CN105906521A - Synthesis method of chlorthalidone medicine intermediate 2-(3-amino-4-chlorobenzoyl)benzoic acid - Google Patents
Synthesis method of chlorthalidone medicine intermediate 2-(3-amino-4-chlorobenzoyl)benzoic acid Download PDFInfo
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- CN105906521A CN105906521A CN201610255816.8A CN201610255816A CN105906521A CN 105906521 A CN105906521 A CN 105906521A CN 201610255816 A CN201610255816 A CN 201610255816A CN 105906521 A CN105906521 A CN 105906521A
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Abstract
The invention discloses a synthesis method of a chlorthalidone medicine intermediate 2-(3-amino-4-chlorobenzoyl)benzoic acid. The method comprises the following steps: reacting 2-(3-nitro-4-chlorobenzoyl)benzoic acid with cuprous chloride and potassium iodide, washing the obtained reaction product, carrying out suction pumping, and dehydrating the reaction product to obtain 2-(3-amino-4-chlorobenzoyl)benzoic acid. The whole reaction time is controlled to be 8h or shorter, and the reaction yield can reach 90% or above. The method provides a new synthesis route, and lays a good foundation for further increase of the reaction yield.
Description
Technical field
The present invention relates to the preparation method of a kind of medicine intermediate, belong to organic synthesis field, particularly relate to a kind of chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method.
Background technology
Thiophene ketone medicine be mainly used in treating congestive heart failure, cirrhotic ascites, nephrotic syndrome, acute and chronic nephritis edema, chronic renal failure in early days, adrenocortical hormone and the sodium retention caused by estrin treatment.Can individually or with other depressor use in conjunction, be mainly used in treat essential hypertension.Oral absorption is incomplete, is mainly combined with intracellular carbonic anhydrase, and is combined with plasma protein seldom, and during severe anemia, the combination with plasma protein (mainly albumin) increases.It is administered orally and works for 2 hours, peak time is 2 hours, acting duration is 24～72 hours, half-life is 35～50 hours, this medicine half-life and acting duration are considerably longer than the reason of other phenothiazine drugs, it is owing to this medicine is mainly combined with erythrocyte carbonic anhydrase, therefore excretion and metabolism are the slowest.Mainly draining from urine with original shape, part is metabolized in vivo, and by kidney outer approach excretion, biliary tract is not main excretion pathway.This class mechanism of drug action mainly suppresses distal tubule leading portion and the proximal tubule (acting on lighter) the heavily absorption to sodium chloride, thus the Na ion increasing distal tubule and collecting tubule exchanges with K ion, and K ion secretion increases.This class medicine can suppress carbonic anhydrase activity to some extent, therefore can explain its effect to proximal tubule.This class medicine can also suppress phosphodiesterase activity, reduces renal tubules and consumes picked-up and the mitochondrion oxygen of fatty acid, thus suppresses renal tubules heavily to absorb the active of Na ion, Cl ion.In addition to diuresis row's sodium effect, the outer mechanism of action of kidney may be also had to participate in blood pressure lowering, it may be possible to increase the gastrointestinal tract excretion to Na ion.On renal hemodynamics and the impact of detection of glomeruli filtration function, owing to renal tubules is to water, Na ion heavily absorbs minimizing, and in renal tubules, pressure raises, and flows through the water of Distal convoluted tubule and Na ion increases, macula densa is stimulated to be reflected by pipe-ball, making feritin, angiotensin secretion increase in kidney, cause Renal vascular to shrink, renal blood flow declines, glomerule goal and efferent glomerular arteriole shrink, and glomerular filtration rate also declines.2-(3-amino-4-chlorobenzoyl) benzoic acid is as chlortalidone pharmaceutical intermediate, and its synthetic method is good and bad for improving pharmaceutical synthesis product quality, reduces by-products content and has Important Economic meaning.
Wang Zhonghan (Wang Zhong Chinese chlortalidone improvement in synthesis [J]. medical industry, 1982,04:20-21.) use nitrification, reduction etc. that 2-(3-amino-4-chlorobenzoyl) benzoic acid is synthesized, the method is after 2-(3-nitro-4-chlorobenzoyl) benzoic acid and ethanol put into reaction bulb, add hydrazine hydrate and active nickel catalysis, after reaction overnight, filtration drying obtains 2-(3-amino-4-chlorobenzoyl) benzoic acid, and document yield can reach more than 91%.But this response time overlength, generally more than 16 hours, reaction yield still had much room for improvement, therefore, it is necessary to propose a kind of new synthetic method.
Summary of the invention
The technical problem existed based on background technology, the present invention proposes a kind of chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method.
A kind of chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method, follows the steps below:
A, in reaction vessel add 2-(3-nitro-4-chlorobenzoyl) benzoic acid (2) 0.23mol, sodium nitrate solution 300ml, solution of potassium carbonate 500ml, rising solution temperature, to 60--65 DEG C, adds 2-amino-5-chlorobenzoic acid solution 1.3L, Cu-lyt. 0.31mol, potassium iodide 0.2mol, controlling mixing speed 160 190rpm, rising solution temperature is to 70--76 DEG C, and reflux 3 4h；
B, reduce solution temperature to 20---26 DEG C, filter, filter cake with sodium sulfite solution wash, merge cleaning mixture, raise solution temperature to 50--55 DEG C, add 300ml ammonium chloride solution, be sufficiently stirred for 90 130min；
C, reduction solution temperature are to 10 15 DEG C, and sucking filtration, brine, dehydrant is dehydrated, obtains 2-(3-amino-4-chlorobenzoyl) benzoic acid (1).
Preferably, described sodium nitrate solution mass fraction is 30 37%.
Preferably, described solution of potassium carbonate mass fraction is 20 26%.
Preferably, described 2-amino-5-chlorobenzoic acid liquid quality fraction is 40 45%.
Preferably, described sodium sulfite solution mass fraction is 50 56%.
Preferably, described ammonium chloride solution mass fraction is 35 39%.
Preferably, described saline solution is any one in potassium bromide, sodium sulfate.
Preferably, described dehydrant is any one in anhydrous magnesium sulfate, dead plaster.
Whole course of reaction can represent with following reaction equation:
Compared to synthetic method disclosed in background technology, chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) the benzoic synthetic method that the present invention provides, response time is greatly shortened, reaction yield is also improved, the invention provides a kind of new synthetic route simultaneously, lay a good foundation for promoting reaction yield further.
Detailed description of the invention
Embodiment 1:
A kind of chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method, follows the steps below:
A, in reaction vessel add 2-(3-nitro-4-chlorobenzoyl) benzoic acid (2) 0.23mol, mass fraction is 35% sodium nitrate solution 300ml, mass fraction is 24% solution of potassium carbonate 500ml, rising solution temperature, to 60 DEG C, adds 2-amino-5-chlorobenzoic acid solution 1.3L, Cu-lyt. 0.31mol that mass fraction is 42%, potassium iodide 0.2mol, controlling mixing speed 160rpm, rising solution temperature is to 70 DEG C, and reflux 3h；
B, reduction solution temperature, to 20 DEG C, filter, and filter cake mass fraction is the sodium sulfite solution washing of 52%, merge cleaning mixture, and rising solution temperature is to 50 DEG C, and addition 300ml mass fraction is the ammonium chloride solution of 37%, is sufficiently stirred for 90min；
C, reduction solution temperature are to 10 DEG C, and sucking filtration, potassium bromide solution washs, and anhydrous magnesium sulfate dehydrant is dehydrated, and obtains 2-(3-amino-4-chlorobenzoyl) benzoic acid 60.30g, yield 95%.
Embodiment 2:
A kind of chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method, follows the steps below:
A, in reaction vessel add 2-(3-nitro-4-chlorobenzoyl) benzoic acid (2) 0.23mol, mass fraction is 33% sodium nitrate solution 300ml, mass fraction is 24% solution of potassium carbonate 500ml, rising solution temperature, to 63 DEG C, adds 2-amino-5-chlorobenzoic acid solution 1.3L, Cu-lyt. 0.31mol that mass fraction is 42%, potassium iodide 0.2mol, controlling mixing speed 170rpm, rising solution temperature is to 73 DEG C, and reflux 3h；
B, reduction solution temperature, to 23 DEG C, filter, and filter cake mass fraction is the sodium sulfite solution washing of 53%, merge cleaning mixture, and rising solution temperature is to 52 DEG C, and addition 300ml mass fraction is the ammonium chloride solution of 37%, is sufficiently stirred for 110min；
C, reduction solution temperature are to 13 DEG C, and sucking filtration, potassium bromide solution washs, and dead plaster dehydrant is dehydrated, and obtains 2-(3-amino-4-chlorobenzoyl) benzoic acid 59.03g, yield 93%.
Embodiment 3:
A kind of chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method, follows the steps below:
A, in reaction vessel add 2-(3-nitro-4-chlorobenzoyl) benzoic acid (2) 0.23mol, mass fraction is 37% sodium nitrate solution 300ml, mass fraction is 26% solution of potassium carbonate 500ml, rising solution temperature is to 65 DEG C, and adding mass fraction is 45%2-amino-5-chlorobenzoic acid solution 1.3L, Cu-lyt. 0.31mol, potassium iodide 0.2mol, controlling mixing speed 190rpm, rising solution temperature is to 76 DEG C, and reflux 4h；
B, reduction solution temperature, to 26 DEG C, filter, and filter cake mass fraction is 56% sodium sulfite solution washing, merge cleaning mixture, and rising solution temperature is to 55 DEG C, and addition 300ml mass fraction is 39% ammonium chloride solution, is sufficiently stirred for 130min；
C, reduction solution temperature are to 15 DEG C, and sucking filtration, metabisulfite solution washs, and anhydrous magnesium sulfate dehydrant is dehydrated, and obtains 2-(3-amino-4-chlorobenzoyl) benzoic acid 59.39g, yield 92%.
The response time of embodiment 1-3 is all less than 6 hours, and yield is above 85%, therefore synthetic method provided by the present invention was greatly shortened than the synthetic method in background technology, response time, and yield is greatly improved.
Below embodiment 4-13 is contrasted with embodiment 1, the impact of the percent mass comparison yield of each solution in research reaction.
Embodiment 4:
The mass fraction of the sodium nitrate solution in embodiment 1 is adjusted to 20%, 25%, 28%, 30%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 65%, 73%, 87%, 93%.
Embodiment 5:
The mass fraction of the sodium nitrate solution in embodiment 1 is adjusted to 37%, 39%, 42%, 47%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 93%, 85%, 78%, 70%.
From embodiment 4 and 5, the mass fraction of sodium nitrate solution is too high or too low all can affect reaction yield, and it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 30-37%.
Embodiment 6:
The mass fraction of the solution of potassium carbonate in embodiment 1 is adjusted to 10%, 15%, 18%, 20%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 68%, 75%, 83%, 92%.
Embodiment 7:
The mass fraction of the solution of potassium carbonate in embodiment 1 is adjusted to 26%, 28%, 33%, 36%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 93%, 82%, 72%, 67%.
From embodiment 6 and 7, the mass fraction of solution of potassium carbonate is too high or too low all can affect reaction yield, and it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 20-26%.
Embodiment 8:
The mass fraction of the 2-amino-5-chlorobenzoic acid solution in embodiment 1 is adjusted to 30%, 35%, 38%, 40%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 74%, 79%, 83%, 91%.
Embodiment 9:
The mass fraction of the 2-amino-5-chlorobenzoic acid solution in embodiment 1 is adjusted to 45%, 47%, 50%55%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 93%, 82%, 76%, 70%.
From embodiment 8 and 9, the mass fraction of 2-amino-5-chlorobenzoic acid solution is too high or too low all can affect reaction yield, and it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 40-45%.
Embodiment 10:
The mass fraction of the sodium sulfite solution in embodiment 1 is adjusted to 40%, 45%, 48%, 50%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 67%, 75%, 83%, 91%.
Embodiment 11:
The mass fraction of the sodium sulfite solution in embodiment 1 is adjusted to 56%, 58%, 61%, 66%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 92%, 85%, 79%, 72%.
From embodiment 10 and 11, the mass fraction of sodium sulfite solution is too high or too low all can affect reaction yield, and it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 50-56%.
Embodiment 12:
The mass fraction of the ammonium chloride solution in embodiment 1 is adjusted to 25%, 30%, 33%, 35%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 63%, 72%, 80%, 92%.
Embodiment 13:
The mass fraction of the ammonium chloride solution in embodiment 1 is adjusted to 39%, 41%, 44%, 49%, and remaining preparation condition is same as in Example 1 with proportioning raw materials, and gained yield is respectively 65%, 79%, 86%, 93%.
From embodiment 12 and 13, the mass fraction of ammonium chloride solution is too high or too low all can affect reaction yield, and it becomes normal distribution, peak value to occur in mass fraction with reaction yield is 35-39%.
Described in above example; it is only the present invention preferably detailed description of the invention; but protection scope of the present invention is not limited thereto; any those familiar with the art is in the technical scope that the invention discloses; according to technical scheme and inventive concept equivalent or change in addition thereof, all should contain within protection scope of the present invention.
Claims (9)
1. chlortalidone pharmaceutical intermediate 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method, its
It is characterised by, follows the steps below:
A, in reaction vessel add 2-(3-nitro-4-chlorobenzoyl) benzoic acid 0.23mol, sodium nitrate is molten
Liquid 300ml, solution of potassium carbonate 500ml, rising solution temperature, to 60-65 DEG C, adds 2-amino-5-chlorobenzoic acid
Solution 1.3L, Cu-lyt. 0.31mol, potassium iodide 0.2mol, control mixing speed 160-190rpm, raise molten
Liquid temp is to 70-76 DEG C, and reflux 3-4h；
B, reduction solution temperature, to 20-26 DEG C, filter, and filter cake sodium sulfite solution washs, and merging is washed
Washing liquid, rising solution temperature, to 50-55 DEG C, adds 300ml ammonium chloride solution, is sufficiently stirred for 90-130min；
C, reduction solution temperature are to 10-15 DEG C, and sucking filtration, brine, dehydrant is dehydrated, obtains 2-(3-
Amino-4-chlorobenzoyl) benzoic acid.
2. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levying and be, sodium nitrate solution mass fraction is 30-37%.
3. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levying and be, solution of potassium carbonate mass fraction is 20-26%.
4. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levying and be, 2-amino-5-chlorobenzoic acid liquid quality fraction is 40-45%.
5. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levying and be, sodium sulfite solution mass fraction is 50-56%.
6. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levying and be, ammonium chloride solution mass fraction is 35-39%.
7. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levying and be, saline solution is any one in potassium bromide, sodium sulfate.
8. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levying and be, dehydrant is any one in anhydrous magnesium sulfate, dead plaster.
9. 2-(3-amino-4-chlorobenzoyl) benzoic synthetic method as claimed in claim 1, it is special
Levy and be, follow the steps below:
A, in reaction vessel add 2-(3-nitro-4-chlorobenzoyl) benzoic acid 0.23mol, mass fraction
Being 35% sodium nitrate solution 300ml, mass fraction is 24% solution of potassium carbonate 500ml, raises solution temperature extremely
60 DEG C, add 2-amino-5-chlorobenzoic acid solution 1.3L, Cu-lyt. 0.31mol that mass fraction is 42%,
Potassium iodide 0.2mol, controls mixing speed 160rpm, and rising solution temperature is to 70 DEG C, and reflux 3h；
B, reduction solution temperature, to 20 DEG C, filter, and filter cake mass fraction is the sodium sulfite solution of 52%
Washing, merges cleaning mixture, and rising solution temperature is to 50 DEG C, and adding 300ml mass fraction is the ammonium chloride of 37%
Solution, is sufficiently stirred for 90min；
C, reduction solution temperature are to 10 DEG C, and sucking filtration, potassium bromide solution washs, and anhydrous magnesium sulfate dehydrant takes off
Water, obtains 2-(3-amino-4-chlorobenzoyl) benzoic acid.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB311465A (en) * | 1928-02-16 | 1929-05-16 | Herbert Wilfrid Hereward | Improvements in and relating to the production of benzoic acid derivatives |
| RO91632A2 (en) * | 1985-02-18 | 1987-05-15 | Intreprinderea De Medicamente"Terapia",Ro | PROCESS FOR THE PREPARATION OF 4-CHLORIN-3-AMINO-BENZOPHENONE-2'-CARBOXYLIC ACID |
| RU1768584C (en) * | 1990-04-16 | 1992-10-15 | Ярославский государственный университет | Method of 3ъ-amino-4ъ-chlorobenzophenone-2-carboxylic acid synthesis |
| CN1456565A (en) * | 2003-05-14 | 2003-11-19 | 华东师范大学 | Bismuth color reagent of azofluorophosphine-DBF and its synthesis and use |
-
2016
- 2016-04-22 CN CN201610255816.8A patent/CN105906521A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB311465A (en) * | 1928-02-16 | 1929-05-16 | Herbert Wilfrid Hereward | Improvements in and relating to the production of benzoic acid derivatives |
| RO91632A2 (en) * | 1985-02-18 | 1987-05-15 | Intreprinderea De Medicamente"Terapia",Ro | PROCESS FOR THE PREPARATION OF 4-CHLORIN-3-AMINO-BENZOPHENONE-2'-CARBOXYLIC ACID |
| RU1768584C (en) * | 1990-04-16 | 1992-10-15 | Ярославский государственный университет | Method of 3ъ-amino-4ъ-chlorobenzophenone-2-carboxylic acid synthesis |
| CN1456565A (en) * | 2003-05-14 | 2003-11-19 | 华东师范大学 | Bismuth color reagent of azofluorophosphine-DBF and its synthesis and use |
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