CN106946786A - A kind of preparation method of the indazole sodium salts of 1 benzyl, 3 hydroxyl 1H 3 - Google Patents
A kind of preparation method of the indazole sodium salts of 1 benzyl, 3 hydroxyl 1H 3 Download PDFInfo
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- CN106946786A CN106946786A CN201710233892.3A CN201710233892A CN106946786A CN 106946786 A CN106946786 A CN 106946786A CN 201710233892 A CN201710233892 A CN 201710233892A CN 106946786 A CN106946786 A CN 106946786A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- QZVCQSLKTWIKJQ-UHFFFAOYSA-N [Na].N1N=CC2=CC=CC=C12 Chemical class [Na].N1N=CC2=CC=CC=C12 QZVCQSLKTWIKJQ-UHFFFAOYSA-N 0.000 title abstract 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title abstract 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 25
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000007787 solid Substances 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 9
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 8
- 239000011734 sodium Substances 0.000 claims abstract description 8
- 230000000977 initiatory effect Effects 0.000 claims abstract description 7
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 3
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 16
- 239000000843 powder Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 9
- 238000013019 agitation Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 238000005352 clarification Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000010583 slow cooling Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003610 charcoal Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000003541 multi-stage reaction Methods 0.000 abstract 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 8
- 206010001497 Agitation Diseases 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- -1 1- benzylindoles ketone Chemical class 0.000 description 2
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- SWEICGMKXPNXNU-UHFFFAOYSA-N 1,2-dihydroindazol-3-one Chemical class C1=CC=C2C(O)=NNC2=C1 SWEICGMKXPNXNU-UHFFFAOYSA-N 0.000 description 1
- UYXKSJRBCLSBNE-UHFFFAOYSA-N 1-(4-phenyldiazenylphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1N=NC1=CC=CC=C1 UYXKSJRBCLSBNE-UHFFFAOYSA-N 0.000 description 1
- XWJHQOWAYSWCRY-UHFFFAOYSA-N 1-benzylindazole Chemical compound N1=CC2=CC=CC=C2N1CC1=CC=CC=C1 XWJHQOWAYSWCRY-UHFFFAOYSA-N 0.000 description 1
- VXZOBNZOEBYBFR-UHFFFAOYSA-N 2-[benzyl(nitroso)amino]benzoic acid Chemical class OC(=O)C1=CC=CC=C1N(N=O)CC1=CC=CC=C1 VXZOBNZOEBYBFR-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 229960000333 benzydamine Drugs 0.000 description 1
- 150000005524 benzylchlorides Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004900 laundering Methods 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation method of the indazole sodium salts of 1 benzyl, 3 hydroxyl 1H 3.This method is with ortho-aminobenzoic acid, concentrated hydrochloric acid, NaNO2Solution and solid Na2SO3For initiation material, appropriate NaOH solution and benzyl chloride are added, the indazole sodium salts of 1 benzyl, 3 hydroxyl 1H 3 are obtained by multistep reaction filtering means dehydration.This method raw material is easy to get, and reaction condition is gentle, low cost, is suitable for factory's large-scale production.
Description
Technical field
The present invention relates to a kind of medicine intermediate, exactly the present invention relates to a kind of 1- benzyls -3- hydroxyl -1H-3- indazoles
The preparation method of sodium salt.
Background technology
1- benzyl -3- hydroxyl -1H-3- indazoles are also known as 1- benzylindoles ketone or 1- benzyl -1H- indazole -3- alcohol, and molecular formula is
C14H12N2O, as the important intermediate of benzydamine hydrocloride, can also be used to synthesize 3- (5- hydroxymethyl -2- furyls) -1- phenyl Yin
The compound such as diindyl and 1- benzyl -3- methoxyl group -1H- indazoles.Although the domestic and international producer for producing the product at present is a lot of, such as lark
Numerous factories such as the female Chemical Co., Ltd. of prestige Science and Technology Ltd., Shanghai Mai Ruier chemical technologies Co., Ltd and Zhengzhou Ai Ke
Family, but the specific synthesis technique and method of 1- benzyl -3- hydroxyl -1H-3- indazoles and its sodium salt are not disclosed, more only
The synthetic route of directiveness：By ortho-aminobenzoic acid and benzyl chloride heating response, N- benzyls-ortho-aminobenzoic acid is condensed to obtain, so
Afterwards with natrium nitrosum, hydrochloric acid nitrosation, N- benzyl-N- nitroso ortho-aminobenzoic acids are obtained, the latter is made through reduction and cyclization
The product.It is as follows：
Synthetic route as the 3- hydroxyl -1H- indazoles of direct synthesis material is more, therefore 1- benzyl -3- hydroxyls -1H-
Also species is various for 3- indazoles and its alternative initiation material of sodium salt.In actual production process, raw material type, concrete technology
Parameter, production cost and combined coefficient etc. all need further research and probe.
The content of the invention
It is an object of the invention to overcome the deficiencies in the prior art, a kind of 1- benzyls -3- hydroxyls -1H-3- indazole sodium is proposed
The preparation method of salt.
A kind of preparation method of 1- benzyls -3- hydroxyls -1H-3- indazole sodium salts of the present invention, it is characterised in that synthetic route
For：
With ortho-aminobenzoic acid, concentrated hydrochloric acid, NaNO2Solution and solid Na2SO3React, fully stop after reaction for initiation material
Only heat, the pH of regulation system, filtration drying after stirring obtains pale yellow powder BZ-01；Stirred into BZ-01 obtained above
Appropriate NaOH solution is added dropwise and benzyl chloride continues to react, fully filtration drying obtains gray solid BZ-02 after reaction；By BZ-02
Stirring is soluble in water, adds appropriate NaOH solution, fully adds activated carbon after reaction, agitation and filtration obtains off-white powder, by class
White solid is dehydrated to obtain 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that specific step
It is rapid as follows：
1) with ortho-aminobenzoic acid, concentrated hydrochloric acid, NaNO2Solution and solid Na2SO3For initiation material, in 80 DEG C of reaction temperature
Fully reaction under degree, it is 5.5 then to stop calorifying the pH for adding NaOH solution tune system at a temperature of 0~14 DEG C, and ice bath is stirred
Filtration drying after 1h is mixed, pale yellow powder BZ-01 is obtained；
2) at a temperature of 40 DEG C, the appropriate NaOH solution of agitation and dropping and benzyl chloride into BZ-01 obtained above, then
70 DEG C are heated to, insulation fully reaction, filtration drying obtains gray solid BZ-02；
3) BZ-02 is stirred soluble in water, adds appropriate NaOH solution, be warming up to 80~85 DEG C, fully added after reaction
Activated carbon, stirring 30min filters to obtain off-white powder BZ-03, and off-white powder is dehydrated to obtain into 1- benzyl -3- hydroxyl -1H-3- Yin
Azoles sodium salt.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that step 1)
Described in ortho-aminobenzoic acid in need slowly to add water stirring, be to mass fraction of the ortho-aminobenzoic acid in its aqueous solution
13%, continue that appropriate concentrated hydrochloric acid is added dropwise, it is 31.5% that mass fraction is added at a temperature of being controlled in 0~5 DEG C after system clarification
NaNO2Solution, insulated and stirred 30min；Question response liquid is in rufous, continues to be cooled to -8 DEG C, appropriate solid is added portionwise
Na2SO3, insulated and stirred 4h；Continue to be slowly added dropwise appropriate concentrated hydrochloric acid reaction solution in rufous, stir after 30min, system is changed into yellow
Color, separates out solid.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that step 1)
Described in course of reaction need under 80 DEG C of reaction temperature amount to reaction 38h.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that step 2)
The mass fraction of the NaOH solution of middle addition is about 4%.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that step 2)
Described in course of reaction need to react 7h under 70 DEG C of reaction temperature.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that step 3)
Described in the mass fraction of NaOH solution be about 30%.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that step 3)
Described in filter process for heat filter, by filtrate slow cooling after filtering, ice bath stirring 1h after filter again.
Further, the preparation method of 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the invention, it is characterised in that step 3)
Described in dehydration be specifically be dehydrated at a temperature of 140 DEG C with dimethylbenzene.
Compared with prior art, the present invention has filled up relevant 1- benzyl -3- hydroxyl -1H-3- indazoles and its sodium salt at present and had
Blank in terms of body synthesis technique, this method raw material is easy to get, and reaction condition is gentle, low cost, is suitable for factory's large-scale production.
Embodiment
With reference to specific embodiment, the present invention is described in further detail.
1- benzyl -3- hydroxyl -1H-3- indazole sodium salts, with ortho-aminobenzoic acid, concentrated hydrochloric acid, NaNO2Solution and solid
Na2SO3For initiation material, specific synthetic route is as follows：
1) addition 250g ortho-aminobenzoic acids and 1665g water first into a 15L four-hole boiling flasks, mechanical agitation, then slowly
Add 361.25mL concentrated hydrochloric acids, after system clarification after ice bath by temperature drop to 2 DEG C.Then control temperature between 0~5 DEG C again
Add NaNO2Solution, wherein NaNO2It is respectively 125.75g and 273.25g, insulated and stirred 30min with water；Question response liquid is in reddish brown
Color, continues to be cooled to -8 DEG C, and 627.25g solids Na is added portionwise2SO3, need to be added in 16min, now produce a large amount of foams.
Then temperature is risen into 5 DEG C, insulated and stirred 4h；It is in gradually rufous to be further continued for that the reaction of 555mL concentrated hydrochloric acids is slowly added dropwise.Control temperature
Degree is no more than 15 DEG C, continues to stir after 30min, system is changed into yellow, has solid precipitation.Oiling bath is slowly heated to after 80 DEG C
Insulation reaction, the reaction time amounts to 38h.
2) after stopping heating after abundant reaction, room temperature is back to naturally, 1665ml water, bath on the rocks is added.Control temperature 0~
The NaOH solution that addition 750mL mass fractions are 30% at 14 DEG C is 5.5 to system pH, is added dropwise to complete repetition measurement pH after 15min, ice
Filtration drying after bath stirring 1h, filter cake is washed with massive laundering to no salt, obtains 216.43g pale yellow powder BZ-01, purity is
96.54, yield is 88.52%.
3) 200g BZ-01 obtained above and 65gNaOH are taken in a 3L four-hole boiling flasks, 1500g water dispenser tools is added and stirs
Mix, reaction solution gradually becomes clarification.Control temperature continues that 188.67g benzyl chlorides are added dropwise thereto at 40 DEG C, has a small amount of solid
Separate out.Then temperature is heated to 70 DEG C of insulation reaction 7h, stops heating, room temperature is down to naturally, is stirred overnight, was sampled within second day
Filter, filter cake 60mL water washings 3 times, is dried to obtain 367.63g gray solid BZ-02, purity is 73.8%, and yield is 109%.
4) take 300g BZ-02 obtained above to add in a 3L there-necked flasks, add 1200g water magnetic agitations, then delay
Slow to add the NaOH solution that 357g mass fractions are 30%, reaction system is suspended；It is fully anti-that oil bath is warming up to 80~85 DEG C of Inner temperature
Should, 25g activated carbons are added after solution becomes clarification, 30min is stirred；Heat filter, by filtrate slow cooling after filtering, ice bath stirring 1h
Filter again afterwards, filter cake with 600mL toluene and 600mL ethyl acetate mashing 10min, obtains off-white powder 326.0gBZ- respectively
03；Take 120g off-white powders to be dehydrated at a temperature of 140 DEG C with dimethylbenzene, obtain water 45mL, 1- benzyl -3- hydroxyls -1H-3-
Indazole sodium salt 75g.Conversion step 4) in 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts 203.75g is always obtained.
The preparation method of the 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts of the present invention, the purity of gained final product is
97.94%, yield is 62.4%.This method raw material is easy to get, and reaction condition is gentle, and low cost is suitable for batch production and given birth on a large scale
Production.
Claims (9)
1. a kind of preparation method of 1- benzyls -3- hydroxyls -1H-3- indazole sodium salts, it is characterised in that synthetic route is：
With ortho-aminobenzoic acid, concentrated hydrochloric acid, NaNO2Solution and solid Na2SO3Reacted for initiation material, fully stop adding after reaction
Heat, the pH of regulation system, filtration drying after stirring obtains pale yellow powder BZ-01；The agitation and dropping into BZ-01 obtained above
Appropriate NaOH solution and benzyl chloride continue to react, and fully filtration drying obtains gray solid BZ-02 after reaction；BZ-02 is stirred
It is soluble in water, appropriate NaOH solution is added, fully activated carbon is added after reaction, agitation and filtration obtains off-white powder, by off-white color
Solid is dehydrated to obtain 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts.
2. preparation method according to claim 1, it is characterised in that comprise the following steps that：
1) with ortho-aminobenzoic acid, concentrated hydrochloric acid, NaNO2Solution and solid Na2SO3For initiation material, under 80 DEG C of reaction temperature
Fully reaction, then stops heating, and it is 5.5 that NaOH solution is added at a temperature of 0~14 DEG C and adjusts the pH of system, ice bath stirring 1h
Filtration drying, obtains pale yellow powder BZ-01 afterwards；
2) at a temperature of 40 DEG C, into BZ-01 obtained above, the appropriate NaOH solution of agitation and dropping and benzyl chloride, are then heated
To 70 DEG C, insulation fully reaction, filtration drying obtains gray solid BZ-02；
3) BZ-02 is stirred soluble in water, adds appropriate NaOH solution, be warming up to 80~85 DEG C, fully add activity after reaction
Charcoal, stirring 30min filters to obtain off-white powder, and off-white powder is dehydrated to obtain into 1- benzyl -3- hydroxyl -1H-3- indazole sodium salts.
3. preparation method according to claim 2, it is characterised in that in step 1) in, in described ortho-aminobenzoic acid
Need to slowly be added water stirring, be 13% to mass fraction of the ortho-aminobenzoic acid in its aqueous solution, continue that appropriate concentrated hydrochloric acid is added dropwise,
It is 31.5% NaNO after controlling to add mass fraction at a temperature of 0~5 DEG C after system clarification2Solution, insulated and stirred
30min；Question response liquid is in rufous, continues to be cooled to -8 DEG C, appropriate solid Na is added portionwise2SO3, insulated and stirred 4h；Continue slow
Slowly appropriate concentrated hydrochloric acid reaction solution is added dropwise in rufous, stirs after 30min, system is changed into yellow, solid is separated out.
4. preparation method according to claim 3, it is characterised in that in step 1) in, described course of reaction need to be 80
DEG C reaction temperature under amount to reaction 38h.
5. preparation method according to claim 4, it is characterised in that in step 2) in, the quality of the NaOH solution of addition
Fraction is about 4%.
6. preparation method according to claim 5, it is characterised in that in step 2) in, described course of reaction need to be 70
DEG C reaction temperature under react 7h.
7. preparation method according to claim 6, it is characterised in that in step 3) in, the quality of described NaOH solution
Fraction is about 30%.
8. preparation method according to claim 7, it is characterised in that in step 3) in, described filter process is filtered for heat,
By filtrate slow cooling after filtering, filtered again after ice bath stirring 1h.
9. preparation method according to claim 8, it is characterised in that in step 3) in, described dehydration is specifically
It is dehydrated at a temperature of 140 DEG C with dimethylbenzene.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710233892.3A CN106946786A (en) | 2017-04-11 | 2017-04-11 | A kind of preparation method of the indazole sodium salts of 1 benzyl, 3 hydroxyl 1H 3 |
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| CN201710233892.3A CN106946786A (en) | 2017-04-11 | 2017-04-11 | A kind of preparation method of the indazole sodium salts of 1 benzyl, 3 hydroxyl 1H 3 |
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| CN106946786A true CN106946786A (en) | 2017-07-14 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1714076A (en) * | 2002-11-21 | 2005-12-28 | 神经研究公司 | Novel aryl ureido benzoic acid derivatives and their use |
-
2017
- 2017-04-11 CN CN201710233892.3A patent/CN106946786A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1714076A (en) * | 2002-11-21 | 2005-12-28 | 神经研究公司 | Novel aryl ureido benzoic acid derivatives and their use |
Non-Patent Citations (2)
| Title |
|---|
| HONG SHEN ET AL.: "Synthesis and biological evaluations of novel bendazac lysine analogues as potent anticataract agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 李东风等: "《有机化学》", 31 August 2007, 华中科技大学出版社 * |
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Application publication date: 20170714 |