CN107298655B - 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride and preparation method thereof - Google Patents
7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Abstract
The invention discloses 7,8- dimethoxys -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochlorides and preparation method thereof, and with 3,4- dimethoxy benzenpropanoic acid for starting material, in thionyl chloride catalysis, then aminolysis obtains 3,4- dimethoxy hydrocinnamamide；Boron trifluoride ether, sodium borohydride reduction obtain 3,4- dimethoxy amphetamine；Reaction obtains N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene in sulfuric acid and paraformaldehyde after acetyl group protection；Deacetylate, Boc protect to obtain N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene；It is passed through HCl gas and obtains 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochlorides, the preparation method condition is relatively mild, the easy to handle purifying of product, and batch is suitble to prepare.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of new compound 7,8- dimethoxy -2,3, and 4,
5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride and preparation method thereof.
Background technique
Benzazepine hydrochloride class compound has very various pharmacological activity, if any stronger antiviral, anti-frightened
It faints activity, antiepileptic activity etc., benzazepine hydrochloride structure or piece is all contained in many drug molecule and natural products
Section, thus benzazepine hydrochloride derivative is important pharmaceutical intermediate.But benzazepine hydrochloride class compound
Synthesis prepare complexity mostly, step is longer, expensive starting materials, and not easy to operate and yield is not high, and this strongly limits benzo-azas
The efficient preparation of azepine hydrochloride salt and application demand.Especially to the type and synthetic method report of dimethoxy tetrahydro azatropylidene hydrochloride
Road is very few, so far without finding that the synthetic method of dimethoxy tetrahydro azatropylidene is reported.
Summary of the invention
The object of the present invention is to provide a kind of new compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos [c]
Azatropylidene hydrochloride and its preparation method, 7,8- dimethoxy -2,3 obtained, 4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochlorides
There are potential pharmacological activity for salt, and react relatively mild, the easy to handle purifying of product, and batch is suitble to prepare.
To achieve the above object, the invention adopts the following technical scheme:
A kind of new compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochlorides, described 7,
The structural formula of 8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride is
。
The system of described new compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] the azatropylidene hydrochloride
Preparation Method, steps are as follows:
(1) with 3,4- dimethoxy benzenpropanoic acid for starting material, in methyl alcohol, under thionyl chloride catalysis, 70-80 DEG C, instead
It answers 6-8 hours, obtains 3,4- dimethoxy methyl phenylpropionate；
(2) 3,4- dimethoxy methyl phenylpropionate is dissolved in the mixed liquor of methanol and ammonium hydroxide, 80-85 DEG C, reacts 10-12
Hour, crystallisation by cooling filters to obtain white solid, is 3,4- dimethoxy hydrocinnamamide；
(3) 3,4- dimethoxy hydrocinnamamide is dissolved in tetrahydrofuran, adds sodium borohydride, boron trifluoride second is then added dropwise
Ether, finish in 80-85 DEG C reaction 8-10 hours, after solvent is removed under reduced pressure, ethyl acetate extracts to obtain 3,4- dimethoxy amphetamine；
(4) after 3,4- dimethoxy amphetamine being dissolved in methylene chloride, triethylamine is added to make acid binding agent, then plus chloroacetic chloride,
20-35 DEG C reaction 2-4 hours, decompression is except molten N- acetyl group -3,4- dimethoxy amphetamine after washing；
(5) it will obtain in N- acetyl group -3,4- dimethoxy amphetamine vitriolization, and add polyformaldehyde, 60-80 DEG C,
Reaction 5-6 hours, pours into ice water, ethyl acetate extracts to obtain N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos
[c] azatropylidene crude product；
(6) N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidenes are dissolved in methanol, then
Add potassium carbonate, 70-80 DEG C, reacts 12-15 hours, solvent is then removed under reduced pressure, water and ethyl acetate is added to extract to obtain 7,8- diformazan
Oxygroup -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene；
(7) 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidenes are dissolved in methylene chloride, and Boc acid is added
Acid anhydride and triethylamine, react 1-2 hours, column chromatographs to obtain N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- by 25-35 DEG C
Benzo [c] azatropylidene；
(8) by N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidenes are dissolved in methylene chloride, logical
Enter hydrogen chloride gas, filtered after 2-3 hours white flakes shape crystal be 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos
[c] azatropylidene hydrochloride；
It is as follows specifically to prepare reaction route:
。
3,4- dimethoxy benzenpropanoic acid in the step (1), thionyl chloride molar ratio be 1:1.0 ~ 1:1.2.
1mol 3 in the step (2), 4- dimethoxy methyl phenylpropionate need ammonium hydroxide 1000mL, the body of methanol and ammonium hydroxide
Product is than being 1:1.0 ~ 1:1.2.
3,4- dimethoxy hydrocinnamamide in the step (3), sodium borohydride, boron trifluoride ether molar ratio be 1:2:
2~1:2.5:2.5。
3,4- dimethoxy amphetamine in the step (4), triethylamine, chloroacetic chloride molar ratio be 1:2:1.2 ~ 1:2:
1.5。
N- acetyl group -3,4- dimethoxy amphetamine in the step (5), paraformaldehyde molar ratio be 1:2 ~ 1:3.
N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene, carbonic acid in the step (6)
The molar ratio of potassium is 1:2.0 ~ 1:2.5.
7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene, Boc acid anhydrides, three second in the step (7)
The molar ratio of amine is 1:1.1:1.5 ~ 1:1.2:2.
Using petroleum ether and ethyl acetate, 10:1 is eluted step (7) the center pillar chromatographic elution by volume.
Beneficial effects of the present invention: 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride is one
Class new compound has no document report at present, and has potential pharmacological activity, therefore dimethoxy -2 7,8- of the invention,
The preparation method of 3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride has significant application value.System disclosed in this invention
Preparation Method, raw material are easy to get, and preparation method used is easy to operate, high income, easy purification, and batch is suitble to prepare.Due to suchization
Closing object is valuable pharmaceutical intermediate, therefore present disclosure has important research and practical value, while
The preparation of other similar derivative can be pushed to extend significantly.
Specific embodiment
Combined with specific embodiments below, the present invention will be further described.Following embodiment be merely to illustrate the present invention and
The person skilled in the art of the range being not intended to limit the invention, the field can make some non-according to the content of foregoing invention
The modifications and adaptations of matter.
Embodiment 1
The preparation method of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride of the present embodiment
It is as follows:
(1) synthesis of 3,4- dimethoxy methyl phenylpropionate
3,4- dimethoxy benzenpropanoic acid 4.21g(0.02mol) it is dissolved in methanol 60mL, thionyl chloride 2.39g is then added
(0.02mol) is heated to 70 DEG C, reacts 6 hours, later pour into reaction solution in cucurbit, rotary evaporation, and remnants are added
Suitable water and methylene chloride extract 2 times, and dichloromethane layer is washed with water 1 time, and washing water layer is extracted with dichloromethane 1 again
It is secondary, merge organic layer and pour into cucurbit removing solvent, obtains oil product 4.16g, yield 93%.
(2) synthesis of 3,4- dimethoxy hydrocinnamamide
Claim 3,4- dimethoxy methyl phenylpropionate 3.36g(0.015mol), ammonium hydroxide 15mL and 15mL methanol solution is added, adds
Heat is warming up to 80 DEG C, reacts 10 hours, freezes, and crystallization obtains white solid 3,4- dimethoxy hydrocinnamamide 2.92g, yield
93%。
(3) synthesis of 3,4- dimethoxy amphetamine
Claim 3,4- dimethoxy hydrocinnamamide 2.09g(0.01mol), it is dissolved in the tetrahydrofuran solution of 40ml, adds hydroboration
Sodium 0.76g (0.020mol), then boron trifluoride ether 2.82g (0.020mol) is slowly added to reaction system, setting reaction temperature
80-85 DEG C of degree reacts 8-10 hours, adds water and EA to be extracted after revolving, obtains 3,4- dimethoxy amphetamine 1.56g, receives
Rate 80%.
(4) synthesis of N- acetyl group -3,4- dimethoxy amphetamine
Claim 3,4- dimethoxy amphetamine 1.56g (0.008mol), after being dissolved in the methylene chloride of 40ml, adds triethylamine
1.65g (0.016mol) does acid binding agent, and then plus chloroacetic chloride 0.79g (0.0096mol), temperature are 25 DEG C, reaction 2 hours, so
After washed, then carry out decompression except molten, obtain N- acetyl group -3,4- dimethoxy amphetamine product 2.39g, yield 96%.
(5) synthesis of N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
N- acetyl group -3,4- dimethoxy amphetamine 1.75g(0.007mol) is dissolved in the sulfuric acid of 30mL, and is added poly-
Formaldehyde 0.42g (0.014mol) is heated to 60 DEG C, reacts 5 hours, is subsequently poured into ice water, is extracted with ethyl acetate
It takes, ethyl acetate layer need to be primary with soda lye wash, obtains N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos
[c] azatropylidene 1.35g, yield 78%.
(6) synthesis of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
By N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.49g(0.006mol)
It is dissolved in the methanol of 40ml, potassium carbonate 1.66g(0.012mol is added), 70 DEG C are heated to, is reacted 12 hours, then with rotation
Turn evaporimeter and carry out revolving removing solvent, adds suitable quantity of water and ethyl acetate to be extracted, obtain free dimethoxy -2 7,8-,
3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.23g, yield 84%.
(7) synthesis of N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
Weigh 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.26g(0.006mol) it is dissolved in 40mL
Methylene chloride in, Boc acid anhydrides 1.44g(0.0066mol is added) and triethylamine 0.909g (0.009mol), temperature is 25 DEG C,
Reaction 1 hour, then plus water and ethyl acetate are extracted, and after extraction 2 times, carry out column layer with ethyl acetate: petroleum ether=10:1
Analysis, affords N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.82g, yield 93%.
(8) synthesis of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride
N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.63g(0.005mol), it is dissolved in
Methylene chloride is passed through hydrogen chloride gas, carries out reaction 2 hours, dimethoxy -2 white flakes shape crystal i.e. 7,8- are obtained by filtration,
3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride 1.11g, yield 92%.
LC:99%(214nm)
MS:m/z:[M+1]+:208
1H NMR (400 MHz, DMSO-d6): 9.13 (s, 2H), 7.07 (s, 1H), 6.88 (s, 1H),
4.21 (s, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 3.31-3.24 (m, 2H), 2.89 (d, J=
10.3Hz,2H),1.82(s,2H)。
Elemental analysis C12H18O2NCl theoretical value (%): C:59.14; H: 7.39;N:5.75; Cl:14.58；Measured value:
C:59.26; H:7.37;N:5.69; Cl:14.58。
Embodiment 2
(1) synthesis of 3,4- dimethoxy methyl phenylpropionate
3,4- dimethoxy benzenpropanoic acid 4.21g(0.02mol) it is dissolved in methanol 60mL, thionyl chloride 2.63g is then added
(0.022mol) is heated to 75 DEG C, reacts 7 hours, later pour into reaction solution in cucurbit, rotary evaporation, and remnants add
Enter suitable water and methylene chloride extracts 2 times, dichloromethane layer is washed with water 1 time, washing water layer is extracted with dichloromethane 1 again
It is secondary, merge organic layer and pour into cucurbit removing solvent, obtains oil product 4.25g, yield 95%.
(2) synthesis of 3,4- dimethoxy hydrocinnamamide
Claim 3,4- dimethoxy methyl phenylpropionate 3.36g(0.015mol), ammonium hydroxide 17mL and 17mL methanol solution is added, adds
Heat is warming up to 85 DEG C, reacts 11 hours, freezes, and crystallization obtains white solid 3,4- dimethoxy hydrocinnamamide 2.89g, yield
92%。
(3) synthesis of 3,4- dimethoxy amphetamine
Claim 3,4- dimethoxy hydrocinnamamide 2.09g(0.01mol), it is dissolved in the tetrahydrofuran solution of 40ml, adds hydroboration
Sodium 0.87g (0.023mol), then boron trifluoride ether 3.26g (0.023mol) is slowly added to reaction system, setting reaction temperature
85 DEG C of degree reacts 9 hours, adds water and EA to be extracted after revolving, obtains 3,4- dimethoxy amphetamine 1.62g, yield 83%.
(4) synthesis of N- acetyl group -3,4- dimethoxy amphetamine
Claim 3,4- dimethoxy amphetamine 1.56g (0.008mol), after being dissolved in the methylene chloride of 40ml, adds triethylamine
1.65g (0.016mol) does acid binding agent, and then plus chloroacetic chloride 1.15g (0.014mol), temperature are 30 DEG C, reaction 3 hours, then
It is washed, then carries out decompression except molten, obtain N- acetyl group -3,4- dimethoxy amphetamine product 2.34g, yield 95%.
(5) synthesis of N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
N- acetyl group -3,4- dimethoxy amphetamine 1.75g(0.007mol) is dissolved in the sulfuric acid of 30mL, and is added poly-
Formaldehyde 0.54g (0.018mol) is heated to 70 DEG C, reacts 5.5 hours, is subsequently poured into ice water, is carried out with ethyl acetate
Extraction, ethyl acetate layer need to be primary with soda lye wash, obtains N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzene
And [c] azatropylidene 1.38g, yield 80%.
(6) synthesis of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
By N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.49g(0.006mol)
It is dissolved in the methanol of 40ml, potassium carbonate 1.93g(0.014mol is added), 75 DEG C are heated to, is reacted 14 hours, then with rotation
Turn evaporimeter and carry out revolving removing solvent, adds suitable quantity of water and ethyl acetate to be extracted, obtain free dimethoxy -2 7,8-,
3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.20g, yield 82%.
(7) synthesis of N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
Weigh 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.26g(0.006mol) it is dissolved in 40mL
Methylene chloride in, Boc acid anhydrides 1.53g(0.007mol is added) and triethylamine 1.01g (1.00mol), temperature is 30 DEG C, is reacted
1.5 hours, then plus water and ethyl acetate were extracted, and after extraction 2 times, carried out column layer with ethyl acetate: petroleum ether=10:1
Analysis, affords N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.80g, yield 92%.
(8) synthesis of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride
N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.63g(0.005mol), it is dissolved in
Methylene chloride is passed through hydrogen chloride gas, carries out reaction 2.5 hours, white flakes shape crystal i.e. 7,8- dimethoxy-is obtained by filtration
2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride 1.12g, yield 93%.
Embodiment 3
(1) synthesis of 3,4- dimethoxy methyl phenylpropionate
3,4- dimethoxy benzenpropanoic acid 4.21g(0.02mol) it is dissolved in methanol 60mL, thionyl chloride 2.87g is then added
(0.024mol) is heated to 80 DEG C, reacts 8 hours, later pour into reaction solution in cucurbit, rotary evaporation, and remnants add
Enter suitable water and methylene chloride extracts 2 times, dichloromethane layer is washed with water 1 time, washing water layer is extracted with dichloromethane 1 again
It is secondary, merge organic layer and pour into cucurbit removing solvent, obtains oil product 4.21g, yield 94%.
(2) synthesis of 3,4- dimethoxy hydrocinnamamide
Claim 3,4- dimethoxy methyl phenylpropionate 3.36g(0.015mol), ammonium hydroxide 18mL and 18mL methanol solution is added, adds
Heat is warming up to 85 DEG C, reacts 12 hours, freezes, and crystallization obtains white solid 3,4- dimethoxy hydrocinnamamide 3.01g, yield
96%。
(3) synthesis of 3,4- dimethoxy amphetamine
Claim 3,4- dimethoxy hydrocinnamamide 2.09g(0.01mol), it is dissolved in the tetrahydrofuran solution of 40ml, adds hydroboration
Sodium 0.95g (0.025mol), then boron trifluoride ether 3.55g (0.025mol) is slowly added to reaction system, setting reaction temperature
85 DEG C of degree reacts 10 hours, adds water and EA to be extracted after revolving, obtains 3,4- dimethoxy amphetamine 1.60g, yield 82%.
(4) synthesis of N- acetyl group -3,4- dimethoxy amphetamine
Claim 3,4- dimethoxy amphetamine 1.56g (0.008mol), after being dissolved in the methylene chloride of 40ml, adds triethylamine
1.65g (0.016mol) does acid binding agent, and then plus chloroacetic chloride 0.88g (0.012mol), temperature are 35 DEG C, reaction 4 hours, then
It is washed, then carries out decompression except molten, obtain N- acetyl group -3,4- dimethoxy amphetamine product 2.37g, yield 95%.
(5) synthesis of N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
N- acetyl group -3,4- dimethoxy amphetamine 1.75g(0.007mol) is dissolved in the sulfuric acid of 30mL, and is added poly-
Formaldehyde 0.63g (0.021mol) is heated to 80 DEG C, reacts 6 hours, is subsequently poured into ice water, is extracted with ethyl acetate
It takes, ethyl acetate layer need to be primary with soda lye wash, obtains N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos
[c] azatropylidene 1.41g, yield 80%.
(6) synthesis of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
By N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.49g(0.006mol)
It is dissolved in the methanol of 40ml, potassium carbonate 2.07g(0.015mol is added), 80 DEG C are heated to, is reacted 15 hours, then with rotation
Turn evaporimeter and carry out revolving removing solvent, adds suitable quantity of water and ethyl acetate to be extracted, obtain free dimethoxy -2 7,8-,
3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.20g, yield 82%.
(7) synthesis of N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene
Weigh 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.26g(0.006mol) it is dissolved in 40mL
Methylene chloride in, Boc acid anhydrides 1.57g(0.0072mol is added) and triethylamine 1.21g (1.00mol), temperature is 35 DEG C, instead
Answer 2 hours, then plus water and ethyl acetate are extracted, and after extraction 2 times, carry out column layer with ethyl acetate: petroleum ether=10:1
Analysis, affords N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.86g, yield 95%.
(8) synthesis of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride
N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene 1.63g(0.005mol), it is dissolved in
Methylene chloride is passed through hydrogen chloride gas, carries out reaction 3 hours, dimethoxy -2 white flakes shape crystal i.e. 7,8- are obtained by filtration,
3,4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochloride 1.15g, yield 95%.
Basic principles and main features and advantages of the present invention of the invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (9)
1. a kind of compound 7,8- dimethoxy -2,3, the preparation method of 4,5- tetrahydro -1H- benzo [c] azatropylidene hydrochlorides,
It is characterized in that steps are as follows:
(1) with 3,4- dimethoxy benzenpropanoic acid for starting material, in methyl alcohol, under thionyl chloride catalysis, 70-80 DEG C, 6-8 is reacted
Hour, obtain 3,4- dimethoxy methyl phenylpropionate；
(2) 3,4- dimethoxy methyl phenylpropionate is dissolved in the mixed liquor of methanol and ammonium hydroxide, 80-85 DEG C, reaction 10-12 is small
When, crystallisation by cooling filters to obtain white solid, is 3,4- dimethoxy hydrocinnamamide；
(3) 3,4- dimethoxy hydrocinnamamide is dissolved in tetrahydrofuran, adds sodium borohydride, boron trifluoride ether is then added dropwise,
Finish in 80-85 DEG C reaction 8-10 hours, after solvent is removed under reduced pressure, ethyl acetate extracts to obtain 3,4- dimethoxy amphetamine；
(4) after 3,4- dimethoxy amphetamine being dissolved in methylene chloride, triethylamine is added to make acid binding agent, then plus chloroacetic chloride, 20-35
DEG C reaction 2-4 hour, after washing decompression except it is molten obtain N- acetyl group -3,4- dimethoxy amphetamine；
(5) it will obtain in N- acetyl group -3,4- dimethoxy amphetamine vitriolization, and add polyformaldehyde, 60-80 DEG C, reaction
5-6 hours, ice water is poured into, ethyl acetate extracts to obtain N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos [c]
Azatropylidene crude product；
Then plus carbon (6) N- acetyl group -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidenes are dissolved in methanol,
Sour potassium, reacts 12-15 hours, solvent is then removed under reduced pressure, water and ethyl acetate is added to extract to obtain 7,8- dimethoxy by 70-80 DEG C
Base -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene；
(7) 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidenes are dissolved in methylene chloride, be added Boc acid anhydrides and
Triethylamine, reacts 1-2 hours, column chromatographs to obtain N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos by 25-35 DEG C
[c] azatropylidene；
(8) by N-Boc-7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidenes are dissolved in methylene chloride, are passed through chlorine
Change hydrogen, filtered after 2-3 hour white flakes shape crystal be 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzos [c]
Azatropylidene hydrochloride；
The structural formula of 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] the azatropylidene hydrochloride is
。
2. compound N -7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azatropylidene salt according to claim 1
The preparation method of hydrochlorate, it is characterised in that: 3,4- dimethoxy benzenpropanoic acid in the step (1), thionyl chloride molar ratio be
1:1.0~1:1.2。
3. compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochloride according to claim 1
The preparation method of salt, it is characterised in that: 1mol 3 in the step (2), 4- dimethoxy methyl phenylpropionate need ammonium hydroxide
The volume ratio of 1000mL, methanol and ammonium hydroxide is 1:1.0 ~ 1:1.2.
4. compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochloride according to claim 1
The preparation method of salt, it is characterised in that: 3,4- dimethoxy hydrocinnamamide, sodium borohydride, boron trifluoride second in the step (3)
The molar ratio of ether is 1:2:2 ~ 1:2.5:2.5.
5. compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochloride according to claim 1
The preparation method of salt, it is characterised in that: the molar ratio of 3,4- dimethoxy amphetamine, triethylamine, chloroacetic chloride in the step (4)
For 1:2:1.2 ~ 1:2:1.5.
6. compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochloride according to claim 1
The preparation method of salt, it is characterised in that: N- acetyl group -3,4- dimethoxy amphetamine in the step (5), paraformaldehyde rub
You are than being 1:2 ~ 1:3.
7. compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochloride according to claim 1
The preparation method of salt, it is characterised in that: N- acetyl group -7,8- dimethoxy -2,3 in the step (6), 4,5- tetrahydro -1H- benzene
And the molar ratio of [c] azatropylidene, potassium carbonate is 1:2.0 ~ 1:2.5.
8. compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochloride according to claim 1
The preparation method of salt, it is characterised in that: 7,8- dimethoxy -2,3 in the step (7), 4,5- tetrahydro -1H- benzo [c] azepines
Zhuo, Boc acid anhydrides, triethylamine molar ratio be 1:1.1:1.5 ~ 1:1.2:2.
9. compound 7,8- dimethoxy -2,3,4,5- tetrahydro -1H- benzo [c] azepine azepine hydrochloride according to claim 1
The preparation method of salt, it is characterised in that: step (7) the center pillar chromatographic elution uses petroleum ether and ethyl acetate by volume
10:1 is eluted.
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| WO2010053127A1 (en) * | 2008-11-05 | 2010-05-14 | 協和発酵キリン株式会社 | MODULATOR OF α1GABAA RECEPTOR OR α5GABAA RECEPTOR |
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| Title |
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| Marı＇a F. Dalence-Guzma＇n,等.SAR studies of capsazepinoid bronchodilators. Part 1:The importance of the catechol moiety and aspects of the B-ring structure.《Bioorganic & Medicinal Chemistry》.2007,第16卷2499–2512. * |
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