim is realized, the yield is improved, the highest yield of the crude product can reach 80.66%, and the highest yield after refining can reach 94.1%.
Detailed Description
Specific embodiments of the present invention are described below.
Example 1
The invention relates to a synthetic method of trimethoprim, which comprises the following steps:
a, performing condensation reaction on acrylonitrile and methanol and 3,4, 5-trimethoxybenzaldehyde under the catalysis of sodium methoxide to generate an intermediate A; the method specifically comprises the following steps:
aa, mixing
Mixing 48g of acrylonitrile and 30g of methanol, wherein the mass concentration of sodium methoxide is 20% -30%, and the mass concentration of acrylonitrile is 95% -99%, so as to prepare an acrylonitrile-methanol mixed solution for later use; and adding 340g of sodium methoxide into a reactor, cooling to 5-10 ℃ by ice water, uniformly dropwise adding the prepared acrylonitrile-methanol mixed solution, and dropwise adding the prepared acrylonitrile-methanol mixed solution within 50-60 min to prepare the 3-methoxypropionitrile, wherein the reaction temperature is not more than 25 ℃.
Ab, condensation reaction
After the dripping is finished, maintaining the temperature at 23-26 ℃, adding 100g of 3,4, 5-trimethoxybenzaldehyde, wherein the mass concentration of the 3,4, 5-trimethoxybenzaldehyde is 95% -98%, carrying out heat preservation reaction for 12 hours, cooling to below 10 ℃ after the condensation reaction is finished, dripping 450-500 mL of water, keeping the temperature at not more than 20 ℃, cooling to below 10 ℃ after the water is added, carrying out centrifugal separation, washing with anhydrous mixed alcohol, and obtaining 115.2g of intermediate A, wherein the calculated yield is 85.7%.
B, preparation of intermediate B
The intermediate A reacts with ethanol under the catalysis of sodium methoxide to generate an intermediate B; the method specifically comprises the following steps:
126g of sodium methoxide, 125g of absolute ethyl alcohol and 5g of ethyl acetate are added into a reactor, the temperature is raised, the reflux is carried out for 30min, the temperature is reduced to 45 ℃, 110g of intermediate A is added, the temperature is raised to 80 ℃, the reflux reaction is carried out for 4 hours, and the temperature is reduced to below 60 ℃ to obtain intermediate B.
C, cyclization reaction
The intermediate B and guanidine hydrochloride undergo a cyclization reaction to obtain trimethoprim; the trimethoprim is a crude product, and specifically comprises the following steps:
Continuously adding 72g of guanidine hydrochloride into a reactor, heating and refluxing for reaction for 2 hours, after the reaction is finished, reacting distilled alcohol at 95-100 ℃ for 4 hours, adding 400mL of water while the distilled alcohol is hot, heating and refluxing for 30 minutes, then cooling to below 15 ℃, filtering, washing with mixed alcohol, and washing with water to obtain a trimethoprim crude product, and calculating to obtain the yield of more than 79.1%.
D, refining
Refining the trimethoprim crude product prepared in the step c, which specifically comprises the following steps:
Adding 900mL of purified water into a reactor, adding 40g of acetic acid and 100g of trimethoprim crude product, heating to 90 ℃ for heat preservation and dissolution, cooling to 80 ℃, adding active carbon, heating to 90 ℃, decolorizing for 30min to obtain a trimethoprim product (pharmacopoeia standard) with the purity of 99.4% -100%, filtering for removing carbon, washing carbon with proper amount of heat purification water, mixing filtrate and a crystallization reactor, heating to 80-90 ℃, neutralizing with ammonia water to the pH value of 9, keeping the temperature for 30min, cooling to 10 ℃, filtering and washing to obtain 93.2g of dried trimethoprim refined product, and calculating to obtain the yield of 93.2%.
Example 2
The invention relates to a synthetic method of trimethoprim, which comprises the following steps:
a, performing condensation reaction on acrylonitrile and methanol and 3,4, 5-trimethoxybenzaldehyde under the catalysis of sodium methoxide to generate an intermediate A; the method specifically comprises the following steps:
aa, mixing
Mixing 58g of acrylonitrile and 30g of methanol, wherein the mass concentration of sodium methoxide is 20% -30%, and the mass concentration of acrylonitrile is 95% -99%, so as to prepare an acrylonitrile-methanol mixed solution for later use; and (3) adding 360g of sodium methoxide into a reactor, cooling to 5-10 ℃ by ice water, uniformly dropwise adding the prepared acrylonitrile-methanol mixed solution, and dropwise adding the prepared acrylonitrile-methanol mixed solution within 50-60 min to prepare the 3-methoxypropionitrile, wherein the reaction temperature is not more than 25 ℃.
Ab, condensation reaction
After the dripping is finished, maintaining the temperature at 23-26 ℃, adding 100g of 3,4, 5-trimethoxybenzaldehyde, wherein the mass concentration of the 3,4, 5-trimethoxybenzaldehyde is 95% -98%, carrying out heat preservation reaction for 9 hours, cooling to below 10 ℃ after the condensation reaction is finished, dripping 450-500 mL of water, keeping the temperature at not more than 20 ℃, cooling to below 10 ℃ after the water is added, carrying out centrifugal separation, washing with anhydrous mixed alcohol, and obtaining 117.4g of intermediate A, wherein the calculated yield is 87.4%.
B, preparation of intermediate B
The intermediate A reacts with ethanol under the catalysis of sodium methoxide to generate an intermediate B; the method specifically comprises the following steps:
145g of sodium methoxide, 125g of absolute ethyl alcohol and 5g of ethyl acetate are added into a reactor, the temperature is raised, the reflux is carried out for 30min, the temperature is reduced to 45 ℃, 110g of intermediate A is added, the temperature is raised to 80 ℃, the reflux reaction is carried out for 4 hours, and the temperature is reduced to below 60 ℃ to obtain intermediate B.
C, cyclization reaction
The intermediate B and guanidine hydrochloride undergo a cyclization reaction to obtain trimethoprim; the trimethoprim is a crude product, and specifically comprises the following steps:
Adding 86g of guanidine hydrochloride into a reactor, heating and refluxing for reaction for 2 hours, reacting distilled alcohol at 95-100 ℃ for 4 hours, adding 400mL of water while the distilled alcohol is hot, heating and refluxing for 30 minutes, then cooling to below 15 ℃, filtering, washing with mixed alcohol, and washing with water to obtain a trimethoprim crude product, and calculating to obtain the yield of more than 80.66%.
D, refining
Refining the trimethoprim crude product prepared in the step c, which specifically comprises the following steps:
adding 960mL of purified water into a reactor, adding 40g of acetic acid and 100g of trimethoprim crude product, heating to 90 ℃ for heat preservation and dissolution, cooling to 80 ℃, adding active carbon, heating to 90 ℃, decolorizing for 30min to obtain a trimethoprim product (pharmacopoeia standard) with the purity of 99.4% -100%, filtering for removing carbon, washing carbon with proper amount of heat purification water, mixing filtrate and a crystallization reactor, heating to 80-90 ℃, neutralizing with ammonia water to the pH value of 9, keeping the temperature for 30min, cooling to 10 ℃, filtering and washing to obtain 93.3g of dried trimethoprim refined product, and calculating to obtain the yield of 93.3%.
Example 3
The invention relates to a synthetic method of trimethoprim, which comprises the following steps:
a, performing condensation reaction on acrylonitrile and methanol and 3,4, 5-trimethoxybenzaldehyde under the catalysis of sodium methoxide to generate an intermediate A; the method specifically comprises the following steps:
aa, mixing
Mixing 52g of acrylonitrile with 32.5g of methanol, wherein the mass concentration of sodium methoxide is 20% -30%, and the mass concentration of acrylonitrile is 95% -99%, so as to prepare an acrylonitrile-methanol mixed solution for later use; and adding 350g of sodium methoxide into a reactor, cooling to 5-10 ℃ by ice water, uniformly dropwise adding the prepared acrylonitrile-methanol mixed solution, and dropwise adding the prepared acrylonitrile-methanol mixed solution within 50-60 min to prepare the 3-methoxypropionitrile, wherein the reaction temperature is not more than 25 ℃.
Ab, condensation reaction
After the dripping is finished, maintaining the temperature at 23-26 ℃, adding 100g of 3,4, 5-trimethoxybenzaldehyde, wherein the mass concentration of the 3,4, 5-trimethoxybenzaldehyde is 95% -98%, carrying out heat preservation reaction for 10 hours, cooling to below 10 ℃ after the condensation reaction is finished, dripping 450-500 mL of water, keeping the temperature at not more than 20 ℃, cooling to below 10 ℃ after the water is added, carrying out centrifugal separation, washing with anhydrous mixed alcohol, and obtaining 118.3g of intermediate A, wherein the yield is 88.2% by calculation.
B, preparation of intermediate B
The intermediate A reacts with ethanol under the catalysis of sodium methoxide to generate an intermediate B; the method specifically comprises the following steps:
140g of sodium methoxide, 130g of absolute ethyl alcohol and 5g of ethyl acetate are added into a reactor, the temperature is raised, the reflux is carried out for 30min, the temperature is reduced to 45 ℃, 110g of intermediate A is added, the temperature is raised to 80 ℃, the reflux reaction is carried out for 4 hours, and the temperature is reduced to below 60 ℃ to obtain intermediate B.
C, cyclization reaction
The intermediate B and guanidine hydrochloride undergo a cyclization reaction to obtain trimethoprim; the trimethoprim is a crude product, and specifically comprises the following steps:
Continuously adding 80g of guanidine hydrochloride into a reactor, heating and refluxing for reaction for 2 hours, after the reaction is finished, reacting distilled alcohol at 95-100 ℃ for 4 hours, adding 400mL of water while the distilled alcohol is hot, heating and refluxing for 30 minutes, then cooling to below 15 ℃, filtering, washing with mixed alcohol, and washing with water to obtain a trimethoprim crude product, and calculating to obtain the yield of more than 80.4%.
D, refining
Refining the trimethoprim crude product prepared in the step c, which specifically comprises the following steps:
Adding 860mL of purified water into a reactor, adding 40g of acetic acid and 100g of trimethoprim crude product, heating to 90 ℃ for heat preservation and dissolution, cooling to 80 ℃, adding active carbon, heating to 90 ℃, decolorizing for 30min to obtain a trimethoprim product (pharmacopoeia standard) with the purity of 99.4% -100%, filtering for removing carbon, washing carbon with proper amount of heat purification water, mixing filtrate and a crystallization reactor, heating to 80-90 ℃, neutralizing with ammonia water to the pH value of 9, keeping the temperature for 30min, cooling to 10 ℃, filtering and washing to obtain 94.1g of dried trimethoprim refined product, and calculating to obtain the yield of 94.1%.
The scope of the present invention is not limited to the above embodiments, and various modifications and alterations of the present invention will become apparent to those skilled in the art, and any modifications, improvements and equivalents within the spirit and principle of the present invention are intended to be included in the scope of the present invention.
Claims (6)
1. A method for synthesizing trimethoprim is characterized in that: the method comprises the following steps:
a, acrylonitrile and methanol react under the catalysis of sodium methoxide to generate 3-methoxy propionitrile, and then the 3-methoxy propionitrile and 3,4, 5-trimethoxybenzaldehyde undergo condensation reaction to generate an intermediate A;
b, reacting the intermediate A with ethanol under the catalysis of sodium methoxide to generate an intermediate B;
c, performing cyclization reaction on the intermediate B and guanidine hydrochloride to obtain trimethoprim;
the structural formula of the intermediate A is
；
The structural formula of the intermediate B is
。
2. The method for synthesizing trimethoprim according to claim 1, wherein the method comprises the following steps: the method comprises the following steps:
aa, mixing
Mixing 48-58 parts of acrylonitrile and 30-32.5 parts of methanol to prepare an acrylonitrile-methanol mixed solution for later use; adding 340-360 parts of sodium methoxide into a reactor, cooling to 5-10 ℃ by ice water, uniformly dropwise adding the prepared acrylonitrile-methanol mixed solution, and dropwise adding for 50-60 min at the reaction temperature of not more than 25 ℃ to prepare 3-methoxy propionitrile;
ab, condensation reaction
After the dripping is finished, keeping the temperature at 23-26 ℃, adding 100 parts of 3,4, 5-trimethoxybenzaldehyde, carrying out heat preservation reaction for 9-15 h, after the condensation reaction is finished, cooling to below 10 ℃, dripping 450-500 parts of water at the temperature of not more than 20 ℃, cooling to below 10 ℃ after the water is added, carrying out centrifugal separation, and washing by using anhydrous mixed alcohol to obtain an intermediate A;
B, preparation of intermediate B
Adding 126-145 parts of sodium methoxide, 125-130 parts of absolute ethyl alcohol and 5 parts of ethyl acetate into a reactor, heating and refluxing for 30min, cooling to 45 ℃, adding 110 parts of intermediate A, heating to 80 ℃, carrying out reflux reaction for 4 hours, and cooling to below 60 ℃ to obtain an intermediate B;
c, cyclization reaction
Continuously adding 72-86 parts of guanidine hydrochloride into a reactor, heating and refluxing for reaction for 2 hours, finishing the reaction, reacting distilled alcohol at 95-100 ℃ for 4 hours, finishing the reaction, adding 400 parts of water when the reaction is hot, heating and refluxing for 30 minutes, then cooling to below 15 ℃, filtering, washing with mixed alcohol, and washing with water to obtain a trimethoprim crude product.
3. The method for synthesizing trimethoprim according to claim 1, wherein the method comprises the following steps: the method also comprises a step of refining the trimethoprim crude product.
4. A method of synthesizing trimethoprim according to claim 3, wherein: the refining comprises the following steps:
d, refining
Adding 860-960 parts of purified water into a reactor, adding 40 parts of acetic acid and 100 parts of trimethoprim crude product, heating to 90 ℃ for heat preservation and dissolution, cooling to 80 ℃, adding active carbon, heating to 90 ℃, decolorizing for 30min, filtering to remove carbon, washing carbon with a proper amount of heat purification water, mixing filtrate and crystallization reactor, heating to 80-90 ℃, neutralizing with ammonia water to pH value to 9, keeping temperature for 30min, cooling to 10 ℃, filtering and washing to obtain the dry trimethoprim fine product.
5. The method for synthesizing trimethoprim according to claim 2, wherein the method comprises the following steps: and (3) dropwise adding the acrylonitrile-methanol mixed solution for 50-90 min.
6. The method for synthesizing trimethoprim according to claim 2, wherein the method comprises the following steps: the mass concentration of the sodium methoxide is 20% -30%, the mass concentration of the acrylonitrile is 95% -99%, and the mass concentration of the 3,4, 5-trimethoxybenzaldehyde is 95% -98%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202410065716.3A CN117903067A (en) | 2024-01-17 | 2024-01-17 | Synthesis method of trimethoprim |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410065716.3A CN117903067A (en) | 2024-01-17 | 2024-01-17 | Synthesis method of trimethoprim |
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