CN104447368A - Preparation method of 3-halogeneated-2-methylaminobenzoic acid - Google Patents
Preparation method of 3-halogeneated-2-methylaminobenzoic acid Download PDFInfo
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Abstract
The invention discloses a preparation method for preparing 3-halogeneated-2-methylaminobenzoic acid from o-halogenated aniline and aims at solving the defects of the preparation of o-aminobenzoic acid compounds in the prior art, such as use of not easily available raw materials, complex process, severe reactions, relatively high cost and unsuitability for large-scale industrial production. According to the preparation method, o-halogeneated aniline is taken as raw material to prepare an intermediate N-methyl-7-halogenated isatin through three steps of reaction; next, N-methyl-7-halogenated isatin is refined by virtue of an oxidation reaction in the presence of alkali and an oxidizing agent and thus the final product 3-halogeneated-2-methylaminobenzoic acid is obtained. The preparation method has the advantages of use of cheap and easily available raw materials, stable process, simple operation, high reaction yield, high product purity, low cost and no serious environmental pollution, and can be applied to large-scale industrial production.
Description
Technical field
The present invention relates to the preparation method of 3-halo-2-methylamino acid, particularly a kind of with adjacent halo aniline for the method for 3-halo-2-methylamino acid prepared by raw material.
Background technology
Anthranilic acid compound is the widely used medicine intermediate of a class and dyestuff intermediate, if NSAID (non-steroidal anti-inflammatory drug) is N-aryl-anthranilic acid analog derivative, all there is stronger anti-inflammatory analgesic action, be used for the treatment of rheumatic and rheumatoid arthritis clinically.
3-halo-2-methylamino acid is the important anthranilic acid compound of a class, be mainly used in new drug synthesis field, can directly as the pharmacophoric group of drug molecule, based on the characteristic of its structure, this compounds as pharmacophoric group is applied to the support of macromole new drug neutral body structure and adjustment segment simultaneously, use macromolecular drug and target spot effect stronger, and multiple target spot may be applicable to, thus make medicine possess high efficiency and pleiotropy, therefore, 3-halo-2-methylamino acid compounds is a kind of medicine intermediate with far-reaching academic significance and marketable value, its synthesis preparation method seems especially important.
Current 3-halo-2-methylamino acid compounds has no bibliographical information, only has the synthesis of related compound 3-fluoro-2-methylamino acid methyl esters and 3-fluoro-2-methylamino acid ethyl ester to have bibliographical information, specific as follows:
(1) document J.Med.Chem.2004, discloses with adjacent fluoroaniline for starting raw material in 47,2075-2088, by N-Boc protection, carboxylated, twoly to methylate, de-Boc protection obtains 3-fluoro-2-methylamino acid methyl esters, its operational path is as follows:
this technique for starting raw material, is obtained by reacting 3-fluoro-2-methylamino acid methyl esters by 4 steps with adjacent fluoroaniline, and in technique, second step uses highly basic n-Butyl Lithium, needs low temperature, anhydrous and oxygen-free condition carries out;
(2) patent documentation PCT Int.Appl., 2007090752 report with the fluoro-1H-benzene [d] [1 of 8-, 3] and oxazole-2,4-diketone is initiator, by methylating, esterification, hydrolysis decarboxylation obtain 3-fluoro-2-methylamino acid ethyl ester, and two step yields are 60%, and operational path is as follows:
This technique seems simple, but the fluoro-1H-benzene [d] [1,3] of starting raw material 8-oxazole-2,4-diketone are not easy to obtain and prepare complexity;
(3) document Organic & Biomolecular Chemistry, 11 (43), 7455-7457; 2013 disclose with 7-fluoro indole for material oxidation is prepared into the fluoro-1H-benzene [d] [1,3] of 8-and oxazole-2,4-diketone, but yield is 32%, and the 7-fluoro indole of raw material is difficult to obtain and price is high, and its operational path is as follows:
(4) document Organic Chemistry:An Indian Journal, 3 (3), 112-117; 2007 disclose with adjacent fluoroaniline for starting raw material prepares the fluoro-1H-benzene [d] [1,3] of intermediate 8-and oxazole-2,4-diketone by condensation, cyclisation, oxidation three step, and wherein use heavy metal oxidation chromium, its operational path is as follows:
As can be seen from above-mentioned bibliographical information, though the synthetic method of the ester of the fluoro-2-methylamino acid of 3-has bibliographical information, but operational path or highly basic n-Butyl Lithium need be used, require at low temperature, anhydrous and oxygen-free condition is carried out, there is very large potential safety hazard, require high to conversion unit, reaction is harsh, be unfavorable for large production, its operational path raw material is not easy to obtain, yield is too low, operational path is long, heavy metal need be used, environmental pollution can be caused, and yield is low, and above-mentioned two lines all just obtain the ester of the fluoro-2-methylamino acid of 3-, just target compound of the present invention need can be prepared again by an one-step hydrolysis reaction.
Therefore, exploitation 3-halo-2-methylamino acid, particularly exploitation is applicable to large-scale industrial production to prepare the method for 3-fluoro-2-methylamino acid too impatient to wait.
Summary of the invention
The object of the present invention is to provide a kind of with adjacent halo aniline for the method for 3-halo-2-methylamino acid prepared by raw material, to overcome, the raw materials of anthranilic acid compound in prior art is not easy to obtain, complex process, reaction is harsh, cost is higher and be not suitable for the defect of large-scale industrial production.
The technical solution used in the present invention is:
(1) with adjacent halo aniline for raw material, prepare product N-(2-halogenophenyl)-2-(oximido) ethanamide with the condensation reaction under 50 DEG C ~ 60 DEG C conditions of Chloral Hydrate, oxammonium hydrochloride, sodium sulfate, 2mol/l hydrochloric acid;
(2) N-(2-halogenophenyl)-2-(oximido) ethanamide and 98% sulfuric acid obtain 7-haloisatoic at 65 DEG C ~ 90 DEG C condition ShiShimonoseki rings;
(3) by 7-haloisatoic in organic solvent, methylate under acid binding agent condition, prepare N-methyl-7-haloisatoic;
(4) N-methyl-7-haloisatoic prepares 3-halo-2-methylamino acid salt under alkali, oxygenant condition, gained reaction solution is with after water-insoluble organic solvent extraction removing impurity, it is 4 ~ 6 that reaction solution is acidified to pH, crystallization, filter, dry to obtain 3-halo-2-methylamino acid;
Above reaction scheme is only illustrated embodiment, and only representative reaction special case and part, can not be explained or be interpreted as limitation of the scope of the invention.
X is halogen, and wherein halogen comprises the one in fluorine, chlorine, bromine;
The preferred sodium hydroxide of step (4) described alkali or potassium hydroxide;
The described alkali consumption of step (4) is: be calculated as 3 ~ 5mol by 1mol 7-halo-N-methyl-isatin, preferably 3.5 ~ 4.5mol;
Step (4) described oxygenant preferably 30% hydrogen peroxide;
The described oxygenant consumption of step (4) is: be calculated as 1 ~ 3mol by 1mol 7-halo-N-methyl-isatin, preferably 1.3 ~ 2.7mol;
Step (4) described temperature of reaction is 20 ~ 40 DEG C, preferably 25 ~ 35 DEG C;
One in the described organic solvent ethyl acetate of step (4), methylene dichloride, trichloromethane, methyl tert-butyl ether;
The acid of pH value is regulated to be one in sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid described in step (4), one preferably in 5 ~ 20% aqueous sulfuric acids, 5 ~ 20% phosphate aqueous solutions, 5 ~ 20% aqueous hydrochloric acids, more excellent is one in 10% aqueous sulfuric acid, 10% phosphate aqueous solution, 10% aqueous hydrochloric acid;
PH value described in step (4) preferably 4.5 ~ 5.5, more excellent is 4.5 ~ 5.2.
The preparation of target compound 3-halo-2-methylamino acid of the present invention has no reported in literature.The preparation method of a kind of 3-halo-2-methylamino acid provided by the invention, more existing correlation technique is compared, there is raw material cheap and easy to get, process stabilizing, simple to operate, reaction yield is high, product purity is high, cost is low, also can not cause the pollution of overall situation, can be applicable in technical scaleization production.
Embodiment
Embodiment 1:
(1) preparation of N-(2-chloro-phenyl-)-2-(oximido) ethanamide
In the there-necked flask of 2L, add 1L process water, start stirring, add 50ml 2mol/L hydrochloric acid successively, 17ml ethanol, 18.9g Ortho-Chloro aniline, 37.0g oxammonium hydrochloride, 168.0g sodium sulfate, 29.4g Chloral Hydrate, finishes, and is warming up to 50 ~ 60 DEG C and temperature control reaction 15h, TLC follows the tracks of confirmation and reacts completely, and stops heating, cools to 15 ~ 25 DEG C, suction filtration, filter cake 50mL frozen water washs 3 times, obtains off-white color solid wet product, dry white solid 22.95g, yield 78%, HPLC purity 99.2%;
(2) preparation of 7-chlorisatide
98% sulfuric acid 78ml is added in the there-necked flask of 250m L, be heated to 55 ~ 60 DEG C, add N-(2-chloro-phenyl-)-2-(oximido) ethanamide 25.3g in batches, control temperature is not higher than 65 DEG C, finish, keep temperature of reaction 65 DEG C, stir after 30 minutes and be warmed up to 80 DEG C of reactions 15 minutes, reaction system is slowly joined 1000ml mixture of ice and water, separates out a large amount of solid, filter, filter cake, with 300ml water washing, is drained, and filter cake dries to obtain red solid 11.35g, yield 49%, HPLC purity 96.6%;
(3) preparation of N-methyl-7-chlorisatide
11.0g 7-chlorisatide is added successively, 54ml DMF, 18.5g Cs in the there-necked flask of 200ml
2cO
3under ice-water bath, 13.1g MeI is dripped after stirring, in dropping process, maintenance system temperature is within 25 DEG C, is warmed up to 50 ~ 60 DEG C of reaction 3 ~ 5h, is joined by reaction solution in the frozen water of 170mL after finishing, stirring and crystallizing 40 ~ 50min, suction filtration, obtains dark red solid, dries to obtain dark red solid 9.4g, yield 79%, HPLC purity 98.4%;
(4) preparation of the chloro-2-methylamino acid of 3-
In the there-necked flask of 500ml, add N-methyl-7-chlorisatide 21.8g, add 2.5mol/L NaOH aqueous solution 200ml, in adition process, temperature control is within 25 DEG C, finishes, and drips 30%H
2o
2solution 30ml, continues temperature control within 25 DEG C, is warmed up to 30 DEG C of reaction 4hr. after dripping off, react complete, with 100ml dichloromethane extraction twice, aqueous phase adds activated carbon decolorizing half an hour, suction filtration, filtrate with acetic acid adjust ph to 4.0, stirring and crystallizing, suction filtration, filter cake with 0 ~ 5 DEG C of cold water drip washing twice, each 20ml, filter cake dries to obtain off-white color solid 14.3 grams, yield 69.1%, HPLC:99.7%.
1HNMR(400MHz，CDCl
3):δ：9.22(brs，2H),7.89(d，J＝8.0Hz,1H),7.47(d，J＝8.0Hz,1H),6.65(dd，J＝8.0,8.0Hz,1H),3.08(s,3H)
(mass spectrum) ESIMS:186.0 [M+H]
+
Embodiment 2:
(1) preparation of N-(2-bromophenyl)-2-(oximido) ethanamide
In the there-necked flask of 2L, add 1L process water, start stirring, add 50ml 6mol/L hydrochloric acid successively, 25.5g o-bromoaniline, 37.0g oxammonium hydrochloride, 168.0g sodium sulfate, 29.4g Chloral Hydrate, finishes, and is warming up to 50 ~ 60 DEG C and temperature control reaction 15h, TLC follows the tracks of confirmation and reacts completely, and stops heating, cools to 15 ~ 25 DEG C, suction filtration, filter cake 50ml frozen water washs 3 times, obtains off-white color solid wet product, dry light yellow solid 31.0g, yield 86%, HPLC purity 98.2%;
(2) preparation of 7-bromo-isatin
98% sulfuric acid 78ml is added in the there-necked flask of 250m L, be heated to 55 ~ 60 DEG C, add 31.0g N-(2-bromophenyl)-2-(oximido) ethanamide in batches, control temperature of reaction not higher than 65 DEG C, finish, about 65 DEG C stirring reactions are warmed up to 80 DEG C of reactions 15 minutes after 30 minutes, reaction system is slowly joined 1000ml mixture of ice and water, separate out a large amount of solid, filter, filter cake is with 300ml water washing, drain, filter cake dries to obtain dark red solid 13.0g, yield 45%, HPLC purity 95.3%;
(3) preparation of N-methyl-7-bromo-isatin
13.7g 7-bromo-isatin is added successively, 54ml DMF, 18.5g Cs in the there-necked flask of 200ml
2cO
3under ice-water bath, 13.1g MeI is dripped after stirring, in dropping process, maintenance system temperature is within 25 DEG C, be warmed up to 35 ~ 40 DEG C of reaction 3 ~ 5h after finishing, reaction solution joined in the frozen water of 170mL, stirring and crystallizing 40 ~ 50min, suction filtration, dry to obtain red solid 13.1g, yield 90%, HPLC purity 98.1%;
(4) preparation of the bromo-2-methylamino acid of 3-
In the there-necked flask of 500ml, add 26.8g N-methyl-7-bromo-isatin, add 2.5mol/L NaOH solution and enter 200ml, in adition process, temperature control is within 25 DEG C, finishes, and drips 30%H
2o
2solution 30ml, continues temperature control within 25 DEG C, is warmed up to 30 DEG C of reaction 4hr. after dripping off, react complete, with 100ml chloroform extraction twice, aqueous phase adds activated carbon decolorizing half an hour, suction filtration, filtrate with vinegar acid for adjusting pH for 5.5, stirring and crystallizing, suction filtration, filter cake with 0 ~ 5 DEG C of cold water drip washing twice, each 20ml, filter cake dries to obtain off-white color solid 19.5 grams, yield 75%, HPLC:99.0%.
1HNMR(400MHz，CDCl
3):δ：8.86(brs，2H),7.82(m,1H),7.53(m,1H),6.55(m,1H),2.98(s,3H)
(mass spectrum) ESIMS:231.0 [M+H]
+
Embodiment 3:
(1) (E)-N-(2-fluorophenyl)-2-(oximido) ethanamide preparation
Suction 226kg process water in the enamel reaction still of 500L, 2mol/L hydrochloric acid 11.8L, starts stirring, add the adjacent fluoroaniline of 3.92kg successively, 8.84kg oxammonium hydrochloride, 46kg sodium sulfate, 7.0kg Chloral Hydrate, finishes, be warming up to 50 ~ 60 DEG C and temperature control reaction 20h to reacting completely, cool to 15 ~ 25 DEG C, stirring and crystallizing, centrifuging, filter cake 10L frozen water washs 3 times, dry, obtains white solid 5.27kg, it is 99.0% that yield 82.0%, HPLC detects purity.
1H NMR(400MHz,DMSO-d6)δ7.21(m,2H),7.30(m,1H),7.73(s,1H),7.86(m,1H),9.83(s,1H),12.35(s,1H)
ESIMS：183.0[M+H]
+
(2) 7-fluoro indigo red preparation
98% sulfuric acid 46L is pressed in the glass reaction still of 100L, be heated to 70 ~ 75 DEG C, add 14kg (E)-N-(2-fluorophenyl)-2-(oximido) ethanamide in batches, control temperature of reaction not higher than 80 DEG C, finish, be warming up to about 90 DEG C stirring reaction 2h, reaction system is cooled to 17 ~ 25 DEG C, then be slowly transferred in 460L mixture of ice and water and 92L ethyl acetate mixture, holding temperature stirs 0.5h at 0 ~ 5 DEG C, separatory, aqueous phase is again with 90L extraction into ethyl acetate twice, merge organic phase, Sodium sulfate anhydrous.min(99) is dry, suction filtration, concentrated, obtain orange solids 6.5kg, yield 51.2%, HPLC detects purity 98.4%.
1H NMR(400MHz，DMSO-d6):δ：11.56(s，1H),7.54(dd，J＝9.6,8.4Hz,1H),7.33(d，J＝7.2Hz,1H),7.08(td,J＝8.0,4.0Hz,1H)
ESIMS：166.0[M+H]
+
(3) preparation of N-methyl-7-fluoro indigo red
In the glassed steel reaction vessels of 200L, drop into 88L DMF, start stirring, add 16.35kg 7-fluoro indigo red successively, 30kg Cs
2cO
3, finish, drip 21.4kg MeI, in dropping process, maintenance system temperature is within 25 DEG C, be warmed up to 35 ~ 50 DEG C of reaction 4h after finishing, react complete, reaction system is extracted in previously prepared cold water reaction solution is joined in the frozen water of 280L, stirring and crystallizing 1.5h, centrifugal rejection filter, obtains wine-colored solid, dries to obtain orange solids 15.6kg, yield 87.9%, HPLC detects purity 99.32%.
1H NMR(400MHz,CDCl3):δ：7.49(m,1H),7.31(m,1H),7.08(m,1H),3.52(s,3H)；
ESIMS：180.0[M+H]
+
(4) preparation of the fluoro-2-methylamino acid of 3-
Suction 2.5mol/L NaOH solution 156L (390mol) in 500L enamel reaction still, be cooled to 10 ~ 20 DEG C, add N-methyl-7-fluoro indigo red 15.6Kg (87.15mol), control temperature in the kettle below 15 ~ 20 DEG C, 30% hydrogen peroxide 26kg (229mol) is added by header tank, finish, be warming up to 25 ~ 35 DEG C of reactions 4 hours, react complete, impurity is carried twice with 60kg methyl tertiary butyl ether extraction, aqueous phase adds activated carbon decolorizing half an hour again, suction filtration, filtrate is with vinegar acid for adjusting pH to 5.2, stirring and crystallizing, centrifugal rejection filter, filter cake is with 0 ~ 5 DEG C of cold water drip washing twice, each 10L, dry to obtain white solid 11.0kg, yield 74.7%, HPLC:99.56%.
1HNMR(400MHz，CDCl
3):δ：8.90(brs，2H),7.77(d，J＝8.0Hz,1H),7.14(ddd，J＝13.6,8.0,1.6Hz,1H),6.57(td,J＝8.0,4.4Hz,1H),3.15(d,J＝6.8Hz,3H)
ESIMS：170.1[M+H]
+
Embodiment 4:
In the present embodiment, except preparation method's difference of the fluoro-2-methylamino acid of 3-, all the other detection methods are all identical with embodiment 3, and concrete preparation method is as follows:
N-methyl-7-fluoro indigo red 20.0g (0.11mol) is added in the there-necked flask of 500ml, add 2.5mol/L NaOH solution 220ml (0.55mol), in adition process, temperature control is within 10 DEG C, finish, drip 30% hydrogen peroxide 33.7ml (0.33mol), dripping off rear maintenance oxidizing reaction temperature is 20 ~ 25 DEG C, , to reacting complete, with 100ml extraction into ethyl acetate twice, aqueous phase adds activated carbon decolorizing 0.5h, suction filtration, filtrate with 10% sulphur acid for adjusting pH for 4.0, stirring and crystallizing, suction filtration, filter cake dries to obtain off-white color solid 12.8 grams, yield 67.8%, HPLC:98.5%.
Embodiment 5:
In the present embodiment, except preparation method's difference of the fluoro-2-methylamino acid of 3-, all the other detection methods are all identical with embodiment 3, and concrete preparation method is as follows:
N-methyl-7-fluoro indigo red 20.0g is added in the there-necked flask of 500ml, add 2.5mol/L NaOH solution 192ml (0.48mol), in adition process, temperature control is within 10 DEG C, finish, drip 30% hydrogen peroxide 23ml (0.22mol), temperature control is within 10 DEG C, 30 ~ 35 DEG C are warmed up to after dripping off, to reacting complete, with 100ml methyl tertiary butyl ether extracting twice, aqueous phase adds activated carbon decolorizing 0.5h, suction filtration, filtrate with 10% salt acid for adjusting pH for 4.5, stirring and crystallizing, suction filtration, filter cake is with 0 ~ 5 DEG C of cold water drip washing twice, each 20ml, filter cake dries to obtain off-white color solid 13.65 grams, yield 72.3%, HPLC:98.9%.
Embodiment 6:
In the present embodiment, except preparation method's difference of the fluoro-2-methylamino acid of 3-, all the other detection methods are all identical with embodiment 3, and concrete preparation method is as follows:
N-methyl-7-fluoro indigo red 20.0g is added in the there-necked flask of 500ml, add 2.5mol/L KOH solution 156ml (0.39mol), in adition process, temperature control is within 20 DEG C, finish, drip 30% hydrogen peroxide 16.4ml (0.16mol), temperature control is within 20 DEG C, oxidizing reaction temperature is kept to be 20 ~ 25 DEG C, to reacting complete, with 100ml methyl tertiary butyl ether extracting twice, aqueous phase adds activated carbon decolorizing 0.5h, suction filtration, filtrate with lemon acid for adjusting pH for 4.5, stirring and crystallizing, suction filtration, filter cake is with 0 ~ 5 DEG C of cold water drip washing twice, each 20ml, filter cake dries to obtain white solid 13.3 grams, yield 70.5%, HPLC:99.0%.
Embodiment 7:
In the present embodiment, except preparation method's difference of the fluoro-2-methylamino acid of 3-, all the other detection methods are all identical with embodiment 3, and concrete preparation method is as follows:
N-methyl-7-fluoro indigo red 20.0g is added in the there-necked flask of 500ml, add 2.5mol/L NaOH solution 132ml (0.33mol), in adition process, temperature control is within 30 DEG C, finish, drip 30% hydrogen peroxide 11.2ml (0.11mol), temperature control is within 30 DEG C, oxidizing reaction temperature is kept to be 30 ~ 40 DEG C, to reacting complete, with 100ml methyl tertiary butyl ether extracting twice, aqueous phase adds activated carbon decolorizing 0.5h, suction filtration, filtrate with lemon acid for adjusting pH for 6, stirring and crystallizing, suction filtration, filter cake is with 0 ~ 5 DEG C of cold water drip washing twice, each 20ml, filter cake dries to obtain white solid 13.8 grams, yield 73%, HPLC:99.3%.
Claims (10)
1. a preparation method for 3-halo-2-methylamino acid, is characterized in that: comprise the following steps:
(1) with adjacent halo aniline for raw material, prepare product N-(2-halogenophenyl)-2-(oximido) ethanamide with Chloral Hydrate, oxammonium hydrochloride, sodium sulfate, the condensation reaction of 2mol/L hydrochloric acid;
(2) 7-haloisatoic is prepared by N-(2-halogenophenyl)-2-(oximido) ethanamide and sulfuric acid through cyclization;
(3) by 7-haloisatoic in organic solvent, methylate under acid binding agent condition, prepare N-methyl-7-haloisatoic;
(4) 3-halo-2-methylamino acid salt brine solution is prepared by N-methyl-7-haloisatoic oxidizing reaction under alkali, oxygenant condition, 3-halo-2-methylamino acid salt brine solution is removed impurity with organic solvent extraction, its acidified aqueous solution is 4 ~ 6 to pH, crystallization, filter, dry and obtain 3-halo-2-methylamino acid.
2. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: alkali described in step (4) is any one in sodium hydroxide, potassium hydroxide.
3. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: described in step (4), oxygenant is hydrogen peroxide.
4. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: organic solvent described in step (4) is any one in ethyl acetate, methylene dichloride, trichloromethane, methyl tert-butyl ether.
5. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: the acid of adjust ph described in step (4) is any one in sulfuric acid, hydrochloric acid, acetic acid, citric acid.
6. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: the alkali consumption described in step (4) is calculated as 3 ~ 5mol by 1mol N-methyl-7-haloisatoic.
7. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: the oxygenant consumption described in step (4) is calculated as 1 ~ 3mol by 1molN-methyl-7-haloisatoic.
8. the preparation method of 3-halo-2-methylamino acid according to claim 7, is characterized in that: the oxygenant consumption described in step (4) is calculated as 1.3 ~ 2.7mol by 1molN-methyl-7-haloisatoic.
9. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: the temperature of reaction described in step (4) is 20 DEG C ~ 40 DEG C.
10. the preparation method of 3-halo-2-methylamino acid according to claim 1, is characterized in that: the pH described in step (4) is 4.5 ~ 5.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114890952A (en) * | 2022-04-17 | 2022-08-12 | 重庆医科大学 | Preparation method of 5-halogenated-2-aminobenzene nitrogen heterocyclic compound |
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| US20100331327A1 (en) * | 2005-12-23 | 2010-12-30 | Centre National De La Recherche Scientifique (Cnrs) | 7-substituted indirubin-3'oximes and their applications |
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| US20100331327A1 (en) * | 2005-12-23 | 2010-12-30 | Centre National De La Recherche Scientifique (Cnrs) | 7-substituted indirubin-3'oximes and their applications |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114890952A (en) * | 2022-04-17 | 2022-08-12 | 重庆医科大学 | Preparation method of 5-halogenated-2-aminobenzene nitrogen heterocyclic compound |
| CN114890952B (en) * | 2022-04-17 | 2023-06-06 | 重庆医科大学 | Preparation method of 5-halogeno-2-aminobenzoazacyclic compound |
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