CN106045908A - Novel compound-6, 7-dibromo-1, 2, 3, 4-tetrahydroisoquinoline and preparation method thereof - Google Patents
Novel compound-6, 7-dibromo-1, 2, 3, 4-tetrahydroisoquinoline and preparation method thereof Download PDFInfo
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- CN106045908A CN106045908A CN201610419783.6A CN201610419783A CN106045908A CN 106045908 A CN106045908 A CN 106045908A CN 201610419783 A CN201610419783 A CN 201610419783A CN 106045908 A CN106045908 A CN 106045908A
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- tetrahydroisoquinoline
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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Abstract
The invention discloses a novel compound-6, 7-dibromo-1, 2, 3, 4-tetrahydroisoquinoline and a preparation method thereof. The preparation method includes: adding 1, 2, 3, 4-tetrahydroisoquinoline into a dichloromethane solution, adding triethylamine, adding acetyl chloride, and allowing reaction at 0-5 DEG C for 2-3 h to obtain N-acetyl 1, 2, 3, 4- tetrahydroisoquinoline; suspending N-acetyl 1, 2, 3, 4- tetrahydroisoquinoline in a concentrated sulfuric acid solution, adding N-bromosuccinimide, and allowing reaction at 60-80 DEG C for 1-2 h to obtain N-acetyl-6, 7-bromine- tetrahydroisoquinoline; dissolving N-acetyl-6, 7-bromine- tetrahydroisoquinoline in methanol, adding potassium carbonate, and allowing reaction at 80-90 DEG C for 10-12 h to obtain 6, 7-dibromo-1, 2, 3, 4-tetrahydroisoquinoline. The preparation method is relatively mild in reaction condition, and 6, 7-dibromo-1, 2, 3, 4-tetrahydroisoquinoline is easy to treat and purify and suitable for mass preparation.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of new compound 6,7-bis-bromo-1,2,3,4-tetra-
Hydrogen isoquinoline and preparation method thereof.
Background technology
Tetrahydroisoquinolicompounds compounds has the most various pharmacologically active, loses if any stronger resisting hypertension, the anti-rhythm of the heart
Often, antithrombotic acitivity etc., many drug molecules and natural product all contain tetrahydroisoquinoline structure or fragment, thus tetrahydrochysene
Isoquinilone derivatives is important pharmaceutical intermediate.But the synthesis of tetrahydroisoquinolicompounds compounds is mostly by phenethylamine class
Molecule realizes preparation by cyclization, and step is longer, expensive starting materials, is difficult to operation and yield is the highest, this strongly limits halo
Efficiently preparation and the application demand of tetrahydroisoquinoline.Especially kind and synthetic method to dihalo tetrahydroisoquinoline is reported very
Few, the most do not find the synthetic method report of two bromo tetrahydroisoquinolines, for compound disclosed by the invention: 6,7-bis-
Bromo-1,2,3,4-tetrahydroisoquinolines, the most do not announce cas number, reflect the novel degrees of this material, and it is synthesized
Research the most more be nobody shows any interest in, and synthetic route disclosed in this invention is brief, totally 3 step；Preparation method used is easy and simple to handle, is
A kind of inexpensive method being suitable for being prepared on a large scale.Owing to this compounds is valuable pharmaceutical intermediate, therefore the present invention is public
The content opened has important research and practical value, and the preparation that simultaneously also can greatly promote other like derivatives produces.
Summary of the invention
It is an object of the invention to provide a kind of new compound 6,7-bis-bromo-1,2,3,4-tetrahydroisoquinoline and preparation is done
Method, prepared 6, there is potential pharmacologically active, and react relatively mild in bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, product is easy
Process purification, be suitable for batch preparation.
For achieving the above object, the present invention is by the following technical solutions:
A kind of new compound 6, bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, bromo-1,2,3, the 4-tetrahydroisoquinolines of described 6,7-bis-
Structural formula be
。
Described new compound 6, the preparation method of bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, step is as follows:
(1) by 1,2,3,4-tetrahydroisoquinolines join in dichloromethane solution, add triethylamine, then add chloroacetic chloride, 0 ~ 5
2 ~ 3h is reacted, then through extracting, wash, be dried to obtain N-acetyl group 1,2,3,4-tetrahydroisoquinoline under conditions of DEG C；
(2) N-acetyl group 1,2,3,4-tetrahydroisoquinoline is suspended in concentrated sulfuric acid solution, adds N-bromo-succinimide,
React 1 ~ 2 hour under conditions of 60 ~ 80 DEG C, then through extracting, wash, be dried to obtain N-acetyl group-6, the bromo-Tetrahydroisoquinoli-of 7-
Quinoline；
(3) by N-acetyl group-6, the bromo-tetrahydroisoquinoline of 7-is re-dissolved in methanol, adds potassium carbonate, the condition of 80 ~ 90 DEG C
Lower reaction 10 ~ 12 hours, removes unnecessary methanol after completion of the reaction under reduced pressure, then through extracting, being dried to obtain 6,7-bis-bromo-1,2,3,
4-tetrahydroisoquinoline；
Concrete reaction equation is as follows:
In described step (1), triethylamine, chloroacetic chloride are 1.2 ~ 1.5:1.1 ~ 1.3 with the mol ratio of 1,2,3,4-tetrahydroisoquinoline:
1。
In described step (2), N-bromo-succinimide with the mol ratio of N-acetyl group 1,2,3,4-tetrahydroisoquinoline is
2.1:1~2.2:1。
In described step (3), potassium carbonate is 2.0:1 ~ 2.5:1 with the mol ratio of the N-bromo-tetrahydroisoquinoline of acetyl group-6,7-.
Beneficial effects of the present invention: 6,7-bis-bromo-1,2,3,4-tetrahydroisoquinolines are class new compounds, have no at present
Document is reported, and has potential pharmacologically active.The preparation method that the present invention provides, reacts relatively mild, the disposable purification of product,
Being suitable for batch preparation, 6 therefore invented, the preparation method of bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-has significant application value.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention will be further described.Should be understood that following example are merely to illustrate this
Inventing not for limiting the scope of the present invention, the person skilled in the art in this field can make one according to the content of foregoing invention
A little nonessential improvement and adjustment.
Embodiment 1
The preparation method of the 6,7-bis-bromo-1,2,3,4-tetrahydroisoquinoline of the present embodiment is as follows:
(1) synthesis of N-acetyl group 1,2,3,4-tetrahydroisoquinoline
Take a 100ml single port bottle to be placed in ice bath, add 1,2,3,4-tetrahydroisoquinoline 2.66g(0.02mol), and add two
Chloromethanes 100mL, stirring and dissolving, then add triethylamine 3.03g(0.03mol), weigh chloroacetic chloride 2.04g after stirring
(0.026mol) it is slowly dropped in reaction system, stirs 3 hours under ice bath after dropping, pour reactant liquor into separatory afterwards
In funnel, it is added thereto to appropriate water and dichloromethane extracts 3 times, dichloromethane layer is washed with water 1-2 time, same to washings
Layer extracts 1 time with dichloromethane again, merges organic layer, and after anhydrous sodium sulfate is dried extract, Rotary Evaporators removes solvent, residual
Excess column chromatography purifies, and petrol ether/ethyl acetate=1/1 eluting obtains pale yellow oil 3.36g, yield 96%；
MS:m/z:[M+1]: 176
1H NMR (400 MHz, CDCl3): 7.48 (d, 1H), 7.37 (m, 1H), 7.21 (m, 1H), 7.17
(d, 1H), 4.45 (s, 2H), 3.86 (t, 2H), 3.10 (t, 2H), 2.33 (s, 3H)。
Elementary analysis C11H13NO theoretical value (%): C:75.40; H:7.48; N:7.99;O:9.13
Measured value: C:75.24;H:7.52; N:7.89
(2) synthesis of the bromo-tetrahydroisoquinoline of N-acetyl group-6,7-
Claim N-acetyl group 1,2,3,4-tetrahydroisoquinoline 1.75g(0.01mol), add concentrated sulphuric acid 15mL, after stirring and dissolving, then claim
Amount NBS 3.92g(0.22mol) it is slowly added to reaction system, reaction temperature 80 DEG C heating 2h is set.After completion of the reaction will reaction
Liquid is poured in separatory funnel, is added thereto to appropriate water and ethyl acetate extracts 3 times, ethyl acetate washed with water is washed 1-2
Secondary, to wash away the most unnecessary concentrated sulphuric acid, the aqueous layer with ethyl acetate of gained is also extracted 1-2 time simultaneously, merge organic layer, nothing
After aqueous sodium persulfate is dried extract, Rotary Evaporators removes solvent, obtains Chinese red oily liquids 2.94g, yield 89%；
MS:m/z:[M+1]: 335
1H NMR (400 MHz, CDCl3): 7.28 (s, 1H), 7.27 (s, 1H), 4.52 (s, 2H), 3.84
(t, 2H), 3.14 (t, 2H), 2.34 (s, 3H)。
Elementary analysis C11H11Br2NO theoretical value (%): C:39.67; H:3.33; N:4.21; O:4.80;
Br:47.99
Measured value: C, 39.45;H:3.12; N:4.13;Br:48.39
(3) synthesis of the bromo-tetrahydroisoquinoline of 6,7-
Claim N-acetyl group-6, bromo-1,2,3, the 4-tetrahydroisoquinoline 1.67g(0.005mol of 7-bis-), add absolute methanol 15mL, then
Weigh potassium carbonate 1.73g(0.0125mol) add reaction system, reaction temperature 90 DEG C heating 12h is set, after completion of the reaction first
Remove methanol therein, the appropriate water of remaining addition and ethyl acetate under reduced pressure to extract 3 times, after anhydrous sodium sulfate is dried extract,
Rotary Evaporators removes solvent, obtains brown oil liquid 1.32g, yield 91 %
MS:m/z:[M+1]: 292
1H NMR (400 MHz, CDCl3): 7.2 (s, 8 1H), 7.27 (s, 1H), 3.82 (s, 2H), 3.34
(t, 2H), 3.04 (t, 2H), 2.30 (br, 1H)。
Elementary analysis C9H9Br2N theoretical value (%): C:37.15; H:3.12; N:4.81; Br:54.92
Measured value: C:37.28; H:3.16; N:4.67; Br:54.89.
Embodiment 2
The preparation method of the 6,7-bis-bromo-1,2,3,4-tetrahydroisoquinoline of the present embodiment is as follows:
(1) synthesis of N-acetyl group 1,2,3,4-tetrahydroisoquinoline
Take a 100ml single port bottle to put, add 1,2,3,4-tetrahydroisoquinoline 2.66g(0.02mol), and add dichloromethane
100mL, stirring and dissolving, then add triethylamine 2.82g(0.028mol), weigh chloroacetic chloride 1.88g after stirring
(0.024mol) it is slowly dropped in reaction system.Drip complete rear chamber temperature to react 3 hours.Afterwards reactant liquor is poured into separatory leakage
In bucket, it is added thereto to appropriate water and dichloromethane extracts 3 times.Dichloromethane layer is washed with water 1 time, with washing water layer again
Extracting 1 time with dichloromethane, merge organic layer, after anhydrous sodium sulfate is dried extract, Rotary Evaporators removes solvent, residue
Purifying with column chromatography, petrol ether/ethyl acetate=1/1 eluting obtains pale yellow oil 3.29g, yield 94%；
(2) synthesis of the bromo-tetrahydroisoquinoline of N-acetyl group-6,7-two
Claim N-acetyl group 1,2,3,4-tetrahydroisoquinoline 1.75g(0.01mol), add concentrated sulphuric acid 15mL, after stirring and dissolving, then claim
Amount NBS 3.74g(0.021mol) it is slowly added to reaction system, reaction temperature 80 DEG C heating 2h is set.After completion of the reaction will reaction
Liquid is poured in separatory funnel, is added thereto to appropriate water and ethyl acetate extracts 3 times.Ethyl acetate washed with water is washed 1-2
Secondary, to wash away the most unnecessary concentrated sulphuric acid, the aqueous layer with ethyl acetate of gained is also extracted 1-2 time simultaneously, merge organic layer.Nothing
After aqueous sodium persulfate is dried extract, Rotary Evaporators removes solvent, obtains Chinese red oily liquids 2.83g, yield 85%；
(3) synthesis of the bromo-tetrahydroisoquinoline of 6,7-bis-
Claim N-acetyl group-6, bromo-1,2,3, the 4-tetrahydroisoquinoline 1.67g(0.005mol of 7-bis-), add absolute methanol 15mL, then
Weigh potassium carbonate 1.73g(0.0125mol) add reaction system, reaction temperature 80 DEG C heating 12h is set, the most first subtracts
Pressure is evaporated off methanol therein, the appropriate water of remaining addition and ethyl acetate and extracts 3 times, after anhydrous sodium sulfate is dried extract, and rotation
Turn evaporimeter and remove solvent, obtain brown oil liquid 1.28g, yield 88 %
Embodiment 3
The preparation method of the 6,7-bis-bromo-1,2,3,4-tetrahydroisoquinoline of the present embodiment is as follows:
(1) synthesis of N-acetyl group 1,2,3,4-tetrahydroisoquinoline
Take a 100ml single port bottle to put, add 1,2,3,4-tetrahydroisoquinoline 2.66g(0.02mol), and add dichloromethane
100mL, stirring and dissolving, then add triethylamine 2.42g(0.024mol), weigh chloroacetic chloride 1.73g after stirring
(0.022mol) it is slowly dropped in reaction system.Drip complete rear chamber temperature to react 3 hours.Afterwards reactant liquor is poured into separatory leakage
In bucket, it is added thereto to appropriate water and dichloromethane extracts 3 times.Dichloromethane layer is washed with water 1 time, with washing water layer again
Extracting 1 time with dichloromethane, merge organic layer, after anhydrous sodium sulfate is dried extract, Rotary Evaporators removes solvent, residue
Purifying with column chromatography, petrol ether/ethyl acetate=1/1 eluting obtains pale yellow oil 3.12g, yield 89%.
(2) synthesis of the bromo-tetrahydroisoquinoline of N-acetyl group-6,7-two
Claim N-acetyl group 1,2,3,4-tetrahydroisoquinoline 17.5g(0.1mol), add concentrated sulphuric acid 150mL, after stirring and dissolving, then claim
Amount NBS 37.4g(0.21mol) it is slowly added to reaction system, reaction temperature 60 DEG C heating 2h is set.After completion of the reaction will reaction
Liquid is poured in separatory funnel, is added thereto to appropriate water and ethyl acetate extracts 3 times.Ethyl acetate washed with water is washed 1-2
Secondary, to wash away the most unnecessary concentrated sulphuric acid, the aqueous layer with ethyl acetate of gained is also extracted 1-2 time simultaneously, merge organic layer.Nothing
After aqueous sodium persulfate is dried extract, Rotary Evaporators removes solvent, obtains Chinese red oily liquids 27g, yield 81%；
(3) synthesis of the bromo-tetrahydroisoquinoline of 6,7-bis-
Claim N-acetyl group-6, bromo-1,2,3, the 4-tetrahydroisoquinoline 1.67g(0.005mol of 7-bis-), add absolute methanol 15mL, then
Weigh potassium carbonate 1.52g(0.012mol) add reaction system, reaction temperature 80 DEG C heating 10h is set, the most first subtracts
Pressure is evaporated off methanol therein, the appropriate water of remaining addition and ethyl acetate and extracts 3 times, after anhydrous sodium sulfate is dried extract, and rotation
Turn evaporimeter and remove solvent, obtain brown oil liquid 1.22g, yield 84 %
Embodiment 4
(1) synthesis of N-acetyl group 1,2,3,4-tetrahydroisoquinoline:
Take a 100ml single port bottle to be placed in ice bath, add 1,2,3,4-tetrahydroisoquinoline 2.66g(0.02mol), and add two
Chloromethanes 100mL, stirring and dissolving, then add triethylamine 2.42g(0.024mol), weigh chloroacetic chloride after stirring
1.73g(0.022mol) be slowly dropped in reaction system, stir 2 hours under ice bath after dropping, afterwards reactant liquor is fallen
Enter in separatory funnel, be added thereto to appropriate water and dichloromethane extracts 3 times, dichloromethane layer is washed with water 1-2 time, with
Washing water layer extracts 1 time with dichloromethane again, merges organic layer, and after anhydrous sodium sulfate is dried extract, Rotary Evaporators removes
Solvent, residue column chromatography purifies, and petrol ether/ethyl acetate=1/1 eluting obtains pale yellow oil 2.98g, yield 85%.
(2) synthesis of the bromo-tetrahydroisoquinoline of N-acetyl group-6,7-two
Claim N-acetyl group 1,2,3,4-tetrahydroisoquinoline 17.5g(0.1mol), add concentrated sulphuric acid 150mL, after stirring and dissolving, then claim
Amount NBS 37.4g(0.21mol) it is slowly added to reaction system, reaction temperature 60 DEG C heating 1h is set.After completion of the reaction will reaction
Liquid is poured in separatory funnel, is added thereto to appropriate water and ethyl acetate extracts 3 times.Ethyl acetate washed with water is washed 1-2
Secondary, to wash away the most unnecessary concentrated sulphuric acid, the aqueous layer with ethyl acetate of gained is also extracted 1-2 time simultaneously, merge organic layer.Nothing
After aqueous sodium persulfate is dried extract, Rotary Evaporators removes solvent, obtains Chinese red oily liquids 26g, yield 78%.
(3) synthesis of the bromo-tetrahydroisoquinoline of 6,7-bis-
Claim N-acetyl group-6, bromo-1,2,3, the 4-tetrahydroisoquinoline 1.67g(0.005mol of 7-bis-), add absolute methanol 15mL, then
Weigh potassium carbonate 1.38g(0.01mol) add reaction system, reaction temperature 80 DEG C heating 10h is set, the most first reduces pressure
Therein methanol, remaining addition appropriate water and ethyl acetate are evaporated off extract 3 times, after anhydrous sodium sulfate is dried extract, rotate
Evaporimeter removes solvent, obtains brown oil liquid 1.16g, yield 80 %.
The ultimate principle of the present invention and principal character and advantages of the present invention have more than been shown and described.The skill of the industry
The art personnel simply explanation it should be appreciated that the present invention is not restricted to the described embodiments, described in above-described embodiment and description
The principle of the present invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, these
Changes and improvements both fall within scope of the claimed invention.Claimed scope by appending claims and
Its equivalent defines.
Claims (5)
1. a new compound 6, bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, it is characterised in that: described 6,7-bis-bromo-1,2,
The structural formula of 3,4-tetrahydroisoquinoline is
。
2. the new compound 6 described in claim 1, the preparation method of bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, its feature exists
As follows in step:
(1) by 1,2,3,4-tetrahydroisoquinolines join in dichloromethane solution, add triethylamine, then add chloroacetic chloride, 0 ~ 5
2 ~ 3h is reacted, then through extracting, wash, be dried to obtain N-acetyl group 1,2,3,4-tetrahydroisoquinoline under conditions of DEG C；
(2) N-acetyl group 1,2,3,4-tetrahydroisoquinoline is suspended in concentrated sulfuric acid solution, adds N-bromo-succinimide,
React 1 ~ 2 hour under conditions of 60 ~ 80 DEG C, then through extracting, wash, be dried to obtain N-acetyl group-6, the bromo-Tetrahydroisoquinoli-of 7-
Quinoline；
(3) by N-acetyl group-6, the bromo-tetrahydroisoquinoline of 7-is re-dissolved in methanol, adds potassium carbonate, the condition of 80 ~ 90 DEG C
Lower reaction 10 ~ 12 hours, removes unnecessary methanol after completion of the reaction under reduced pressure, then through extracting, being dried to obtain 6,7-bis-bromo-1,2,3,
4-tetrahydroisoquinoline；
Concrete reaction equation is as follows:
。
New compound 6 the most according to claim 2, the preparation method of bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, it is special
Levy and be: the mol ratio of triethylamine in described step (1), chloroacetic chloride and 1,2,3,4-tetrahydroisoquinoline be 1.2 ~ 1.5:1.1 ~
1.3:1。
New compound 6 the most according to claim 2, the preparation method of bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, it is special
Levy and be: in described step (2), N-bromo-succinimide with the mol ratio of N-acetyl group 1,2,3,4-tetrahydroisoquinoline is
2.1:1~2.2:1。
New compound 6 the most according to claim 2, the preparation method of bromo-1,2,3, the 4-tetrahydroisoquinolines of 7-bis-, it is special
Levy and be: in described step (3), potassium carbonate is 2.0:1 ~ 2.5:1 with the mol ratio of the N-bromo-tetrahydroisoquinoline of acetyl group-6,7-.
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-
2016
- 2016-06-14 CN CN201610419783.6A patent/CN106045908B/en not_active Expired - Fee Related
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|---|---|---|---|---|
| JPH11222486A (en) * | 1998-02-03 | 1999-08-17 | Sumitomo Pharmaceut Co Ltd | Tetrahydroisoquinolinylpththalazine derivative |
| WO2008079277A1 (en) * | 2006-12-22 | 2008-07-03 | Millennium Pharmaceuticals, Inc. | Certain pyrazoline derivatives with kinase inhibitory activity |
| CN101910166A (en) * | 2007-11-13 | 2010-12-08 | 沃泰克斯药物股份有限公司 | Heterocyclic derivatives as modulators of ion channels |
| WO2010042998A1 (en) * | 2008-10-17 | 2010-04-22 | Akaal Pharma Pty Ltd | S1p receptors modulators |
| CN103694170A (en) * | 2013-04-01 | 2014-04-02 | 常州夏青化工有限公司 | Synthetic method of 6,7-difluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride |
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