CN105622372A - Synthetic method for trimethoprim drug intermediate-p-hydroxy benzaldehyde - Google Patents
Synthetic method for trimethoprim drug intermediate-p-hydroxy benzaldehyde Download PDFInfo
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- CN105622372A CN105622372A CN201510982275.4A CN201510982275A CN105622372A CN 105622372 A CN105622372 A CN 105622372A CN 201510982275 A CN201510982275 A CN 201510982275A CN 105622372 A CN105622372 A CN 105622372A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthetic method for a trimethoprim drug intermediate-p-hydroxy benzaldehyde. The method comprises the following steps: (i) adding 0.17mol of p-aminotenzaldehyde (2) and 150-200ml of water into a reaction container with the volume of 800-1,000mL, slowly adding 50mL of strong phosphoric acid, controlling the temperature of a solution to be increased to 80-95 DEG C, generating phosphate, obtaining a suspension liquid, cooling the solution to 15-20 DEG C, slowly dropwise adding 0.25mol of sodium hydrogen sulfite, performing dissolution in 100ml of an aqueous solution, controlling the stirring speed to be 100-300rpm in the dropwise adding process, and testing a termination point by potassium iodide test paper; and (ii) controlling the temperature of the solution to be 30 DEG C, standing for 20 minutes, adding 5g of urea, controlling the temperature of the solution to be gradually increased, after a large amount of gas escapes, heating the solution to 90-95 DEG C, keeping the temperature for 10 minutes, performing decolorization by using a molecular sieve, immediately filtering, washing a filter cake with a solvent, combining a filter liquor with a washing liquid, after the temperature is reduced, separating out solid, adding the solid into a sodium chloride solution for recrystallization, filtering, and drying to obtain p-hydroxy benzaldehyde.
Description
Technical field
The present invention relates to the synthetic method of a kind of trimethoprim pharmaceutical intermediate p-Hydroxybenzaldehyde.
Background technology
Trimethoprim be broad spectrum antibiotic, antimicrobial spectrum and sulfa drugs seemingly, have the effect suppressing Tetrahydrofolate dehydrogenase, but bacterium more easily produces resistance, is seldom used alone. Sulfa drug then suppresses dihydrofolate synthetase. Both share, and the folic acid metabolism of bacterium can be made to be subject to double blocking, and thus anti-microbial effect increases substantially (can synergy several times to tens times), therefore has the title of Trimpex, and can reduce the appearance of drug resistance strain. P-Hydroxybenzaldehyde is as trimethoprim pharmaceutical intermediate, and its synthetic method is good and bad for raising pharmaceutical synthesis quality product, reduces by-products content and has important economic implications.
Summary of the invention
It is an object of the invention to provide the synthetic method of a kind of trimethoprim pharmaceutical intermediate p-Hydroxybenzaldehyde, comprise the steps:
I () adds the p-Aminobenzaldehyde (2) of 0.17mol in the reaction vessel that volume is 800 1000mL, water 150 200ml, slowly add strong phosphoric acid 50mL, control solution temperature rises to 80--95 DEG C, generates phosphoric acid salt, obtain suspension, cooling solution is to 15--20 DEG C, slowly drip and add sodium bisulfite 0.25mol and be dissolved in the 100ml aqueous solution, drip that to add process control stirring velocity be 100 300rpm, test terminal with potassium iodide starch paper;
(ii) control solution temperature at 30 DEG C, leave standstill 20min, add 5g urea, control solution temperature progressively rises, and after having treated that a large amount of gas is overflowed, heated solution is to 90--95 DEG C, keep 10min, with molecular sieve decolouring, filtered while hot, filter cake solvent wash, merging filtrate and washings, precipitate out solid after decrease in temperature, solid is joined recrystallization in sodium chloride solution, filter, dry, obtain p-Hydroxybenzaldehyde;
The massfraction of the strong phosphoric acid described in step (i) is 50%--70%, and the described speed slowly adding strong phosphoric acid is that 10 12ml are per hour;
Filter cake solvent wash described in step (ii), solvent used is any one in ether, acetone, ethyl acetate; The massfraction of the sodium chloride solution described in step (ii) is 10%--15%.
Whole reaction process can represent with following reaction formula:
The invention has the advantages that: the middle-chain decreasing reaction, reduce temperature of reaction and reaction times, it is to increase reaction yield.
Embodiment
Below in conjunction with concrete embodiment, the invention will be further described:
The synthetic method of a kind of trimethoprim pharmaceutical intermediate p-Hydroxybenzaldehyde
Example 1:
I () adds the p-Aminobenzaldehyde (2) of 0.17mol in the reaction vessel that volume is 800mL, water 150ml, slowly adding massfraction is 50% strong phosphoric acid 50mL, control solution temperature rises to 80 DEG C, generates phosphoric acid salt, obtain suspension, cooling solution to 15 DEG C, slowly drip and add sodium bisulfite 0.25mol and be dissolved in the 100ml aqueous solution, drip that to add process control stirring velocity be 100rpm, test terminal with potassium iodide starch paper;
(ii) control solution temperature at 30 DEG C, leave standstill 20min, add 5g urea, control solution temperature progressively rises, after having treated that a large amount of gas is overflowed, and heated solution to 90 DEG C, keep 10min, with molecular sieve decolouring, filtered while hot, filter cake ether solvent washs, merging filtrate and washings, precipitates out solid after decrease in temperature, it is recrystallization in 10% sodium chloride solution that solid joins massfraction, filters, dry, obtain p-Hydroxybenzaldehyde 16.18g, receipts rate 78%.
Example 2:
I () adds the p-Aminobenzaldehyde (2) of 0.17mol in the reaction vessel that volume is 900mL, water 180ml, slowly adding massfraction is 60% strong phosphoric acid 50mL, control solution temperature rises to 90 DEG C, generates phosphoric acid salt, obtain suspension, cooling solution to 17 DEG C, slowly drip and add sodium bisulfite 0.25mol and be dissolved in the 100ml aqueous solution, drip that to add process control stirring velocity be 200rpm, test terminal with potassium iodide starch paper;
(ii) control solution temperature at 30 DEG C, leave standstill 20min, add 5g urea, control solution temperature progressively rises, after having treated that a large amount of gas is overflowed, and heated solution to 92 DEG C, keep 10min, with molecular sieve decolouring, filtered while hot, filter cake acetone solvent washs, merging filtrate and washings, precipitates out solid after decrease in temperature, it is recrystallization in 12% sodium chloride solution that solid joins massfraction, filters, dry, obtain p-Hydroxybenzaldehyde 17.21g, receipts rate 83%.
Example 3:
I () adds the p-Aminobenzaldehyde (2) of 0.17mol in the reaction vessel that volume is 1000mL, water 200ml, slowly add strong phosphoric acid 50mL, control solution temperature rises to 95 DEG C, generates phosphoric acid salt, obtain suspension, cooling solution to 20 DEG C, slowly drip and add sodium bisulfite 0.25mol and be dissolved in the 100ml aqueous solution, drip that to add process control stirring velocity be 300rpm, test terminal with potassium iodide starch paper;
(ii) control solution temperature at 30 DEG C, leave standstill 20min, add 5g urea, control solution temperature progressively rises, after having treated that a large amount of gas is overflowed, and heated solution to 95 DEG C, keep 10min, with molecular sieve decolouring, filtered while hot, filter cake ethyl acetate solvent washs, merging filtrate and washings, precipitates out solid after decrease in temperature, it is recrystallization in 15% sodium chloride solution that solid joins massfraction, filters, dry, obtain p-Hydroxybenzaldehyde 17.84g, receipts rate 86%.
Claims (3)
1. the synthetic method of a trimethoprim pharmaceutical intermediate p-Hydroxybenzaldehyde, it is characterised in that, comprise the steps:
I () adds the p-Aminobenzaldehyde (2) of 0.17mol in the reaction vessel that volume is 800 1000mL, water 150 200ml, slowly add strong phosphoric acid 50mL, control solution temperature rises to 80--95 DEG C, generates phosphoric acid salt, obtain suspension, cooling solution is to 15--20 DEG C, slowly drip and add sodium bisulfite 0.25mol and be dissolved in the 100ml aqueous solution, drip that to add process control stirring velocity be 100 300rpm, test terminal with potassium iodide starch paper;
(ii) control solution temperature at 30 DEG C, leave standstill 20min, add 5g urea, control solution temperature progressively rises, and after having treated that a large amount of gas is overflowed, heated solution is to 90--95 DEG C, keep 10min, with molecular sieve decolouring, filtered while hot, filter cake solvent wash, merging filtrate and washings, precipitate out solid after decrease in temperature, solid is joined recrystallization in sodium chloride solution, filter, dry, obtain p-Hydroxybenzaldehyde; The massfraction of the strong phosphoric acid described in step (i) is 50%--70%, and the described speed slowly adding strong phosphoric acid is that 10 12ml are per hour.
2. the synthetic method of a kind of trimethoprim pharmaceutical intermediate p-Hydroxybenzaldehyde according to claim 1, it is characterised in that, the filter cake solvent wash described in step (ii), solvent used is any one in ether, acetone, ethyl acetate.
3. the synthetic method of a kind of trimethoprim pharmaceutical intermediate p-Hydroxybenzaldehyde according to claim 1, it is characterised in that, the massfraction of the sodium chloride solution described in step (ii) is 10%--15%.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510982275.4A CN105622372A (en) | 2015-12-23 | 2015-12-23 | Synthetic method for trimethoprim drug intermediate-p-hydroxy benzaldehyde |
| CN201610824158.XA CN106431874A (en) | 2015-12-23 | 2016-09-17 | Synthetic method for trimethoprim medicine midbody parahydroxybenzaldehyde |
| AU2016102204A AU2016102204A4 (en) | 2015-12-23 | 2016-12-23 | Trimethoprim drug intermediates p-hydroxy benzaldehyde synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510982275.4A CN105622372A (en) | 2015-12-23 | 2015-12-23 | Synthetic method for trimethoprim drug intermediate-p-hydroxy benzaldehyde |
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| Publication Number | Publication Date |
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| CN105622372A true CN105622372A (en) | 2016-06-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510982275.4A Pending CN105622372A (en) | 2015-12-23 | 2015-12-23 | Synthetic method for trimethoprim drug intermediate-p-hydroxy benzaldehyde |
| CN201610824158.XA Pending CN106431874A (en) | 2015-12-23 | 2016-09-17 | Synthetic method for trimethoprim medicine midbody parahydroxybenzaldehyde |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201610824158.XA Pending CN106431874A (en) | 2015-12-23 | 2016-09-17 | Synthetic method for trimethoprim medicine midbody parahydroxybenzaldehyde |
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2015
- 2015-12-23 CN CN201510982275.4A patent/CN105622372A/en active Pending
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Application publication date: 20160601 |