CN105017152A - Preparation method of 3-chloro(bromo)-6-nitroisoquinoline - Google Patents
Preparation method of 3-chloro(bromo)-6-nitroisoquinoline Download PDFInfo
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention relates to a preparation method of 3-chloro(bromo)-6-nitroisoquinoline. The preparation method comprises that 2-chloro-4-nitrobenzoic acid as a raw material undergoes a nucleophilic substitution reaction to produce 2-(2-methoxy-2-oxoethyl)-4-nitrobenzoic acid, the 2-(2-methoxy-2-oxoethyl)-4-nitrobenzoic acid is hydrolyzed to form 2-(carboxymethyl)-4-nitrobenzoic acid, the 2-(carboxymethyl)-4-nitrobenzoic acid, acetyl chloride and ammonium hydroxide undergo a reaction to produce 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid, the 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid undergoes a cyclization reaction to produce 6-nitroisoquinolin-1,3(2H,4H)-dione, the 6-nitroisoquinolin-1,3(2H,4H)-dione undergoes a chlorination (bromination) reaction to produce 1,3-dichloro(bromo)-6-nitroisoquinoline, because of activity of isoquinoline at the first site, chlorine(bromine) at the first site is replaced by methoxybenzylamine so that 3-chloro(bromo)-N-(4-methoxybenzyl)-6-nitroisoquinolin-1-amine is formed, the p-methoxybenzyl group is removed by trifluoroacetic acid so that 3-chloro(bromo)-6-nitroisoquinolin-1-amine is formed, 1-amine is subjected to diazotization, and the hydrogen produced by diazotization is removed by heating so that a product is obtained. The preparation method is convenient for operation and has a high yield in each process.
Description
Technical field
The invention belongs to medicine intermediate field, be specifically related to the preparation method of 3-chlorine (bromine)-6-nitroisoquinoline.
Background technology
Isoquinoline 99.9 and derivative thereof are the important alkaloids of a class, and have important biological activity, be widely used in the field such as medicine, agricultural chemicals, therefore the synthesis of isoquinilone derivatives receives extensive concern.
The structural formula of isoquinoline 99.9:
The derivative of isoquinoline 99.9 has a wide range of applications, and is especially widely used in medicine intermediate.Document has the synthetic method of the chloro-5-nitroisoquinoline of report 3-, and its method is: obtain 3-chlorine isoquinoline 99.9 with the hydrogenation of 1,3-dichloro isoquinoline 99.9, and 3-chlorine isoquinoline 99.9 is nitrated again obtains the chloro-5-nitroisoquinoline of 3-.Due to the characteristic of isoquinoline molecule, the method can not be generalized in the synthesis of other similar structures.
Summary of the invention
The object of the present invention is to provide a kind of 3-chlorine (bromine)-6-nitroisoquinoline and preparation method thereof, its preparation method has easy to operate, often walks all higher advantage of productive rate.
For achieving the above object, the technical scheme taked of the present invention is as follows:
A kind of medicine intermediate 3-chlorine (bromine)-6-nitroisoquinoline, has structure shown in formula (1):
A kind of 3-chlorine (bromine)-6-nitroisoquinoline preparation method, comprises the steps:
S1, first chloro-for 2-4-nitrobenzoic acid is joined in dimethyl malonate, cuprous bromide and the sodium methylate of catalytic amount is added under protection of inert gas, 12-16 hour is reacted under temperature is 90-100 DEG C of condition, cooling, washing, extraction, is drying to obtain crude product 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid;
2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid prepared by S2, described step S1 issues raw hydrolysis reaction at alkaline environment, generates 2-(carboxymethyl)-4-nitrobenzoic acid;
2-(carboxymethyl)-4-nitrobenzoic acid prepared by S3, described step S2 is about 1-2h with excess acetyl chloride in organic solvent, after steaming desolventizes, join in ice ammoniacal liquor again, stir 15-20 minute, steam and be added to the water again except after ammoniacal liquor, regulate pH=2-3 with 6-7N HCl, separate out product 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid;
2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid prepared by S4, described step S3 joins in orthodichlorobenzene, under 170-175 DEG C of condition, react 3-5h, cooling, suction filtration, dries, obtains 6-nitroisoquinoline-1,3 (2H, 4H)-diketone;
6-nitroisoquinoline-1,3 (2H, 4H)-diketone prepared by S5, described step S4 is dissolved in phosphenyl oxychloride, under 150-155 DEG C of condition, react 3-3.5h; Or to be dissolved in Isosorbide-5-Nitrae-dioxane and to add tribromo oxygen phosphorus, under 105-110 DEG C of condition, react 3-3.5h, be separated and obtain 1,3-dichloro (bromine)-6-nitroisoquinoline;
Particularly, 6-nitroisoquinoline-1 prepared by described step S4,3 (2H, 4H)-diketone is dissolved in phosphenyl oxychloride, under 150-155 DEG C of condition, react 3-3.5h, (the operation of X=Br: be dissolved in 1, in 4-dioxane, add the tribromo oxygen phosphorus of 5 molar equivalents, under 105-110 DEG C of condition, react 3-3.5h) be separated and obtain 1,3-dichloro (bromine)-6-nitroisoquinoline;
S6, described step S5 prepare 1, in the 120-125 DEG C of 2-2.5h that reacts after 3-dichloro (bromine)-6-nitroisoquinoline mixes with 4-Methoxybenzylamine, be cooled to 20-25 DEG C, directly add methylene chloride and mix sample and cross post, obtain 3-chlorine (bromine)-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine;
S7,3-chlorine (bromine)-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine is joined in trifluoroacetic acid, back flow reaction 2-3h, be cooled to 20-25 DEG C, revolve and add water except after trifluoroacetic acid, regulate pH=8-10, separate out solid suction filtration, the mixed solvent washing of filter cake sherwood oil and ethyl acetate, obtains 3-chlorine (bromine)-6-nitroisoquinoline-1-amine; The volume ratio of described sherwood oil and ethyl acetate is 10:1-9:1;
S8,3-chlorine (the bromine)-6-nitroisoquinoline-1-amine prepared by described step S7 join in tetrahydrofuran (THF) or acetonitrile, Isopentyl nitrite is dripped under backflow, drip and continue to stir 1-2h, reaction solution is directly spin-dried for, and crosses post and namely obtains 3-chlorine (bromine)-6-nitroisoquinoline.
Preferably, described step S1 is:
First chloro-for 2-4-nitrobenzoic acid is joined in dimethyl malonate, then logical 1-2h under nitrogen being deep into liquid level, then add cuprous bromide and the sodium methylate of catalytic amount, keep nitrogen, be then warming up to 90-100 DEG C of reaction 12-16h, be cooled to room temperature, add water and sherwood oil, aqueous phase sherwood oil and toluene are respectively washed once, with the pH=2-3 of hydrochloric acid soln water transfer phase, separate out solid suction filtration, obtain 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid.
Described step S1 comprises further: will separate out the aqueous phase petroleum ether extraction after solid, merge organic phase, the saturated NaCl of organic phase washs, dry, is spin-dried for, obtains 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid.
Described step S2 is preferably: under water bath condition, it is the methanol solution adding 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid prepared by described step S1 in the NaOH aqueous solution of 20-25wt% to concentration, reaction 3-3.5h, after TLC monitoring display reacts completely, steam except after methyl alcohol, adopt the pH=1-2 of dilute hydrochloric acid solution regulator solution, separate out solid, filter, dry, obtain 2-(carboxymethyl)-4-nitrobenzoic acid.
Described step S2 comprises further: continue after the filtrate after filtration is cooled to 0-5 DEG C to separate out 2-(carboxymethyl)-4-nitrobenzoic acid.
Described step S3 is: 2-(carboxymethyl)-4-nitrobenzoic acid prepared by described step S2 joins in acetone, then reflux after adding Acetyl Chloride 98Min. 1-2h, joined 0-5 DEG C again after being spin-dried for solvent, concentration is in the ammonia soln of 70-75wt%, continues to stir 15-20min, spin off ammoniacal liquor, add water, with the pH=2-3 of dilute hydrochloric acid solution regulator solution, separate out solid, suction filtration is dried, and obtains 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid.
Separation in described step S5 is in the following way:
Be cooled to room temperature, add tetrahydrofuran (THF) in reaction solution, then pour in beaker, drip shrend and to go out reaction, about 20-30 minute adds.Then adjust pH=8-10 with ammoniacal liquor, suction filtration, filter cake is dried, and filtrate is extracted with ethyl acetate, and the solid being spin-dried for and drying obtains pure product with purification by column chromatography in the lump.
3-chlorine (bromine)-6-nitroisoquinoline prepared by aforesaid method is used as medicine intermediate.
Compared with prior art, the advantage of 3-chlorine (bromine)-6-nitroisoquinoline of the present invention is:
The synthetic method of 3-chlorine (bromine)-6-nitroisoquinoline provided by the invention is with the chloro-4-nitrobenzoic acid of 2-for raw material, and nucleo philic substitution reaction forms 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid; Then hydrolysis obtains 2-(carboxymethyl)-4-nitrobenzoic acid; Condition through Acetyl Chloride 98Min. and ammoniacal liquor forms 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid; Close ring again and form 6-nitroisoquinoline-1,3 (2H, 4H)-diketone; Then in chlorine (bromine) generation, forms 1,3-dichloro (bromine)-6-nitroisoquinoline; Utilize the characteristic that the isoquinoline 99.9 of 1-position is active, the chlorine (bromine) of 1-position is replaced by 4-Methoxybenzylamine, forms 3-chlorine (bromine)-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine; Remove methoxy-benzyl with trifluoroacetic acid again, form 3-chlorine (bromine)-6-nitroisoquinoline-1-amine; Then 1-amine diazotization, heating removes diazonium formation hydrogen and obtains product.Make use of 1 cleverly herein, the feature that 1-position chlorine (bromine) of 3-dichloro (bromine)-6-nitroisoquinoline is more active than 3-position chlorine (bromine), first the chlorine of 1-position (bromine) is become 4-Methoxybenzylamine, oxy-benzyl is left away formation amine, amine generation diazotization reaction, remove formation hydrogen by heating, the chlorine (bromine) of 3-position still retains.This technique has easy to operate, often walks all higher feature of productive rate.
Accompanying drawing explanation
Fig. 1 is the HNMR spectrogram of the chloro-6-nitroisoquinoline of 3-;
Fig. 2 is the HPLC spectrogram of the chloro-6-nitroisoquinoline of 3-.
Embodiment
Below will the invention will be further described by specific embodiment.
The present invention can implement in many different forms, and should not be understood to be limited to embodiment set forth herein.On the contrary, provide these embodiments, make the disclosure to be thorough and complete, and design of the present invention fully will be conveyed to those skilled in the art, the present invention will only be limited by claim.
The preparation method of 3-chlorine (bromine)-6-nitroisoquinoline provided by the invention, its operational path is as follows:
The synthetic method of 3-chlorine (bromine)-6-nitroisoquinoline of the present invention is with the chloro-4-nitrobenzoic acid of 2-for raw material, and nucleo philic substitution reaction forms 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid; Then hydrolysis obtains 2-(carboxymethyl)-4-nitrobenzoic acid; Condition through Acetyl Chloride 98Min. and ammoniacal liquor forms 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid; Close ring again and form 6-nitroisoquinoline-1,3 (2H, 4H)-diketone; Then in chlorine (bromine) generation, forms 1,3-dichloro (bromine)-6-nitroisoquinoline; Utilize the characteristic that the isoquinoline 99.9 of 1-position is active, the chlorine (bromine) of 1-position is replaced by 4-Methoxybenzylamine, forms 3-chlorine (bromine)-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine; Remove methoxy-benzyl with trifluoroacetic acid again, form 3-chlorine (bromine)-6-nitroisoquinoline-1-amine; Then 1-amine diazotization, heating removes diazonium formation hydrogen and obtains product.
Embodiment 1
The chloro-6-nitroisoquinoline of 3-of the present embodiment is adopted and is prepared with the following method:
A kind of 3-chloro-6-nitroisoquinoline preparation method, is characterized in that comprising the steps:
S1, first chloro-for 200g 2-4-nitrobenzoic acid is joined in 2000ml dimethyl malonate, then nitrogen is deep into commensurability 1h under liquid level, then 2g cuprous bromide and 117g sodium methylate is added, keep nitrogen, then 90-100 DEG C of reaction 16h is warming up to, after TLC monitoring reacts completely, be cooled to room temperature, add 2L water and 2L sherwood oil, aqueous phase is respectively washed once with 500ml sherwood oil and 500ml toluene respectively, and then aqueous phase 2NHCl adjusts pH=2-3, separates out solid suction filtration, obtain most of product, about 160g.Aqueous phase continues to use 500mL petroleum ether extraction, merges organic phase, washes with saturated NaCl, dry, is spin-dried for, obtains crude product, about 60g.Add up to product 220g.Yield 93%.
S2, under water bath condition, be the methanol solution 2000mL adding 500g 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid in the NaOH aqueous solution of 20wt% to 1250g concentration, reaction 3.5h, after TLC display reacts completely, steam the pH=1-2 except regulator solution again after methyl alcohol, separate out solid, dry, obtain 2-(carboxymethyl)-4-nitrobenzoic acid.Continue after filtrate is cooled to 0 DEG C to separate out portioned product 2-(carboxymethyl)-4-nitrobenzoic acid.Obtain product 400g altogether, yield 85%.
2-(carboxymethyl)-4-nitrobenzoic acid 350g prepared by S3, described step S2 joins in 3000ml acetone, then reflux after adding 420ml Acetyl Chloride 98Min. 1h, joined in the ammoniacal liquor of the 2200ml 75wt% of 0 DEG C after being spin-dried for solvent again, naturally, after rising to room temperature, continue to stir 15min.Revolve except ammoniacal liquor, add water, with the pH=2-3 of the hydrochloric acid soln regulator solution of 6N, separate out solid, suction filtration is dried, and obtains 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid 300g, yield 86%.
2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid 250g prepared by S4, described step S3 joins in 750ml orthodichlorobenzene, 4h is reacted under 170-175 DEG C of condition, cooling, suction filtration, dry, obtain 6-nitroisoquinoline-1,3 (2H, 4H)-diketone 200g, yield 87%.
6-nitroisoquinoline-1,3 (2H, 4H) prepared by S5, described step S4-diketone 200g is dissolved in 400ml phosphenyl oxychloride, under 150-155 DEG C of condition, react 3h, cooling, adds tetrahydrofuran (THF) in reaction solution, pour in beaker, then drip shrend and to go out reaction, within about 25 minutes, add; Adjust pH=9 with ammoniacal liquor, have solid to separate out, suction filtration, filter cake is dried.Filtrate is extracted with ethyl acetate, the solid that extraction liquid is spin-dried for and dries uses silica column purification in the lump, silicagel column employing eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=3:1, obtain product 1,3-bis-chloro-6-nitroisoquinoline 200g, yield 85%;
S6, described step S5 prepare 1, about 2 hours are reacted in 120-125 DEG C after 3-bis-chloro-6-nitroisoquinoline 200g mixes with 400mL 4-Methoxybenzylamine, TLC monitoring is to after reacting completely, cooling, directly add 500ml methylene dichloride and mix sample, with silica column purification, silicagel column employing eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=5:1, obtain the chloro-N-of 3-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine 180g, yield 64%;
S7, chloro-for 3-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine 100g is joined in trifluoroacetic acid 500mL, back flow reaction is about 2h, TLC monitoring is to after reacting completely, be cooled to 20 DEG C, revolve and add water except after trifluoroacetic acid, regulate pH=9, separate out solid suction filtration, mixed solvent washing (volume ratio is 10:1) of filter cake 100mL sherwood oil and ethyl acetate, obtains the chloro-6-nitroisoquinoline of 3--1-amine 53g, yield 81%;
S8, the chloro-6-nitroisoquinoline of the 3--1-amine 50g prepared by described step S7 join in tetrahydrofuran (THF) 250mL, backflow is lower drips 120ml Isopentyl nitrite, drip and continue to stir 1.5h, TLC monitoring to after reacting completely, revolve and desolventize, use silica column purification product,, silicagel column employing eluent is the mixed solution of sherwood oil and ethyl acetate, and the volume ratio of the two is sherwood oil: ethyl acetate=2:1, obtain product 3-chloro-6-nitroisoquinoline 39g, yield 84%.
Fig. 1 is the HNMR spectrogram of the chloro-6-nitroisoquinoline of 3-prepared by the present embodiment, and the solvent of the detection of described HNMR spectrogram is DMSO-d
6.Fig. 2 is the HPLC spectrogram of the chloro-6-nitroisoquinoline of 3-prepared by the present embodiment, and the testing conditions of described HPLC spectrogram is gradient 10%-90% (acetonitrile) 15 minutes, and gradient keeps 5 minutes 90%.Moving phase: A:0.1% phosphoric acid; B: acetonitrile.
The chloro-6-nitroisoquinoline of 3-prepared by the present invention can as medicine intermediate, preparation several formulations.
Embodiment 2
The bromo-6-nitroisoquinoline of 3-of the present embodiment is adopted and is prepared with the following method:
A kind of 3-bromo-6-nitroisoquinoline preparation method, is characterized in that comprising the steps:
The 6-nitroisoquinoline-1 that described in S5, embodiment 1 prepared by step S4,3 (2H, 4H)-diketone 50g is dissolved in 250ml 1, in 4-dioxane, add tribromo oxygen phosphorus 348g, under 105-110 DEG C of condition, react 3.5h, cooling, pour in beaker, drip shrend and to go out reaction, within about 30 minutes, add; Adjust pH=10 with ammoniacal liquor, have solid to separate out, suction filtration, filter cake is dried.Filtrate is extracted with ethyl acetate, the solid that extraction liquid is spin-dried for and dries uses silica column purification in the lump, and silicagel column employing eluent is the mixed solution of sherwood oil and ethyl acetate, and the volume ratio of the two is sherwood oil: ethyl acetate=3:1, obtain the bromo-6-nitroisoquinoline of product 1,3-bis-;
S6, described step S5 prepare 1, about 2.5 hours are reacted in 120-125 DEG C after 3-bis-bromo-6-nitroisoquinoline 30g mixes with 150mL 4-Methoxybenzylamine, TLC monitoring is to after reacting completely, cooling, directly add 150ml methylene dichloride and mix sample, with silica column purification, silicagel column employing eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=5:1, obtains the bromo-N-of 3-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine;
S7, bromo-for 3-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine 30g is joined in trifluoroacetic acid 150mL, back flow reaction is about 3h, TLC monitoring is to after reacting completely, be cooled to about 23 DEG C, revolve and add water except after trifluoroacetic acid, regulate pH=8, separate out solid suction filtration, mixed solvent washing (volume ratio is 9:1) of filter cake 150ml sherwood oil and ethyl acetate, obtains the bromo-6-nitroisoquinoline of 3--1-amine;
S8, the bromo-6-nitroisoquinoline of the 3--1-amine 30g prepared by described step S7 join in tetrahydrofuran (THF) 150mL, backflow is lower drips 60ml Isopentyl nitrite, drip and continue to stir 1h, TLC monitoring is to after reacting completely, revolve and desolventize, use silica column purification product, silicagel column employing eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=2:1, obtains the bromo-6-nitroisoquinoline of product 3-.
Embodiment 3
The chloro-6-nitroisoquinoline of 3-of the present embodiment is adopted and is prepared with the following method:
A kind of 3-chloro-6-nitroisoquinoline preparation method, is characterized in that comprising the steps:
S1, first chloro-for 100g 2-4-nitrobenzoic acid is joined in 1000ml dimethyl malonate, then nitrogen is deep into commensurability 2h under liquid level, then 1g cuprous bromide and 58.5g sodium methylate is added, keep nitrogen, then 90-100 DEG C of reaction 12h is warming up to, after TLC monitoring reacts completely, be cooled to room temperature, add 1L water and 1L sherwood oil, aqueous phase is respectively washed once with 250ml sherwood oil and 250ml toluene respectively, and then aqueous phase 2NHCl adjusts pH=2-3, separates out solid suction filtration, obtain most of product, about 80g.Aqueous phase continues to use 250mL petroleum ether extraction, merges organic phase, washes with saturated NaCl, dry, is spin-dried for, obtains crude product, general 27g product.Add up to product 107g, yield 90%.
S2, under water bath condition, be the methanol solution 200mL adding 50g 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid in the NaOH aqueous solution of 25wt% to 125g concentration, reaction 3h, after TLC display reacts completely, steam the pH=1-2 except regulator solution again after methyl alcohol, separate out, dry, obtain 2-(carboxymethyl)-4-nitrobenzoic acid.Continue after filtrate is cooled to 5 DEG C to separate out portioned product 2-(carboxymethyl)-4-nitrobenzoic acid, obtain product 40g altogether, yield 85%.
2-(carboxymethyl)-4-nitrobenzoic acid 35g prepared by S3, described step S2 joins in 300ml acetone, then reflux after adding 42ml Acetyl Chloride 98Min. 2h, joined in the ammoniacal liquor of the 220ml 70wt% of 3 DEG C after being spin-dried for solvent again, after naturally rising to room temperature, continue to stir 15min.Spin off ammoniacal liquor, add water, with the pH=1-2 of the hydrochloric acid soln regulator solution of 7N, separate out solid, suction filtration is dried, and obtains 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid 29g, yield 83%.
2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid 25g prepared by S4, described step S3 joins in 75ml orthodichlorobenzene, 5h is reacted under 170-175 DEG C of condition, cooling, suction filtration, dry, obtain 6-nitroisoquinoline-1,3 (2H, 4H)-diketone 20.5g, yield 89%.
6-nitroisoquinoline-1,3 (2H, 4H) prepared by S5, described step S4-diketone 20g is dissolved in 40ml phosphenyl oxychloride, under 150-155 DEG C of condition, react 3.5h, cooling, adds tetrahydrofuran (THF) in reaction solution, then pour in beaker, drip shrend and to go out reaction, within about 30 minutes, add; Adjust pH=10 with ammoniacal liquor, have solid to separate out, suction filtration, filter cake is dried.Filtrate is extracted with ethyl acetate, the solid that extraction liquid is spin-dried for and dries uses silica column purification in the lump, what silicagel column adopted eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=3:1, obtain product 1,3-bis-chloro-6-nitroisoquinoline 20.5g, yield 87%;
S6, described step S5 prepare 1, about 2.5 hours are reacted in 120-125 DEG C after 3-bis-chloro-6-nitroisoquinoline 20g mixes with 40mL 4-Methoxybenzylamine, TLC monitoring is to after reacting completely, cooling, directly add 50ml methylene dichloride and mix sample, with silica column purification, what silicagel column adopted eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=5:1, obtain the chloro-N-of 3-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine 16.9g, yield 60%;
S7, chloro-for 3-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine 20g is joined in trifluoroacetic acid 100mL, back flow reaction is about 3h, TLC monitoring is to after reacting completely, be cooled to 23 DEG C, revolve and add water except after trifluoroacetic acid, regulate pH=8, separate out solid suction filtration, mixed solvent washing (volume ratio is 9:1) of filter cake 20ml sherwood oil and ethyl acetate, obtains the chloro-6-nitroisoquinoline of 3--1-amine 10.6g, yield 81%;
S8,3-chlorine (the bromine)-6-nitroisoquinoline-1-amine 10g prepared by described step S7 join in tetrahydrofuran (THF) 50mL, backflow is lower drips 24ml Isopentyl nitrite, drip and continue to stir 1h, TLC monitoring, to after reacting completely, is revolved and is desolventized, use silica column purification product, what silicagel column adopted eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=2:1, obtains product 3-chlorine bromo-6-nitroisoquinoline 8g, yield 86%.
Embodiment 4
The chloro-6-nitroisoquinoline of 3-of the present embodiment is adopted and is prepared with the following method:
A kind of 3-chloro-6-nitroisoquinoline preparation method, is characterized in that comprising the steps:
S1, first chloro-for 100g 2-4-nitrobenzoic acid is joined in 1000ml dimethyl malonate, then nitrogen is deep into commensurability 1.5h under liquid level, then 1g cuprous bromide and 58.5g sodium methylate is added, keep nitrogen, then 90-100 DEG C of reaction 14h is warming up to, after TLC monitoring reacts completely, be cooled to room temperature, add 1L water and 1L sherwood oil, aqueous phase is respectively washed once with 250ml sherwood oil and 250ml toluene respectively, and then aqueous phase 2NHCl adjusts pH=2-3, separates out solid suction filtration, obtain most of product, about 80g.Aqueous phase continues to use 250mL petroleum ether extraction, merges organic phase, washes with saturated NaCl, dry, is spin-dried for, obtains crude product, general 30g, yield 93%.
S2, under water bath condition, be the methanol solution 200mL adding 50g 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid in the NaOH aqueous solution of 22wt% to 125g concentration, reaction 3.5h, after TLC display reacts completely, steam the pH=1-2 except regulator solution again after methyl alcohol, separate out, dry, obtain 2-(carboxymethyl)-4-nitrobenzoic acid.Continue after filtrate is cooled to 5 DEG C to separate out portioned product 2-(carboxymethyl)-4-nitrobenzoic acid, obtain product 41g altogether, yield 87%.
2-(carboxymethyl)-4-nitrobenzoic acid 35g prepared by S3, described step S2 joins in 300ml acetone, then reflux after adding 42ml Acetyl Chloride 98Min. 1.5h, joined in the ammoniacal liquor of the 220ml 72wt% of 5 DEG C after being spin-dried for solvent again, naturally, after rising to room temperature, continue to stir 20min.Spin off ammoniacal liquor, add water, with the pH=2-3 of the hydrochloric acid soln regulator solution of 6.5N, separate out solid, suction filtration is dried, and obtains 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid 29g, yield 83%.
2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid 25g prepared by S4, described step S3 joins in 75ml orthodichlorobenzene, 3h is reacted under 170-175 DEG C of condition, cooling, suction filtration, dry, obtain 6-nitroisoquinoline-1,3 (2H, 4H)-diketone 20.5g, yield 89%.
6-nitroisoquinoline-1,3 (2H, 4H) prepared by S5, described step S4-diketone 20g is dissolved in 40ml phosphenyl oxychloride, under 150-155 DEG C of condition, react 3h, cooling, adds tetrahydrofuran (THF) in reaction solution, then pour in beaker, drip shrend and to go out reaction, within about 25 minutes, add; Adjust pH=8 with ammoniacal liquor, have solid to separate out, suction filtration, filter cake is dried.Filtrate is extracted with ethyl acetate, the solid that extraction liquid is spin-dried for and dries uses silica column purification in the lump, what silicagel column adopted eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=3:1, obtain product 1,3-bis-chloro-6-nitroisoquinoline 20.5g, yield 87%;
S6, described step S5 prepare 1, substitution reaction is there is about 2.5 hours in 120-125 DEG C after 3-bis-chloro-6-nitroisoquinoline 20g mixes with 40mL 4-Methoxybenzylamine, TLC monitoring is to after reacting completely, cooling, directly add 50ml methylene dichloride and mix sample, with silica column purification, what silicagel column adopted eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=5:1, obtain the chloro-N-of 3-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine 16.9g, yield 60%;
S7, chloro-for 3-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine 20g is joined in trifluoroacetic acid 100mL, back flow reaction is about 2.5h, TLC monitoring is to after reacting completely, be cooled to 25 DEG C, revolve and add water except after trifluoroacetic acid, regulate pH=10, separate out solid suction filtration, mixed solvent washing (volume ratio is 10:1) of filter cake 20ml sherwood oil and ethyl acetate, obtains 3-chlorine (bromine)-6-nitroisoquinoline-1-amine 10.4g, yield 80%;
S8,3-chlorine (the bromine)-6-nitroisoquinoline-1-amine 10g prepared by described step S7 join in tetrahydrofuran (THF) 50mL, backflow is lower drips 24ml Isopentyl nitrite, drip and continue to stir 2h, TLC monitoring, to after reacting completely, is revolved and is desolventized, use silica column purification product, what silicagel column adopted eluent is the mixed solution of sherwood oil and ethyl acetate, the volume ratio of the two is sherwood oil: ethyl acetate=2:1, obtains product 3-chloro-6-nitroisoquinoline 7.8g, yield 84%.
Although describe the present invention in conjunction with the embodiments, the present invention is not limited to above-described embodiment, should be appreciated that, under the guiding of the present invention's design, those skilled in the art can carry out various amendment and improvement, and claims summarise scope of the present invention.
Claims (9)
1. medicine intermediate 3-chlorine (bromine)-6-nitroisoquinoline, is characterized in that, has structure shown in formula (1):
。
2. 3-chlorine (bromine)-6-nitroisoquinoline preparation method, is characterized in that comprising the steps:
S1, first chloro-for 2-4-nitrobenzoic acid is joined in dimethyl malonate, cuprous bromide and sodium methylate is added under protection of inert gas, 12-16 hour is reacted under temperature is 90-100 DEG C of condition, cooling, washing, extraction, is drying to obtain crude product 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid;
2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid prepared by S2, described step S1 issues raw hydrolysis reaction at alkaline environment, generates 2-(carboxymethyl)-4-nitrobenzoic acid;
2-(carboxymethyl prepared by S3, described step S2)-4-nitrobenzoic acid is about 1-2h with excess acetyl chloride in organic solvent, after steaming desolventizes, join in ice ammoniacal liquor again, stir 15-20 minute, steam and be added to the water again except after ammoniacal liquor, regulate pH=2-3 with 6-7N HCl, separate out product 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid;
2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid prepared by S4, described step S3 joins in orthodichlorobenzene, under 170-175 DEG C of condition, react 3-5h, cooling, and suction filtration is dried, obtained 6-nitroisoquinoline-1,3(2H, 4H)-diketone;
6-nitroisoquinoline-1 prepared by S5, described step S4,3(2H, 4H)-diketone is dissolved in phosphenyl oxychloride, under 150-155 DEG C of condition, react 3-3.5h; Or to be dissolved in Isosorbide-5-Nitrae-dioxane and to add tribromo oxygen phosphorus, under 105-110 DEG C of condition, react 3-3.5h, be separated and obtain 1,3-dichloro (bromine)-6-nitroisoquinoline;
S6, described step S5 prepare 1, in the 120-125 DEG C of 2-2.5h that reacts after 3-dichloro (bromine)-6-nitroisoquinoline mixes with 4-Methoxybenzylamine, be cooled to 20-25 DEG C, directly add methylene chloride and mix sample and cross post, obtain 3-chlorine (bromine)-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine;
S7,3-chlorine (bromine)-N-(4-methoxy-benzyl)-6-nitroisoquinoline-1-amine is joined in trifluoroacetic acid, back flow reaction 2-3h, be cooled to 20-25 DEG C, revolve and add water except after trifluoroacetic acid, regulate pH=8-10, separate out solid suction filtration, the mixed solvent washing of filter cake sherwood oil and ethyl acetate, obtains 3-chlorine (bromine)-6-nitroisoquinoline-1-amine; The volume ratio of described sherwood oil and ethyl acetate is 10:1-9:1;
S8,3-chlorine (the bromine)-6-nitroisoquinoline-1-amine prepared by described step S7 join in tetrahydrofuran (THF) or acetonitrile, Isopentyl nitrite is dripped under backflow, drip and continue to stir 1-2h, reaction solution is directly spin-dried for, and crosses post and namely obtains 3-chlorine (bromine)-6-nitroisoquinoline.
3. the preparation method of 3-chlorine (bromine)-6-nitroisoquinoline according to claim 2, it is characterized in that, described step S1 is:
First chloro-for 2-4-nitrobenzoic acid is joined in dimethyl malonate, then logical 1-2h under nitrogen being deep into liquid level, then add cuprous bromide and the sodium methylate of catalytic amount, keep nitrogen, be then warming up to 90-100 DEG C of reaction 12-16h, be cooled to room temperature, add water and sherwood oil, aqueous phase sherwood oil and toluene are respectively washed once, with the pH=2-3 of hydrochloric acid soln water transfer phase, separate out solid suction filtration, obtain 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid.
4. the preparation method of 3-chlorine (bromine)-6-nitroisoquinoline according to claim 3, it is characterized in that, described step S1 comprises further: will separate out the aqueous phase petroleum ether extraction after solid, merge organic phase, the saturated NaCl of organic phase washs, drying, is spin-dried for, and obtains 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid.
5. the preparation method of 3-chlorine (bromine)-6-nitroisoquinoline according to claim 2, it is characterized in that, described step S2 is:
Under water bath condition, it is the methanol solution adding 2-(2-methoxyl group-2-oxoethyl)-4-nitrobenzoic acid prepared by described step S1 in the NaOH aqueous solution of 20-25wt% to concentration, reaction 3-3.5h, after TLC monitoring display reacts completely, steam except after methyl alcohol, adopt the pH=1-2 of hydrochloric acid soln regulator solution, separate out solid, filter, dry, obtain 2-(carboxymethyl)-4-nitrobenzoic acid.
6. the preparation method of 3-chlorine (bromine)-6-nitroisoquinoline according to claim 5, it is characterized in that, described step S2 comprises further: continue after the filtrate after filtration is cooled to 0-5 DEG C to separate out 2-(carboxymethyl)-4-nitrobenzoic acid.
7. the preparation method of 3-chlorine (bromine)-6-nitroisoquinoline according to claim 2, it is characterized in that, described step S3 is:
2-(carboxymethyl prepared by described step S2)-4-nitrobenzoic acid joins in acetone, then reflux after adding Acetyl Chloride 98Min. 1-2h, joined 0-5 DEG C again after being spin-dried for solvent, concentration is in the ammonia soln of 70-75wt%, continues to stir 15-20min, spin off ammoniacal liquor, add water, with the pH=2-3 of dilute hydrochloric acid solution regulator solution, separate out solid, suction filtration is dried, and obtains 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid.
8. the preparation method of 3-chlorine (bromine)-6-nitroisoquinoline according to claim 7, is characterized in that, the separation in described step S5 in the following way:
Be cooled to room temperature, add tetrahydrofuran (THF) in reaction solution, then pour in beaker, drip shrend and to go out reaction, about 20-30 minute adds.Then adjust pH=8-10 with ammoniacal liquor, suction filtration, filter cake is dried, and filtrate is extracted with ethyl acetate, and the solid being spin-dried for and drying obtains pure product with purification by column chromatography in the lump.
9. 3-chlorine (the bromine)-6-nitroisoquinoline that prepared by claim 2-8 either method is used as medicine intermediate.
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| CN115417816A (en) * | 2022-09-05 | 2022-12-02 | 江苏南大光电材料股份有限公司 | Preparation method of 3,6-dibromo-1-chloro-isoquinoline |
| CN115417816B (en) * | 2022-09-05 | 2024-01-26 | 江苏南大光电材料股份有限公司 | Preparation method of 3, 6-dibromo-1-chloro-isoquinoline |
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