CN108929270A - A kind of synthesis of the disubstituted nitrogenous heterocyclic aminated compounds of pharmaceutical intermediate - Google Patents
A kind of synthesis of the disubstituted nitrogenous heterocyclic aminated compounds of pharmaceutical intermediate Download PDFInfo
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- CN108929270A CN108929270A CN201810925769.2A CN201810925769A CN108929270A CN 108929270 A CN108929270 A CN 108929270A CN 201810925769 A CN201810925769 A CN 201810925769A CN 108929270 A CN108929270 A CN 108929270A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
A kind of synthesis of the disubstituted nitrogenous heterocyclic aminated compounds of pharmaceutical intermediate, is to be reacted using the bromo- 2- carboxylphenylaceticacid acid of 5-, urea, o-dichlorohenzene as raw material, obtains 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone；6- bromo-isoquinoline -1,3 (2H, 4H)-diketone is reacted with diphenylphosphoryl dichloro, and addition tetrahydrofuran is precipitated, and is crossed column after adjusting pH value, is obtained the chloro- 6- bromo-isoquinoline of 1,3- bis-；Ice acetic acid, red phosphorus, hydroiodic acid again, TLC determines fully reacting after reaction, and filtrate and filter cake fine processing repeatedly obtain the chloro- 6- bromo-isoquinoline of 3-；By cupric sulfate pentahydrate, the bromo- 3- chlorine isoquinolin of 6-, a large amount of 15% ammonium hydroxide reacted in autoclave, extract simultaneously repeatedly required column according to different, obtain the chloro- 6- aminoisoquinoline of final product 3-.
Description
Technical field
The present invention relates to medicine intermediate fields, and in particular to a kind of conjunction of the chloro- 6- aminoisoquinoline of pharmaceutical intermediate 3-
At method.
Background technique
Isoquinolin and its derivative are a kind of important compounds, have stronger bioactivity, be widely used in medicine,
The fields such as pesticide, therefore the synthesis of isoquinilone derivatives has received widespread attention, it is extensive especially among medicine intermediate
Using.Give a kind of 8- nitro -1,2 in CN2016100987718, the preparation method of 3,4- tetrahydroisoquinolines,
A kind of synthetic method of 4- hydroxyl -8- bromo-isoquinoline is given in CN201610042580.X, is given in CN201210340505.3
A kind of preparation method of 7- bromo-isoquinoline is gone out, this is all the example of isoquinoline class derivate application and synthesis, but the application
The chloro- 6- aminoisoquinoline of the 3- referred to is rarely used as the application of medicine intermediate to occur, and either has document or data to disclose
Out.
Due to the characteristic of the molecule, this method cannot be generalized in the synthesis of other similar structure.This is by trying many times
What originality, higher yields and the non-reproduction of shorter reaction time for the preparation method tested determined, other routes
Substantially can not there are higher yields or acceptable reaction time.
Summary of the invention
The present invention is mainly to provide a kind of chloro- 6- aminoisoquinoline of 3- and preparation method thereof.This method step is clear, waste
Few, yield is higher, saves raw material, whole relatively inexpensive.For the needs of medicine preparation, now by structural analysis, to shaped like 3-
The compound of chloro- 6- aminoisoquinoline has demand, is the important intermediate and bridge for further preparing drug, and the application is not had
Record, manufacture experimently the compound around how to take using various raw materials by various routes, intermediate certainty problem is encountered that
Cost problem, yield problem, matter of time, reaction repeat difficulty problem etc., and these problems all annoying the preparation of the intermediate,
Cost problem is that used raw material cannot be too expensive first, if being difficult to very much to obtain too expensive or also needing many steps
Obtain, then produce accordingly the intermediate be can not be actable because having no economic value, yield problem is also critically important, if
For the too low then synthetic route of yield also without practical significance, the final actual recovery of the route of the application is greater than 98%*43%*
Within the acceptable range, yield can be more than 10% under accurate operation by 68%*27 ≈ 7.7%, actually yield, there is one
Fixed economy；Matter of time is also puzzlement point, and the route that the application is taken does not need the too many reaction time, operates as early as possible
It is then overall to be completed within 36h, meet general production requirement；The favorable repeatability of reaction, the preparation route warp of the application
Hundred times or more the repetitions that more people carry out jointly have been gone through, set yield is all maintained, can be very useful in this way, application feature
Stablize.
Above-mentioned technical problem of the invention is mainly to be addressed by following technical proposals:
A kind of chloro- 6- aminoisoquinoline of pharmaceutical intermediate compound 3-, which is characterized in that there is formula (1) described structure:
A kind of preparation method of the chloro- 6- aminoisoquinoline of foregoing 3-, it is characterised in that include the following steps.
Urea, the 1.4-1.6L of step S1: the 5- of raw material preparation 200g-220g bromo- 2- carboxylphenylaceticacid acid and 100-110g
O-dichlorohenzene, choose a 2.5L volume more than four-hole bottle as reaction vessel, at 140-160 DEG C, holding thermotonus
2-3h is filtered after reaction mixture is completely cooling, and filter cake uses individually 150-250ml ethyl acetate, 150-250ml
Water, the washing of 50-150ml methanol three times, obtained solid are dried, S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-is obtained
Diketone.
Step S2: choosing the four-hole bottle of a 4L volume or more as reaction vessel, by bromo-isoquinoline -1 S1 step product 6-,
3 (2H, 4H)-diketone take 190g-210g, are added in the diphenylphosphoryl dichloro of 390-410ml, are heated to 140-160 DEG C, keep temperature
Degree reaction 2.5-3.5h quickly adds the tetrahydrofuran of room temperature before reaction mixture temperature drops to 100-120 DEG C while hot
1900-2100mL dissolves out a large amount of solids, and the distilled water that 450-550ml is added dropwise is quenched, and removes whole four with extremely slow speed revolving
Hydrogen furans adds excessive 15% ammonium hydroxide for remaining water phase, until PH to 8-9.5 is adjusted, then with excessive ethyl acetate
It is extracted, isolates organic phase, be spin-dried for extremely slow speed, the 200 mesh silica gel of 180-220g are added in surplus materials, with stone
Oily ether: mixture is crossed column by ethyl acetate=20:1 proportion, obtains S2 step product 1, the chloro- 6- bromo-isoquinoline of 3- bis-.
Step S3: the four-hole bottle of a 2L or 2L volume or more is chosen as reaction vessel, glacial acetic acid 450- is first added
550ml takes S2 step product 1, and the chloro- 6- bromo-isoquinoline 40-60g of 3- bis- is added, and adds red phosphorus 13-15g and 90-110ml
Hydroiodic acid, configured in the one outlet of four-hole bottle and reflux condensing tube and be equipped with high speed returned cold condensate, then system heats back
Stream turns heating firepower down after generating obvious reflux, reacts about 4-6h, detected by TLC, determine fully reacting, and reaction is mixed
It closes object to be cooled to room temperature, is all filtered to obtain filter cake A and filtrate A, add distilled water 450-550ml to mix filter cake A, it is used
The ammonium hydroxide tune PH=7.5-8.5 of amount 15%, carries out filtering to obtain liquor B and filter cake B later, liquor B and filtrate A use ethyl acetate
Organic phase A is extracted to obtain, filter cake B is impregnated with Excess ethyl acetate, and ethyl acetate phase therein is spin-dried for, and adds water alkali tune, then use second
Organic phase B is obtained by extraction in acetoacetic ester, merges organic phase A and B, with saturated common salt water washing 1-3 times, with suitable anhydrous sodium sulfate
It is spin-dried for again after drying, with petroleum ether: ethyl acetate=50:1 to 20:1 proportion crosses column with 200-300 mesh silica gel, obtains S3 step
The chloro- 6- bromo-isoquinoline of rapid product 3-.
Step S4: it takes a volume to be not less than two liters of autoclave, the five water sulfuric acid of 90-110g is first added after clean dry
Copper takes the bromo- 3- chlorine isoquinolin of the 6- of 90-110g to be added in the ammonium hydroxide of 1000-1200ml 15%, is then added to aforementioned high pressure
In kettle, it is first warming up to 105-115 DEG C of holding at least 1h, is then warming up to 128-136 DEG C of degree again, keeps thermotonus 5-7h, it will
Then reaction mixture cooling cooling filters reaction mixture after cooling to obtain liquor C and filter cake C, liquor C is used suitable
It measures ethyl acetate to extract twice, the ethyl acetate phase that twice is obtained by extraction merges, and mixes sample together with the filter cake C of drying and cross column
Three times, cross column for the first time and first use petroleum ether: ethyl acetate=10:1 mistake crosses column for the second time and petroleum ether: ethyl acetate=3:1 is arranged
And adding triethylamine, third time crosses column petroleum ether: ethyl acetate=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
Preferably, aforementioned all reagents are the pure above purity of chemistry, or are excellent pure grade.The water is deionization
Water, it is therefore preferable to distilled water.
Compared with the prior art, the advantages of the present invention are as follows: using the bromo- 2- carboxylphenylaceticacid acid of 5-, urea, o-dichlorohenzene as
Raw material is reacted, washing and drying after suction filtration, obtains 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone；6- bromo-isoquinoline -1,3 (2H,
4H)-diketone is reacted with diphenylphosphoryl dichloro, adds a large amount of tetrahydrofuran and substance is precipitated, and is crossed column after adjusting pH value, is obtained 1,3-
Two chloro- 6- bromo-isoquinolines；By glacial acetic acid, the chloro- 6- bromo-isoquinoline of 1,3- bis-, red phosphorus, hydroiodic acid as raw material, TLC is true after reaction
Determine fully reacting, by filtrate and filter cake fine processing repeatedly, obtains the chloro- 6- bromo-isoquinolines of 3- more as far as possible；Finally by five water sulphur
The bromo- 3- chlorine isoquinolin of sour copper, 6-, a large amount of 15% ammonium hydroxide reacted in autoclave, to reaction mixture extract and repeatedly according to
Difference required column, obtained the chloro- 6- aminoisoquinoline of final product 3-.S3 the and S4 step of this paper yield if extensive preparation
Obvious insufficient, the present invention is embodied by crossing column repeatedly under accurate operation repeatedly for filtration product and different requirements
Extremely strong inventive concept and creativeness achieve good preparation effect, have no more similar open letter in the prior art
For breath for using for reference, the present invention program has originality.This method has step clear, and waste is few, and yield is higher, and the time is short, section
Save raw material and easily operated advantage.
Detailed description of the invention
Fig. 1 is the HNMR spectrogram for the chloro- 6- aminoisoquinoline of 3- that the present invention is prepared.
Specific embodiment
The preferred embodiment of the present invention is described in detail with reference to the accompanying drawing, so that advantages and features of the invention energy
It is easier to be readily appreciated by one skilled in the art, so as to make a clearer definition of the protection scope of the present invention.This hair
It is bright to be embodied in many different forms, and should not be construed as limited to embodiment set forth herein.On the contrary, providing these
Design of the invention so that this disclosure will be thorough and complete, and will be fully conveyed to art technology by embodiment
Personnel, the present invention will only be defined by the appended claims.The preparation method of the chloro- 6- aminoisoquinoline of 3- provided by the invention, work
Skill route is as follows:
Its synthetic method can be summarized as follows: be using the bromo- 2- carboxylphenylaceticacid acid of 5-, urea, o-dichlorohenzene as raw material into
Row reacts, and washing and drying after suction filtration obtains 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone；6- bromo-isoquinoline -1,3 (2H, 4H)-two
Ketone is reacted with diphenylphosphoryl dichloro, adds a large amount of tetrahydrofuran and substance is precipitated, and crosses column after adjusting pH value, it is chloro- to obtain 1,3- bis-
6- bromo-isoquinoline；By glacial acetic acid, the chloro- 6- bromo-isoquinoline of 1,3- bis-, red phosphorus, hydroiodic acid as raw material, TLC determines reaction after reaction
Completely, by filtrate and filter cake fine processing repeatedly, the chloro- 6- bromo-isoquinolines of 3- more as far as possible is obtained；Finally by cupric sulfate pentahydrate, 6-
Bromo- 3- chlorine isoquinolin, a large amount of 15% ammonium hydroxide reacted in autoclave, to reaction mixture extract and repeatedly according to different requirements
Column is crossed, the chloro- 6- aminoisoquinoline of final product 3- is obtained.
Embodiment 1
S1, the urea of the bromo- 2- carboxylphenylaceticacid acid of 5- of raw material preparation 200g and 100g, 1.4L o-dichlorohenzene, choose one
The four-hole bottle of 2.5L is as reaction vessel, at 140 DEG C, keeps thermotonus 2h, filters after reaction mixture is completely cooling,
Filter cake uses individually 150ml ethyl acetate, 150ml water, the washing of 50ml methanol three times, and obtained solid is dried, is obtained
S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone.
S2, choose a 4L four-hole bottle as reaction vessel, by S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-two
Ketone takes 190g, is added in the diphenylphosphoryl dichloro of 390ml, is heated to 140 DEG C, thermotonus 2.5h is kept, in reaction mixture
Temperature drops to before 100 DEG C, quickly adds the tetrahydrofuran 1900mL of room temperature while hot, dissolves out a large amount of solids, be added dropwise 450ml's
Distilled water is quenched, and removes whole tetrahydrofurans with extremely slow speed revolving, for remaining water phase, adds excessive 15% ammonium hydroxide,
Until adjusting PH to 8-8.5, is then extracted with excessive ethyl acetate, isolates organic phase, be spin-dried for extremely slow speed,
The 200 mesh silica gel of 180g are added in surplus materials, with petroleum ether: mixture is crossed column by ethyl acetate=20:1 proportion, obtains S2
Step product 1, the chloro- 6- bromo-isoquinoline of 3- bis-.
S3, the four-hole bottle for choosing a 2L volume are first added glacial acetic acid 450ml, take S2 step product 1 as reaction vessel,
The chloro- 6- bromo-isoquinoline 40g of 3- bis- is added, and adds the hydroiodic acid of red phosphorus 13g and 90ml, configures in the one outlet of four-hole bottle
Reflux condensing tube is simultaneously equipped with high speed returned cold condensate, and then system is heated to reflux, and turns heating firepower down after generating obvious reflux,
About 4h is reacted, is detected by TLC, determines fully reacting, reaction mixture is cooled to room temperature, all filtered to obtain filter cake
Filter cake A is added distilled water 450ml to mix by A and filtrate A, with excessive 15% ammonium hydroxide tune PH=7.5, carries out filtering to obtain filter later
Organic phase A is extracted with ethyl acetate to obtain in liquid B and filter cake B, liquor B and filtrate A, and filter cake B is impregnated with Excess ethyl acetate, by it
In ethyl acetate phase be spin-dried for, add water alkali tune, then be extracted with ethyl acetate to obtain organic phase B, merge organic phase A and B, with saturation
It brine It 1 time, is spin-dried for again after being dried with suitable anhydrous sodium sulfate, with petroleum ether: ethyl acetate=50:1 to 20:1
Proportion, crosses column with 200-300 mesh silica gel, obtains the chloro- 6- bromo-isoquinoline of S3 step product 3-.
The cupric sulfate pentahydrate of 90g is first added after clean dry, takes the 6- of 90g bromo- by S4, the autoclave for taking two liters of a volume
3- chlorine isoquinolin is added in the ammonium hydroxide of 1000ml15%, is then added in aforementioned autoclave, is first warming up to 105 DEG C and is kept at least
Then 1h is warming up to 128 DEG C of degree again, keep thermotonus 5h, reaction mixture is cooled down, then to reaction after cooling
Mixture is filtered to obtain liquor C and filter cake C, and liquor C is extracted twice with appropriate ethyl acetate, the second that twice is obtained by extraction
Acetoacetic ester mutually merges, and mixes sample together with the filter cake C of drying and cross column three times, crosses column for the first time and first uses petroleum ether: ethyl acetate=
10:1 mistake, second, which crosses column, is arranged petroleum ether: ethyl acetate=3:1 is simultaneously plus triethylamine, third time cross column petroleum ether: acetic acid second
Ester=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
Embodiment 2
S1, the urea of the bromo- 2- carboxylphenylaceticacid acid of 5- of raw material preparation 210g and 105g, 1.5L o-dichlorohenzene, choose one
The four-hole bottle of 3L volume is as reaction vessel, at 150 DEG C, keeps thermotonus 2.5h, after reaction mixture is completely cooling
It filters, filter cake uses individually 200ml ethyl acetate, 200ml water, the washing of 100ml methanol three times, and obtained solid is dried
It is dry, obtain S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone.
S2, choose the four-hole bottle of a 4.5L volume as reaction vessel, by S1 step product 6- bromo-isoquinoline -1,3 (2H,
4H)-diketone takes 200g, is added in the diphenylphosphoryl dichloro of 400ml, is heated to 150 DEG C, keeps thermotonus 3h, mixed in reaction
It closes object temperature to drop to before 110 DEG C, quickly adds the tetrahydrofuran 2000mL of room temperature while hot, dissolve out a large amount of solids, be added dropwise
The distilled water of 500ml is quenched, and removes whole tetrahydrofurans with extremely slow speed revolving, for remaining water phase, adds excessive 15%
Ammonium hydroxide, until adjust PH to 8.5-9, then extracted with excessive ethyl acetate, isolate organic phase, with extremely slow speed
Degree is spin-dried for, and the 200 mesh silica gel of 200g are added in surplus materials, with petroleum ether: ethyl acetate=20:1 proportion is by mixture mistake
Column obtains S2 step product 1, the chloro- 6- bromo-isoquinoline of 3- bis-.
S3, the four-hole bottle for choosing a 2.5L volume are first added glacial acetic acid 500ml, take S2 step product as reaction vessel
1,3- bis- chloro- 6- bromo-isoquinoline 50g is added, and the hydroiodic acid of red phosphorus 14g and 100ml is added, in the one outlet of four-hole bottle
Configuration reflux condensing tube is simultaneously equipped with high speed returned cold condensate, and then system is heated to reflux, and turns heating down after generating obvious reflux
Firepower reacts about 5h, is detected by TLC, determine fully reacting, reaction mixture is cooled to room temperature, all carry out filtering
To filter cake A and filtrate A, adds distilled water 500ml to mix filter cake A, with excessive 15% ammonium hydroxide tune PH=8, filtered later
Liquor B and filter cake B are obtained, organic phase A is extracted with ethyl acetate to obtain in liquor B and filtrate A, and filter cake B is impregnated with Excess ethyl acetate,
Ethyl acetate phase therein is spin-dried for, water alkali tune is added, then is extracted with ethyl acetate to obtain organic phase B, merges organic phase A and B, uses
It saturated common salt water washing 2 times, is spin-dried for again after being dried with suitable anhydrous sodium sulfate, with petroleum ether: ethyl acetate=50:1 to 20:
1 proportion crosses column with 200-300 mesh silica gel, obtains the chloro- 6- bromo-isoquinoline of S3 step product 3-.
The cupric sulfate pentahydrate of 100g is first added after clean dry, takes the 6- of 100g bromo- by S4, the autoclave for taking 3 liters of a volume
3- chlorine isoquinolin is added in the ammonium hydroxide of 1100ml 15%, is then added in aforementioned autoclave, is first warming up to 110 DEG C and is kept extremely
Few 1h, is then warming up to 132 DEG C of degree again, keeps thermotonus 6h, and reaction mixture is cooled down, then to after cooling anti-
Mixture is answered to be filtered to obtain liquor C and filter cake C, liquor C is extracted twice with appropriate ethyl acetate, twice is obtained by extraction
Ethyl acetate phase merges, and mixes sample together with the filter cake C of drying and cross column three times, crosses column for the first time and first uses petroleum ether: ethyl acetate
=10:1 mistake, second, which crosses column, is arranged petroleum ether: ethyl acetate=3:1 is simultaneously plus triethylamine, third time cross column petroleum ether: acetic acid
Ethyl ester=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
Embodiment 3
S1, the urea of the bromo- 2- carboxylphenylaceticacid acid of 5- of raw material preparation 220g and 110g, 1.6L o-dichlorohenzene, choose one
The four-hole bottle of 3.5L volume is as reaction vessel, at 160 DEG C, keeps thermotonus 3h, after reaction mixture is completely cooling
It filters, filter cake uses individually 250ml ethyl acetate, 250ml water, the washing of 150ml methanol three times, and obtained solid is dried
It is dry, obtain S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone.
S2, choose the four-hole bottle of a 5L volume as reaction vessel, by S1 step product 6- bromo-isoquinoline -1,3 (2H,
4H)-diketone takes 210g, is added in the diphenylphosphoryl dichloro of 410ml, is heated to 160 DEG C, keeps thermotonus 3.5h, is reacting
Mixture temperature drops to before 120 DEG C, quickly adds the tetrahydrofuran 2100mL of room temperature while hot, dissolves out a large amount of solids, is added dropwise
The distilled water of 550ml is quenched, and removes whole tetrahydrofurans with extremely slow speed revolving, for remaining water phase, adds excessive 15%
Ammonium hydroxide, until adjust PH to 9-9.5, then extracted with excessive ethyl acetate, isolate organic phase, with extremely slow speed
Degree is spin-dried for, and the 200 mesh silica gel of 220g are added in surplus materials, with petroleum ether: ethyl acetate=20:1 proportion is by mixture mistake
Column obtains S2 step product 1, the chloro- 6- bromo-isoquinoline of 3- bis-.
S3, the four-hole bottle for choosing a 2L or 2L volume or more are first added glacial acetic acid 550ml, S2 are taken to walk as reaction vessel
Rapid product 1, the chloro- 6- bromo-isoquinoline 60g of 3- bis- are added, and the hydroiodic acid of red phosphorus 15g and 110ml are added, the one of four-hole bottle
A outlet configures reflux condensing tube and is equipped with high speed returned cold condensate, and then system is heated to reflux, and adjusts after generating obvious reflux
Small heating firepower reacts about 6h, is detected by TLC, determine fully reacting, reaction mixture is cooled to room temperature, and all carries out
Suction filtration obtains filter cake A and filtrate A, adds distilled water 550ml to mix filter cake A, with excessive 15% ammonium hydroxide tune PH=8.5, later
It carries out filtering to obtain liquor B and filter cake B, organic phase A, filter cake B excessive acetic acid is extracted with ethyl acetate to obtain in liquor B and filtrate A
Ethyl ester impregnates, and ethyl acetate phase therein is spin-dried for, water alkali tune is added, then is extracted with ethyl acetate to obtain organic phase B, merges organic
Phase A and B are spin-dried for after being dried with suitable anhydrous sodium sulfate again with saturated common salt water washing 3 times, with petroleum ether: ethyl acetate=
The proportion of 50:1 to 20:1 crosses column with 200-300 mesh silica gel, obtains the chloro- 6- bromo-isoquinoline of S3 step product 3-.
S4, autoclave of the volume not less than two liters is taken, the cupric sulfate pentahydrate of 110g is first added after clean dry, takes 110g
The bromo- 3- chlorine isoquinolin of 6- be added in the ammonium hydroxide of 1200ml 15%, be then added in aforementioned autoclave, be first warming up to 115 DEG C
At least 1h is kept, is then warming up to 136 DEG C of degree again, keeps thermotonus 7h, reaction mixture is cooled down, then to cooling
Reaction mixture afterwards is filtered to obtain liquor C and filter cake C, and liquor C is extracted twice with appropriate ethyl acetate, and twice is extracted
Obtained ethyl acetate phase merges, and mixes sample together with the filter cake C of drying and cross column three times, crosses column for the first time and first uses petroleum ether: second
Acetoacetic ester=10:1 mistake, second, which crosses column, is arranged petroleum ether: ethyl acetate=3:1 is simultaneously plus triethylamine, third time cross column petroleum
Ether: ethyl acetate=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
Embodiment 4
5- bromo- 2- carboxylphenylaceticacid acid 210g and urea 105g are added in o-dichlorohenzene 1.5L, 150 DEG C of 2.5h are heated.Afterwards
Processing: cooling to filter, filter cake is washed with 150ml ethyl acetate, 150ml water, 50ml methanol respectively, solid drying.Obtain product 6-
Bromo-isoquinoline -1,3 (2H, 4H)-diketone 190g, yield 98%.
Product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone 200g is added in diphenylphosphoryl dichloro-4,4 00ml and is heated to 150 DEG C
3h.Post-processing: while hot plus tetrahydrofuran 2000mL dissolves out solid, and the 500mL that drips is quenched, and THF is removed in rotation, and water phase adds 15% ammonia
Water tune PH to 8-9, then ethyl acetate extracts.It is spin-dried for organic phase, 200 grams of 100-200 mesh silica gel are added, crosses column petroleum ether: second
Acetoacetic ester=20:1.Obtain product 1, the chloro- 6- bromo-isoquinoline 100g of 3- bis-, yield 43.4%.
By in 1,3-, bis- chloro- 6- bromo-isoquinoline, 50 grams of addition glacial acetic acid 500mL, 14 grams of red phosphorus are added, hydroiodic acid
100mL, then system is heated to reflux, and reacts about 5h, and TLC determines fully reacting.Post-processing: being cooled to room temperature, and filters, filter cake
Add water 500mL, with 15% ammonium hydroxide tune PH=8, filter, filtrate is extracted with ethyl acetate, and filter cake steeps product with ethyl acetate.Second
Acid is mutually spin-dried for, and adds water alkali tune, and ethyl acetate extraction merges all organic phases, and saturated common salt is washed one time, and anhydrous sodium sulfate is dry
It is dry, it is spin-dried for, crosses column with 200-300 mesh silica gel, petroleum ether: ethyl acetate=50:1 to 20:1.Obtain the chloro- 6- bromo-isoquinoline of product 3-
30g, yield 68.4%.
The bromo- 3- chlorine isoquinolin of 100g 6- is added to the ammonium hydroxide of 1100ml 15%, 100g cupric sulfate pentahydrate is then added
In autoclave, be first warming up to 110 degree, be then warming up to 132 degree again, react 6h, post-processing: then cooling filters, filtrate is used
EA is extracted twice, can probably extract 8g product out, then with dry filter cake mixes sample together and crosses column, it is first excessively former with PE:EA=10:1
Expect to obtain 60g, then increases polarity PE:EA=3:1 and add triethylamine, finally with PE:EA=1:1 mistake, obtain the chloro- 6- amino of product 3-
Isoquinolin about 20g.Yield is 27.2%.
The chloro- 6- aminoisoquinoline of 3- of any one preparation of embodiment 1-3 is specifically used in a kind of application of medicine intermediate
As medicine intermediate to prepare drug, the system of the drug for other based on isoquinolin or for intermediate transition substance
It is standby.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
The change or replacement expected without creative work, should be covered by the protection scope of the present invention.Therefore, of the invention
Protection scope should be determined by the scope of protection defined in the claims.
Claims (6)
1. a kind of chloro- 6- aminoisoquinoline of pharmaceutical intermediate compound 3-, which is characterized in that have formula (1) described structure:
2. a kind of preparation method of the chloro- 6- aminoisoquinoline of 3- as described in claim 1, it is characterised in that including walking as follows
It is rapid:
S1, the urea of the bromo- 2- carboxylphenylaceticacid acid of 5- of raw material preparation 200g-220g and 100-110g, 1.4-1.6L adjacent dichloro
Benzene chooses the four-hole bottle of a 2.5L volume or more as reaction vessel, at 140-160 DEG C, thermotonus 2-3h is kept, to anti-
It is filtered after answering mixture to cool down completely, filter cake uses individually 150-250ml ethyl acetate, 150-250ml water, 50-150ml
Methanol washs three times, and obtained solid is dried, S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone is obtained；
S2, choose the four-hole bottle of a 4L volume or more as reaction vessel, by S1 step product 6- bromo-isoquinoline -1,3 (2H,
4H)-diketone takes 190g-210g, is added in the diphenylphosphoryl dichloro of 390-410ml, is heated to 140-160 DEG C, keeps temperature anti-
2.5-3.5h is answered, before reaction mixture temperature drops to 100-120 DEG C, quickly adds the tetrahydrofuran of room temperature while hot
1900-2100mL dissolves out a large amount of solids, and the distilled water that 450-550ml is added dropwise is quenched, and removes whole four with extremely slow speed revolving
Hydrogen furans adds excessive 15% ammonium hydroxide for remaining water phase, until PH to 8-9.5 is adjusted, then with excessive ethyl acetate
It is extracted, isolates organic phase, be spin-dried for extremely slow speed, the 200 mesh silica gel of 180-220g are added in surplus materials, with stone
Oily ether: mixture is crossed column by ethyl acetate=20:1 proportion, obtains S2 step product 1, the chloro- 6- bromo-isoquinoline of 3- bis-；
S3, the four-hole bottle for choosing a 2L or 2L volume or more are first added glacial acetic acid 450-550ml, S2 are taken to walk as reaction vessel
Rapid product 1, the chloro- 6- bromo-isoquinoline 40-60g of 3- bis- are added, and the hydroiodic acid of red phosphorus 13-15g and 90-110ml are added, four
The one outlet configuration reflux condensing tube of mouth bottle is simultaneously equipped with high speed returned cold condensate, and then system is heated to reflux, obvious generating
It turns heating firepower after reflux down, reacts about 4-6h, detected by TLC, determine fully reacting, reaction mixture is cooled to room
Temperature is all filtered to obtain filter cake A and filtrate A, adds distilled water 450-550ml to mix filter cake A, with excessive 15% ammonium hydroxide
PH=7.5-8.5 is adjusted, carries out filtering to obtain liquor B and filter cake B later, organic phase is extracted with ethyl acetate to obtain in liquor B and filtrate A
A, filter cake B are impregnated with Excess ethyl acetate, and ethyl acetate phase therein is spin-dried for, and add water alkali tune, then be extracted with ethyl acetate
To organic phase B, merge organic phase A and B, with saturated common salt water washing 1-3 times, is revolved again after being dried with suitable anhydrous sodium sulfate
Dry, with petroleum ether: ethyl acetate=50:1 to 20:1 proportion crosses column with 200-300 mesh silica gel, obtains S3 step product 3-
Chloro- 6- bromo-isoquinoline；
S4, autoclave of the volume not less than two liters is taken, the cupric sulfate pentahydrate of 90-110g is first added after clean dry, takes 90-
The bromo- 3- chlorine isoquinolin of the 6- of 110g is added in the ammonium hydroxide of 1000-1200ml 15%, is then added in aforementioned autoclave, is first risen
Then temperature is warming up to 128-136 DEG C of degree again, thermotonus 5-7h is kept, by reaction mixture to 105-115 DEG C of holding at least 1h
Cooling cooling, then filters reaction mixture after cooling to obtain liquor C and filter cake C, the appropriate ethyl acetate of liquor C
Twice of extraction, the ethyl acetate phase that twice is obtained by extraction merge, and mix sample together with the filter cake C of drying and cross column three times, and first
Secondary column of crossing first uses petroleum ether: ethyl acetate=10:1 mistake, cross column for the second time and petroleum ether is arranged: ethyl acetate=3:1 simultaneously adds three second
Amine, third time cross column petroleum ether: ethyl acetate=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
3. a kind of preparation method of the chloro- 6- aminoisoquinoline of 3- as claimed in claim 2, which is characterized in that the S1-S4 step
Suddenly specifically:
S1, the urea of the bromo- 2- carboxylphenylaceticacid acid of 5- of raw material preparation 200g and 100g, 1.4L o-dichlorohenzene, choose a 2.5L
Four-hole bottle as reaction vessel, at 140 DEG C, keep thermotonus 2h, filtered after reaction mixture is completely cooling, filter cake
It uses individually 150ml ethyl acetate, 150ml water, the washing of 50ml methanol three times, obtained solid is dried, obtain S1 step
Rapid product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone；
S2, the four-hole bottle for choosing a 4L take S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone as reaction vessel
190g is added in the diphenylphosphoryl dichloro of 390ml, is heated to 140 DEG C, thermotonus 2.5h is kept, in reaction mixture temperature
Drop to before 100 DEG C, quickly adds the tetrahydrofuran 1900mL of room temperature while hot, dissolve out a large amount of solids, double steamings of 450ml are added dropwise
Water quenching is gone out, and is removed whole tetrahydrofurans with extremely slow speed revolving, for remaining water phase, is added excessive 15% ammonium hydroxide, until
PH to 8-8.5 is adjusted, is then extracted with excessive ethyl acetate, isolates organic phase, be spin-dried for extremely slow speed, it is remaining
The 200 mesh silica gel of 180g are added in substance, with petroleum ether: mixture is crossed column by ethyl acetate=20:1 proportion, obtains S2 step
Product 1, the chloro- 6- bromo-isoquinoline of 3- bis-；
S3, the four-hole bottle for choosing a 2L volume are first added glacial acetic acid 450ml, take S2 step product 1,3- bis- as reaction vessel
Chloro- 6- bromo-isoquinoline 40g is added, and adds the hydroiodic acid of red phosphorus 13g and 90ml, configures reflux in the one outlet of four-hole bottle
Condenser pipe is simultaneously equipped with high speed returned cold condensate, and then system is heated to reflux, and turns heating firepower down after generating obvious reflux, reacts
About 4h is detected by TLC, determines fully reacting, and reaction mixture is cooled to room temperature, all filtered to obtain filter cake A and
Filter cake A is added distilled water 450ml to mix, with excessive 15% ammonium hydroxide tune PH=7.5, carries out filtering to obtain liquor B later by filtrate A
With filter cake B, organic phase A is extracted with ethyl acetate to obtain in liquor B and filtrate A, and filter cake B is impregnated with Excess ethyl acetate, will wherein
Ethyl acetate phase be spin-dried for, add water alkali tune, then be extracted with ethyl acetate to obtain organic phase B, merge organic phase A and B, eaten with saturation
It salt water washing 1 time, is spin-dried for again after being dried with suitable anhydrous sodium sulfate, with petroleum ether: ethyl acetate=50:1 to 20:1 matches
Than crossing column with 200-300 mesh silica gel, obtaining the chloro- 6- bromo-isoquinoline of S3 step product 3-；
The cupric sulfate pentahydrate of 90g is first added after clean dry, takes the bromo- 3- chlorine of the 6- of 90g by S4, the autoclave for taking two liters of a volume
Isoquinolin is added in the ammonium hydroxide of 1000ml15%, is then added in aforementioned autoclave, and 105 DEG C of holding at least 1h are first warming up to,
Then it is warming up to 128 DEG C of degree again, keeps thermotonus 5h, reaction mixture is cooled down, it is then mixed to reaction after cooling
It closes object to be filtered to obtain liquor C and filter cake C, liquor C is extracted twice with appropriate ethyl acetate, the acetic acid that twice is obtained by extraction
Ethyl ester mutually merges, and mixes sample together with the filter cake C of drying and cross column three times, crosses column for the first time and first uses petroleum ether: ethyl acetate=10:
1 mistake, second, which crosses column, is arranged petroleum ether: ethyl acetate=3:1 is simultaneously plus triethylamine, third time cross column petroleum ether: ethyl acetate
=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
4. a kind of preparation method of the chloro- 6- aminoisoquinoline of 3- as claimed in claim 2, which is characterized in that the S1-S4 step
Suddenly specifically:
S1, the urea of the bromo- 2- carboxylphenylaceticacid acid of 5- of raw material preparation 210g and 105g, 1.5L o-dichlorohenzene, choose a 3L hold
Long-pending four-hole bottle is as reaction vessel, at 150 DEG C, keeps thermotonus 2.5h, filters after reaction mixture is completely cooling,
Filter cake uses individually 200ml ethyl acetate, 200ml water, the washing of 100ml methanol three times, and obtained solid is dried, is obtained
S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone；
S2, choose a 4.5L volume four-hole bottle as reaction vessel, by S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H) -
Diketone takes 200g, is added in the diphenylphosphoryl dichloro of 400ml, is heated to 150 DEG C, thermotonus 3h is kept, in reaction mixture
Temperature drops to before 110 DEG C, quickly adds the tetrahydrofuran 2000mL of room temperature while hot, dissolves out a large amount of solids, be added dropwise 500ml's
Distilled water is quenched, and removes whole tetrahydrofurans with extremely slow speed revolving, for remaining water phase, adds excessive 15% ammonium hydroxide,
Until adjusting PH to 8.5-9, is then extracted with excessive ethyl acetate, isolates organic phase, be spin-dried for extremely slow speed,
The 200 mesh silica gel of 200g are added in surplus materials, with petroleum ether: mixture is crossed column by ethyl acetate=20:1 proportion, obtains S2
Step product 1, the chloro- 6- bromo-isoquinoline of 3- bis-；
S3, the four-hole bottle for choosing a 2.5L volume are first added glacial acetic acid 500ml, take S2 step product 1,3- as reaction vessel
Two chloro- 6- bromo-isoquinoline 50g are added, and add the hydroiodic acid of red phosphorus 14g and 100ml, configure in the one outlet of four-hole bottle
Reflux condensing tube is simultaneously equipped with high speed returned cold condensate, and then system is heated to reflux, and turns heating firepower down after generating obvious reflux,
About 5h is reacted, is detected by TLC, determines fully reacting, reaction mixture is cooled to room temperature, all filtered to obtain filter cake
Filter cake A is added distilled water 500ml to mix, with excessive 15% ammonium hydroxide tune PH=8, carries out filtering to obtain liquor B later by A and filtrate A
With filter cake B, organic phase A is extracted with ethyl acetate to obtain in liquor B and filtrate A, and filter cake B is impregnated with Excess ethyl acetate, will wherein
Ethyl acetate phase be spin-dried for, add water alkali tune, then be extracted with ethyl acetate to obtain organic phase B, merge organic phase A and B, eaten with saturation
It salt water washing 2 times, is spin-dried for again after being dried with suitable anhydrous sodium sulfate, with petroleum ether: ethyl acetate=50:1 to 20:1 matches
Than crossing column with 200-300 mesh silica gel, obtaining the chloro- 6- bromo-isoquinoline of S3 step product 3-；
The cupric sulfate pentahydrate of 100g is first added after clean dry, takes the bromo- 3- chlorine of the 6- of 100g by S4, the autoclave for taking 3 liters of a volume
Isoquinolin is added in the ammonium hydroxide of 1100ml 15%, is then added in aforementioned autoclave, and 110 DEG C of holding at least 1h are first warming up to,
Then it is warming up to 132 DEG C of degree again, keeps thermotonus 6h, reaction mixture is cooled down, it is then mixed to reaction after cooling
It closes object to be filtered to obtain liquor C and filter cake C, liquor C is extracted twice with appropriate ethyl acetate, the acetic acid that twice is obtained by extraction
Ethyl ester mutually merges, and mixes sample together with the filter cake C of drying and cross column three times, crosses column for the first time and first uses petroleum ether: ethyl acetate=10:
1 mistake, second, which crosses column, is arranged petroleum ether: ethyl acetate=3:1 is simultaneously plus triethylamine, third time cross column petroleum ether: ethyl acetate
=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
5. a kind of preparation method of the chloro- 6- aminoisoquinoline of 3- as claimed in claim 2, which is characterized in that the S1-S4 step
Suddenly specifically:
S1, the urea of the bromo- 2- carboxylphenylaceticacid acid of 5- of raw material preparation 220g and 110g, 1.6L o-dichlorohenzene, choose a 3.5L
The four-hole bottle of volume is as reaction vessel, at 160 DEG C, keeps thermotonus 3h, filters after reaction mixture is completely cooling,
Filter cake uses individually 250ml ethyl acetate, 250ml water, the washing of 150ml methanol three times, and obtained solid is dried, is obtained
S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-diketone；
S2, choose a 5L volume four-hole bottle as reaction vessel, by S1 step product 6- bromo-isoquinoline -1,3 (2H, 4H)-two
Ketone takes 210g, is added in the diphenylphosphoryl dichloro of 410ml, is heated to 160 DEG C, thermotonus 3.5h is kept, in reaction mixture
Temperature drops to before 120 DEG C, quickly adds the tetrahydrofuran 2100mL of room temperature while hot, dissolves out a large amount of solids, be added dropwise 550ml's
Distilled water is quenched, and removes whole tetrahydrofurans with extremely slow speed revolving, for remaining water phase, adds excessive 15% ammonium hydroxide,
Until adjusting PH to 9-9.5, is then extracted with excessive ethyl acetate, isolates organic phase, be spin-dried for extremely slow speed,
The 200 mesh silica gel of 220g are added in surplus materials, with petroleum ether: mixture is crossed column by ethyl acetate=20:1 proportion, obtains S2
Step product 1, the chloro- 6- bromo-isoquinoline of 3- bis-；
S3, the four-hole bottle for choosing a 2L or 2L volume or more are first added glacial acetic acid 550ml, S2 step are taken to produce as reaction vessel
Product 1, the chloro- 6- bromo-isoquinoline 60g of 3- bis- are added, and add the hydroiodic acid of red phosphorus 15g and 110ml, and one in four-hole bottle goes out
Mouth configuration reflux condensing tube is simultaneously equipped with high speed returned cold condensate, and then system is heated to reflux, and turns down and adds after generating obvious reflux
Showing tremendous enthusiasm power reacts about 6h, is detected by TLC, determine fully reacting, reaction mixture is cooled to room temperature, all filtered
Filter cake A and filtrate A are obtained, adds distilled water 550ml to mix filter cake A, with excessive 15% ammonium hydroxide tune PH=8.5, carries out later
Liquor B and filter cake B are filtered to obtain, organic phase A, filter cake B Excess ethyl acetate is extracted with ethyl acetate to obtain in liquor B and filtrate A
It impregnates, ethyl acetate phase therein is spin-dried for, water alkali tune is added, then be extracted with ethyl acetate to obtain organic phase B, merge organic phase A
And B is spin-dried for after being dried with suitable anhydrous sodium sulfate again with saturated common salt water washing 3 times, and with petroleum ether: ethyl acetate=50:
1 arrives the proportion of 20:1, crosses column with 200-300 mesh silica gel, obtains the chloro- 6- bromo-isoquinoline of S3 step product 3-；
S4, autoclave of the volume not less than two liters is taken, the cupric sulfate pentahydrate of 110g is first added after clean dry, takes the 6- of 110g
Bromo- 3- chlorine isoquinolin is added in the ammonium hydroxide of 1200ml 15%, is then added in aforementioned autoclave, and 115 DEG C of holdings are first warming up to
Then at least 1h is warming up to 136 DEG C of degree again, keep thermotonus 7h, reaction mixture is cooled down, then to after cooling
Reaction mixture is filtered to obtain liquor C and filter cake C, and liquor C is extracted twice with appropriate ethyl acetate, twice is obtained by extraction
Ethyl acetate phase merge, and mix sample together with the filter cake C of drying and cross column three times, cross column for the first time and first use petroleum ether: acetic acid second
Ester=10:1 mistake, second, which crosses column, is arranged petroleum ether: ethyl acetate=3:1 is simultaneously plus triethylamine, third time cross column petroleum ether: second
Acetoacetic ester=1:1 mistake obtains the chloro- 6- aminoisoquinoline of final products 3-.
6. a kind of application of medicine intermediate, the chloro- 6- amino of 3- prepared obtained by any one method of claim 2-5
Isoquinolin is used as medicine intermediate to prepare drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113877483A (en) * | 2021-07-20 | 2022-01-04 | 烟台宁远药业有限公司 | Low-temperature continuous synthesis device and method for pharmaceutical intermediate halogenated isoquinoline boric acid |
| CN114591238A (en) * | 2022-03-25 | 2022-06-07 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Synthetic method of isoquinoline drug intermediate |
| 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 |
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| WO2018125548A1 (en) * | 2016-12-30 | 2018-07-05 | Aerie Pharmaceuticals, Inc. | Methods for the preparation of 6-aminoisoquinoline |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113877483A (en) * | 2021-07-20 | 2022-01-04 | 烟台宁远药业有限公司 | Low-temperature continuous synthesis device and method for pharmaceutical intermediate halogenated isoquinoline boric acid |
| CN113877483B (en) * | 2021-07-20 | 2023-11-24 | 烟台宁远药业有限公司 | Low-temperature continuous synthesis device and method for pharmaceutical intermediate halogenated isoquinoline boric acid |
| CN114591238A (en) * | 2022-03-25 | 2022-06-07 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Synthetic method of isoquinoline drug intermediate |
| 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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