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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- 229960001523 chlortalidone Drugs 0.000 title claims abstract description 13
- MQECGSWGDQIHHD-UHFFFAOYSA-N 2-(3-amino-4-chlorobenzoyl)benzoic acid Chemical compound C1=C(Cl)C(N)=CC(C(=O)C=2C(=CC=CC=2)C(O)=O)=C1 MQECGSWGDQIHHD-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title abstract description 10
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 title abstract 2
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 21
- RITAQDHCJBLSSL-UHFFFAOYSA-N 2-(4-chloro-3-nitrobenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 RITAQDHCJBLSSL-UHFFFAOYSA-N 0.000 claims abstract description 12
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 86
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 22
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 22
- 238000010189 synthetic method Methods 0.000 claims description 22
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 17
- 230000000630 rising effect Effects 0.000 claims description 15
- 230000009467 reduction Effects 0.000 claims description 12
- IFXKXCLVKQVVDI-UHFFFAOYSA-N 2-amino-5-chlorobenzoic acid Chemical compound NC1=CC=C(Cl)C=C1C(O)=O IFXKXCLVKQVVDI-UHFFFAOYSA-N 0.000 claims description 11
- 235000019270 ammonium chloride Nutrition 0.000 claims description 11
- JIVPVXMEBJLZRO-UHFFFAOYSA-N chlorthalidone Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-UHFFFAOYSA-N 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 235000010344 sodium nitrate Nutrition 0.000 claims description 11
- 239000004317 sodium nitrate Substances 0.000 claims description 11
- 235000010265 sodium sulphite Nutrition 0.000 claims description 11
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 10
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- 238000004140 cleaning Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000011505 plaster Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000012267 brine Substances 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 abstract 1
- 229940045803 cuprous chloride Drugs 0.000 abstract 1
- 238000005086 pumping Methods 0.000 abstract 1
- 230000035484 reaction time Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 10
- 210000005239 tubule Anatomy 0.000 description 8
- 229910001415 sodium ion Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 230000029142 excretion Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 102000003846 Carbonic anhydrases Human genes 0.000 description 3
- 108090000209 Carbonic anhydrases Proteins 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 210000000512 proximal kidney tubule Anatomy 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 206010041277 Sodium retention Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000005165 macula densa Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- GYICYQJEVCIYJY-UHFFFAOYSA-N thiophen-1-ylidenemethanone Chemical compound O=C=S1C=CC=C1 GYICYQJEVCIYJY-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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